Sulfonamides, the pharmaceutical composition based on them, a method of treating endothelin-related disorders, the method of inhibiting the binding endothelioma peptide with endothelina-(noaorb-(nob) receptors, the method changes caused endothelium receptor activity.

 

(57) Abstract:

Describes the new sulfonamides of General formula I, where the values Ar2, R1, R2specified in paragraph 1 of the claims that can be used to inhibit the binding endothelioma peptide with endothelium receptor by contact of the receptor with a sulfonamide. Also describes methods for treating endothelin-related disorders, the method of inhibiting the binding endothelioma peptide with endothelin A-(NOAorB(NOB) receptors, as well as how changes caused endothelioma receptor activity and a pharmaceutical composition based on compounds of the formula I. 15 C. and 112 C.p. f-crystals, 13 PL.

< / BR>

This claim is partly a continuation of the following applications: Application U.S. N 08/222,287, authors Chan and others, filing date April 5, 1994, "Thiophenyl-, furyl - and pirralhasumida and their derivatives, affecting the activity of endothelin", the application of the U.S. N 08/142,552, authors Chan and others, filing date October 21, 1993, "N-(4-Halogen-isoxazolyl)-sulfonamides and derivatives thereof that affect the activity of endothelin", the application of the U.S. N 08/142.159, the authors Chan and others, filing date October 21, 1993, " N-(5-Isoxazolyl)-diphenylsulfone, N-(3-isoxazol., filing date October 21, 1993, "N-(5-Isoxazolyl)benzenesulfonamide, N-(3-Isoxazolyl)benzosulfimide and derivatives affecting the activity of endothelin"; application U.S. N 08/100,565, authors Chan and others, filing date July 30, 1993, "N-(5-Isoxazolyl)sulfonamides and derivatives thereof that affect the activity of endothelin"; application U.S. N 08/100.125 the authors Chan and others, filing date July 30, 1993, "N-(3-Isoxazolyl)sulfonamides and derivatives thereof that affect the activity of endothelin"; application U.S. N 08/065.202, author Chan, filing date may 20, 1993, "Sulfonylamides and their derivatives, affecting the activity of endothelin".

Application USA N 08/222,287 is partly a continuation of application U.S. NN 08/142,159, 08/142.559, 08/142,631, 08/100,565, 08/100,125 and 08/056,202. Applications USA NN 08/142.159, 08/142,559, 08/142,631 are partly a continuation of application U.S. NN 08/100,565, 08/100,125 and 08/065,202, and bids US NN 08/100,565 and 08/100,125 are partially a continuation of application U.S. N 08/065,202.

The content of each of the applications USA NN 08/222,287, 08/142,159, 08/142,559, 08/142,631, 08/100,565, 08/100,125 and 08/065,202 included in this application fully.

THE AREA TO WHICH THE INVENTION RELATES.

The presented invention relates to compounds that affect the activity of a family of peptides endothelin. In particular, the proposed sulfonamides and their derivatives, the s endothelin. The assignment of these compounds to medicines and their use as agonists and antagonists of endothelin is also provided here. The aforementioned compounds may also be used in vitro methods to distinguish peptides endothelin, endothelin receptors and affinity separation of endothelin receptors.

THE LEVEL OF TECHNOLOGY.

Vascular endothelium secretes a variety of vasoactive substances, including produced by the endothelium reduces vessels peptide endothelin (ET) (see, for example, Vanhoutte and others (1986) Annual. Rev. Physiol. 48: 307 - 320; Furchgott and Zawadski (1980), Nature, 288: 373-376). Endothelin, which was originally determined in the culture supernatant of endothelial cells in the aorta of pigs (see Yanagisawa and others (1988) Nature 332:411-415), is a potent vasoconstrictor peptide means, consisting of twenty-one amino acids. This is one of the most potent known vasoconstrictor funds and secreted by numerous cell types, including endothelial cells, trachea, kidney and brain. Endothelin is synthesized as a precursor preproendothelin consisting of duchartre amino acids, which contains a signal sequence that is cleaved by endogenous protease OBR is e, called big endothelin, is converted in vivo into Mature biologically active form by using the proposed endothelin converting enzyme (ECE), which, apparently, is meteozavisimost neutral protease (see , for example, Kashiwabara and others (1989) FEBS Lettrs. 247: 337-340). Splitting is required to obtain physiological response (see, for example, von Geldern and others (1991) Peptide Res. 4: 32-35). In the endothelial cells of the aorta of a pig intermediate, consisting of thirty-nine amino acids, big endothelin, hydrolyzed communications Trp21-Val22with the formation of endothelin-1 and C-terminal fragments. A similar decomposition takes place in human cells in tridtsativosmiletnyaya the intermediate. Identified three different isopeptide: the endothelium-1, endothelin-2 and the endothelium-3, which show a strong vasoconstrictor activity.

A family of three isopeptides the endothelium-1, endothelin-2 and endothelin-3 are encoded by a family of three genes (see, Inoue and others (1989) Proc. Natl. Acad. Sci, USA 86: 2863-2867; see also Saida and others, (1989) J. Biol. Chem. 264: 14613-14616). Nucleotide sequences of three human genes are highly constant within a region that encodes the active peptide containing 21 amino acid and the C-terminal fra is the telin-1, and endothelin-3 is substituted in provisions (Trp2, Phe4, Thr5, Tyr6, Lys7, Tyr14) endothelin-1. Thus, these peptides are very conservative on the C-end.

The selection of endopeptidase from cultured endothelial cells is modulated by various chemical and physical stimuli and appears to be regulated at the level of transcription and/or translation. Expression of the gene encoding endothelin-1, is amplified using chemical stimulants, including epinephrine, thrombin and Ca2+-ionophor. The production and secretion of endothelin from endothelial stimulated by angiotensin II, vasopressin, endotoxin, cyclosporine and other factors (see, Brooks and others (1991) Eur. J. Pharm. 194: 115-117), and is inhibited by nitric oxide. Apparently, endothelial cells secrete short-lived produced by endothelial relaxing factors (EDRF), including nitric oxide or a related substance (Palmer and others (1987) Nature 327: 524-526), while stimulation of vasoactive agents, such as acetylcholine and bradykinin. Vasoconstriction occurring under the action of endothelin, also attenuated natriuretic peptide atrial (ANP).

The peptides of the endothelin are numerous b and in preparations of isolated smooth tissues of the vessels; it also causes release of eicosanoids and produced by endothelial relaxing factor (EDRF) from perfoirmance vascular preparations. Intravenous administration of endothelin-1 and adding in vitro for vascular and other smooth muscle tissues cause long-lasting effects of pressure and decreased, respectively (see, for example, Bolger and others (1991) Can. J. Physiol. Pharmacol. 69: 406-413). In isolated muscle of blood vessels, for example, endothelin-1 is (EC50= 410-10M) a powerful, slowly but constantly active reducing agent. In vivo, a single dose increases blood pressure over time from twenty to thirty minutes. On caused by endothelin reduction vessels are not affected antagonists known neurotransmitter or hormonal factors, but the influence of antagonists of calcium channel. However, the effect of antagonists of calcium channel is most likely the result of inhibiting the influx of calcium, because, apparently, calcium influx is necessary for long-term contractile response to endothelin.

The endothelium is also the mediator selection renin stimulates the secretion of ANP and has a positive inotropic effect on the atrium of Guinea pigs. In the lung endothelin-the e vessels of the kidneys, reduces renal bleeding and reduces the rate of glomerular (pea) filter. He is a strong mitogen for nodule mesangial cells and causes phosphoinositide cascade in these cells (Simonson and others, (1990) J. Clin. Invest. 85: 790-797).

In the vascular system and other tissues, including the intestine, heart, lung, kidney, spleen, adrenal glands and brain, are highly specific binding of endothelin (dissociation constants are in the range 2-610-10M). The binding is not inhibited by catecholamines, vasoactive peptides, neurotoxins and calcium channel antagonists. Endothelin binds and interacts with regions of the receptors that are different from other Autonomous receptors and depends on the voltage calcium channels. Study competitive binding shows that there are numerous classes of receptors with different affinities to isopeptides endothelin. Sarafotoxin, a group of peptide toxins from the venom of the snake Atractaspis eingadensis that cause serious coronary vascular spasm of the victims of snake bite, have structural and functional homology with respect to endothelin-1 and competitively bind to the same receptors serdechnoy, denoted by ETAand ETBand there is proof that there are other subtypes (see, for example, Emori and others (1990) FEBS Lett. 263: 261-264; and Sokolovsky and others, (1992) J. Biol Chem. 267:20551-20554). Were selected DNA clones encoding the receptors ETAand ETB(Arai and others, (1992) Nature 348: 730-732; Sakurai and others, (1990) Nature 348: 732-735). On the basis of the amino acid sequences of the proteins encoded by cloned DNA, it is obvious that each receptor contains seven membrane overlapping areas, and shows structural similarity with the binding of G protein-membrane proteins. Transfer RNA encoding both receptor, was detected in several tissues, including heart, lung, kidney and brain.

The distribution of receptor subtypes is tissue-specific (Martin and others , (1989) Biochem. Biophys. Res. Commun. 162:130-137) and affinity affinity of each receptor for peptides member of the endothelin family may differ. Apparently, receptors ETAselective for the endothelin-1 predominate in vascular tissues of the heart. Receptors ETBpredominate in tissues other than the blood vessels of the heart, including the Central nervous system and the kidney, and interact with three isopeptide endothelin (Sakurai and others, (1990) Nature 348: 732-734). In addition, receptors ETAexisting in CH is th nervous system, while ETBreceptors are located on vascular endothelium associated with vasodilatation (Takayanagi and others, (1991) FEBS Lett. 282: 103 - 106) and is associated with impaired contraction of the bronchi. Apparently, ETAreceptor modulates mainly the reduction of blood vessels caused by ET-1 (lhara and others, (1993) Lif. Sci 50:247-255), and subtype ETBmediates specific endothelium expansion vessels (Takayanagi and others , (1991) FEBS Lett. 282:103-106). However, some stimulating ETBcaused by the antagonist, can cause a reduction in blood vessels (see, for example, MCMurdo and others, (1993) Br. J. Pharmac. 108:557-561; and Moreland and. others, (1992) Biochem. Biophys. Res. Comimm. 184:100-106).

Due to the distribution of the types of receptors and the different affinity of each isopeptide to each type of receptor activity isopeptide endothelin varies in different tissues. For example, the endothelium-1 inhibits the binding of labeled125I-endothelin-1 in the tissues of the heart vessels in forty - seven hundred times more potent than endothelin-3. The binding of labeled125I-endothelin-1 in tissues other than the blood vessels of the heart, such as kidney, adrenal gland, and cerebellum, is inhibited to the same extent by endothelin-1 and endothelin-3, which indicates that ETAreceptors predominate in the tissues of the heart vessels and ET

Agonists and antagonists of endothelin.

Due to the fact that endothelin is associated with certain painful conditions and is involved in numerous physiological phenomena of interest compounds that can hamper or enhance associated with endothelin activities, such as the interaction of endothelin-a receptor and acudose the structure to endothelin. This includes cyclic Pentapeptide, illtreated, Hexapeptide analogs, some derivatives of anthraquinone, endocarpon acids, some N-pyrimidinecarbonitrile, some benzosulfimide, certain naphthalenesulfonate (NaKajima and others , (1991) J. Antibiot. 44: 1348-1356; Miyata and others , (1992) J. Antibiot. 45: 74-78; Ishikawa and others, (1992) J. Med. Chem, 35:2139-2142; U.S. Patent N 5,114,918, the authors Ishikawa and others ; European patent A1, 0 569 193; European patent A1, 0 558 258; European patent A1, 0436 189, owned by BANYU PHARMACEUTICAL Co, LTD (October 7, 1991); the order of Canada 2,067,288; the order of Canada 2,071,193; U.S. Patent N 5,208.243; U.S. Patent N 5,270,313; Cody and others (1993) Med. Chem. Res.3: 154-162; Myata and others (1992) J. Antibiot 45:1041-1046; Miyata and others (1992) J. Antibiot 45:1029-1040, Fujimoto and others (1992) FEBS Lett. 305:41-44; Oshashi and others (1992) J. Antibiot. 45: 1684-1685; European patent A1, 0496 452; Clzel and others (1993) Nature 365:759-761; international application WO93/08799, Nishikibe and others (1993) Life Sci. 52: 717-724: and Benigni and others (1993) Kidney Int. 44:440-444).

In particular, the fermentation product of Streptomyces misakiensis, marked BE-18257B, was identified as an antagonist of ETA-receptor. BE-18257B is cyclic Pentapeptide, cyclo(D-Glu-L-Ala-allo-D-lle-L-Leu-D-Trp), which inhibits binding125I-labeled angelina-1 in the tissues of the heart vessels, depending on the concentration (IC501.4 microns in smooth muscu binding to receptors in the tissues, in which ETB- receptors predominate in concentrations up to 100 μm. Were synthesized cyclic Pentapeptide related to BE-1825 IN, such as cyclo (D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123), which has been shown to have activity antagonist ETAreceptor (see U.S. patent N 5,114,918, the authors Ishikawa and others, as well as the European patent A1, 0436 189, owned by BANYU PHARMACEUTICAL CO. LTD., (October 7, 1991). Methods that measure the inhibition of these cyclic peptides binding of endothelin-1 to endothelin-specific receptors indicate that these cyclic peptides are predominantly associated with ETA- receptors.

An important task is also improving ones antagonists. Check thousands of chemical compounds for the ability to inhibit the binding of ET-1 with membrane preparations from human placenta revealed a class of pyrimidinemethanol that weakly inhibit the binding of ET-1. Modification of these compounds led to the discovery of pyrimidinecarbonitrile, which inhibits the binding of ET-1 to ETAreceptors at a concentration of IC50about 0.2 microns and with ETBreceptors at a concentration of about 0.1 μm (see, for example, application Canada 2,067,288, application Canada 2,071 is recognized animal models of the vascular system and, as it is promising for therapeutic treatment of the vascular system (Clozel and others (1993) Nature 365: 759-61).

Check other compounds led to the discovery of sulfathiazole as an inhibitor of binding of endothelin with ETA(IC50= 69 µm, see Stein and others (1994), J. Med. Chem. 37: 329-31) and sulfisoxazole (IC50< 1 μm, see Stein and others (1994) J. Med. Chem. 37: 329-31, but see also joint application U.S. N 08/065,202, on which there is a reference, and to which in this application has a priority). It has been shown that certain N-(3,4-dimethyl-5-isoxazolyl)naphthalene-1 - sulfonamide have activity of endothelin antagonists. One derivative of 5-diethylamino-N-(3,4-dimethyl-5-isoxazolyl)naphthalene-1 - sulfonamide, as reported, is set to 1050 = 150 RMB for inhibition of binding of endothelin with ETAreceptors and, apparently, has oral activity on the model rats (see Stem and others (1994), J. Med. Chem.37: 329-31).

Antagonists and agonists endothelin as a therapeutic agent.

Due to the numerous physiological effects of endothelin and its undoubted connection with certain diseases, endothelin, apparently, plays a role in the pathophysiological events, including g the e l e C asthma, pulmonary hypertension, ischemia, coronary artery spasm, cerebral vasospasm and others (see, for example, Saito and others (1990), Hypertention 15: 734-738; Tomita and others (1989) N. Engl. J. Med. 321: 1127; Doherty (1992), J. Med.Chem. 35: 1493-1508, Morel and others (1989), Eur.Pharm.J. 167: 427-28). Because endothelin is associated with these and other painful conditions, requires more detailed knowledge of the functions and structure of a family of peptides endothelin to provide insight into the development and treatment of these conditions.

In order to acquire this knowledge and to use the possibilities of endothelin as a therapeutic agent, it is necessary to identify additional compounds that modulate or alter the activity of endothelin. Compounds that modulate the activity of endothelin, in particular compounds that act as specific antagonists or agonists, can not only help in the evaluation of the function of endothelin, but can also be useful in the treatment of. In particular, compounds that specifically interfere in the interaction of peptides with endothelin ETA-, ETBand other receptors could be useful in making therapeutic agents and as therapeutic agents against diseases.

is it the biological activity of one or more isopeptide endothelin. Another objective of the present invention to provide compounds that are used as a specific endothelin antagonists, the Goal is also the use of compounds that specifically interact with or inhibit the interaction of peptides with endothelin ETAand ETB-receptors as therapeutic agents for the treatment of endothelin-dependent diseases and disorders.

THE SUBJECT OF INVENTION.

Offers sulfonamides and methods for modulating the interaction of the peptide endothelin with ETA- and/or ETB-receptors. In particular, it relates to sulfonamides and methods of inhibiting the binding of the peptide endothelin with ETAand ETB-receptors. Also available sulfonamides and methods using sulfonamides, which act as agonists endothelin in relation to ETAand ETB-receptors.

Methods are made through contacting the receptor with one or more sulfonamide before, simultaneously with or after contacting the receptor with a peptide endothelin family. The sulfonylamides can be substituted or unsubstituted, aliphatic, monocyclic or polycyclic aromatic or heterogeneity have the formula 1:

< / BR>
where Ar1substituted or unsubstituted aryl group with one or more Deputy, including alkyl group, aryl group, substituted aryl group, a nitrogroup, amino group or halogen, or is an alkyl group. In particular, Ar1represents alkyl, or represents 5 - or 6 - membered substituted or unsubstituted aromatic or heteroaromatic ring including a 3 - or 5-isoxazolyl, 2-thiazolyl, 2-pyrimidinyl, pyrazolyl, 3 - or 5-isothiazole, pyrazinyl or substituted benzene group, including aryloxy-substituted benzene group or a condensed aliphatic or heteroaromatics ring containing from 6 to 21 carbon atoms in the ring structure, such as bicyclic or tricyclic structures, including groups, naphthyl, hinely, dibenzofuran, dibenzopyrene, dibenzothiophenes, purines, phenanthrenes.

In one of the embodiments, Ar1selected from groups of the following row:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
which is substituted by one or more substituents selected from the R.

R is selected from a range that contains H, NH2, halogen, pseudohalogen, alkylaminocarbonyl, formyl, an aromatic or shall alocally, halodrol, carbonyl, in which the aryl and the alkyl part is substituted or unsubstituted any of the listed groups are linear or branched chain containing from about 1 up to about 10-12 carbons, mainly from 1 to about 5-6 carbon atoms. R preferably represents H, NH2, a halogen, CH3CH3O or aromatic group.

Ar2is any such group to the resulting sulfonamide inhibited the binding by 50%, compared to binding in the absence of sulfonamida peptide endothelin to an endothelin receptor at a concentration of less than 100 μm, except in those cases when Ar2is not phenyl or naphthyl group, when Ar1represents N-(5 - isoxazolyl)- or N-(3 - isoxazolyl) - except in those cases where isoxazol is a 4-gaelicisation or if it increased the affinity of ETBthe 4-(tertiary alkyl)-isoxazol, and when Ar2is a phenyl group, it is not substituted in the para - position by a group NH2, NO2CH3, OH or substituted amines.

There are also some isoxazolecarboxylic and ethoxytrimethylsilane in which irbesartane and N - isoxazolidinone, in which the substituent in position 4 in isoxazoline group is a higher alkyl from C9H19to C13H27. These connections increase the affinity of ETBcompared with the corresponding compounds in which the substituent in position 4 is lower alkyl or other groups, selected from the range: pseudohalide, halogen, alkylaryl, aryl, lower alkyl, carboxamido, alkoxy, and others.

Thus, Ar2is selected from Akilov, including linear and branched chains, aromatic rings, condensed aromatic rings and heterocyclic rings, including a 5-membered heterocycles with one, two or more heteroatoms, and their analogues with condensed rings, 6-membered rings with one, two or more heteroatoms and their analogues with condensed rings. Thus, Ar2may be, but is not limited to, alkyl, norbornyl, adamantium, phenyl, naphthyl, chinaillon, ethanolism, acridinium, stillam, diphenyl, isoxazolyl, thiazolyl, oxazolyl, imidazolyl, dibenzofuran, indolium (dibenzobarrelenes), dibenzothiophene (tianeptine), carbazolyl, paranilam, financila, AstraZeneca, fullam, pirrallo, titaniam, IMM, morpholinium, thiomorpholine, hydrohematocele, hinazolinam, khinoksalinona, phthalazinium, cinnoline, phenazinium, phenoxyimino, phenothiazinium, benzoxazolium, benzimidazolium, benzothiazolium and the like. In a preferred embodiment, the Ar2is phenyl, naphthyl, fullam, pirrallo, titaniam, diphenyl and thiadiazolyl.

In the described embodiment, the Ar1are isoxazol, and connections can be represented by the following formula II:

< / BR>
< / BR>
where R1and R2can be any of (i), (ii) or (iii) in accordance with the following:

(i) R1and R2independently selected from the following groups:

H, NH2, NO2, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, hydroxyalkyl, alkoxyalkyl, alkylthio, haloalkyl, haloalkoxy, haloalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, halodrol, alkoxycarbonyl, alkylsulphonyl, aminocarbonyl, arylcarbamoyl, formyl, substituted and unsubstituted amido, substituted and unsubstituted, ureido, in which alkyl, alkeline and alkyline parts are Linara from about 4 to about 16 carbon atoms, provided what R2is not halogen or pseudohalogen, or

(ii) R1and R2together form-(CH2)nwhere n= 3-6, or

(iii) R1and R2together form 1,3-butadienyl provided that Ar2is not phenyl or naphthyl, if R1is not a halide or higher alkyl, in particular from C9H19to C13H27.

In preferred versions of the R1selected from Akilov, lower alkenyl, lower alkinyl, lower haloalkyl, halides, pseudohalides, a R2selected among lower Akilov, lower alkenyl, lower alkinyl and lower haloalkyl.

Ar2is any such group that the resulting sulfonamide inhibits binding by 50%, compared to binding in the absence of sulfonamida peptide endothelin with endothelium receptor at a concentration of less than 50 μm, except in the case where the compound is N-isoxazolidinone, zamechennym in position 4 isoxazoline group halogen or higher alkyl, preferably C9H19to C13H27.

In particular, Ar1is isoxazolyl group, and Ar2is an aliphatic linear or more, usually from 1 to 3, ring or is a group or isomeric group, selected with the proviso that Ar2neither phenyl or naphthyl, if R1(the substituent in position 4 on isoxazoline group (Ar1)) is not halide or higher alkyl with more than 8 carbon atoms, preferably from C9H19to C13H27. Ar2in some embodiments, the execution is selected from the following groups: alkyl,

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where n=0-10, preferably from 0 to 6, more preferably from 0 to 3, X represents O,S or NR11where R11is hydrogen or contains up to 30 carbon atoms, usually from 1 to 16 carbon atoms, and selected from the following range: hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, C(O)R15and S(O)nR15where n=0-2, R15is hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl; R11and R15are unsubstituted or substituted by one or more substituents, each selected independently from Z, which is golodner, cycloalkenyl, OH, CN, C(O)R16, CO2R16, SH, S(O)nR16where n=0-2, NHOH, NR12R16NO2N3, OR16, R12NCOR16, CONR12R16; R16is hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, or cycloalkenyl; R12which is independently selected from R11and Z is hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl; C(O)R17and S(O)nR17where n= 0-2, R17is hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl or cycloalkenyl; each of the radicals R11, R12, R15and R16may further be substituted with any of the groups defined for Z;

each of the substituents R3, R4, R5, R6and R7selected independently from (i)-(iv) with the proviso that when Ar2is phenyl, (a) at least one of the radicals R3, R4R5, R6and R7is not hydrogen, and (b) when Ar1is a 3-isoxazolyl, R3not assetstudio from the following number of: hydrogen, NHOH, NH2, NO2N3aminoalkyl, alkylamino, dialkylamino, carboxyl, carbonyl, hydroxyl, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, heterocycle, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, Allakaket, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, halodrol, haloalkoxy, alkoxycarbonyl, alkylsulphonyl, arylcarbamoyl, formyl, substituted or unsubstituted amido group, a substituted or unsubstituted, ureido-group, where each of these groups may be unsubstituted or substituted with such substituents as H, NH2, NO2, alkyl, halogen, pseudohalogen; or alternatively,

(ii) R4and R7together are substituted or unsubstituted 1,3-butadienyl, 1-chloro-1,3-bouhadjera, 4-dimethylamino-1,3-butadienyl, 1-Aza-1,3-butadienyl or 2-Aza-1,3-butadienyl, a R3, R5and R6are such groups that were defined above in paragraph (i); or alternatively,

(iii) R7and R3together represent a substituted or unsubstituted 1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-Chloro-1,3-butadienyl, 1-Aza-1,3-butadienyl, or 2-Aza-1,3-butadienyl, a R4, R5and R6are groups who th of groups R4and R6selected independently from the following range: alkyl, alkoxy, halogen, amino, aminoalkyl in which each of the groups R8, R9, R10selected independently from (i) or (ii) as follows:

(i) each of the radicals R8, R9, R10that contain hydrogen or up to 50 or so values of carbon atoms, generally up to 30 atoms or around this value, preferably 20 atoms or less, selected independently from a number of: hydrogen, halogen, pseudohalide, alkyl, alkoxy, alkenyl, quinil, aryl, aryloxy, heterocycle, Alcoxy, aralkyl, cycloalkyl, cycloalkenyl, cycloalkenyl, OH, CN, C(O)R18, CO2R18, SH, S(O)nR18where n=0-2, NHOH, NR18R19, NO2N3, OR18, R19NCOR18, CONR19R18; where R19is hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, C(O)R20, S(O)nR20where n=0-2, R18and R20independently selected from a number of: hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl or cycloalkenyl; any group that far is uppy, henceforth referred to as Z, includes halogen, pseudohalide, alkyl, alkoxy, alkenyl, quinil, aryl, aryloxy, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl; OH, CN, C(O)R21, CO2R21, SH, S(O)nR21where n=0-2, NHOH, NR22R21, NO2N3, OR21, R22NCOR21, CONR22R21, R22is hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, alkoxy, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, C(O)R23, S(O)nR23where n=0-2, a R21and R23independently selected from a number of: hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl or cycloalkenyl; or

(ii) any two groups of R8, R9and R10form an aryl, aromatic ring, heteroaromatic ring, alicyclic or heterocyclic ring which is saturated or unsaturated, containing from about 3 or this value to 16 or around that level members, preferably from 3 to 10 or so values, more preferably from 5 to 7 members, and which are unsubstituted or substituted by one or more substituents, each and the tx2">

In the above embodiments perform alkyl, alkyline and alkeneamine of each of the above substituents are linear or branched chains, are acyclic or cyclic, and preferably have from 1 or about this value to 10 or so values of carbon atoms, in more preferred versions of they may have from 1 to 6 carbons, and they may have less than 6 carbons. Aryl, alicyclic, aromatic rings and heterocyclic groups can have from 3 to 16, usually 3-7, often 5-7 members in the ring, and can be single or condensed ring, ring Size and the length of the carbon chain is selected so that the resulting molecule is necessarily remained active as an antagonist or agonist endothelin so that the resulting compound inhibits binding of the peptide endothelin with endothelium receptor at a concentration of less than 50 microns, preferably less than 10 μm, 50%, compared to binding in the absence of sulfonamida.

Thus, Ar2is substituted or asamasinda group selected from a number of: naphthyl, phenyl, diphenyl, hinely, still, thiophenyl, furyl, ethynodiol, pyrrolyl, benzofuranyl, tenantry, thiazolyl, isoxazolyl, anthracene, alkenyl, quinil and alkyl.

It is clear that the provisions specified for the deputies, including sulfonamidnuyu group may vary. For example, these compounds contain groups that include thiophene-3-sulfonamide and thiophene-2-sulfonamides.

In detailed embodiments described herein perform, Ar1is isoxazolyl. All versions of the 4-gaelicization or 4-methylisoxazole are preferred, except in those cases when Ar2is phenyl or naphthyl, 4-gaelicization and 4-(higher alkyl)-isoxazolyl are preferred. In General, 4-gallodesoxycholic show a significant increase in activity against at least one of the ET receptors (from twice to twenty-fold increase in activity), which is confirmed by methods such as presented here, by which measure the binding of ETA- and/or ETB-receptors compared with the corresponding sulfonamides in which the substituent in position 4 in isoxazoline differs from halogen, for example, alkyl. For example, (1) IC50when competitive ingebyra the place for the last of 9.4 μm, at that time, as the IC50for 2,5-dimethyl-N-(4-chloro-3-methyl-5-isoxazolyl) benzosulfimide is to 0.19 μm, and 2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide is 0.044 µm (see, for example. Table 1, below); (2) IC50for N-(3,4-dimethyl-5-isoxazolyl)-2-diphenylsulfone for ETAreceptors is about 0,008 μm, while the IC50for N-(4-bromo-3-methyl-5-isoxazolyl)-2-diphenylsulfone is about 0,0016 μm (see Table 2); and (3) the IC50for N-(3,4-dimethyl-5-isoxazolyl)-3 - diphenylsulfone for ETBreceptors is about 3,48 μm, and the IC50for N-(4-bromo-3-methyl-5-isoxazolyl)-3 - diphenylsulfone for ETBreceptors is about 0,76 µm and IC50for N-(4-chloro-3-methyl-5-isoxazolyl)-3 - biphenylcarboxylic for ETBreceptors is about 0,793 μm (see Table 2).

Other selected compounds include benzene and naphthalenedisulfonate in position 4 isoscaling rings Ar1is a methyl group in position 3 is relatively long alkyl group containing about 8 this value to 15 or so values, primarily 13 or so values of carbon). Such compounds, which shows show high affinity for ETB-receptors compared to compounds in which the group in position 3 is methyl.

In some preferred embodiments, execution, R11is aryl, such as phenyl or alkylphenyl, hydrogen or lower alkyl, a R8, R8R10chosen independently from a number of: hydrogen, halogen, lower alkyl, lower aryl, lower heterocycle, lower aralkyl, C(O)2R18, CO2R18, NO2, OR18SR18, NR18COR19or CONR18R19, R18and R19preferably are hydrogen, lower alkyl, lower aryl, Z is a hydrogen, halogen, pseudohalogen, lower alkyl, lower alkoxygroup or pseudohalide - or halogen (lower alkyl)om. In some preferred versions of the R8and R10are hydrogen, halogen or stands, more preferably hydrogen or halogen, a R9chosen independently from a number of: hydrogen, halogen, aryl, pseudohalide and lower alkyl, preferably methyl or ethyl, COR18, CONR18R19, NR18COR19.

In these compounds R2preferably selected from the range of: alkyl, lower alkene the th haloalkyl, more preferably R1is bromine, chlorine, stands or ethyl. In most represented here by the active compounds, as proven by a study linking in vitro, R1is bromine or chlorine.

In a preferred embodiment, the compounds have the formula II in which R1is halogen or stands, R2, Ar2, R3, R5R6, R8, R9, R10and R11are as defined above. In the most preferred versions of the R1is bromine. Thus, in the General case, the most preferred compounds, in particular with respect to ETA-affinity, are N-(4-bromoisoquinoline) sulfonamides. Compounds in which R1is stands, and Ar2different from phenyl or naphthyl are preferred.

For preferred compounds include those that have selectivity for ETBthe receptor or which are associated with ETBreceptors with IC50less than 1 μm. In these compounds Ar2is a 3-diphenyl, 4-diphenyl, in some connections, Ar2is a phenanthrene or five-membered heterocycle, in particular titaniam, others on C13H27). R2selected among alkyl, lower haloalkyl and hydrogen, a R1is halogen, lower alkyl or lower haloalkyl, or, when Ar2is phenyl or naphthyl, R1is higher alkyl (9 or more carbon atoms, preferably from 9 to 13 carbon atoms). To the five-membered heterocyclic compounds which have affinity or selectivity for ETB-receptor, are those in which R9and R10independently selected from a number of: hydrogen, lower alkyl, mainly methyl or ethyl, halogen, and R8that is a substituent in position 5 (see, for example, formulas, introducing the numbering of the compounds of the 5-membered heterocyclic ring) represents an aryl or a heterocycle, in particular phenyl and isoxazolyl that have or do not have substituents from the series Z, which is mostly lower alkilani or halides.

Of these compounds, preference is given to those which inhibit or increase the activity of binding of endothelin to 50% at concentrations less than 10 μm. More preferred are those compounds that inhibit or increase the activity of binding of endothelin to 50% in concentration is her 0.01 µm, most preferably less than 0,005 mm.

Among the preferred compounds for use in the proposed methods are those that have ETA-selectivity, i.e., interact with ETAreceptors at concentrations significantly lower (IC50below, at least 10 times, mostly in 100 times) than the concentrations at which they interact with ETB- receptors. Other preferred compounds are ETB-selective. These compounds interact with ETBreceptors at concentrations IC50that, at least 10 times lower than those that they interact with ETA-receptors. Preferred in particular compounds that interact with ETAreceptors with IC50less than 10 microns, preferably less than 1 μm, preferably of 0.1 μm, and with ETBreceptors with IC50more than 10 microns, or compounds that interact with ETBwhen IC50less than 10 microns, preferably less than 1 μm, more preferably less than 0.1 μm, and with ETAwhen IC50more than 10 microns.

Other preferred compounds for use in these methods are any connected is considerable less than 1 μm, more preferably less than 0.1 μm, then less than 0.01 μm, most preferably less than 0,005 mm.

Offers pharmaceutical compositions created for the application accordingly, and means containing effective concentrations of one or more of the compounds presented herein, or pharmaceutically applicable their salts or acids in quantities that are effective in the treatment of hypertension, paralysis, asthma, shock, ocular hypertension, glaucoma, kidney failure, inadequate perfusion of the retina and other conditions that might in some way influence the peptide endothelin and accompanied by compression of blood vessels or symptoms, which can be removed with the use of antagonists or agonists endothelin. Particularly preferred compositions are those which contain an effective amount for the treatment of hypertension and renal failure. These effective amounts and concentrations effective at removing any symptoms of these disorders.

The methods of treatment of disorders associated with endothelin, including, but not limited to, hypertension, asthma, shock, ocular hypertension, glaucoma, inadequate ocular perfusion, etc is including the reduction of blood vessels, or such symptoms are reduced through the use of the antagonist or agonist endothelin.

In particular, the methods of treatment-dependent endothelin violations by introducing effective amounts of sulfonamides, precursors of drugs or other suitable derivatives of sulfonamides. In particular, methods for treatment related to endothelin disorders, including hypertension, cardiovascular

disease, heart disease, including myocardial infarction, pulmonary hypertension, hypertension induced by erythropoietin, respiratory diseases and endemic diseases, including asthma, bronchial spasm, eye diseases, gastrointestinal disturbances, renal failure, ischemia, menstrual disorders, disorders of childbirth, wounds, anaphylactic shock, hemorrhagic shock, and other diseases are caused by endothelin physiological responses through the use of effective amounts of one or more proposed here compounds in pharmaceutically acceptable carriers. Preferred treatment methods are methods for the treatment of hypertension and renal failure.

Preferred methods laciniata endothelin-1 with ETAreceptors at a concentration of IC50less than 10 microns, preferably less than 5 microns, more preferably less than 1 μm, even more preferably less than 0.1 μm, most preferably less than 0.05 μm. Other preferred methods are those in which the compositions contain one or more compounds, which are ETA-selective, or one or more compounds, which are ETB-selective. Methods that use ETA-selective compounds used to treat diseases such as hypertension, and those that use ETB-selective compounds used to treat diseases such as asthma, when you want the bronchi.

In the practical application of methods of effective amounts of compositions containing therapeutically effective concentrations of the compounds intended for oral, intravenous, local and topical application in the treatment of hypertension, cardiovascular diseases, heart diseases, including myocardial infarction, respiratory diseases, including asthma, inflammation, eye diseases, diseases of the gastrointestinal tract, kidney failure, caused by immunoepidemiological shock, pulmonary hypertension and other diseases, which is caused by endothelin physiological response, entered a patient who is experiencing a symptom of one or more of these diseases. These amounts sufficient to reduce or remove one or more of the symptoms of these diseases.

Methods for identification and isolation of subtypes endothelioma receptors. In particular, methods for detection, differentiation and selection endothelioma receptors with the proposed use of the described compounds. In particular, methods for detection, differentiation and selection endothelioma receptors using here connections.

In addition, there are also methods of identifying compounds that are suitable for use in the treatment of certain diseases, osnovannyy on their pre-emption based on certain subtypes endothelioma receptors.

There are also factory products containing packaging material, here a compound, which is effective to improve the condition when caused by endothelin disease, counteracting the effects of endothelin or inhibiting svyatiteyal, and a label that indicates that the compound or its salt is used to counteract the effects of endothelin, treating caused by endothelin disease or inhibiting the binding of the peptide with endothelin ET-a receptor.

A DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT OF THE INVENTION.

Definitions.

If not defined otherwise, all technical and scientific terms used herein have the same meaning as generally understood by experts in the field of technology to which the invention belongs. All patents and publications referred to referred to by specifying data.

Here it is assumed that the peptides of the endothelin (ET) include peptides, which largely have the amino acid sequence of endothelin-1, endothelin-2 and endothelin-3 and acts as a potent endogenous vasoconstrictor peptides.

Here, it is assumed that associated with endothelin condition is a condition, which is caused by abnormal activity of endothelin, or the state in which compounds that inhibit the activity of endothelin have therapeutic applications. Such diseases include, but are not limited to only inye violations complications during childbirth, diseases of the gastrointestinal tract, renal failure, pulmonary hypertension, ischemia, anaphylactic shock, hemorrhagic shock. Conditions associated with endothelin, also include conditions that are the result of treatment with these agents, as erythropoietin and immunosuppressants, which increase the level of endothelin.

In the sense used here, an effective amount for the treatment of certain diseases is one which is sufficient to improve or a reduce symptoms associated with the disease, This number can be used as a single dose or in accordance with the effective mode. This quantity can cure the disease, but usually it is used to reduce the symptoms of the disease. Usually requires re-application to achieve the desired improvement.

In the sense used here, the agonist endothelin is a compound that increases the biological activity or has biological activity, which is characteristic of the peptides of the endothelin or associated with them.

In the sense used here, the endothelin antagonist is compound, and other related endothelin physiological reactions. The antagonist can act by interfering with the interaction of endothelin from endothelial-specific receptor, or through intervention in physiological reactions or biological activity of isopeptide endothelin, for example, the reduction of blood vessels. Thus, in the sense used here, the endothelin antagonist interferes with caused by endothelin reduction of vessels or other response, or interfere in the interaction of endothelin from endothelial-specific receptors, such as ETAreceptors, which is confirmed by methods known in the art.

The effectiveness of potential agonists and antagonists can be evaluated using methods known in the art. For example, the activity of the agonist endothelin can be identified by its ability to stimulate the contraction of blood vessels isolated thoracic aorta of rats or ring segments of the portal vein (Borges and others (1989) "Tissue selectivity values of endothelin" Eur. J. Pharmacol. 165; 223-30), the activity of the endothelin antagonist can be evaluated according to their ability to interfere caused by endothelin-reduction vessels.

In the sense used here, the biological activity or the biological activity of endothelin includes any and sposobnosti contact with specific receptors and cause functional response, for example, the reduction of blood vessels. It can be estimated by the methods of in vivo or in vitro, such as in the examples. Relevant activities include, but are not limited to only these, vasoconstriction, reducing blood vessels and bronchi. For example, ETBreceptors, apparently, is expressed in vascular endothelial cells and may serve as a mediator in the expansion of blood vessels and other similar reactions, while ETAreceptors, which are endothelin-1-specific, are found in smooth muscle and is associated with reduction of blood vessels. Any method known in the art to measure or detect such activity may be used to assess such activity (see, for example, Spokes and others (1989) J. Cardiovasc. Pharmacol 13(Suppl. 5): S191-92; Spiliella and others (1991) Proc. Natl, Acad. USA 88: 7443-46; Cardell and others (1991) Neurochem. Int. 18: 571-574) and the examples given here).

In the sense used here, the IC50corresponds to the amount, concentration or dosage of the compounds in which achieved 50% inhibition compared to the maximum response, for example, binding of endothelin to receptors fabric, in the method, which measured this response.

In the sense used here, EC

In the sense used here, the sulfonamide is ETB-selective sulfonamide, if IC50with respect to ETB-receptors is lower than the ETAreceptors, at least 10 times.

In the sense used here, the sulfonamide is ETA-selective sulfonamide, if IC50with respect to ETA-receptors is lower than the ETBreceptors, at least 50-100 times.

In the sense used here, pharmaceutically applicable salts, esters or other derivatives of the compounds include any salts, esters and other derivatives, which can be easily obtained by experts, using the known methods of producing such derivatives and compounds that can be used to treat animals and humans without substantial toxic effects and that are, or pharmaceutically active or are precursors of drugs. For example, the hydroxy-group can be atrificial with getting simple or complex esters.

In the sense used here, treatment means any method, which improves the symptoms comprising the fight pharmaceutical use of these compounds, for example, the use of contraceptives.

In the sense used here, the improvement of symptoms of certain irregularities in the application of special pharmaceutical compositions means any reduction, permanent or temporary, stable or transient that can be attributed to or associated with the use of a composition.

In the sense used here, almost pure means sufficiently homogeneous to appear free from impurities, which can be easily found when determining the standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis and high performance liquid chromatography(HPLC), used by experts to assess such purity, in other words, almost pure means that further purification of the substances does not change in measurable amounts of its physical and chemical properties, such as enzymatic and biological activity. Methods of cleaning compounds to obtain almost pure compounds well known in the art. Almost chemically pure compounds can, however, be a mixture of stereoisomers. In this case, further treatment could increase the specific activity of connections or physiological reactions, that is the result of the application of in vivo compound, composition or other mixture. Biological activity, thus, includes therapeutic effects and pharmaceutical activity of such compounds, compositions, mixtures.

In the sense used here, the precursor drug is a compound which, when applied in vivo is included in the metabolism or otherwise transformed into a biologically, pharmaceutically or therapeutically active form of connection. To obtain a precursor drugs pharmaceutically active compound is modified so that the active connection will be regenerated in the process of metabolism. Predecessor medications can be used to change the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the smell of the medicine or change other characteristics or properties of drugs. Thanks to the knowledge of pharmacodynamic processes and metabolism of drugs in vivo specialists can create the predecessors of the drug, if known pharmacologically active compound (see, e.g., Nogrady (1985) Med, Chem. A Biochem. Appr., Oxford Univ is sulfonamida (sulfathiazole), which changes the transport properties.

In the sense used here, the halogen or halogen means F, Cl, Br, I.

In the sense used here, pseudohalide are compounds, which behave very similar to halides. Such compounds can be used in the same way and processed in the same way that the halogen (X, where X is halogen, such as Cl or Br). Pseudohalide include, but are not limited to, the following: cyanide, cyanate, thiocyanate, selenocyanate and azide.

In the sense used here, alkyl, alkenyl and quinil mean a linear or branched carbon chain which may be substituted or unsubstituted, having from 1 to 24 or so values carbon atoms, preferably from 1 to 10 or so values carbons, more preferably from 1 to 7 carbons. Thus, for example, alkyl includes linear chain, branched chain and substituted carbon chain, including benzyl and camphor group.

In the sense used here, lower alkyl, lower alkenyl and lower quinil means a carbon chain having 6 or less around this value of carbon. In a preferred embodiment of obtained here is thought, used here, the aryl means an aromatic cyclic group containing from 3 to 15 to 16 carbon atoms, preferably from 5 to 10. Aryl groups include, but are not limited to, phenyl, substituted phenyl, naphthyl, substituted naphthyl in which the substituents are lower alkyl, lower alkoxy group or halogen. Preferred aryl groups are lower aryl groups that contain less than 7 carbon atoms in the ring structure.

In the sense used here, the nomenclature of alkyl, alkenyl, carbonyl, etc. are used in the usual sense of its specialists. For example, when used herein, the designation alkyl means saturated carbon chain which contains one or more carbons; the chain may be linear or branched or include cyclic or be circular.

In the sense used here, alicyclic means that the alkyl group is cyclic.

In the sense used here, haloalkyl means a lower alkyl radical, in which one or more hydrogen atoms replaced by halogen, including but not limited to only these, chloromethyl, trifluoromethyl, 1-chloro-2 - foradil and the like.

In uppoi.

In the sense used here, aminocarbonyl means the group-C(O)NH2.

In the sense used here, alkylaminocarbonyl means the group-C(O)other, where R is hydrogen, alkyl, mainly lower alkyl or aryl, mainly lower aryl.

In the sense used here, dialkylaminoalkyl means-C(O)NR1R, where R1and R is independently selected from alkyl or aryl, preferably lower alkyl and lower aryl.

In the sense used here, carboxamid means a group NR1COR.

In the sense used here, alkoxycarbonyl means the group-C(O)OR where R is alkyl, preferably lower alkyl, or aryl, preferably lower aryl.

In the sense used here, alkoxy, dialkoxy mean group - OR and - SR, where R is alkyl, mainly lower alkyl, and aryloxy, aaltio mean-OR and-SR, where R is aryl, mainly lower aryl.

In the sense used here, cycloalkyl means saturated cyclic carbon chain, and cycloalkenyl and cycloalkyl means cyclic carbon chain which contains at least one unsaturated double is more condensed rings.

In the sense used here, a heterocycle or heteroaryl means a ring structure containing at least one carbon atom and one or more atoms such as N, S, O. Ring can be a single or condensed, containing two or more rings.

In the sense used here, the abbreviations for any protective groups, amino acids and other compounds correspond to their normal use, unless otherwise specified, in accordance with the recognized abbreviations, or biochemical nomenclature IUPAC (see (1972), Biochem. 11: 1726).

A. Compounds for use in the treatment of endothelium-dependent diseases.

Provides compounds and methods for treatment of dependent endothelin diseases, corresponding to the formula I. In the particular case presented here, the compounds have formula II in which Ar2selected from the group including, but not limited to only these, the following radicals: alkyl, phenyl, diphenyl, dibenzofuran, dibenzothiophene, carbazole, naphthyl, thiophenyl, furyl, pyrrolyl, ethanolic, hinely, tenantry, still, pyridinyl, and heterocycles with two or more heteroatoms, including heterocycles with one ring, or two or more condenser is the established levels.

1. Isoxazolecarboxylic in which Ar2is a phenyl, diphenyl and condensed aromatic rings.

Available compounds in which Ar2is selected from phenyl, diphenyl and aromatic condensed ring groups include naphthyl, anthracene, tenantry, indenyl, azulene, fluorene and phenazines. When Ar2is a phenyl, diphenyl or naphthyl, the compounds are preferably (4-halogen-isoxazolyl)sulfonamide or (4-higher alkyl-isoxazolyl) sulfonamide in which the alkyl group contains 8 or more around this value, preferably from 9 to 15, more preferably 9 to 13, carbon atoms. These compounds have the formula III:

< / BR>
or

< / BR>
where n=0-10, preferably from 0 to 6, more preferably from 0 to 3;

R3, R4, R5, R6and R7selected from (i), (ii), (iii) or (iv) provided that

a) when Ar2is phenyl, at least one of the radicals R3, R4, R5, R6and R7is not hydrogen,

b) when Ar1is 4-halogen-5-methylisoxazole, R3neither NH2or CH3;

c) when Ar2is phenyl, naphthyl or 2-UP>5, R6and R7selected independently from the groups: H, NHOH, NH2, NO2N3, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, halodrol, alkoxycarbonyl, alkylsulphonyl, arylcarbamoyl, formyl, substituted or unsubstituted amido-substituted or unsubstituted, ureido-, where alkyl, alkenyl, quinil are linear or branched chain containing from 1 or about this value to 10 or so values carbon atoms, preferably from 1 to 5-6 or so values of carbon, and aryl contains from 3 to 10 or so values carbons, preferably 6 carbons, or alternative,

(ii) R4and R7together represent a substituted or unsubstituted 1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl, 1-Aza-1,3-butadienyl or 2-Aza-1,3 - butadienyl, a R3R5, R6are as defined above in (i), or alternative,

(iii) R3and R7together represent a substituted or unsubstituted 1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl, 1-Aza-), or

(iv) R3R5and R7are hydrogen, as defined in (i), a R4, R6independently selected from the groups: alkyl, alkoxy, haloaluminate, dialkylaminoalkyl, where the alkyl and alkoxy groups contain from 1 to 10, preferably from 1 to 6 carbons and have a linear or branched chain.

In a more preferred embodiment, R2is H, CH3C2H5, R1is Cl, Br or CH3X is O or S, n=0-1, a R3, R4, R5, R6and R7choose either from (i), (ii), (iii) or (iv) as follows:

(i) R5, R6are hydrogen, R4and R7independently selected from hydrogen, halogen, NH2, CF3, phenyl, CH3; R3selected from H, NHOH, NH2, NO2C2H5NH2, (CH3)2NH, C6H5CH2NH, F, Cl, Br, I, CN, CH3, (CH3)3C, C5H11CH3O, n-C4H9O, CH2= H, C6H5CH=CH, CHC C6H5CC C6H5, 3-(ethoxycarbonylmethyl)ureido, 3 cyclohexylurea, or:

(ii) R4and R7together form 1,3-butadienyl, 4 - dimethylamino-1,3-butadienyl, 4-chloro-1,3-butadienyl or 1-Aza-1,3-butadienyl, a R3, R5 form 1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 3-chloro-1,3-butadienyl, 1-Aza - 1,3-butadienyl, a R4, R5, R6are as defined above in paragraph (i), or

(iv) R3, R5and R7are hydrogen, as defined in (i), a R4, R6each independently selected from the groups: alkyl, alkoxy, halogen, aminoalkyl, acylaminoalkyl or dialkylaminoalkyl, where the alkyl and alkoxy groups contain from 1 to 10, preferably from 1 to 6 carbons and have a linear or branched chain.

More preferred among the above described compounds are those in which Ar2is substituted or unsubstituted phenyl or naphthyl; R1is bromine, chlorine or iodine; R2is H, CH3C2H3, CF3C2F5n-C3H7, cyclo-C3H5C4H8, a R3, R4, R5, R6and R7are either (i), (ii), (iii), (iv) or (v):

(i) R5, R6and R7are hydrogen, n=0, a R3is H, NH2CH3, CF3, halogen, C2H5NH, C6H5; R4is H, CF3, NH2; R7is H or CF3, a R5and R6are H, or

(ii) R3, R4, RAvenel, 4-chloro-1,3-butadienyl, or

(iii) R4, R5and R6are H, n=0, a R3and R7together form 1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl, 1-Aza-1,3-butadienyl, or

(iv) R4is H or NH2; R5and R6are H, n=1, a R3is H, NH2and halogen, CH3, Br, Cl, F, CF3, NH2, R7is H, CH3, Br, Cl, F, NH2or CF3; a R5and R6are H; or

(v) R3, R5and R7are hydrogen, as defined in (i), a R4, R6each independently selected from alkyl groups that contain from 1 to 6 carbons and contain linear or branched chain lower alkoxy groups, and Halogens.

In more preferred embodiments perform benzosulfimide and nationalholiday are N-(4-halogen)-substituted N-isoxazolecarboxylic or 4-higher alkyl-substituted N-isoxazolidinone, in which R2represents H, CH3C2H5, CF3C2F5, a R3, R4, R5R6and R7are either (i) or (ii) in accordance with the following:

(i) R4, R5, R6and R7independently selected from H, halogen, NH2H3)2N, C6H5CH2NH, NO2, F, Cl, Br, I, CN, CH3, (CH3)3C, C5H11CH3O n-C4H9O, CH2=CH, C6H5CH=CH, CHC C6H5CC C6H5, 3-(ethoxycarbonylmethyl)ureido, 3 cyclohexylurea, or:

(ii) R3, R5, R6and R7are H, a R4and R6are both alkyl groups that contain from 1 to 3 carbons and have a linear or branched chain.

In an even more preferred embodiment, R1most preferably is Br, a R2is CH3C2H5or CF3; R3, R4, R6and R7are (i) or (ii) in accordance with the following:

(i) R3is H, NH2, CF3CH3, halogen or C2H5NH, a R4, R5, R6independently selected from H, CF3, halogen, especially Br, and Cl, NH2; R7is H, CH3CH2C6H5, (CH3)2CH, F, or CF3; or

(ii) each of the groups R3, R4, R5, R6and R7is stands or ethyl.

All versions of the R1most preferred is bromine, with the exception of t is in which R1is stands, then most preferably, R1was higher alkyl (from 9 to 15 carbons, preferably from 9 or 10 to 13 carbons).

A. Compounds in which Ar2is phenyl and diphenyl, n=0.

Compounds in which Ar2is a phenyl or diphenyl, have the following formula:

< / BR>
or

< / BR>
where R3, R4, R5, R6and R7selected from (i), (ii), (iii) or (iv), provided that (a) when Ar2is phenyl, at least one of the radicals R3, R4, R5R6and R7is not hydrogen;

(b) when Ar2is phenyl and Ar1is a 3-isoxazolyl, R3neither NH2or CH3;

(c) when Ar2is naphthyl, 2-diphenyl, phenyl, different from benzofuran, dibenzothiophene and dibenzopyrene, R1is halide or higher alkyl:

(i) R3, R4, R5, R6and R7selected independently from the following series: hydrogen, NHOH, NH2, NO2N3, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfonyl, alkylsulfonyl, arikace, arylamino, aaltio, ermesinda or unsubstituted amido group, substituted or unsubstituted, ureido - group in which alkyl, alkenyl, quinil are linear or branched chain containing from 1 or about this value to 10 or so values carbons, preferably from 1 up to 5 or 6 carbons and the aryl portion contains from 3 to 10 or so values, preferably 6 carbons, each group independently selected as described above; or alternatively,

(ii) R3, R5and R7are hydrogen, a R4, R6chosen independently from a number of: alkyl, alkoxy, halogen, aminoalkyl, dialkylaminoalkyl, which are substituted or unsubstituted alkyl groups, and the alkyl and alkoxy contain smaller schools from 1 to 10, preferably from 1 to 6 carbons, and are linear or branched chains.

Among the above-mentioned phenyl and diphenylene compounds are compounds with the following formula (V):

< / BR>
or

< / BR>
where R3, R5and R7are each independently:

(a) hydrogen, and at least one of the radicals R3, R5and R7is not hydrogen,

(and) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkylation, cycloalkenyl, cycloalkenyl, aryl, ar is the conclusion of those cases, when one of the radicals R3, R5and R7is alkyl in the 4-position, then at least one of the other two radicals R3, R5and R7is not hydrogen;

(C) halogen;

(d) hydroxyl;

(f) a cyano group;

(f) a nitro group, except in those cases where one of the radicals R3, R5and R7is 4-nitro-group, then at least one of the other two radicals R3, R5and R7is not hydrogen;

(g) -C(O)H or-C(O)R27;

(h) -CO2H or-CO2R27;

(i) -SH, -S(O)nR27, -S(O)m-H, -S(O)m-OR27, -OS(O)mOH, -OS(O)mOR27;

(j) -W4NR28R29except in those cases where R3, R5and R7are 4 - W4NR28R29then, at least one of the other two radicals R3, R5and R7are not hydrogen; or

(k) -W4N(R32)-W5NR30R31;

R1is halide or higher alkyl (containing more than 8 or so values up to 9 or so values of carbons in the chain); R2selected from the series:

(a) hydrogen;

(b) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cyclol is substituted W1, W2and W3;

(c) hydroxyl;

(d) cyano;

(e) nitro;

(f) -C(O)H or-C(O)R27;

(g) -CO2H or - CO2R27;

(h) -SH, -S(O)nR27, -S(O)m-OH, -S(O)mOR27, -O-S(O)m-R27; O-S(O)mOH or-O-S(O)m-OR27;

(i) -W4-NR28R29; or

(j) -W4N(R32)-W5-NR30R31;

R27represents alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of which may be substituted by W1, W2and W3;

R28represents a group:

(a) hydrogen

(b) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of which may be substituted by W1, W2and W3;

(C) cyano;

(d) hydroxyl;

(e) -C(O)H or-C(O)R27;

(f) -CO2R27;

(g) -SH, -S(O)nR27, -S(O)m-OH, -S(O)m-OR27, -O-S(O)m-R27; -O-S(O)mOH or-O-S(O)m-OR27except for the case when W4represents-S(O)n-;

R29represents a

(a) hydrogen

(b) -C(O)H or-C(O)R27, with the exception of the/SUB>R27;

(C) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of which may be substituted by W1W2and W3;

or

R28and R29together they are alkylene or albaniles (each of which may be substituted by W1, W2and W3), making a 3-8 membered saturated, unsaturated or aromatic cycle, together with the nitrogen atom to which they are attached;

R30represents a group

(a) hydrogen

(b) hydroxyl

(C) -C(O)H or-C(O)R27;

(d) CO2R27;

(e) -SH, -S(O)nR27, -S(O)m-OH, -S(O)mOR27, -O-S(O)m-R27, -O-S(O)mOH or-O-S(O)m-OR27;

(f) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of which may be substituted by W1, W2and W3;

R31represents a group

(a) hydrogen

(b) -C(O)H or-C(O)R27except for the cases when W5represents-C(O)- and R30represents-C(O)H, - C(O)R27or-CO2R27; or

(c) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cyclea the>
and W3;

R2represents a

(a) hydrogen

(b) hydroxyl

(C) -C(O)H, -C(O)R27or-CO2R27; or

(d) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of which may be substituted by W1, W2and W3; or any two radicals of R30, R31and R32together they are alkylene or albaniles (each of which may be substituted by W1, W2and W3, comprising a 3-8 membered saturated, unsaturated or aromatic cycle, together with the atoms to which they are linked;

W1, W2and W3represent each independently

(a) hydrogen;

(b) halogen;

(C) hydroxy;

(d) alkyl;

(e) alkenyl;

(f) aralkyl;

(g) alkoxy;

(h) aryloxy;

(i) arakaki;

(j) -SH, -S(O)nW6, -S(O)m-OH, -S(O)m-OW6, -O-S(O)m-W6, O-S(O)mOH, or-O-S(O)m-OW6;

(k) oxo;

(l) nitro;

(m) cyano;

(n) -C(O)H or-C(O)W6;

(Oh) -CO2H or-CO2W6;

(p) -W4NW7W8;

(q) -W4-N(W11)-W5-W6; or

(r) -W4-N(W11)-W5NW7(b) -W9-S(O)n-W10-;

(s) -W9-C(O)n-W10-;

(d) -W9-C(S)-W10-;

(e) -W9-O-W10-;

(f) -W9-S-W10-; or

(g) -W9-O-C(O)-W10-;

thus W6, W7and W8are each independently hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, or W7and W8together they are alkylene or albaniles comprising 3-8 membered saturated, unsaturated or aromatic cycle, together with the nitrogen atom to which they are attached;

W9and W10each independently represent a simple bond, alkylene, albaniles, or akinyan;

W11represents a group:

(a) hydrogen

(b) hydroxyl

(C) -C(O)H, -C(O)W6or-CO2W6;

(d) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, or any two of the radicals W7, W8and W11constitute a 3-8 membered saturated, unsaturated or aromatic cycle, together with the atoms to which they are attached;

m = 1 or 2; and

n = 0, 1, or 2.

Preferred are t, the connections in which one of the radicals R3R5or R7is hydrogen, one of the other two radicals R3, R5or R7is in position 2 and is not hydrogen, and the second from the group R3, R5and R7is located in position 5. Thus, the preferred compounds are substituted in position 2 benzosulfimide and substituted in positions 2, 5 benzosulfimide. Additionally, in preferred compounds, R1preferably represents halogen. Preferred substituents are lower alkyl, mainly methyl, ethyl and propyl, halogen, amino, dimethylamino and metoxygroup.

(1) Ar2represents phenyl.

Ar2has, as a rule, formula (VI):

< / BR>
in which R1represents a halogen or high-molecular alkyl (more than 8 carbon atoms); R2selected from the group comprising H, NH2, NO2, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, aralkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, aminocarbonyl, haloalkyl, halodrol, al unsubstituted of raidgroup, where alkyl, alkeline and alkyline parts are linear or branched, containing from 1 to 10 or so values of carbon atoms and the aryl portion contains from 4 or so Values up to 14 or so values carbon atoms; and R3R4, R5, R6and R7represent (i) or (ii) in accordance with the following:

(i) R3, R4, R5, R6and R7independently selected from the group consisting of H, NHOH, NH2, NO2pseudohalide, including N3, halogen, alkenyl, quinil, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, alkoxycarbonyl, alkylsulphonyl, arylcarbamoyl, formyl, zameshannye or unsubstituted of raidgroup, where alkyl, alkeline and alkyline parts are linear or branched, containing from about 1 to about 10 carbon atoms, predominantly from 1 to 5-6 carbon atoms, unsubstituted or substituted by the groups mentioned above for R8, R9, R10and R11and the aryl portion contains from 3 to 10 or so values of carbon atoms, mostly 3-6 carbon atoms, and t>1
; R4and R6such as defined in (i); or

(ii) R3R5and R7represent H; a R4and R6independently each selected from the group consisting of alkyl, alkoxy, halogen, aminoalkyl, dialkylamino, dialkylaminoalkyl, which are unsubstituted or substituted alkyl groups, and in which the alkyl and alkoxy groups contain from 1 to 10, mainly 1-6 carbon atoms and are straight or branched chains.

Compounds in which at least one of the radicals R3-R7represents phenyl, are considered below in the discussion of diphenylene connections.

In some preferred versions of the R1is a halide or higher alkyl selected from the group of C9H19to C13H27; R2selected independently from the group consisting of alkyl, lower alkenyl, lower quinil, lower haloalkyl and H; a, R3, R4, R5, R6and R7are either (i) or (ii) according to the following:

(i) R4, R5, R6and R7each independently selected from the group consisting of H, lower alkyl, NH2, NO2, halogen, pseudohalogen; R3selected from the group is laksi, alkylamino, alkylthio, alkoxyalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, halodrol, alkoxycarbonyl, alkylsulphonyl, arylcarbamoyl, formyl, substituted or unsubstituted of aminogroup, substituted or unsubstituted of raidgroup, where alkyl, alkeline, alkyline parts have a linear or branched chain containing from 1 to 5-6 carbon atoms, and aryl part containing 4-14 carbon atoms; or

(ii) R3, R5and R7represent H, a R4and R6each independently selected from the group consisting of alkyl, alkoxy, halogen, aminoalkyl and dialkylaminoalkyl, which are unsubstituted or substituted alkyl groups, and alkyl - and alkoxygroup contain 1-6 carbon atoms and are linear or branched chains.

In a more preferred embodiment, R1represents Cl or Br, or higher preferred activity activity ETBpreferred is a higher alkyl (C9H19-C13P27); R2selected from the group consisting of H, CH3C2H5, CF3C2F5n-C3H7, cyclo-C3H5(i) or (ii) according to the following:

(i) R4, R5, R6and R7each independently selected from the group consisting of H, halogen, NH2, CF3C6H5and CH3; R3selected from the group consisting of H,

NHOH, NH2C2H5NH, (CH3)2N, C6H5-CH2NH, NO2, F, Cl, Br, J, CN, CH3, (CH3)3C, C5H11CH3O n-C4H9O, CH2=CH, C6H5-CH=CH, CHC C6H5-CHC C6H5, 3-(ethoxycarbonylmethyl)ureido and 3 cyclohexylurea; or

(ii) R3, R5and R7represent H; a R4and R6each independently represents an alkyl or aminoalkyl, in which the alkyl groups have 1-6 carbon atoms and may be linear or branched chain.

In an even more preferred embodiment, R1represents Br, Cl or group from C9H19to C13H27; R2represents H, CH3C2H5or CF3; R3, R4, R5, R6and R7are either (i) or (ii) according to the following:

(i) R3represents H, NH2CH3CF3, halogen or C2H5NH; R4, R5and R6independently selected Yves>2; a R7represents H, CH3CH2CH5(CH3)2CH, F, or CF3; or

(ii) R3, R5and R7represent H; a R4and R6each independently chosen from a set of alkyl groups having 1-3 carbon atoms and which may form a linear or branched chain.

Of the above compounds, preferable are those which are ortho - or meta-substituents or those that are substituted in positions 2 and 5 of the benzene ring. The exception is the case when the compound obtained is a diphenyl and ETB-activity. In this case, preferred are the corresponding para-substituted compounds. Compounds with ortho-substituents in the General case is more preferable than the corresponding meta-substituted compounds. This observation is particularly important when taking into account the activity in relation to ETA-receptors. Additionally, in preferred compounds, R1primarily represents halogen. Preferred substituents are lower alkyl, especially methyl, ethyl and propyl, halogen, amino, dimethylamino and methoxypropylamine were synthesized and tested using the examples of test methods (see examples), and the results are shown in Table 1 (N-(3,4-dimethyl-5-isoxazolyl)benzosulfimide mainly given for comparison with the corresponding N-(4-halogen-3-methyl-5 - isoxazolyl)benzosulfimide).

(2) Ar2represents a diphenyl

In some embodiments, execution of the invention described here Ar1represents N-(5-isoxazolyl) or N-(3 - isoxazolyl) with radicals R1and R2selected, as described above, and Ar2represents a substituted benzene group, in which one of the radicals R3, R4, R5, R6and R7selected independently from the group consisting of phenyl and substituted phenyl. The other radicals R3, R4, R5, R5and R6selected, as described above in (1) for embodiments in which Ar represents phenyl. R1and R2also selected as described in (1) above, except when one of the radicals R3, R4, R5, R6and R7is in position 3 or 4, so that the resulting compounds are 3 - or 4-biphenyls. In these cases, R2selected, as described above, but R1may be a halide or higher alkyl, and in addition, it may be any halogen, lower alkyl, in particular, CH3or C9H19- C13H27. In some embodiments, performing Ar2represents an unsubstituted or substituted diphenylene group of the formula (VII):

< / BR>
in which each ring may have one or more substituents, each of which is independently selected from R26and R13where:

(i) R26and R13independently selected from the group consisting of H, OH, OHNH, NH2, NO2, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, halodrol, alkoxycarbonyl, carbonyl, alkylaryl, aminocarbonyl, arylcarbamoyl, formyl, substituted or unsubstituted amido-substituted or unsubstituted of raidgroup, where alkyl, alkeline and alkyline parts contain from 1 to 14, or about the value of carbon atoms, predominantly from 1 to 6 atoms, and are linear or branched chains or cycles, and the aryl portion contains from 4 or so values up to 16 or so values of atoms of carbon, mainly from 4 to 10 carbon atoms; or
11represents a group as defined above, mainly H or alkyl, mainly lower alkyl. It is clear that either (i) or (ii) each ring Ar2may be unsubstituted or substituted with more than one Deputy, each of which is independently selected from the set specified in (i) for R26and R13.

These compounds thus include diphenylsulfone, condensed tricyclic substituted sulfonamides, dibenzothiophene, dibenzofuransulfonate, dibenzoyltartaric, (carbosulfan) and phenanthrenequinone. Dibenzothiophene, dibenzofuransulfonate, dibenzobarrelenes and fantranslated are discussed separately together with the compounds in which Ar2represents a heterocycle with one heteroatom and two or more condensed cycles.

In preferred versions of the Ar2has the formula (VIII):

< / BR>
or

< / BR>
where R26and R13selected from the group consisting of H, lower alkyl, haloalkyl and halogen. It is clear that Ar2can be substituted by more than one Deputy, each of which is independently selected from the range set for W diphenylsulfone, a R1is a halogen, R2selected from the group consisting of alkyl, lower alkenyl, lower alkyl halide or H; and R26and R13selected from the group consisting of H, lower alkyl, haloalkyl and halogen. In preferred embodiments, R1represents Cl or Br, and 3-diphenylsulfone and 4-diphenylsulfone R1also represents CH3; R2selected from the group consisting of H, CH3C2H5, CF3C2F5n-C3H7and cyclo-C3H5, a R26and R13each independently selected from the group consisting of H, halogen, NH2, CF3CH3, CN, CH3, (CH3)3C, C5H11CH3OH, H-C4H9O and CH2=CH.

In an even more preferred embodiment, R2represents H, CH3C2H5or CF3; R26and R13independently selected from the group consisting of H, CH3C2H5, CF3and halogen; X represents O.

In another preferred embodiment of diphenylsulfone represent a 3 - or 4-diphenylsulfone, a R1represents preferably a halogen or methyl. Such compounds have activity ET1selected from the group consisting of halogen, CH3C2H5, CF3C2F5n-C3H7and cyclo-C3H5mainly halogen and CH3, a R2selected from the group consisting of H, CH3C2H5, CF3C2F5n-C3H7and cyclo-C3H5; R26and R13each independently selected from the group consisting of H, halogen, NH2, CF3CH3, CN, CH3, (CH3)3C, C5H11CH3O n-C4H9O and CH2=CH. In a more preferred of these options R1represents a halogen or CH3, a R2selected from the group consisting of H, CH3C2H5or CF3; R26and R13independently selected from the group consisting of H, CH3C2H5, CF3and halogen.

Specific diphenylsulfone listed in this list and in table 2:

N-(4-bromo-3-methyl-5-isoxazolyl)-4-diphenylsulfone

N-(4-chloro-3-methyl-5-isoxazolyl)-4-diphenylsulfone

N-(4-bromo-5-methyl-3-isoxazolyl)-4-diphenylsulfone

N-(4-chloro-5-methyl-3-isoxazolyl)-4-diphenylsulfone

Diphenylene connection, here, in the General case are ETB-aktivnaya endothelin to ETBreceptors at concentrations approximately 10 - 30 times less than they inhibit the accession to endothelin ETA-receptors. ETB-selective (especially 4-diphenylsulfone.

Diphenylene compounds were tested using reflected in the examples of test methods (see, EXAMPLES), and the results are shown in the following table (table 2).

b. Compounds in which Ar2represents phenyl and diphenyl, and n>0. Ar2has the formula (IX):

< / BR>
These compounds include those described above in 1a, for which n is 1-10, mainly from 1 to 6, more preferably from 1 to 3; R1, R2correspond to (i), (ii) or (iii) as follows:

(i) R1and R2each independently selected from the group consisting of H, NH2, NO2, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, aminocarbonyl, haloalkyl, halodrol, alkoxycarbonyl, alkylsulphonyl, arylcarbamoyl, formyl, substituted or unsubstituted of aminogroup, substituted or unsubstituted of raidgroup where alkylator values carbon atoms, and the aryl portion contains from 4 or so values up to 14 or so values of carbon atoms, except that when R2is not halogen or pseudohalogen, or

(ii) R1and R2together form -(CH2)n-, where n = 3-6, or

(iii) R1and R2together form 1,3-butadienyl; and

R3, R4, R5, R6and R7selected from (i), (ii), (iii) or (iv):

(i) R3, R4, R5, R6and R7each independently selected from the group consisting of H, NHOH, NH2, NO2N3- halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, halodrol, alkoxycarbonyl, alkylsulphonyl, arylcarbamoyl, formyl, substituted or unsubstituted of aminogroup, substituted or unsubstituted of raidgroup, where alkyl, alkeline, alkyline parts have a linear or branched chain containing from 1 or about this value to 10 or so values of atoms of carbon, mainly from 1 to 5-6 or so values carbon atoms, and the aryl portion contains from 3 to 10 or so value is SUP>4and R7together represent a substituted or unsubstituted 1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl, 1-Aza-1,3 - butadienyl or 2-Aza-1,3-butadienyl, a R3, R5and R6these, which were defined in (i) above; or, in the alternative execution order,

(iii) R7and R3together represent a substituted or unsubstituted 1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1 - chloro-1,3-butadienyl, 1-Aza-1,3-butadienyl or 2-Aza-1,3-butadienyl, a R4, R5and R7these are what defined in (i) above; or

(iv) R3, R5and R7represent H, and as defined in (i), and R4and R6each independently selected from the group consisting of alkyl, alkoxy, halogen, aminoalkylated, dialkylaminoalkyl, which are unsubstituted or substituted alkyl groups, where the alkyl and alkoxy groups contain from 1 to 10, mostly from 1 to 6 carbon atoms and are linear or branched chains.

In more preferred versions of the R2represents H, CH3C2H5, CF3C2F5n-C3H7, cyclo-C3H5and C4H8, R1represents Br, Cl, CH3P>5, R6, R7selected from the group mentioned in (i), (ii), (iii) or (iv) as follows:

(i) R5and R6represent H; R4and R7each independently selected from the group consisting of H, halogen, NH2, CF3C6H5CH3; a R3selected from the group consisting of H, NHOH, NH2C2H5NH2, (CH3)2N, C6H5CH2NH, NO2, F, Cl, Br, J, CN, CH3, (CH3)3C, C5H11CH3O n-C4H9O, CH2=CH, C6H5-CH=CH, CHC, Ph-CC, C6H5, 3-(ethoxycarbonylmethyl)ureido and 3 cyclohexylurea; or

(ii) R4and R7together form 1,3-butadienyl, 4-chloro-1,3-butadienyl, 4-dimethylamino-1,3-butadienyl or 1-Aza-1,3-butadienyl; R3, R5and R6defined as in (i) in this embodiment; or

(iii) R7and R3together form 1,3-butadienyl, 3-chloro - 1,3-butadienyl, 4-dimethylamino-1,3 - butadienyl or 1-Aza-1,3-butadienyl; R4, R5and R6are as defined in (i) this option execution; or

(iv) R3, R5and R7represent H as defined in (i); a R4and R6each independently selected from the group consisting of alkyl, alkoxy, halo the different groups, where alkyl and alkoxygroup contain from 1 to 10, mostly from 1 to 6 carbon atoms, and which have a linear or branched chain.

Most preferred among these compounds are those where n = 1-3; R1represents Br, Cl, J or CH3or if you want a higher ETBthe activity represents a C9H19-C13H27; R2represents H, CH3C2H5, CF3C2F5n-C3H7, cyclo-C3H5and C4H8; R3, R4, R5, R6and R7represents a group defined in (i), (ii), (iii), (iv) or (v):

(i) R3, R5and R6represent H; R3represents H, NH2CH3, CF3, halogen, C2H5NH or C6H5, R4represents H, CF3, NH2, R7represents H or CF3, a R5and R6represent H; or

(ii) R3, R5and R6represent H; R4and R7together form 1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl, or 4-chloro-1,3-butadienyl; or

(iii) R4, R5and R6represent H; R7and R3 (iv) R4represents H or NH2, R5and R6represent H; R3represents H, NH2, a halogen, CH3, Br, Cl, F, CF3, NH2, R7represents H, CH3, Br, Cl, F, NH2or CF3, a R5and R6represent H; or

(v) R3, R5and R6represent H as defined in (i); R4and R6each independently selected from alkyl groups containing 1-6 carbon atoms, and contain linear or branched chain.

In more preferred embodiments, the implementation of the compounds are N-(4-halogen-isoxazolyl)-sulfonamides, where R2represents H, CH3C2H5C2F5or CF3; R3, R4, R5, R6and R7represent (i) or (ii) as follows:

(i) R4, R5, R6and R7each independently selected from the group consisting of H, halogen, NH2, CF3C6H5and CH3; R3selected from the group consisting of H, NHOH, NH2C2H5NH2, (CH3)2NH, C6H5-CH2NH, NO2, F, Cl, Br, J, CN, CH3, (CH3)3C, C5H11CH3O n-C4H9
(ii) R3, R5and R7represent H; R4and R6each represent an alkyl group that contains from 1 to 3 carbon atoms, linear or branched chain.

In still more preferred versions of the n=1, most preferably represent Br, Cl or CH3; R2represents CH3C2H5or CF3; R3, R4, R6and R7represent (i) or (ii) according to the following:

(i) R3represents H, NH3CH3, CF3, halogen or C2H5NH; R4, R5and R6independently selected from the group consisting of H, CF3, halogen, especially Br, and Cl, NH2; R7represents H, CH3CH2CH3, (CH3)2CH, F, or CF3; or

(ii) R3, R5and R7and R4and R6independently represent a nitrogroup, hydrogen, methyl or ethyl.

These selected compounds are an example of the above compounds (see. table.3)

c. Compounds in which Ar2contains a condensed aromatic ring.

It provides compounds in which Ar2
(1) Ar2is naphthyl

The proposed compounds in which Ar2is naphthyl,

< / BR>
These compounds have the formula (X):

< / BR>
or

< / BR>
where R1and R2selected from the group defined above, R2preferably represents H, lower alkyl or lower haloalkyl; R1preferably represents halogen, or, if you want to increase ETBactivity, higher alkyl (8 or so values up to 15, mostly from 9 to 13 carbon atoms, arranged in linear or branched chains); R3, R4, R5, R6and R7selected from (i) or (ii):

(i) R4and R7together represent a substituted or unsubstituted 1,3-butadienyl, 4-dimethylamino-1,3 butadienyl, 1-chloro-1,3-butadienyl, 1-Aza-1,3-butadienyl or 2-Aza-1,3-butadienyl; R3, R5and R6each independently selected from the group consisting of H, NHOH, NH2, NO2N3, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, halodrol, alkoxycarbonyl, alkylsulphonyl, Arik the ilen, alkeneamine, alkyline parts contain linear or branched chain containing from 1 or about this value to 10 or so values of atoms of carbon, mainly from 1 to 5-6 or so values of carbon atoms and the aryl portion contains from 3 to 10 or so values of carbon atoms, predominantly 6 carbon atoms, or, in an alternative embodiment,

(ii) R7and R3together represent a substituted or unsubstituted 1,3 - butadienyl, 4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl, 1-Aza - 1,3-butadienyl or 2-Aza-1,3-butadienyl; R4, R5and R6each independently selected from the group consisting of H, NHOH, NH2, NO2N3, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, halodrol, alkoxycarbonyl, alkylsulphonyl, arylcarbamoyl, formyl, substituted or unsubstituted amido group, a substituted or unsubstituted, ureido-group, where the alkyl, alkeline, alkyline parts contain linear or branched chain, containing from 1 or about this value to 10 or approximately the s part contain from 3 to 10 or so values carbon atoms, mostly 6 carbon atoms.

In a preferred embodiment, the R2represents H, CH3C2H5or CF3, a R1represents a halogen or, in an embodiment where the increase in ETBactivity, R1represents a higher alkyl in which the alkyl group contains 8 to 15, mainly 9-13 carbon atoms and may be straight or branched chain.

In certain embodiments of the implementation of the compounds have the formula (XI):

< / BR>
or

< / BR>
which is substituted by substituents R4, R5and R6selected independently from the following groups, provided that at least one of the substituents R4, R5and R6is not hydrogen:

(a) hydrogen;

(b) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of which may be substituted by W1, W2and W3;

(c) halogen;

(d) hydroxyl;

(e) cyano;

(f) nitro;

(g) -C(O)H or-C(O)R27;

(h) -CO2H or-CO2R27;

(i) -SH, -S(O)nR27, -S(O)m-OH, -S(O)m-OR27, -O-S(O)m-R27, -O-S(O)mOH or-O-S(O)<1
;

R1represents a halogen or higher alkyl (more than 8 carbon atoms, up to 15 or around this value).

R2represents a

(a) hydrogen;

(b) alkyl, alkenyl, quinil, alkyloxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of which may be substituted by W1, W2and W3;

(C) hydroxyl;

(d) cyano;

(e) nitro;

(f) C(O)H or-C(O)R27;

(g) -CO2H or-CO2R27;

(h) -SH, -S(O)nR27, -S(O)m-OH, -S(O)m-OR27, -O-S(O)m-R27, -O-S(O)mOH or-O-S(O)m-OR27;

(i) -W4-NR28R27or

(j) -W4-N(R32)-W6-NR30R31;

R27represents alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, each of which may be substituted by W1, W2and W3;

R28represents a

(a) hydrogen;

(b) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of which may be substituted by W1, W2and W3;

(C) cyano;

(d) hydroxyl;

(e)m-OR27, -O-S(O)m-R27, -O-S(O)mOH or-O-S(O)m-OR27except for the cases when W4represents-S(O)n-;

R29represents a

(a) hydrogen;

(b) -C(O)H or-C(O)R27except for the cases when W4represents-C(O)-, and R28represents C(O)H, -C(O)R27, -CO2H or-CO2R27,

(C) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of which may be substituted by W1, W2and W3; or R28and R29together they are alkylene or albaniles (each of which can be mixed W1, W2W3), form a 3-8-membered saturated, unsaturated or aromatic cycle, together with the nitrogen atom to which they are attached;

R30represents a

(a) hydrogen;

(b) hydroxyl;

(C) -C(O)H or-C(O)R27;

(d) CO2H or-CO2R27;

(e) -SH, -S(O)nR27, -S(O)m-OH, -S(O)m-OR27, -O-S(O)m-R27, -O-S(O)mOH or-O-S(O)m-OR27;

(f) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or R> (a) hydrogen;

(b) -C(O)H or-C(O)R27except for the cases when W6represents-C(O)- and R30represents-C(O)H, -C(O)R27, - CO2H or-CO2R27;

(C) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of which may be substituted by W1, W2and W3;

R32represents a

(a) hydrogen

(b) hydroxyl, CO2R27or CO2H, except when one of the radicals R30and R31represents hydroxyl, CO2R27or CO2H;

(C) -C(O)H or-C(O)R27; or

(d) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of which may be substituted by W1, W2and W3;

or any two of R30, R31and R32together form alkylene or albaniles (each of which may be substituted by W1, W2and W3), form a 3-8-membered saturated, unsaturated or aromatic cycle, together with the atoms to which they are attached;

W1, W2and W3each independently represent

(a) hydrogen;

(b)-O-S(O)m-W6, -O-S(O)mOH or-O-S(O)m-OW6;

(f) oxo;

(g) nitro;

(h) cyano;

(i) -C(O)H or-C(O)W6;

(j) -CO2H or-CO2W6; or

(k) NW7W8, -C(O)NW7W8, -S(O)nW7W8;

W4and W5each represent independently

(a) simple link

(b) -S(O)n-;

(C) -C(O)-;

(d) -C(S)-; or

(e) alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of which may be substituted by W1, W2and W3;

W1, W2and W3each independently represent hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, or W7and W8together they are alkylene or albaniles, form a 3-8-membered saturated, unsaturated or aromatic cycle, together with the nitrogen atom to which they relate;

m = 1 or 2; and

n = 0, 1, or 2

At least one of the radicals R4, R5and R6primarily represents a di(lower alkyl)amino group or a (lower alkyl) amino group and the other radicals from the group R4, R5and R6represent Zabolotnyi 1 or 2, mainly in position 1, with naftilos group, and at least one of the substituents is located in position 5.

Naphthalenesulfonate were synthesized and tested using the examples of test methods (see Examples), and the results are shown in Table 4 (connect 4-gaelicisation are preferred).

(2) Phenanthrene and anthracene

It also gives isoxazolecarboxylic in which Ar2contains three condensed aromatic cycle. R1and R2selected as described above for compounds in which Ar2represents phenyl and diphenyl, and n>0. Condensed cycles may be substituted by one or more substituents selected from the group consisting of R13and R26where R26and R13independently selected from the group consisting of H, OH, OHNH, NH2, NO2, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, halodrol, alkoxycarbonyl, carbonyl, alkylaryl, aminocarbonyl, Arik the s alkyl, alkeneamine and alkyline parts contain from 1 to 14, or about the value of carbon atoms, predominantly from 1 to 6 atoms, and are linear or branched chains or are cyclic, and the aryl portion contains from 4 or so values up to 16 or so values of atoms of carbon, mainly from 4 to 10 atoms.

More preferably R1represents halogen or methyl; R2selected from the group consisting of alkyl, lower alkenyl, lower quinil and lower haloalkyl; R26and R13selected from the group consisting of H, lower alkyl, haloalkyl and halogen. In more preferred versions of the R1represents Cl, Br or CH3; R2selected from the group consisting of H, CH3C2H5, CF3n-C3H5, cyclo-C3H5and C4H8; R26and R13each independently selected from the group consisting of H, halogen, NH2, CF3CH3, CN, CH3, (CH3)3C, C5H11CH3O n-C4H9O and CH2= CH. In an even more preferred embodiment, R2represents H, CH3C2H5or CF3; R26and R13independently selected from the group of N-(4-bromo-3-methyl-5-isoxazolyl)phenanthrene-3-sulfonamide, N-(4-bromo-5-methyl-3-isoxazolyl)phenanthrene-3-sulfonamide and N-(3,4-dimethyl-5-isoxazolyl)phenanthrene-3-sulfonamide. Separate results for these compounds are given in Table 5.

2. Compounds in which Ar2contains a heterocycle or a condensed cycles, at least one heterocycle.

The proposed compounds in which Ar2represents a heterocycle include sulfonamides, in which Ar2represents the five-membered heterocycle with one heteroatom and its analogues with condensed rings; compounds in which Ar2represents the five-membered heterocycle with two or more heteroatoms and its analogues with condensed rings; compounds in which Ar2represents a six-membered heterocycle with one heteroatom and its analogues with condensed rings; compounds in which Ar2represents a six-membered heterocycle with two or more heteroatoms and its analogues with condensed rings.

Compounds in which Ar2represents the five-membered heterocycle with one heteroatom include, but are not limited to only these, compounds in which Ar2is thiophenyl, furyl, Pirro is/SUP> are similar with condensed rings of five-membered heterocycle with one heteroatom include, but are not limited to only these, compounds in which Ar2is benzofuran, benzothiophene (tanatril), indolyl, indolizinyl and isoindole.

Compounds in which Ar2represents the five-membered heterocycle with two or more heteroatoms and its analogues with condensed rings include, but are not limited to only these, compounds in which Ar2represents oxazolyl, thiazolyl, imidazolyl, 2-imidazolyl, imidazolidinyl, 1,3-DIOXOLANYL, pyrazolyl, 2-pyrazoline, pyrazolidine, toxocaral, isothiazole, 1,2,3-oxadiazolyl, 1,2,3 - triazolyl, 1,3,4-thiadiazolyl, 1H-indazole, benzoxazole, benzimidazole and benzothiazole.

Compounds in which Ar2represents a six-membered heterocycle with one heteroatom and its analogues with condensed rings include, but are not limited to only these, compounds in which Ar2represents pyridinyl, chinoline, ethenolysis, acridine, 4H-hemolysin, 2H-Piran and piperidinyl.

Compounds in which Ar2represents a six-membered heterocycle with two shall rimidine, pyrazinyl, piperazinil, triazinyl, chinoline, phthalazine, hintline, honokalani, 1,8-naphthyridine, pteridinyl, 1,4-dioxane, morpholine, thiomorpholine, phenazines, phenotiazines, phenoxazines, hintline, Hinoki-repaired, naphthyridines and pteridinyl.

A. Ar2is thiophenyl, furyl and pyrrolyl.

In certain embodiments of the invention Ar2can be represented by the formula (XII):

< / BR>
which may have substituents in any or all positions or is an analog of compounds of formula (IV), where the substituents form a condensed aromatic, aliphatic or heterocyclic ring, and X is NR11, O or S, a R11that represents a hydrogen or contains up to 30 or so values of carbon atoms, predominantly 1-10, better 1-6, and selected as defined above; R8, R9and R10selected, as described above.

Thus, in certain embodiments of the implementation described here in detail, Ar2is thiophenyl, furyl, pyrrolyl or such a group as benzofuran, thenafter or indolyl, which are derivative or analog, as described below, thiazolyl), and compounds may be represented by formula XIII:

< / BR>
or

< / BR>
where R1R2represent (i) or (ii) or (iii) as follows:

(i) R1and R2each independently selected from the group consisting of H, NH2, NO2, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, aminocarbonyl, halodrol, alkoxycarbonyl, alkylsulphonyl, arylcarbamoyl, formyl, substituted or unsubstituted amido group, a substituted or unsubstituted, ureido-group in which alkyl, alkeline and alkyline parts contain from 1 to 10 or so values of carbon atoms, have a linear or branched chain, and the aryl portion contains from 4 or so values up to 14 or so values of carbon atoms, except that when R2does not represent halogen, pseudohalogen or higher alkyl; or

(ii) R1and R2together form -(CH2)nwhere n = 3-6, or

(iii) R1and R2together form 1,3-butadienyl; and X, R8, R9and R10selected as defined above.

1is

a N-(5-isoxazolyl) or N-(3-isoxazolyl), which can be represented by formula XIV:

< / BR>
< / BR>
< / BR>
< / BR>
where R1and R2represent (i), (ii) or (iii) as follows:

(i) R1and R2each independently selected from the group consisting of H, NH2, NO2, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, halodrol, alkoxycarbonyl, alkylsulphonyl, aminocarbonyl, arylcarbamoyl, formyl, substituted or unsubstituted amido group, a substituted or unsubstituted, ureido-group in which alkyl, alkeline and alkyline parts contain from 1 to 14, or about the value of carbon atoms and are linear or branched chains or are cyclic, and the aryl portion contains from 4 or around this value to 16 or around that level carbon atoms, or

(ii) R1and R2together form -(CH2)nwhere n = 3-6, or

(iii) R1and R2together form 1,3-butadienyl;

X represents O, S, NH or NR11where R11contains up to 30-50 and inil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, C(O)R15, S(O)nR15where n = 0-2; R15represents hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, m = 0-2; R11and R15are unsubstituted or substituted by one or more substituents, each independently selected from Z, which is hydrogen, halogen, pseudohalide, alkyl, alkoxy, alkenyl, quinil, aryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, IT, CN, C(O)R16, CO2R16, SH, S(O)nR16where n = 0-2, NHOH, NR12R16, NO2N3, OR16, R12NCOR16and CONR12R16; R16represents hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl or cycloalkenyl; R12chosen independently of R11and Z represents hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, Alcoxy, aralkyl, cycloalkyl, cycloalkenyl, cycloalkenyl; C(O)R17and S(O)nR17where n=0-2, a R17is hydrogen, alkyl, alkenyl, quinil, aryl, alkyl is can be further substituted by substituents selected from Z; each of the radicals R8, R9, R10if not is hydrogen, contains up to 30 or around that level or more carbon atoms, typically less than 16 or so values, and independently selected from (i) or (ii) as follows:

(i) R8, R9, R10independently selected from a number of: hydrogen, halogen, pseudohalide, alkyl, alkoxy, alkenyl, quinil, aryl, aryloxy, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, IT, CN, C(O)R18, CO2R18, SH, S(O)nR18where n=0-2, NHOH, NR18R19, NO2N3, OR18, R19NCOR18, CONR19R18; R19is hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, C(O)R20, S(O)nR20where n= 0-2, a R18and R20independently selected from a number of: hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl that represents hydrogen, halogen, pseudohalide, alkyl, alkoxy, alkenyl, quinil, aryl, aryloxy, heterocycle, UP>8, R9, R10is unsubstituted or substituted by any Deputy of the group, called Z, which includes hydrogen, halogen, pseudohalide, alkyl, alkoxy, alkenyl, quinil, aryl, aryloxy, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl; HE, CN, C(O)R21, CO2R21, SH, S(O)nR21, S(O)nR21where n=0-2, NHOH, NR22R21, NO2N3, OR21, R22NCOR21, CONR21R22, R22is hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, C(O)R23, S(O)nR23where n= 0-2, a R21and R23independently selected from a number of: hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, alkoxy, aralkyl, cycloalkyl, cycloalkenyl, cycloalkenyl, C(O)R25and S(O)nR25where n=0-2, R24is hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, and R25is hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, any of the P>23, R24and R25may be unsubstituted, except for special instructions or may be substituted by substituents selected from Z, which is hydrogen, halogen, pseudohalogen, alkyl, alkoxy, alkenyl, quinil, aryl, aryloxy, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl; or

(ii) any two groups of R8, R9, R10form an aromatic ring, heteroaromatic ring, alicyclic or heterocyclic ring which is saturated or unsaturated, containing from about 3 or this value to 16 or around that level members, preferably from 3 to 10 or so values, more preferably from 5 to 7 members, and which is unsubstituted or substituted by one or more substituents, each selected independently from Z, and the other radicals R8, R9, R10selected, as in point (i).

In the above embodiments perform aryl, quinil, alkenyl contain linear or branched chain, are acyclic or cyclic, and have 1 to 10 carbon, in some preferred versions of they may have from 1 to 6 carbon atoms, they may have is ichno 5-7, members in the ring and can be single or condensed rings. The size of the ring and the carbon chain length are selected so that the resulting molecule can be active, typical of the antagonist or agonist endothelin in tests in vivo and in vitro, for example, in the tests, which are given here as an example.

In any of the above preferred embodiments, R1and R2preferably independently selected from the following range: alkyl, lower alkenyl, lower quinil, lower haloalkyl, halogen, pseudohalogen and H, except in those cases where R2neither halogen nor pseudohalogen or higher alkyl.

In preferred versions of the X is S, O, NR11where R11is aryl, preferably hydrogen or lower alkyl, substituted or unsubstituted aryl, especially phenyl, preferably unsubstituted or substituted by lower alkyl or halogen; R1is hydrogen, halogen, pseudohalogen, lower alkyl or lower haloalkyl, most preferably halogen, R2is hydrogen, lower alkyl or lower haloalkyl, a R8, R9, R10are selected, the(O)nR18where n=0-2, C(O)R18, CO2R18, NO2, OR18, CONR18R19, R19preferably is hydrogen, lower alkyl, lower aryl, C(O)R20, S(O)nR20where n=0-2, R18preferably is hydrogen, halogen, lower alkyl, lower aryl, a R20preferably is hydrogen, halogen or lower alkyl; Z is hydrogen, halogen, pseudohalogen, lower alkyl or lower pseudogenization or lower haloalkyl. In particular, at least one of the radicals R8, R9and R10is selected from the following range: methyl, phenyl, pyrazolyl, isoxazolyl, carbomethoxy, carboxamide, halogen, hydrogen, isopropylphenyl, pyridyl, carboxyl, phenyl, phenylenecarbonyl, benzazolyl, (lower alkyl)phenylenecarbonyl, diphenylmethanone, (lower haloalkoxy)phenylenecarbonyl and haloidohydrocarbons and, preferably, R8, R9and R10were hydrogen, halogen or lower alkyl. More preferably in these embodiments perform to X represented S.

In more preferred versions of the two of the radicals R8, R9and R10are hydrogen, gorodischer heteroaryl, lowest aralkyl, C(O)R18C(O)2R18, NO2, OR18, CONR18R19. In still more preferred versions of the R19is phenyl, a R18is hydrogen, halogen or lower alkyl. In more preferred embodiments of this option will perform two of the radicals R8, R9and R10are hydrogen or lower alkyl, and the third is halogen, lower alkyl, C(O)R18C(O)2R18, NO2, OR18, CONR18R19; R18is hydrogen or lower alkyl. All versions of the R1mainly is halogen, H, CH3C2H5, a R2is H, CH3C2H5, CF3C2F5. In still more preferred versions of the R1mainly is Br, Cl or CH3, R2is H, CH3C2H5, CF3.

In some preferred versions of the R8and R10are hydrogen, halogen or lower alkyl; R9is any of the above substituents, in particular when it is desirable to obtain potential ETAantagonist, such group is aminocarbonyl. In other SUP>8
was any of the above substituents. In these variants perform preferably, R1was a halogen, H, CH3or C2H5, a R2would be H, CH3C2H5, CF3C2F5. In even more preferred embodiments, R1is Br, Cl or CH3, R2is H, CH3C2H5, CF3.

In those embodiments, execution, when it is desirable to obtain EMBantagonist, preferably, R9and R10were hydrogen or lower alkyl, a R8was a heterocyclic or aromatic ring, preferably 3-14, more preferably with 5-7 members in the ring. In particular, if X is S, R9and R10are H or lower alkyl, and R8is aryl, in particular unsubstituted or substituted by phenyl, for example 4-ethylphenyl. If X is N, then R11is aryl, in particular unsubstituted or substituted by phenyl, for example, isopropylphenyl, a R8, R9, R10preferably are H, halogen, or lower alkyl.

All versions of the R1preferably is halogen or lower alkyl, most preferably Br, and connection ablauts the preferred compounds obtained here are for ETAreceptors IC50= 0,002 μm to 0.1 μm, defined by methods presented here (see , for example, Table 6). These compounds include: N-(4-bromo-3 - methyl-5-isoxazolyl)-2-[N-(4-methoxyphenyl)aminocarbonyl)] thiophene - 3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-1[N-(3 - methoxyphenyl)aminocarbonyl)] thiophene-3-sulfone-MFA; N-(4-bromo-3 - methyl-5-isoxazolyl)-2-(N-phenylenecarbonyl)thiophene-3 - sulfonamide; N-(4-bromo-5-methyl-3-isoxazolyl)-2-(N - phenylenecarbonyl)thiophene-3-sulfonamide; N - (3,4-dimethyl-5 - isoxazolyl)-2-phenyl-aminocarbonyl)thiophene-3-sulfonamide; N-(4 - bromo-3-methyl-5-isoxazolyl)-2.5-dimethylthiophene-3-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl)-2-(carboxymethyl)thiophene-3 - sulfonamide; N-(4-boundary marker beacon-3-methyl-5-isoxazolyl)-thiophene-2 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-diphenyl) aminocarbonyl)] thiophene-3-sulfonamide; N-(4-bromo-3-methyl-4-5 - isoxazolyl)-2-[N-(2-methoxyphenyl)aminocarbonyl)] thiophene-3 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N - benzylaminocarbonyl)thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5 - isoxazolyl)-2-[N-(4-ethylphenyl)aminocarbonyl)] thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5 - isoxazolyl)-2-[N-(4-diphenyl)aminocarbonyl)] thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4 - methoxyphenyl)aminocarbonyl)] thiophene-3-sulfonamide; N-(4-bromo-3 - methyl-5-isoxazol the Il)-3-phenoxathiin-2-sulfonamide; N-(4-bromo-3 - methyl-5-isoxazolyl)-2-[N-(4-were)aminocarbonyl)] -thiophene - 3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-isopropylphenyl) aminocarbonyl)] thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5 - isoxazolyl)-2-[N-(4-tert-butylphenyl)aminocarbonyl)] thiophene-3 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-N-(4-n - butylphenyl)amino-carbonyl)] thiophene-3-sulfonamide; N-(4-bromo-3 - methyl-5-isoxazolyl)-2-[N-(4-sec-butylphenyl)aminocarbonyl)]thiophene - 3-sulfonamide.

Other preferred compounds include such compounds, which have for ETBreceptors IC50= of 0.05 to 1.0 μm, determined in accordance with the techniques presented here. These compounds include: N-(4-bromo-3-methyl-5 - isoxazolyl)-5-benzosulfimide-2-sulfonamide; N-(4-bromo-3-methyl - 5-isoxazolyl)-1-(4'-isopropylphenyl)pyrrol-2-sulfonamide; N-(4 - bromo-3-methyl-5-isoxazolyl)-1-(4'-isopropylphenyl)pyrrole-3 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-{3-[1-methyl-5- (trifluoromethyl)pyrazolyl]}-thiophene-5-sulfonamide; N-(4-bromo-3-methyl - 5-isoxazolyl)-2-[N-(4-diphenyl)aminocarbonyl)]thiophene-3 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4 - ethylphenyl)aminocarbonyl)] thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-teenlife-2 - sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-what clucalc following compounds: N-(4-chloro-3-methyl-5 - isoxazolyl)-2-(phenylenecarbonyl)thiophene-3-sulfonamide; N-(4 - chloro-3-methyl-5-isoxazolyl)-5-benzothiophen-2-sulfonamide; N-(4 - chloro-3-methyl-5-isoxazolyl)-3-benzothiophen-2-sulfonamide; N-(4 - chloro-3-methyl-5-isoxazolyl)-3-penetrtion-2-sulfonamide; N-(4 - bromo-3-methyl-5-isoxazolyl)-3-stilllife-2-sulfonamide; N-(4 - bromo-3-methyl-5-isoxazolyl)-2-sterilite-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-phenoxathiin-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-benzosulfimide-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-phenylthiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-aminothiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(benzoylamine)thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-benzylthio-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-penetrtion-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-benzylthio-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2[(N-phenyl)methylaminomethyl] thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-benzofuran-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-(hydroxymethyl)furan-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-(carbomethoxy)furan-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2.5-dimethylfuran-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-isopropyl oxazolyl)-3-(phenylenecarbonyl)thiophene-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-benzylthio-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-phenylthiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(dimethylaminoethyl)thiophene - 3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(di-isopropylaminocarbonyl)thiophene - 3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(diethylaminoethyl)thiophene - 3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-isobutylphenyl)furan-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-stillborn-2-sulfonamide; and N-(4-bromo-3-methyl-5-isoxazolyl)-5-stilllife-2-sulfonamide.

b. Ar2is a heterocycle with one heteroatom and two or more condensed rings.

Were obtained the compounds in which Ar2is a heterocycle with one heteroatom and two or more condensed rings. The heteroatom may be O, S or N, and Ar2selected, but not limited to, from the series: hinely, ethanolic, dibenzofuran, dibenzothiophene, dibenzobarrelenes connections, and other similar groups. The condensed ring may be substituted in any position by one or more substituents selected from the substituents indicated for R8, R9and R10.

(1) Ar2is chinaillon or ethanolic the Hema numbering is as follows:

< / BR>
R1and R2chosen as described for compounds containing thiophenyl, furyl and pyrrolyl, any of the rings may be substituted by one or more substituents selected from hydrogen or as described above for R26and R13< / BR>
Examples of chinaincorporated shown in table 7.

(2) Ar2is dibenzofuran, dibenzothiophene and dibenzobarrelenes.

In some embodiments, performing Ar2is dibenzofuran, dibenzothiophene and dibenzobarrelenes and has the following formula (XV):

< / BR>
and may be unsubstituted or substituted by one or more substituents selected from R13and R26. In these versions of the R1and R2chosen as described above for compounds containing thiophenyl, furyl and pyrrolyl. These compounds substituted as described above for compounds containing diphenyl, in which R13, R26X represents-CH=CH-, O, S, NR11where R11is the same as above (compounds in which X is-CH= CH-, are fantranslated discussed above), a R13and R26independently selected from a number of: H, OH, OHNH, NH2, NO2Galatia, haloalkoxy, haloalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, halodrol, alkoxycarbonyl, carbonyl, alkylaryl, aminocarbonyl, arylcarbamoyl, aminocarbonyl, formyl, substituted or unsubstituted amido group, a substituted or unsubstituted, ureido-group, where the alkyl, alkenyl, quinil are linear or branched chains or cycles and contain from 1 to 14 or so values carbon atoms, preferably from 1 to 6 carbons, and aryl contains from 4 to 16 or so values of carbon, preferably from 4 to 10 carbons.

In more preferred versions of the R1is halogen or stands; R2selected from lower alkyl, lower alkenyl, lower quinil and lower haloalkyl; R26and R13selected from a number of: hydrogen, lower alkyl, haloalkyl and halogen. In more preferred versions of the R1is Cl, Br or stands, R2is selected from: H, CH3C2H5n-C3H5, cyclo-C3H5C4H8; and each of R26and R13is selected independently from: H, halogen, NH2, CF3CN, C2H5CH3, (CH32is H, CH3C2H5or CF3; R26and R13are selected independently from: H, halogen, CF3C2H5CH3; X is O. examples of the compounds shown in table 8.

c. Ar2is a six-membered heterocycle with one heteroatom selected from S, O or NR11.

Preferred the six-membered heterocycle ring is pyridine. The group of pyridine may be substituted by one or more substituents selected from R13, R8and R28as described above, and may be 2-, 3 - or 4-sulfonamide, R1and R2are selected as described above for compounds containing phenyl, furyl and pyrrolyl.

Compounds in which Ar2is a group of pyridine, include, but are not limited to, the following: N-(4-bromo-3 - methyl-5-isoxazolyl)pyridine-2-sulfonamide, N-(4-bromo-5-methyl-3 - isoxazolyl)pyridine-2-sulfonamide, N-(3,4-dimethyl-5-isoxazolyl) pyridine-2-sulfonamide, N-(4,5-dimethyl-3-isoxazolyl)pyridine-2 - sulfonamide, 3-methoxycarbonyl-N-(4-bromo-5-methyl-3 - isoxazolyl)pyridine-2-sulfonamide, 3-methoxycarbonyl-N-(4-bromo - 3-methyl-5-isoxazolyl)pyridine-2-sulfonamide, N-(3,4-dimethyl-5 - isoxazolyl)-3-(N-phenylenecarbonyl)pyridine-2-sulfonamide, N-(4 - bromo-5-meperidine-2-sulfonamide. As it turned out, these compounds are ETA-selective when the concentration of the IC50the order of 1-3 microns and less.

d. Ar2is a heterocycle with two or more heteroatoms.

Available compounds in which Ar2is a heterocycle, which contains two or more heteroatoms selected from O, S, N, NR11including, but not limited to, pyrimidinium, paranilam, imidazolium, oxazolium, thiazolium, pyrazolyl, benzofuran, benzothiophene and benzopyrylium. These compounds can be unsubstituted or substituted by one or more substituents selected from the radicals specified for R3, R8, R26. Some of the synthesized compounds are presented in table 9.

3. Compounds in which Ar2is alkyl.

The compounds in which Ar2is alkyl, are those in which Ar2is CH3(CH2)nwhere n is from 0 to 30 or so values, preferably from 0 to 20, more preferably from about 5 or this value to 10 or so values, which may be substituted by halogen, amino, carbonyl-, nitro-group and similar groups, as well as compounds in which Ar

4. Compounds in which Ar2is sterila.

The compounds in which Ar2is sterila. These compounds have the formula (XVI):

< / BR>
or

< / BR>
where R1and R2selected as described above for compounds containing thiophenyl, furyl and pyrrolyl. R1- R9are as defined above, R8and R9can be in CIS - or TRANS-position. The compounds in which Ar2is sterila include, but are not limited to: N-(3,4-dimethyl-5-isoxazolyl) - TRANS-styrelseledamot, N- (4-bromo-3-methyl-5-isoxazolyl) - TRANS-styrelsen-foamed, N-(4 - bromo-5-methyl-3-isoxazolyl) - TRANS-styrelseledamot, 2-nitro-N- (3,4-dimethyl-5-isoxazolyl)styrelseledamot, 2-nitro-N-(4-bromo-3 - methyl-5-isoxazolyl)styrelseledamot, 2-nitro-N-(4-bromo-5-methyl - 3-isoxazolyl)styrelseledamot, 1,2-TRANS-dimethyl-N-(3,4 - dimethyl-5-isoxazolyl)styrene-1-sulfonamide, 1,2-TRANS-dimethyl-N- (4-bromo-3-methyl-5-isoxazolyl)styrene-1-sulfonamide, 1,2 - transit, N-(4-bromo-5-methyl-3-isoxazolyl)-2-fenestral-1 - sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-phenyl-styrene-1 - sulfonamide, 1,2-CIS-dimethyl-N-(3,4-dimethyl-5-isoxazolyl)styrene - 1-sulfonamide, 1,2-CIS-dimethyl-N-(4-bromo-3-methyl-5 - isoxazolyl)styrene-1-sulfonamide, 1,2-CIS-dimethyl-N-(4-bromo-5 - methyl-3-isoxazolyl)styrene-1-sulfonamide. The activity of some compounds are given in table 11.

B. Obtaining compounds.

Receipt of the above compounds is described in detail in the examples. Any such or similar connection can be synthesized in accordance with the method discussed in General terms below and shown in the Examples by selecting the appropriate starting materials.

In General, most of the synthesis involves the condensation of sulphonylchloride with aminoisoquinoline in dry pyridine or tetrahydrofuran (THF) and in the presence of sodium hydride. Sulphonylchloride and aminoisoquinoline can be taken, prepared or synthesized in accordance with methods described in the Examples, or using other suitable methods known in the art (see, for example, U.S. patents NN 4,659,369; 4,861,366; 4,753,672). A typical synthesis of numerous compounds obtained here, presented in Sulphonylchloride in dry pyridine in the presence or in the absence of the catalyst 4-(dimethyl-amino)pyridine. N-(3,4-dimethyl-5-isoxazolyl)sulfonamides and N-(4,5-dimethyl-5-isoxazolyl)sulfonamides can be obtained from the corresponding aminodimethylaniline, for example, 5-amino-3,4 - dimethylisoxazole. N-(3,4-dimethyl-5-isoxazolyl)sulfonamides and N- (4,5-dimethyl-5-isoxazolyl)sulfonamides can be obtained from the corresponding aminodimethylaniline, for example, from 5-amino-3,4 - dimethylisoxazole. For example, N-(3,4-dimethyl-5-isoxazolyl)-2- (carbomethoxy)thiophene-3-sulfonamide was obtained from 2-methoxy - carbonylation-3-sulphonylchloride and 5-amino-3,4-dimethylisoxazole in dry pyridine.

N-(4-Gaelicization)sulfonamides can be obtained by condensing amino-4-gaelicisation with sulphonylchloride in THF in the presence of sodium hydride as a base. For example, N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide was obtained from 5-amino-4-bromo-3-methylisoxazole and thiophene-2-sulphonylchloride in THF and in the presence of sodium hydride. N-(4-bromo-3-methyl-5-isoxazolyl)-5- (3-isoxazolyl)thiophene-2-sulfonamide was obtained from 5-amino-4-bromo-3 - methylisoxazole and 5-(3-isoxazolyl)thiophene-2-sulphonylchloride.

The precursors of drugs and other derivatives of the compounds suitable for application to humans, may also be Sintesi the d University Press, New York, pages 388-392).

Listed and described compounds were synthesized and tested for activity in vitro, and in some cases in vivo in animal models. Nuclear magnetic resonance (NMR), massspectrometry, infrared spectroscopy and high performance liquid chromatography showed that the synthesized compounds have structures that are consistent with the expected for these compounds, and are usually net not less than 98%. All shown here as an example and described compounds have activity of endothelin antagonists.

2. Getting isoxazolecarboxylic in which Ar2is a phenyl, diphenyl and kondensirovannye aromatic rings.

A. Obtaining N-isoxazolecarboxylic in which Ar2is phenyl and diphenyl, and n=0.

(1) Ar2is phenyl.

Compounds such as 4-nitro-N-(4-bromo-3-methyl - 5-isoxazolyl)-benzosulfimide for use in the methods here can be obtained by the reaction of sulphonylchloride with 5-amino-3,4-dimethylisoxazole in a solution of pyridine using as catalyst 4-(dimethylamino)pyridine. After the reaction Piri is Oh is washed with water and dried over anhydrous magnesium sulfate, solvents warialda and the residue purified using column chromatography on silica gel (for example, as used additionally separated by 1% methanol in chloroform). Further purification is effected by recrystallization from a mixture of ethyl acetate: getan with obtaining the pure product. In some cases, it turns out resultonline connection as the primary or sole product. Resultonline derivatives can be easily hydrolyzed to sulfonamida when using aqueous sodium hydroxide and a suitable co-solvent such as methanol or tetrahydrofuran, usually at room temperature.

Compounds such as 3-amino-N-(3,4-dimethyl-5-isoxazolyl)- benzosulfimide and 2-amino-N-(3,4-dimethyl-5-isoxazolyl)- benzosulfimide, can be obtained by the reaction of hydrogenation of the corresponding nitro-N-(3,4-dimethyl-5-isoxazolyl)- benzosulfimide, which is obtained as described above.

In another embodiment, benzosulfimide can be obtained from the corresponding sulphonylchloride and aminoisoquinoline in THF solution containing sodium hydride.

(2) Ar2is diphenyl, dibenzofuran and dibenzobarrelenes.

Such is th pyridine 4-diphenylsulfone and such substituted on the amine of isoxazol, as 5-amino-3,4-dimethylisoxazol. After the reaction, the pyridine is removed under reduced pressure and the residue is distributed between water and ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate, the solvents warialda and the residue purified using column chromatography on silica gel to obtain a solid substance (as additionally separated by using, for example, 1% methanol in chloroform). Further purification is achieved by recrystallization of the obtained solid substance from a mixture of ethyl acetate-hexane or column chromatography to obtain the pure product.

In some cases turn out resultonline derivative as the main or sole product. Resultonline derivatives can be easily hydrolyzed to sulfonamida in an aqueous solution of sodium hydroxide in a suitable co-solvent such as THF or methanol, usually at room temperature.

In another embodiment, the sulfonamides can be obtained from the corresponding aminoisoquinoline in THF solution containing sodium hydride (see for example, Example 90).

b. The formation of compounds in which Ar2is phenyl and difety, as described above in paragraph B using appropriate starting compounds, for example, from 1-toluensulfonate and 5-amino-3,4-dimethylisoxazole.

c. Obtaining N-isoxazolecarboxylic in which Ar2represents a condensed aromatic ring.

(1) Ar2is naphthyl.

Compounds such as N-(4-bromo-5-methyl-3-isoxazolyl)-1 - naphthalenesulfonate and 5-dimethylamino-N-(4-bromo-3-methyl-5-isoxazol - Lil)-1-naphthalene-sulfonamide can be obtained as described above in paragraph B(1) using the appropriate starting compounds, such as 3-amino-4-bromo-5-methylisoxazol and 1-naphthalenesulfonate, or 5-amino-4-bromo-C-methylisoxazole and 5-dimethylaminonaphthalene, respectively. (see Examples 51, 118 and 119).

(2) financila and AstraZeneca.

Compounds such as N-(4-bromo-3-methyl-5-isoxazolyl)-9,10 - dioxo-anthracene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3 - phenanthrenequinone, N-(3,4-dimethyl-5-isoxazolyl)-3 - financial-foamed, can be obtained as described above in paragraph N of the respective aminoethoxyethanol and sulphonylchloride.

2. Obtaining N-isoxazolecarboxylic in which Ar2contains a heterocyclic ring is the Connection in which Ar2is titaniam, fullam and Petroliam can be obtained in the reaction of the corresponding sulphonylchloride with 5-aminoisoquinoline, substituted in the 3 and 4 positions, such as 5-amino-4-bromo-3-methylisoxazole, in THF solution containing a base, such as sodium hydroxide. After the reaction THF is removed under reduced pressure, the residue dissolved in water, acidified and extracted with methylene chloride. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent evaporated, and the residue is purified by means of recrystallization from a mixture of hexane-ethyl acetate to obtain the pure product.

In another embodiment, the sulfonamide can be obtained from the appropriate sulphonylchloride and aminoisoquinoline in pyridine in the presence or in the absence of catalytic amounts of 4-dimethylaminopyridine (DMAP). In some cases formed resultonline derivatives as the primary or sole product. Resultonline derivatives can be easily hydrolyzed to sulfonylamides using an aqueous solution of sodium hydroxide in a suitable co-solvent, such as methanol or tetrahydrofuran, the ene-3-sulfonamide was obtained from N-(4-bromo-3-methyl-5 - isoxazolyl)-2-carboxylate-3-sulfonamida and aniline in the presence of 1-ethyl-3'[3-dimethylaminopropyl] carbodiimide (EDCI). N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(4-methoxyphenyl)aminocarbonyl] thiophene-3-sulfonamide was obtained from 4-methoxyaniline, N, N'-diisopropylethylamine and N-(4-bromo-3-methyl-5-isoxazolyl)- 2-carboxylate-3-sulfonamida. N-(4-bromo-3-methyl-5 - isoxazolyl)-2-(benzylaminocarbonyl] thiophene-3-sulfonamide was obtained from N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylate-3 - sulfonamida and benzylamine, as described above.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-carboxylate-3-sulfonamide was obtained from N-(4-bromo-3-methyl-5-isoxazolyl)-2- (carbomethoxy)thiophene-3-sulfonamide, which was obtained by condensation of 5-amino-4-bromo-3-methylisoxazole with 2- (carbomethoxy)thiophene-3-sulphonylchloride.

(2) N-(4-Bromo-3-methyl - 5-isoxazolyl)-1-(4'-isopropylphenyl) pyrrol-2-sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)-1-(4'- isopropylphenyl)pyrrole-3-sulfonamide was obtained from 5-amino-4-bromo-3-methylisoxazole and a mixture of 1-(4'-isopropylphenyl)pyrrol-2-sulphonylchloride and 1-(4'- isopropylphenyl)pyrrol-3-sulphonylchloride. These sulphonylchloride were obtained from 1-(4'-isopropylphenyl)pyrrol-2-sulfonic acids in the presence of phosphorus oxychloride and pentachloride phosphorus. 1-(4'- Isopropylphenyl)pyrrol-2-acid was obtained from 1-(4'- isopropylphenyl)of pyrrole and chlorosulfonic KIS>b. Ar2is a heterocycle with one heteroatom and two or more condensed rings.

Such compounds can be obtained as described above in paragraph B(1). For example, N-(4-bromo-3-methyl-5-isoxazolyl)-8-chinaincorporated can be obtained from 5-amino-4-bromo-3-methylisoxazole and 8-chinaincorporated suspension of sodium hydride in dry THF (see Examples 99 and 100).

c. Ar2is a six-membered heterocycle with one heteroatom selected from S, O, N, or NR11.

Such compounds can be obtained as described above in paragraph B. for Example, such compounds as N-(3,4-dimethyl-5 - isoxazolyl)-2-dibenzofuransulfonate can be obtained in the reaction of 5-amino-3,4-dimethylisoxazole with 2 dibenzofuransulfonate in dry pyridine (see Example 93).

d. Ar2is a heterocycle with two or more heteroatoms.

Such compounds can be obtained in accordance with the methods presented above in paragraph B (1). For example, N-(4-bromo-3-methyl-5-isoxazolyl)benzo-2,1,3-thiadiazole-4-sulfonamide can be obtained by reaction of 5-amino-4-bromo-3-methylisoxazole with benzo-2,1,3-thiadiazole-4-sulphonylchloride suspension of sodium hydride in dry THF.

3. Getting the tvii methods, described above in paragraph (N (1) (see Examples 101 and 102).

4. The formation of compounds in which Ar2is sterila.

Such compounds can be obtained in accordance with the methods described above in paragraph(1). For example, 2-nitro-N-(3,4-dimethyl-5 - isoxazolyl)--TRANS-styrelseledamot can be obtained from 2-nitro-TRANS-storycontinued (see , for example, Bordwell and others (1946) J. Am.Chem. Soc. 68: 1778) process for the nitration of storycontinued and 5-amino-3,4-dimethylisoxazole.

C. Evaluation of biological activity of compounds.

For testing connections are standard physiological, pharmacological and biochemical methods by which you can identify those compounds that have any biological activity of the peptides of the endothelin or the ability to inhibit or interfere with the activity of the peptides of the endothelin. Those compounds that show activity in vitro, for example, the ability to communicate with endothelium receptors or to compete with one or more peptides of the endothelin binding endothelium receptors, can be useful in methods for the selection of endothelin receptors, and methods for distinguishing specificity endothelioma the ptx2">

Thus, using such methods of analysis, you can identify other preferred compounds having formula I and II in addition to the compounds specifically identified here, which are antagonists or agonists endothelin.

1. Identification of compounds that modulate the activity endothelioma peptide.

Compounds are tested for ability to modulate the activity of endothelin-1. Experts know many techniques (see, for example, U.S. patent N 5114918, author Ishikawa and others; European patent A1 0 436 189, owned by BANYU PHARMACEUTICAL CO., LTD (October 7, 1989); Borges and others (1989) Eur. J. Pharm. 165: 223-230; Filep and others (1991) Biochem. Biophys. Res. Commun. 177: 171-176). In vitro studies can be complemented by in vivo studies (see, for example, U.S. patent N

5,114,918 author Ishikawa and others, European patent A1 0 436 189, owned by BANYU PHARMACEUTICAL CO., LTD (1991)), which is estimated pharmaceutical activity. Such techniques are described in the Examples and include an assessment of the ability to compete for binding with ETAand ETB-receptors on membranes isolated from cell lines that have been created using genetic engineering for the expression of either ETA- or ETB-cocktail recipes. inherent ability to inhibit endothelin activity in vitro. using some fabric, for example, the portal vein of the rat and the aorta and rat uterus, trachea, and outputs the vessels (see, for example, Borges, R., Von Grafenstein, H., Knight, D. E. , Tissue selectivity values of endotelin, Eur. J. Pharmacol. 165: 223-230, (1989)). The ability to act as antagonist of endothelin in vivo can be assessed in hypertensive rats, spontaneously hypertensive rats, laboratory mice or other known animal models (see, for example, Kaltenbronn and others (1990) J. Med.Chem. 33: 838-845; U.S. patent N 5,114,918, author Ishikawa and others; European patent A1 0 436 189, owner BANYU PHARMACEUTICAL CO. , LTD (1991); Bolger and others (1983) J. Pharmacol. Exp. Ther. 225: 291-309; Stein and others (1994) J. Med.Chem. 32: 329-331; Clozel and others (1993) Nature 365: 759-761). Using the results of these animal studies, it is possible to evaluate the pharmacological efficacy and to determine the pharmaceutically effective dose. Can be evaluated in vitro and in vivo potential agonist with well-known experts methods.

The activity of endothelin can be identified by the ability of the studied compounds to stimulate the contraction of the isolated thoracic aorta (see Borges and others, Tissue selectivity values of endotelin, Eur. J. Phannacol. 165: 223-230, (1989). In order to perform the method, the endothelium is removed, and the ring segments are supported under tension in a special device and Obrestad. Can be constructed curves dose-response and used to obtain information concerning the relative inhibitory capacity of the compounds. Other tissues, including heart, skeletal muscle, kidney, uterus, trachea, excretory vessels, can be used to assess the validity of some of the studied compounds on the reduction of fabrics.

Izotopicheskie specific endothelin antagonists can be identified by the ability of these compounds to inhibit the binding of endothelin to various tissues or cells expressing the different subtypes of endothelin receptors, or to intervene in the biological effects of endothelin or isotype endothelin (Takayanagi and others (1991) Reg. Pep. 32: 23-37; Panek and others (1992) Biochem. Biophys. Res. Commun.183: 566-571). For example, ETB-receptors are expressed in endothelial cells of blood vessels, possibly being a link in the secretion of prostacyclin and its derived endothelin relaxing factor (De Nucci and others (1988) Proc. Natl. Acad.Sci. USA 85: 9797). ETAreceptors are not detected in cultured endothelial cells, which Express ETB-receptors.

The binding of compounds or inhibition of binding of endothelin with ETBreceptores the content of his main stable product exchange 6-keto-PGF1ain cultured endothelial cells from bovine aorta (see , for example, Filep and others (1991) Biochem. and Biophys. Res. Commun. 177: 171-176). Thus, the relative affinity of compounds to various receptors of endothelin can be estimated by studying curves dose of inhibitor-response for tissues that differ in type receptors.

Using such techniques, it has been estimated the relative affinity of the compounds for ETAand ETB-receptors. Selected those compounds that have desirable properties, such as specific inhibition of binding of endothelin-1. Selected compounds that have the desired activity may be useful for the treatment and studied for these purposes, using the above described methods of analysis, in which it is possible to evaluate the effectiveness of in vivo (see, for example, U.S. patent N 5,248,807; U.S. patent N 5,240,910; U.S. patent NN 5,198,548; 5,187,195; 5,082,838; 5,230,999; published Canadian application NN 2,067,288; 2,071,193; published UK application N 2,259,450; published PCT application WO 93/08799; Benigi and others (1993) Kidney Int. 44 : 440-44; Nirei and others (1993) Life Sciences 52: 1869-74; Stein and others (1994) J. Med. Chem. 32: 329-331; Clozel and others (1993) Nature 365: 759-761). Compounds that have activity in vitro, correlating with activity in vivo, in the future will be mmohut also be used in methods for the identification and release of endothelium-specific receptor and can help in creating connections, which are more potent antagonists or agonists endothelin, or which are more specific to individual endothelium receptors.

2. Selection endothelioma receptors.

A method is proposed to identify endothelioma receptors. To implement the method attached to the substrate one or more compounds used in the methods for affinity purification of receptors. By selecting compounds with specific characteristics you can identify the different subclasses of ET-receptors.

One or more connections may be attached to a suitable resin, for example, Affi-gel covalently or other communication by using well-known methods for binding of endothelin with such resins (see Schvartz and others (1990) Endocrinology 126: 3218-3222). Related compounds can be those that are specific to ETA- or ETBreceptors or other subclasses of receptors.

Resin pre-equilibrated with a suitable buffer usually at physiological pH (7 to 8). Composition containing dissolved receptors from selected fabrics, mixed with resin, which is associated with the connection, and receptors selectively suiryudan. Prescriptions the other methods, with the help of which identified and characterized proteins. The preparation of the resin, the selection of receptors, the method of elution can be accomplished by modification of the well known standard techniques (see Schvartz and others (1990) Endocrinology 126: 3218-3222).

Offered other methods to distinguish between types of receptors, based on the different affinity of any of these compounds. Any of these methods for measuring the affinity of selected compounds to endothelium receptors can be used to distinguish subtypes of receptors, based on the affinity of some here connections. In particular, an unknown receptor may be identified as ETA- or ETBthe receptor by measuring the affinity of binding to an unknown receptor with the proposed connection, which has a known affinity for one receptor, but not to another. This preferential interaction is useful in the detection of some diseases that can be treated are obtained compounds, as described here. For example, compounds with high affinity for ETAreceptors and little or no affinity for ETB-receptors are candidates for use as paratore are candidates for use as anti-asthma agents.

D. Preparation and use of compositions.

Effective concentrations of one or more sulfonamides of formula I or II or pharmaceutically acceptable salts, esters or other derivatives of them are mixed with a suitable pharmaceutical carrier or excipient.

In those cases, when the connection has a slight solubility, can be used in methods of increasing the solubility of the compounds. Such methods are known and include, but are not limited to, the use of co-solvents, such as dimethylsulfoxide (DMSO), using surfactants, such as tween, or dissolution in aqueous solutions of bicarbonate. Derivative compounds, such as salts of the compounds or the precursors of drugs can also be used for making effective pharmaceutical compositions.

Concentration or compounds are effective to transfer such amount of active ingredient when applied, which reduces the symptoms of endothelium-dependent diseases. Usually the compositions are made for one time use.

By mixing or adding of sulfa compounds can be obtained solutions, suspensibility and solubility of the compounds in the selected carrier or filler. The effective concentration is sufficient for improvement in the treatment of symptoms of a disease, disorder or condition, and can be empirically established.

We offer pharmaceutical carriers or excipients suitable for use compounds include any known carriers that are suitable for specific applications. In addition, the composition can be composed of only pharmaceutically active ingredient, or they may be composed of multiple active ingredients.

The active compounds can be applied in any suitable way, for example, orally, parenterally, intravenously, topically, subcutaneously or topically, in liquid, semi-liquid or solid form and are suitable for each type of application method. Predominant are oral and parenteral methods.

Active compounds are included in the pharmaceutically acceptable carriers in quantities sufficient for the manifestation of therapeutically useful effect in the absence of undesirable side effects in the patient. therapeutically effective concentration may be determined empirically in the study of compounds known in si BANYU PHARMACEUTICAL CO., LTD (October 7, 1991); Borges and others (1989) Eur. J. Pharm. 165: 223-230: Filep and others (1991) Biochem.Biophys. Res. Commun. 177: 171-176), which is then extrapolated to doses suitable for a person.

The concentration of the active compound in the drug composition will depend on the speed of absorption, inactivation and excretion of the active compound, the content of components in the composition, the applied quantity, as well as other well-known specialists of factors. For example, enter the amount is sufficient to treat the symptoms of hypertension. An effective amount for the treatment of endothelium-dependent disorders, as expected, more than this number of sulfonamidnuyu compounds, which are used to treat bacterial infections.

Typically a therapeutically effective dosage should give a concentration of active ingredient in the serum from 0.1 ng/ml 50-100 mcg/ml Pharmaceutical compositions typically should provide content connections from 0.01 mg to 2000 mg per kilogram of live weight per day. The active ingredient can be applied once or may be divided into a number of smaller doses to be applied at certain intervals of time. It is clear that the exact dose and duration of use depends on tableupdate data obtained in experiments in vivo and in vitro. It should be noted that the concentration and the amount of dosages can also be modified to reflect changing conditions. It should further be understood that for each patient the order of the doses must be maintained during the time that corresponds to the individual needs and in accordance with the professional opinion of a specialist, implementing or overseeing the use of the compositions, and that the field concentrations used here are examples only and are not intended to limit the possible or practical application of the claimed compositions.

If it is desirable oral administration, the compound should be included in a composition that protects it from the acidic environment in the mouth. For example, the composition can be enclosed in an outer shell that maintains its integrity in the mouth and isolates the active compound in the gut. The composition may also be prepared in combination with antacids or other similar ingredients.

Oral compositions will generally include an inert diluent or edible carrier, and can be compressed into tablets or enclosed in gelatin capsules. For oral to therapeutants in the form of tablets, capsules or pellets. Pharmaceutically acceptable binding agents and adjuvants may be included as part of the composition.

Tablets, pills, capsules, pellets, and similar forms may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, resin tragakant and gelatin; an excipient such as starch or lactose, a destructive agent, such as alginic acid or corn starch, but not limited to, lubricating substance, such as magnesium stearate, but not limited to, the substance giving the slide, such as colloidal silicon dioxide, sweetening agent such as sucrose or saccharin, giving a flavor agent, such as peppermint, methyl salicylate and fruit flavoring.

When the form containing the dosage is a capsule, it may contain in addition to the above types of substances such liquid carriers, for example, animal fat. In addition, dosage forms can contain various other materials, which change their physical properties, for example, coating with sugar and other enteric agents. These compounds can also be used as an integral part of anomy connection sucrose as a sweetening agent and certain preservatives, the tint dyes and fragrances.

The active substance can also be mixed with other active materials that do not weaken the desired action, or with substances that reinforce the desired action, such as antacids, substances that block H2and diuretics. For example, if the substance is used to treat asthma or hypertension, it can be used with other expand the bronchi substances and protivogipertonicheskoe agents, respectively.

Used for parenteral, intradermal, subcutaneous, or topical application of the solution or suspension may include any of the following materials: sterile solvent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methylparaben; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers, as acetate, citrate and phosphate; and substances to create a tonic solution - sodium chloride or dextrose. Parentline prepa material for several therapeutic doses.

For intravenous administration, suitable carriers include physiological saline or phosphate buffer solutions containing thickening and dissolving agents, such as glucose, polyethylene glycol, polypropyleneglycol and mixtures thereof. Liposomal suspensions, including liposomes of the target tissues may be suitable as pharmaceutically acceptable carriers. They can be prepared according to methods known in the art. For example, liposomal formulations can be prepared as described in U.S. patent N 4,522,811.

The active compounds may be prepared with carriers that protect the compound against rapid excretion from the body, such as slowly emit formulations or coatings. Such media include compositions with controlled time allocation, for example, implants and microencapsulation transmission systems, but is not limited to this, and biodegradable, biocompatible polymers, such as collagen, ethylene, vinyl acetate, polyanhydrides, polyglycolic acid, polyarteritis, polylactic acid and others. The methods of preparation of such compositions is well known to specialists.

The compositions can be formulated for R, the eyes, in the form of a gel, cream, lotion for application to the eye or for intracisternal or intraspinal application. Such solutions, especially those that are used for ophthalmic use, can consist of 0.01% -10% isotonic solutions with appropriate salts and pH 5-7. The composition may be formulated as aerosols for topical application, for example, for inhalation (see , for example, U.S. patents 4,044,126; 4,414,209; 4,364,923 that describe the aerosol steroids used for the treatment of inflammatory diseases, particularly asthma).

Finally, the compounds may be packaged in the form of manufactured products, comprising: a packaging material in the packaging of the obtained compound which has a effectiveness as an antagonist of endothelin, improving the symptoms associated with endothelin diseases, or inhibits binding endothelioma peptide with the ET-a receptor at a concentration of IC50less than 10 μm, the inside of the packaging material, and a label that indicates what the compound or its salt is used as an antagonist of endothelin, or cures caused by endothelin disease or inhibits the binding endothelioma peptide with ET-receptor the applications of the invention.

EXAMPLE 1

N-(4-Bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide.

A solution of 5-amino-4-bromo-3-methylisoxazole (177 mg, 1.0 mm) in dry tetrahydrofuran (THF) (2 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 90 mg, 2.2 mm) in dry THF (1 ml) at 0-5oC. After stirring at 0-5oC for 5 min, the reaction mixture was stirred at room temperature for 10 min to complete the reaction. The reaction mixture was again cooled to 0oC and added dropwise thiophene-2-sulphonylchloride (200 mg, 1.1 mm), dissolved in dry THF (2 ml). Stirring was continued for 1 h, during this time, the reaction mixture is slowly warmed to room temperature. THF was removed under reduced pressure. The residue was dissolved in water (10 ml), the pH was brought to 10-11 by adding 5 n sodium hydroxide solution and was extracted with ethyl acetate (3 x 10 ml) to remove neutral impurities. The aqueous solution was acidified with concentrated hydrochloric acid (pH 2-3) and extracted with methylene chloride (3 x 10 ml). After combining the organic extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamida. Clean ves-127oC.

EXAMPLE 2

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-isoxazolyl)thiophene-2 - sulfonamide.

A solution of 5-amino-4-bromo-3-methylisoxazole (177 mg, 1.0 mm) in dry tetrahydrofuran (THF) (2 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 90 mg, 2.2 mm) in dry THF (1 ml) at 0-5oC. After stirring at 0-5oC for 5 min, the reaction mixture was heated to room temperature within 10 min to complete the reaction. The reaction mixture was again cooled to 0oC and slowly added 5-(3-isoxazolyl)thiophene-2-sulphonylchloride (273 mg, 1.1 mm), dissolved in dry THF (2 ml). Stirring was continued for 1 h, during this time, the reaction mixture was slowly adopted at room temperature. THF was removed under reduced pressure. The residue was dissolved in water (10 ml), the pH was brought up to 2-3 by addition of concentrated HCl and was extracted with methylene chloride (3 x 10 ml). After combining the organic extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3 - isoxazolyl)thiophene-2-sulfonamida. Pure material was obtained by recrystallization using hexane-ethyl acetate (160 mg, yield.

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-pyridyl)thiophene-2-sulfonamide was obtained in the same way as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-(2-pyridyl)thiophene-2 - sulphonylchloride with 40% yield. Pure crystalline substance was obtained by recrystallization from ethyl acetate, so pl. 186-188oC.

EXAMPLE 4

N-(4-Bromo-3-methyl-5-isoxazolyl)-4,5-dibromothiophene-2-sulfonamide.

N-(4-bromo-3-methyl-5-isoxazolyl)-4,5-dibromothiophene-2-sulfonamide was obtained in the same way as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 4,5-dibromothiophene-2-sulphonylchloride with 45% yield. Pure crystalline substance was obtained by recrystallization from a mixture of ethyl acetate-hexane, so pl. 153 to 155oC.

EXAMPLE 5

N-(4-bromo-3-methyl-5-isoxazolyl)-5-chloro-methylbenzo(b)thiophene-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-chloro-methylbenzo(b)thiophene-2 - sulfonamide was prepared as described in Example 2 from 5-amino-4-bromo-C-methylisoxazole and 5-chloro-3-methylbenzo(b)thiophene-2 - sulphonylchloride with the release of 18%. Purification by recrystallization produced from a mixture of ethyl acetate/hexane to obtain crystalline solid with a melting point 153 - 155oC.

isoxazolyl)-5-(4-chlorobenzamido) thiophene-2-sulfonamide was prepared in the same way, as described in Example 2 from 5-amino-4-bromo-C-methylisoxazole and 5-(4-chlorobenzamido)thiophene-2-sulphonylchloride with the release of 27%. The obtained product was passed through a column of silica gel and used a mixture of ethyl acetate/hexane as eluent. Purification was effected by recrystallization from a mixture of ethyl acetate/hexane to obtain crystalline solid, melting point 210 whichoC (decomposition).

EXAMPLE 7

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(benzazolyl)thiophene-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(benzazolyl)thiophene-2 - sulfonamide was obtained as described in Example 2 from 5 - amino-4-bromo-C-methylisoxazole and 4-benzosulfimide-2 - sulphonylchloride with the release of 26%. Clearance made by recrystallization from a mixture of ethyl acetate/hexane to obtain crystalline solid, melting point which 181-184oC.

EXAMPLE 8

N-(4-bromo-3-methyl-5-isoxazolyl)-4-bromo-5-chlorothiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-bromo-5-chlorothiophene-2-sulfonamide was obtained as described in Example 2 from 5-amino-4 - bromo-3-methylisoxazole and 4-bromo-5-chlorothiophene-2-sulphonylchloride with the release of 25%. The cleanup item is the melting point of 143 - 145oC.

EXAMPLE 9

N-(4-bromo-3-methyl-5-isoxazolyl)-2.5-dichlorothiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2.5-dichlorothiophene-3-sulfonamide was obtained as described in Example 2 from 5-amino-4-bromo-3 - methylisoxazole and 2.5-dichlorothiophene-3-sulphonylchloride with the release of 47%. Clearance made by recrystallization from a mixture of ethyl acetate/hexane to obtain crystalline solid with a melting point 135-138oC.

EXAMPLE 10

N-(4-bromo-3-methyl-5-isoxazolyl)-2.5-dimethylthiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2.5-dimethylthiophene-3-sulfonamide was obtained as described in Example 1 from 5-amino-4-bromo-3 - methylisoxazole and 2.5-dimethylthiophene-C-sulphonylchloride with the release of 55%. Clearance made by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 77-80oC.

EXAMPLE 11

N-(4-bromo-3-methyl-5-isoxazolyl)-4,5-dichlorothiophene-2-sulfonamide]

N-(4-bromo-3-methyl-5-isoxazolyl)-4,5-dichlorothiophene-2-sulfonamide was obtained as described in Example 1 from 5-amino-4-bromo-3 - methylisoxazole and 4,5-dichlorothiophene-2-sulphonylchloride with the release of 42%. Clearance made by recrystallization from a mixture of tx2">

EXAMPLE 12

N-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dichloro-4-bromothiophene-3 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dichloro-4-bromothiophene-3 - sulfonamide was obtained as described in Example 1 from 5-amino-4 - bromo-3-methylisoxazole and 4-bromo-2,5-dichlorothiophene-3-sulphonylchloride with the release of 58%. Clearance made by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 146-149oC.

EXAMPLE 13

N-(4-bromo-3-methyl-5-isoxazolyl)-2-{3-[1-methyl-5-(trifluoromethyl) pyrazolyl]}thiophene-5-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-{3-[1-methyl-5-(trifluoromethyl) pyrazolyl] } thiophene-5-sulfonamide was obtained as described in Example 1 from 5-amino-4-bromo-3-methylisoxazole and 2-{3-[1-methyl-5-(trifluoromethyl)pyrazolyl]} thiophene-5-sulphonylchloride with 30% yield. Clearance made by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 121-123oC.

EXAMPLE 14

N-(4-bromo-5-methyl-3-isoxazolyl)thiophene-2-sulfonamide

Thiophene-2-sulphonylchloride (183 mg, 1 mm) was added to a solution of 3-amino-4-bromo-5-methylisoxazol (177 mg, 1 mm) in dry pyridine (0.5 ml). The reaction mixture was stirred at Kyoshi water and ethyl acetate. The organic layer is washed with 1N HCl (3x10 ml), a solution of salt (10 ml) and dried over anhydrous magnesium sulfate. After evaporation of the solvent left an oily residue, which was hardened at -20oC. It was purified by recrystallization from a mixture of ethyl acetate - hexane to obtain the pure product in 51% yield in the form of a brownish solid substance with a melting point 156-158oC.

EXAMPLE 15

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzazolyl)thiophene-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl) 5-(benzazolyl)thiophene-2 - sulfonamide was obtained as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-benzosulfimide-2 - sulphonylchloride with yield 59%. Purification was performed by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 139-142oC.

EXAMPLE 16

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3 - sulfonamide was obtained as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 2-(carbomethoxy)thiophene-3 - sulphonylchloride with the release of 73%. Clearance made by recrystallization from a mixture of ethyl acetate is the EMER 17

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3 - sulfonamide (Example 16) (1,5,, 3,95 mm) was dissolved in 10 ml. of methanol. Then added pellets of sodium hydroxide (1 g, 25 mm) and a few drops of water. The resulting solution was stirred for 16 hours at room temperature. The methanol was removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2x10 ml). The aqueous layer was acidified (pH = 2) with concentrated hydrochloric acid and was extracted with ethyl acetate (CH ml). The organic layers were combined, dried over water-free magnesium sulfate and filtered. After removal of the solvent was obtained N-(4-bromo-3-methyl-5-isoxazolyl)- 2-(carbomethoxy)thiophene-3-sulfonamide (1,2 g, yield 82%), which was purified by column chromatography on silica gel using ethyl acetate as eluent. So pl. 188-194oC.

EXAMPLE 18

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-phenylenecarbonyl) thiophene-3-sulfonamide

Aniline (0,093 g, 1 mm) and 1-ethyl-3'(3-dimethylaminopropyl)- carbodiimide (EDCI) (0,191 g, 1 mm) was added to N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide (0,368 g, 1 mm), suspended in methylene chloride (5 ion mixture was diluted with methylene chloride (50 ml) and washed with 3N hydrochloric acid (g ml). The organic layers were combined, dried over anhydrous magnesium sulfate and filtered. After removal of the solution under reduced pressure was obtained N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N - phenylenecarbonyl)thiophene-3-sulfonamide. The resulting product was then purified column chromatography using ethyl acetate as eluent to obtain the final product (0.32 g, yield 72%, so pl. 168-170oC).

EXAMPLE 19

N-(4-bromo-3-methyl-5-isoxazolyl)-1-(4'-isopropylphenyl)pyrrol-2 - sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)-1-(4'-isopropylphenyl) pyrrole-3-sulfonamide

A. 1-(4'-isopropylphenyl)pyrrol

Glacial acetic acid (100 ml) was added to a mixture of 4-isopropylaniline (10 ml, to 72.4 mmol) and 2,5-dimethoxytetrahydrofuran (9.6 ml, to 72.4 mmol) and the resulting mixture was heated under reflux for 1.5 hour. The reaction mixture was cooled, and acetic acid was removed under reduced pressure. The obtained brown syrupy liquid was dissolved in ethyl acetate (200 ml) and washed with water (I ml). The organic layer was dried over magnesium sulfate and filtered. After removal of the solvent was obtained 1-(4'-isopropylphenyl)pyrrole (13,28 g, yield 99%) as a brown syrup.

B. 1-(4'-isopropylphenyl)pyrrol--isopropylphenyl)pyrrole (5,01 g, 27,08 mmol) in chloroform (100 ml) at 0oC. the resulting solution was stirred at 0oC for 1 hour and additionally for 1 hour at room temperature. The chloroform was removed under reduced pressure. The obtained brown liquid was diluted with ethyl acetate (200 ml) and washed with 1N sodium hydroxide. Then the aqueous layer was acidified with concentrated hydrochloric acid (pH<1), then was extracted with chloroform (CH ml). The organic layers were combined, dried over magnesium sulfate and filtered. After removal of the solvent was obtained 1-(4' isopropylphenyl)pyrrol-2 - sulfonic acid as a brown syrup (3 g, yield 42%).

C. 1-(4'-isopropylphenyl)pyrrol-2-sulphonylchloride and 1-(4'- isopropylphenyl)pyrrole-3-sulphonylchloride

Piatigorsky phosphorus (4.7 g, 22,64 mmol) was slowly added to a solution of 1-(4'-isopropylphenyl)pyrrol-2-sulfonic acid (3 g, 11,32 mmol) in phosphorus oxychloride (8,4 ml, 90,57 mmol). The resulting mixture was heated at 70oC for 10 hours. The reaction mixture was cooled to room temperature, then carefully poured onto crushed ice (500 g) and was extracted with chloroform (200 ml). The organic layers were combined and dried over anhydrous magnesium sulfate. After filtration and St-3-sulphonylchloride at a ratio of 4:1 in the form of a brown oil.

D. N-(4-bromo-3-methyl-5-isoxazolyl)-1- (4'-isopropylphenyl)pyrrol-2-sulfonamide and N-(4-bromo-3-methyl - 5-isoxazolyl)-1-(4'-isopropylphenyl)pyrrole-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-1-(4'-isopropylphenyl) pyrrol-2-sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)-1-(4'- isopropylphenyl)pyrrole-3-sulfonamide was obtained as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and a mixture of 1-(4'- isopropylphenyl)pyrrol-2-sulphonylchloride and 1-(4'- isopropylphenyl)pyrrole-3-sulphonylchloride with a total yield of 65%. The mixture was subjected to preparative of gelchromotography obtaining N- (4-bromo-3-methyl-5-isoxazolyl)-1-(4'-isopropylphenyl)pyrrol-2 - sulfonamida (retention time 22,85 min, 5%-95% acetonitrile in water with 0.1% triperoxonane acid for 30 min, analytical column C18) and N-(4-bromo-3-methyl-5-isoxazolyl)- 1-(4'-isopropylphenyl)pyrrole-3-sulfonamida (retention time 24,56 min, 5%-95% acetonitrile in water with 0.1% triperoxonane acid for 30 min, analytical column C18in the form of oils.

EXAMPLE 20

N-(4-bromo-3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide was obtained as described in Example 2 from 5-amino - 4-bromo-3-methylisoxazole and 5-bromothiophene-2-sulfonyl lifestage solid substance with a melting point 240oC.

EXAMPLE 21

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-methoxyphenyl) aminocarbonyl]thiophene-3-sulfonamide

4-methoxyaniline (0,246 g, 2 mmol), bromo-Tris-pyrrolidino-phosphodiesterase (PyBrop) (0,466 g, 1 mmol) and N,N'-diisopropylethylamine (0.15 ml) was added to N-(4-bromo-3-methyl-5-isoxazolyl)-2- (carboxyl)thiophene-3-sulfonamide (0,368 g, 1 mmol), suspended in methylene chloride (3 ml), resulting in received light solution. Stirring was continued for 24 hours at room temperature. The reaction mixture was diluted with methylene chloride (50 ml) and washed with a solution of 3 N hydrochloric acid, and then 5% sodium carbonate solution (g ml). The organic layers were combined, dried over anhydrous magnesium sulfate and filtered. After removal of the solvent under reduced pressure was obtained N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4 - methoxyphenyl)aminocarbonyl] thiophene-3-sulfonamide. The crude product, thus obtained, was purified by column chromatography using ethyl acetate as eluent. He was recrystallized from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 202-205 areoC (0.08 g, yield 17%).

EXAMPLE 22

N-(4-balil)-2-[N-(3-methoxyphenyl) aminocarbonyl] thiophene-3-sulfonamide was prepared in the same way, as described in Example 21, N-(4-bromo-3-methyl-5-isoxazolyl)-2- (carboxyl)thiophene-3-sulfonamida and 3-methoxyaniline with the release of 23%. The crude product was purified column chromatography using ethyl acetate as eluent. He was recrystallized from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 200-202oC.

EXAMPLE 23

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(2-methoxyphenyl) aminocarbonyl]-thiophene-Z-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(2-methoxyphenyl) aminocarbonyl]-thiophene-3-sulfonamide was obtained as described in Example 21, N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene - 3-sulfonamida and 2-methoxyaniline with the release of 26%. The crude product was purified column chromatography using ethyl acetate as eluent. He was recrystallized from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 74-80oC.

EXAMPLE 24

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-benzylaminocarbonyl) thiophene-3-sulfonamide

Benzylamine (0,214 g, 2 mmol), benzotriazol-1-yl-oxy - Tris(dimethylamino)phosphodiesterase (Bop) (0,442 g, 1 mmol) and N,N'-diisopropylethylamine (spendelove in methylene chloride (3 ml). The resulting solution was stirred for 14 hours at room temperature. The solution was diluted with methylene chloride (50 ml) and washed 3 N hydrochloric acid (3x50 ml), and then a 5% solution of sodium carbonate (g ml). The organic layers were combined, dried over anhydrous magnesium sulfate and filtered. Upon removal of solvent under reduced pressure was obtained N-(4-bromo-3-methyl-5 - isoxazolyl)-2-(N-benzylaminocarbonyl) thiophene-3-sulfonamide. The crude product was purified column chromatography using ethyl acetate as eluent. After recrystallization from a mixture of ethyl acetate-hexane was obtained crystalline solid with a melting point of 186 to 190oC (0.14 g, 30% yield).

EXAMPLE 25

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-ethylphenyl) aminocarbonyl] thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-ethylphenyl) aminocarbonyl] thiophene-3-sulfonamide was obtained as described in Example 24 N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene - 3-sulfonamida and 4-ethylaniline with the release of 31%. The crude product was purified by column chromatography using ethyl acetate as eluent. He was recrystallized from a mixture of ethyl acetate-hexane to obtain crystallizational)-2-[N-(4-diphenyl)aminocarbonyl] thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-diphenyl)aminocarbonyl] thiophene-3-sulfonamide was obtained as described in Example 24 N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamida and 4-phenylaniline with the release of 26%. The crude product was purified column chromatography using ethyl acetate as eluent. He was recrystallized from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 205-212oC.

EXAMPLE 27

N-(3,4-dimethyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3 - sulfonamide

2-methoxycarbonylamino-3-sulphonylchloride (2.50 g, 10.05 mmol) was added to a solution of 5-amino-3,4-dimethylisoxazole (0,98 g is 8.75 mmol) in dry pyridine (5.0 ml). The reaction mixture was stirred at room temperature for 16 hours. The pyridine was removed under reduced pressure, and the residue was subjected to separation between water and dichloromethane. The organic layer was washed 1 N HCl (g ml) and dried over anhydrous magnesium sulfate. After evaporation of the solvents left an oily residue, which, after purification using column chromatography over silica gel (hexane-ethyl acetate with proportion of 1:1 as eluent), consisted of 2.20 mg (65%)San obtaining the pure product as a white solid with a melting point 113-116oC.

EXAMPLE 28

N-(3,4-dimethyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide was obtained as described in Example 17 from N-(3,4-dimethyl-5 - isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamida using basic hydrolysis to yield 94%. Clearance made by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 202-203oC.

EXAMPLE 29

N-(3,4-dimethyl-5-isoxazolyl)-2-(N-phenylenecarbonyl)thiophene - 3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-(N-phenylenecarbonyl)thiophene - 3-sulfonamide was obtained as described in example 18, N-(3,4-dimethyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamida with the release of 40%. Clearance made by recrystallization from methanol-water to obtain crystalline solid with a melting point 176-178oC.

EXAMPLE 30

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2'-thienyl)thiophene-2 - sulfonamide

A. 5-bromo-2,2'-dateopen

N-bromosuccinimide (NBS, 1.12 g, 6.3 mmol) was added in small portions to a stirred solution of 1.0 g (6,01 mmol) 2,2'- dithiolane in 10 ml of glacial acetic acid and 10 ml. of chloroform. Passeriformes (75 ml). The organic layer was washed with an aqueous solution of sodium bicarbonate, water and then dried over magnesium sulfate and evaporated. The residue was subjected to rapid chromatography on silica gel using hexane to obtain 1.3 g (88%) of a light green solid with a melting point 55-56oC.

Century 5-chlorosulfonyl-2,2'-dateopen

The mixed solution of 5-bromo-2,2'-thiophene (1.5 g, 6.1 mmol) in 10 ml dry ether was placed in an argon atmosphere, cooled to -78oC, and it was added within 20 min of 4.3 ml of a 1.7 M solution tributyrate within 20 minutes the Stirring was further continued at this temperature for 20 minutes Then at -78oC through the solution was barbotirovany sulfur dioxide until a yellow precipitate. Bubbling sulfur dioxide addition was continued for 3 minutes , and then immediately added drop by drop N-chlorosuccinimide (NCS, 902 mg, 6,76 mmol) dissolved in THF. The mixture was heated to room temperature and continued stirring additionally for 1.5 hours. Then the mixture was concentrated, and the residue was dissolved in ether. The organic layer was washed with water, brine and dried over magnesium sulfate. After evaporation of the solution was obtained pale-yellow solid substances the effect 63-64oC.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2'-thienyl)thiophene-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2'-thienyl)thiophene-2-sulfonamide was obtained as described in Example 2. In the reaction of 2-chlorosulfonyl-5,2'-dithiolane (300 mg, to 1.14 mmol) with 5-amino-4-bromo-3-methylisoxazole (183 mg, of 1.03 mmol) was obtained after carrying out rapid chromatography using 10% solution of methanol in CHCl3, 430 mg (94%) of light brown solid with a melting point of 210oC.

EXAMPLE 31

N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-3-sulfonamide

A. Thiophene-3-sulphonylchloride

The mixed solution of 3-bromothiophene (1.5 g, 9.2 mmol) in 10 ml dry ether was placed in an atmosphere of argon and cooled to -78oC. for 20 min, the solution was added tert-utility (5.6 ml, 1.7 M), and additional mixing was carried out at this temperature for 20 minutes Then was barbotirovany at -78oC sulfur dioxide, and the solution was heated to 0oC, and then was added dropwise a solution of NCS (1.47 g, 12 mmol) in 8 ml THF. After heating to room temperature, stirring was continued for additional 1 hour, and after evaporation of the solvents left 1.55 g of brown oil. After what was Arevalo when standing with the formation of a yellow crystalline solid with a melting point 38-39oC.

B. N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-3-sulfonamide was prepared as described in Example 2, from thiophene-3-sulphonylchloride and 5-amino-4-bromo-3-methylisoxazole with the release of 22%. In the purification using column chromatography using a mixture of 10% methyl alcohol in CHCl3as eluent was obtained a light brown oil.

EXAMPLE 32

N-(3,4-dimethyl-5-isoxazolyl)-5-phenylthiophene-2-sulfonamide

A. N-(3,4-dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide

A solution of 5-bromothiophene-2-sulphonylchloride (2,75 g, 10 mmol) and 5-amino-3,4-dimethylisoxazole (1.07 g, to 9.57 mmol) in pyridine containing a catalytic amount of 4 - dimethylaminopyridine (DMAP, 10 mg) was stirred at room temperature for 3 hours. The solution was further heated at 50oC for 1.5 hours to bring the reaction to completion. The pyridine was removed under reduced pressure and the residue, after extraction with ethyl acetate, washed with 1N HCl (g ml), water (h), salt solution (g ml) and dried over magnesium sulfate. After evaporation of the solution has received a viscous brown mass, which was subjected to rapid chromatography. In suirou ethyl-5-isoxazolyl)-5 - bromothiophene-2-sulfonamide

N-methyl-3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (680 mg, 2 mmol) in dry THF (2 ml) was added to sodium hydride (121 mg, 60% oil dispersion, 3 mmol) in dry tetrahydrofuran (1 ml). The resulting suspension was cooled to 0oC was added dropwise methoxyethoxymethyl (334 mg, 2.68 mmol) via syringe. The solution was heated to room temperature and left overnight under stirring. After evaporation of the solvent left an oil which was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate and evaporated. After a quick chromatography of the resulting residue on silica gel using 10-15% ethyl acetate in hexane were obtained 480 mg (56%) of colorless oil.

C. N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5 - phenylthiophene-2-sulfonamide

Sodium carbonate (2 ml of 2M aqueous solution), and then phenylboric acid (86 mg, 0.71 mmol) in 2 ml of 95% ethanol was added to a solution of N-(methoxyethoxymethyl)-N-(4-methyl-3-methyl-5-isoxazolyl)-5-bromothiophene - 2-sulfonamida (200 mg, 0.47 mmol) and tetroxide(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol) in dry benzene (4 ml) in an argon atmosphere. The mixture was subjected to reverse distilled for 12 h, diluted with 5 ml water and was extracted was attractively rapid chromatography on silica gel using 25% ethyl acetate in hexane, and received 123 mg (62%) sulfonamida in the form of colorless rubbery substance.

D. N-(3,4-dimethyl-5-isoxazolyl)-5-phenylthiophene-2-sulfonamide

HCl (3 ml of 3N aqueous solution) was added to a solution of N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-phenylthiophene - 2-sulfonamida (100 mg, 0.24 mmol) in 3 ml of 95% ethanol, and the resulting mixture was distilled for 6 hours. Then the mixture was concentrated, diluted with 5 ml of water, neutralized with saturated aqueous sodium bicarbonate solution, and acidified to pH = 4 glacial acetic acid. The mixture was extracted with ethyl acetate (CH ml), the organic extracts were combined, washed with brine (CH ml), dried and evaporated. After a quick chromatography of the residue on silica gel using 2% methanol in CHCl3and further purification by gel-chromatography got to 33.4 mg (42%) of pure sulfonamida in the form of a white powder with a melting point 176-178oC.

EXAMPLE 33

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl)thiophene-2 - sulfonamide

A. N-(5-bromothiophene-2-sulfonyl)pyrrol

Sodium hydride (60% dispersion in oil, 191 mg, 4,78 mmol) was suspended in dry tetrahydrofuran (2 ml) and the resulting cloudy suspension was cooled to 0oC in ice bath was removed, and the solution was stirred at room temperature until gas evolution stops (15 min) and then dropwise through a steel tube was added 5-bromothiophene-2-sulphonylchloride (1.0 g, 3,82 mmol), previously dissolved in tetrahydrofuran. After stirring for 1 hour at room temperature the mixture was filtered through Celite. The filter was washed with tetrahydrofuran. After evaporation remained solid light brown substance, which was recrystallized from methanol to obtain sulfonamida (821 mg, yield 74%) as a white powder.

B. 4-ethylvanillin acid.

A solution of 1-bromo-4-ethylbenzene (2.0 g, 11 mmol) in dry ether (5 ml) was added dropwise to the magnesium turnings (311 mg, 13 mmol), which was suspended in dry ether. After complete addition of the components of the suspension was distilled under reflux for 15 min, after which almost all of the magnesium has reacted. Then the resulting solution was added to trimethylborane (1.12 g, 11 mmol), previously dissolved in ether (5 ml) at -78oC, the solution was heated to room temperature and was stirred for 90 minutes the Reaction was stopped by adding 10% aqueous HCl (2 ml) and the solution was extracted with ether. Essential extras is Ali ether (CH ml). The ether extracts were combined, washed once with water (10 ml), dried and evaporated to obtain white solids (676 mg, yield 38%), melting point 138-140oC.

C. N-(pyrrole)-5-(4-ethylphenyl)thiophene-2-sulfonamide.

N-(pyrrole)-5-(4-ethylphenyl)thiophene-2-sulfonamide was obtained as described in Example 32C from 4-ethylvanillin acid and N-(5 - bronchiopulmonar)pyrrole. After purification using column chromatography using 10% ethyl acetate in hexane received the pure sulfonamide as a yellow-brown solid with a yield of 81%.

D. 5-chlorosulfonyl-2-(4-ethylphenyl)thiophene

A solution of N-(pyrrole)-5-(4-ethylvanillin)-2-sulfonamida (100 mg, 0.32 mmol) and 6N sodium hydroxide (1 ml) in methanol (1.5 ml) was distilled under reflux for about 6 hours. After evaporation of the solvent and drying in vacuum has got the oil. To the oil was added phosphorus oxychloride (258 ml, 2,52 mmol) and Piatigorsky phosphorus (131 mg, 0,63 mmol) and the resulting brown suspension was heated at 50oC for 3 hours. The obtained light brown solution was carefully added to about 20 ml of crushed ice, and then extracted with ethyl acetate (CH ml). The organic layers OLE conduct rapid chromatography on silica gel using 2% ethyl acetate in hexane was obtained (53 mg, 59%) net sulphonylchloride in the form of a light yellow oil.

E. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl)thiophene - 2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl)thiophene-2 - sulfonamide was obtained as described in Example 2. In the reaction of 5-chlorosulfonyl-2-(4-ethylphenyl)thiophene (47,1 mg, 11,16 mmol) with 5-amino-4-bromo-3-methylisoxazole (29 mg, 0.16 mmol) followed by rapid chromatography using 10% methanol in CHCl3got a light brown solid (46 mg, yield 66%) with a melting point 172-1750oC.

EXAMPLE 34

N-(3,4-dimethyl-5-isoxazolyl)benzo[b]thiophene-2-sulfonamide

A. Benzo[b]thiophene-2-sulphonylchloride

Benzo[b] thiophene (1.50 g, and 11.2 mmol) was stirred at 0oC in 20 ml of THF. Within 5 minutes was slowly added tert-utility (t-BuLi, 1,7 M to 16.8 mmol, 9,9 ml). After 15 minutes in the reaction vessel missed the stream 802, and formed a thick white precipitate. The reaction mixture was stirred for 15 minutes at 0oC, and then was added NCS (1.64 g, 12.3 mmol). The reaction mixture was heated to 25oC and was stirred for 30 minutes Then poured into ethyl acetate (150 ml) and washed with brine (CH ml). The organic phase was dried MgSO4that filtered matography (5% ethyl acetate in hexane), resulting in a yellow - brown substance (1.39 g, yield 53%).

B. N-(3,4-dimethyl-5-isoxazolyl)benzo[b]thiophene-2-sulfonamide

3,4-dimethyl-5-amino-isoxazol (0,224 g, 2.0 mmol) and 50 mg of DMAP was stirred in 5 ml of pyridine at 25oC. Then was added benzo[b] thiophene-2-sulphonylchloride (0.16 g, 2.6 mmol), and dark yellow-brown reaction mixture was poured into 100 ml ethyl acetate and washed with 2% HCl (g ml). The organic phase was dried MgSO4was filtered and concentrated, the result of which was collected and 0.61 g of brown oil and solids. Brown butter and a solid substance was subjected to rapid chromatography (30% ethyl acetate in hexane), and received 0,37 g light brown solid. It was stirred in 10 ml of methanol and 0.5 g of NaOH. The methanol solution was heated and distilled under reflux for 1 hour, then was cooled to 25oC, and methanol was removed in vacuum. The resulting residue was acidified to pH 1 with 2% HCl solution (100 ml) and was extracted with ethyl acetate (CH ml). The organic phase was dried over MgSO4was filtered and concentrated, resulting in collected 0,225 g of yellow-orange solid. It was recrystallized from a mixture of CHCl3- hexane, there was obtained a light yellow is R>N-(3,4-dimethyl-5-isoxazolyl)benzo[b]furan-2-sulfonamide

A. Benzo[b]furan-2-sulphonylchloride

Benzo[b] furan-2-sulphonylchloride was obtained as described in Example 34A of benzo[b] furan (1,61 g of 13.6 mmol), tert-BuLi (1.7 M, with 17.7 mmol, 10.4 ml) and NCS (2.0 g, 15.0 mmol). After a quick chromatography (5% ethyl acetate in hexane) was obtained brown solid (1.84 g, yield 62%).

B. N-(3,4-dimethyl-5-isoxazolyl)benzo(b)furan-2-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)benzo(b)furan-2-sulfonamide was obtained as described in Example 34B, 3,4-dimethyl-5-aminoisoquinoline (78 mg, 0.70 mmol) and benzo[b]furan-2-sulphonylchloride ones (0.46 g, 2.1 mmol). As a result of rapid chromatography (30% ethyl acetate in hexane) received 0,186 g of light yellow solid, which was treated 31 mg of NaOH in 10 ml of methanol at 25oC for 30 minutes by Recrystallization from a mixture of CHCl3-hexane received light brown solid (90 mg, yield 44%), melting point 160,5-163oC.

EXAMPLE 36

N-(3,4-dimethyl-5-isoxazolyl)furan-2-sulfonamide

A. Furan-2-sulphonylchloride

Furan-2-sulphonylchloride was obtained as in Example 34A, furan (0.96 g, of 14.2 mmol), tert-BuLi (1.7 M, 17 mmol, 10 ml) and NCS (2,27 g, 17 mmol) with ispolzoval liquid (1.22 g, yield 52%).

B. N-(3,4-dimethyl-5-isoxazolyl)furan-2-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)furan-2-sulfonamide was obtained as described in Example 34B, 3,4-dimethyl-5-aminotetrazole (0,122 g, 1.0 mmol), furan-2-sulphonylchloride (0.50 g, 3.0 mmol) and NaOH (64 mg). After a quick chromatography (50% ethyl acetate in hexane) received 70 mg of yellow solid. As a result of recrystallization from a mixture of CHCl3-hexane got not quite white solid (46 mg, yield 29%), melting point 107-110oC.

EXAMPLE 37

N-(3,4-dimethyl-5-isoxazolyl)-3-methoxy-2-thiophenesulfonyl

A. 3-methoxy-2-thiophenesulfonyl

Chlorosulfonic acid (ClSO3H, 2,31 g, 19,62 mmol) was slowly added at 0oC to a solution of 3-methoxythiophene (to 2.29 g, 19,62 mmol) in CHCl3(80 ml). The resulting mixture was stirred at 0oC for 30 minutes the Solution is evaporated under reduced pressure, at room temperature, the residue suspended in POCl3(15 ml, 156,96 mmol), was slowly added PCl5(8,2 g, 39,24 mmol). The reaction mixture was stirred at 60oC for 18 hours, then cooled to room temperature and poured onto crushed ice (200 g). The aqueous mixture was extracted with CHCl3(G ml) and who has demonstrated with 3-methoxy-2 - thiophenesulfonyl in the form of a brown oil (1,81 g, yield 43%).

B. N-(3,4-dimethyl-5-isoxazolyl)-3-methoxy-2-thiophenesulfonyl

Sodium hydroxide (1,02 g, 25,56 mmol, 60% dispersion in mineral oil) was slowly added to a solution of 3 - methoxy-2-thiophenesulfonyl (1.18 g, charged 8.52 mmol) and 3,4 - dimethyl-5-aminoisoquinoline (1,05 g, 9,37 mmol) in THF (20 ml) at room temperature. The resulting mixture was distilled under reflux for 4 hours. THF was removed under reduced pressure. The residue was dissolved in water (10 ml), the pH was brought to 10-11 by adding 5 N sodium hydroxide solution, and was extracted with ethyl acetate (3x10 ml) to remove neutral impurities. The aqueous layer was acidified with concentrated HCl (pH 2-3) and extracted with methylene chloride (3x10 ml). The combined organic layers were dried over anhydrous magnesium sulfate to obtain crude oil. Further purification by gelchromotography received a yellow oil (retention time 14,94 min, 5%-95% acetonitrile in H2O with 0.1% triperoxonane acid for 30 min, analytical column C18).

EXAMPLE 38

N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenyl-2-thiophenesulfonyl and N-(4-bromo-3-methyl-5-isoxazolyl)4-phenyl-2-thiophenesulfonyl

A. 3-phenyl-2-thiophenesulfonyl and 4-phenyl-2-thiopental who mmol) in Et2O (25 ml) at 0oC. the Ice bath was removed, and the mixture was stirred at room temperature for 2 hours, cooled to -30oC (CO2/acetone), and barbotirovany gaseous SO2through the reaction mixture for 20 min Then the solution was added NCS (6,06 g of 44.5 mmol) in THF (20 ml). The reaction mixture was allowed to heat to room temperature and was stirred for 16 hours. The crude mixture was filtered and the solid is washed with Et2O. the combined organic layers were concentrated, and the residue was subjected to chromatography (hexane/CHCl3) with 3-phenyl-2-thiophenesulfonyl and 4-phenyl-2-thiophenesulfonyl in a mixture 1:1 (1,46 g of 16.5%, white solid).

C. N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenyl-2-thiophenesulfonyl and N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenyl-2-thiophenesulfonyl

N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenyl-2-thiophenesulfonyl and N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenyl-2-thiophenesulfonyl was obtained as described in Example 1. The fraction of the crude mixture of products was purified by gel-chromatography to obtain N-bromo-3-methyl-5 - isoxazolyl)-3-phenyl-2-thiophenesulfonyl (light brown solid, retention time 20,48 min, 5%-95% acetonitrile in water with 0.1% trillion)-4-phenyl-2-thiophenesulfonyl (matte yellow solid, melting point 108-110oC, retention time 21,35 min, the same conditions).

EXAMPLE 39

Other compounds in which Ar2contains a heterocyclic ring, such as thiophenyl-, furyl - and pyrasulfotole if there is interest to them can be obtained as described in Examples 1-38.

EXAMPLE 40

N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

(a) 5-amino-4-bromo-3-methylisoxazol

5-amino-3-methylisoxazole (0,98 g, 10 mmol) was dissolved in chloroform (15 ml) and cooled to 0oC. N-bromosuccinimide (1.78 g, 10 mmol) was added in small portions over 10 minutes In the next 10 minutes was continued stirring at 0oC. the Reaction mixture was diluted with chloroform (50 ml), washed with water (I ml) and the organic layer was dried over magnesium sulfate. After removal of the solvent under reduced pressure was obtained the crude product, which was purified column chromatography using a mixture of hexane-ethyl acetate 9: 1 as eluent to obtain 5-amino-4-bromo-3-methylisoxazole (1.55 g, yield 87%).

(b) N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

A solution of 5-amino-4-bromo-3-methylisoxazole (354 mg, 2.0 mmol) in dry THF (1 ml) was added to suspensionusual at 0-5oC for 10 min, the reaction mixture was heated to room temperature within 10 min to complete the reaction. The reaction mixture was again cooled to 0oC and slowly added benzosulphochloride (0,283 ml, 2.2 mmol). Stirring was continued for 20 min at 0-5oC. an Excess of sodium hydroxide was dissolved by adding methanol (0.4 ml) and then water (0.5 ml). The solvent was removed under reduced pressure. The residue was dissolved in water (20 ml), was podslushivaet to pH 8-9 by adding sodium hydroxide, and was extracted with ethyl acetate (2x10 ml) to remove neutral impurities. The aqueous layer was acidified with concentrated HCl (pH 2-3) and extracted with ethyl acetate (3x10 ml). The combined organic layers were dried over magnesium sulfate, and concentrated under reduced pressure to obtain N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide. Pure material was obtained by recrystallization using a mixture of hexane-ethyl acetate (0,59 g, yield 93%), melting point 142-144oC.

EXAMPLE 41

N-(4-bromo-5-tertbutyl-3-isoxazolyl)benzosulfimide

(a) 3-amino-4-bromo-5-tributyltinoxide

This compound was obtained from 3-amino-5-tributyltinoxide and N-bromosuccinimide, as described in Note shall solarpanel

3-amino-4-bromo-5-tributyltinoxide (219 mg, 1.0 mmol) was dissolved in dry pyridine (1 ml). Added benzosulphochloride (of 0.14 ml, 1.1 mmol) and 4-dimethylaminopyridine (5 mg) and the solution was stirred at 50oC for 6 hours. The reaction mixture was diluted with dichloromethane (75 ml), washed with 1N HCl (50 ml) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to get crude product, which was purified column chromatography (hexane-ethyl acetate 9:1). After recrystallization from a mixture of ethyl acetate-hexane there was obtained a crystalline solid with a melting point 139-141oC.

EXAMPLE 42

N-(3-methyl-4-phenyl-5-isoxazolyl)benzosulfimide

(a) N-(benzazolyl)-N-(3-methyl-4-phenyl-5-isoxazolyl) benzolamide amide 5-amino-3-methyl-4-phenylisoxazol (0,174 g, 1.0 mmol) was dissolved in dry pyridine (2 ml). Benzosulphochloride (0,389 g, 2.2 mmol) was added under stirring at room temperature. Was added N,N - dimethylaminopyridine (5 mg), and stirring was continued at 50oC for 4 hours. The reaction mixture was diluted with dichloromethane (75 ml), washed with 1N HCl (g ml), and dried the organic phase over magnesium sulfate. The solvent was removed using a mixture of hexane-ethyl acetate 5:1, received 0,390 g (yield 85%) of N-benzazolyl-N-(4-bromo-3-methyl-5 - isoxazolyl)benzosulfimide.

(b) N-(3-methyl-4-phenyl-5-isoxazolyl)benzosulfimide

N-benzazolyl-N-(3-methyl-4-phenyl-5-isoxazolyl) benzosulfimide (300 mg, 0.66 mmol) was dissolved in methanol. Was added potassium hydroxide (300 mg, 5.5 mmol) and the solution was heated to 45oC the purpose of dissolution. Stirring was continued for 20 minutes, the Methanol was removed under reduced pressure. The residue was dissolved in water, cooled to 0oC and acidified to pH = 3-4 with concentrated HCl. The solid residue was extracted with ethyl acetate, dried and evaporated in vacuo, resulting in a received 210 mg (yield 100%) of N-(3-methyl-4-phenyl-5-isoxazolyl)benzosulfimide, which was then purified by recrystallization from a mixture of ethyl acetate-hexane, melting point 124-126oC.

EXAMPLE 43

N-(4-bromo-3-phenyl-5-isoxazolyl)benzosulfimide

This compound was obtained from benzosulfimide and 5-amino-4-bromo-3-phenylisoxazole in accordance with the method described in Example 40b, with the release of 36%. As a result of recrystallization from methanol has received a yellow solid with a melting point 113-115oC.

EXAMPLE 44

N-(4-bromo-3-is tributyltinoxide and N-bromosuccinimide with the release of 64%, as described in Example 40A.

(b) N-benzazolyl-N-(4-bromo-3-tertbutyl-5-isoxazolyl)- benzosulfimide

5-amino-4-bromo-3-tributyltinoxide (440 mg, 2.0 mmol) was dissolved in dry pyridine (2 ml). Added benzosulphochloride (344 mg, 2.0 mmol) and 4-dimethylaminopyridine (5 mg) and the reaction mixture was stirred at 50oC for 16 hours. The reaction mixture was diluted with ethyl acetate (20 ml), washed with 1N HCl (2x10 ml) and the organic phase was dried over magnesium sulfate. The solvent was removed under reduced pressure, was obtained the crude product, which was recrystallized from a mixture of ethyl acetate-hexane to obtain 300 mg (yield 60%) of N-benzazolyl-N-(4-bromo-3 - tertbutyl-5-isoxazolyl)-benzosulfimide.

(c) N-(4-bromo-3-tertbutyl-5-isoxazolyl)benzosulfimide

N-benzazolyl-N-(4-bromo-3-tertbutyl-5-isoxazolyl) benzosulfimide (80 mg, 0.16 mmol) was dissolved in methanol (2 ml). Then added sodium hydroxide (0,120 g, 3.0 mmol) in methanol, and the solution was stirred at 45oC for 20 minutes, the Methanol was removed under reduced pressure. The residue was dissolved in water, cooled to 0oC and acidified to pH = 3-4 with concentrated hydrochloric acid, and was extracted with ethyl acetate. The extract was dried of atlantoraja with the release of 94%. Further purification was produced by recrystallization from methanol-water to obtain not quite white solid with a melting point of 108-109oC.

EXAMPLE 45

4-tertbutyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

A solution of 5-amino-4-bromo-3-methylisoxazole (354 mg, 2.0 mmol) in dry THF (1 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 188 mg, 4.4 mmol) in dry THF (1 ml) at 0-5oC. After stirring at 0-5oC for 10 min, the reaction mixture was heated to room temperature within 10 min to complete the reaction. The reaction mixture was again cooled to 0oC and slowly added 4-tributylphosphorotrithioate (512 mg, 2.2 mmol). Stirring was continued for 20 min at 0-5oC. Excess sodium hydride was decomposed by addition of methanol (0.4 ml) and then water (0.5 ml). The reaction mixture was acidified with hydrochloric acid and was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to get crude product, the purification of which is produced by recrystallization from a mixture of ethyl acetate-hexane to obtain a white solid with a yield of 21%, tempermentally

4-isopropyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained as described in Example 45, from 5-amino-4-bromo-3-methylisoxazole and 4 - isopropylbenzenesulfonyl exit 77%. Clearance made by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 130 - 133oC.

EXAMPLE 47

4-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

4-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained as described in Example 45, from 5-amino-4-bromo-3-methylisoxazole and 4-bromobenzaldehyde with yield 74%. Clearance made by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 146-149oC.

EXAMPLE 48

4-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

4-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained as described in Example 45, from 5-amino-4-bromo-3-methylisoxazole and 4-forbindelsesfaneblad with 71% yield. Clearance made by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 142-144oC.

EXAMPLE 49oC.

EXAMPLE 50

N-(4-bromo-5-methyl-3-isoxazolyl)benzosulfimide

(a) 3-amino-4-bromo-5-methylisoxazol

3-Amino-5-methylisoxazole (a 1.96 g, 20 mmol) was dissolved in chloroform (10 ml) and cooled to 0oC. N-bromosuccinimide (of 3.56 g, 20 mmol) was added in small portions over 10 minutes for the next 15 minutes was continued stirring at 0oC. the Reaction mixture was diluted with chloroform (100 ml), washed with water (I ml), and dried the organic layer over magnesium sulfate. After removal of the solvent under reduced pressure was obtained the crude product, which was purified column chromatography using as eluent a mixture of hexane - ethyl acetate 9:1, with 3-amino-4-bromo-5-methylisoxazole (1.40 g, yield 40%).

(b) N-(4-bromo-5-methyl-3-isoxazolyl)benzosulfimide and N-(benzazolyl)N-(4-bromo-5-methyl-3-isoxazol)benzosulfimide

3-amino-4-bromo-5-methylisoxazol (5.31g, 30 mmol) was dissolved in dry pyridine (30 ml). what was added N,N-(dimethyl)aminopyridine (100 mg), and stirring continued at 50oC for 25 hours. The reaction mixture was diluted with dichloromethane (200 ml), washed with 1 N HCl (g ml) and the organic phase was dried over magnesium sulfate. The solvent was removed under reduced pressure, resulting in the obtained crude product, which was purified column chromatography using as eluent a mixture of hexane-ethylacetate 9: 1, and was obtained N-(benzazolyl)-N- (4-bromo-5-methyl-3-isoxazolyl)benzosulfimide (7 g, yield 51%, R1= 0,27 using a mixture of hexane-ethyl acetate 3:1 as eluent) as a solid.

Further elution with ethyl acetate was obtained N-(4-bromo-5-methyl-3-isoxazolyl)benzosulfimide (2 g, yield 21%, R1= 0,08, using a mixture of hexane-ethyl acetate as eluent) with a melting point 128-130oC.

(c) N-(4-bromo-5-methyl-3-isoxazolyl)benzosulfimide

Sodium hydroxide (1.3 g, 30,6 mmol) was added to a solution of N-(bearsley)-N-(4-bromo-5-methyl-3-isoxazolyl)benzosulfimide (7 g, and 15.3 mmol, obtained as described in (a)) in methanol (100 ml). The resulting solution was stirred at 25oC for 30 hours. The excess methanol was removed under reduced pressure. The remainder of the process is chlormethine (g ml), and the combined organic layers were dried over anhydrous magnesium sulfate. After removal of the solvent was obtained N-(4-bromo-5-methyl-3 - isoxazolyl) benzosulfimide, which was purified by recrystallization from a mixture of ethyl acetate-hexane (4.5 g, yield 92%). The connection is identical to that which was selected at the stage (b).

EXAMPLE 51

N-(4-bromo-5-methyl-3-isoxazolyl)-1-naphthalenesulfonate

N-(4-bromo-5-methyl-3-isoxazolyl)-1-naphthalenesulfonate was obtained from 3-amino-4-bromo-5-methylisoxazole and 1-naphthalenesulfonate as described in Example 41, 51% yield. As a result of recrystallization from a mixture of eteltetet-hexane was obtained crystalline solid with a melting point 167-170oC.

EXAMPLE 52

N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide

(a) 5-amino-4-chloro-3-methylisoxazol

5-amino-4-chloro-3-methylisoxazol was obtained using the techniques described in Example 40A, with the release of 90%, from 5-amino-3 - methylisoxazole and N-chlorosuccinimide.

(b) N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide

N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide was obtained in accordance with the procedure described in Example 40b, from 5-amino-4-chloro-3-methylisoxazole and benzosulfimide substance with a melting point 140-143oC.

EXAMPLE 53

N-(4-chloro-5-methyl-3-isoxazolyl)benzosulfimide

(a) 3-amino-4-chloro-5-methylisoxazol

This compound was obtained from 3-amino-5-methylisoxazole and N-chlorosuccinimide as described in Example 40A, except that the reaction was carried out at 35 C and the reaction time was increased to 12 hours. The product yield was 62%, R1= 0,17 (hexane-ethyl acetate 3:1)

(b) N-(4-chloro-5-methyl-3-isoxazolyl)benzosulfimide

N-(4-chloro-5-methyl-3-isoxazolyl)benzosulfimide was obtained from 3-amino-4-chloro-5 - methylisoxazole and benzosulfimide as described in Example 41b with the release of 40%. The crude product was purified column chromatography using 10-100% ethyl acetate in hexane as eluent. Crystalline solid with a melting point 139-141oC was obtained after recrystallization from a mixture of ethyl acetate-hexane. As a less polar products were obtained 3-amino-4-chloro-5-methylisoxazol (regeneration 25%) and N-(benzazolyl)-N-(4-chloro-5-methyl-3-isoxazolyl)benzosulfimide.

EXAMPLE 54

4-iodine-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

4-iodine-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methyl whom the product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain a yellow powder with a melting point 166-173oC, yield 65%.

EXAMPLE 55

4-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

4-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and 4-chlorobenzenesulfonamide in accordance with the procedures described in Example 40b. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain a yellow powder with a melting point 145-150oC, the yield of 93%.

EXAMPLE 56

N-(4-bromo-3-ethyl-5-isoxazolyl)benzosulfimide

(a) 5-amino-4-bromo-3-utilization

5-amino-4-bromo-3-utilization was obtained from 5-amino-3-utilizationa and N-bromosuccinimide as described in Example 40A.

(b) N-(4-bromo-3-ethyl-5-isoxazolyl)benzosulfimide

N-(4-bromo-3-ethyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-utilizationa and benzosulfimide in accordance with the procedures described in Example 40b. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain not quite white crystals with a melting point 90-93oC, yield 70%.

EXAMPLE 57

N-(4-bromo-3-methyl-5-isoxazolyl)-4-toluensulfonate

N-(4-bromo-3-methyl-5-isoxazolyl)-4-toluensulfonate balmy in Example 40b. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain not quite white crystals with a melting point 169-172oC, yield 69%.

EXAMPLE 58

2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and 2.5 - dimethylbenzenesulfonamide in accordance with the procedure described in Example 40b. The crude product was obtained by recrystallization from a mixture of ethyl acetate-hexane to obtain not quite white crystals with a melting point of 102-104oC, yield 81%.

EXAMPLE 59

N-(4-bromo-3-methyl-5-isoxazolyl)-2-toluensulfonate

N-(4-bromo-3-methyl-5-isoxazolyl)-2-toluensulfonate was obtained from 5-amino-4-bromo-3-methylisoxazole and 2-toluensulfonate in accordance with the procedure described in Example 40b. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane, and received a white crystalline substance with a melting point 93-96oC, yield 88%.

EXAMPLE 60

2-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

2-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-AEE 40b. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain a white solid with a melting point 87-89oC, yield 44%.

EXAMPLE 61

3-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

3-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and 3-forbindelsesfaneblad in accordance with the procedures described in Example 40b. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain pale yellow solid with a melting point 125-128oC, yield 88%.

EXAMPLE 62

2,5-dimethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide

2,5-dimethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-chloro-3-methylisoxazole and 2.5-dimethylbenzenesulfonamide in accordance with the procedures described in Example 40b. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain pale yellow solid with a melting point 92-93oC, yield 82%.

EXAMPLE 63

4-acetamido-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

4-acetamido-N-(4-bromo-3-methyl-5-isoxazolyl)benzo is a fool, described in Example 45. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 208-210oC, yield 56%.

EXAMPLE 64

4-nitro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

4-nitro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and 4-nitrobenzenesulfonamide in accordance with the procedures described in Example 45. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point of 146 to 149oC, yield 34%.

EXAMPLE 65

4 butoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

4 butoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and 4-butoxybenzaldehyde in accordance with the procedures described in Example 45. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point of 98 - 100oC, the yield of 33%.

EXAMPLE 66

N-(4-bromo-3-methyl-5-isoxazolyl)benzo-2,1,3-thiadiazole-4 - sulfonamide
La and 2,1,3-thiadiazole-4-sulphonylchloride in accordance with the procedures described in Example 45. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid, melting point 177-179oC, yield 34%.

EXAMPLE 67

N-(4-bromo-3-methyl-5-isoxazolyl)-2-thiophenesulfonyl

N-(4-bromo-3-methyl-5-isoxazolyl)-2-thiophenesulfonyl was obtained from 5-amino-4-bromo-3-methylisoxazole and 2-thiophenesulfonyl in accordance with the procedures described in Example 45. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 125-127oC, yield 34%.

EXAMPLE 68

3-chloro-2-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

3-chloro-2-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3 - methylisoxazole and 3-chloro-2-methylbenzenesulfonamide in accordance with the procedures described in Example 45. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain a solid crystalline substance with a melting point of 185-187oC, yield 34%.

EXAMPLE 69

2,4,6-trimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

2,4,6-trim is albenzaalbenza in accordance with the procedure described in Example 40b. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain pink solid with a melting point 92-95oC, yield 64%.

EXAMPLE 70

N-(4-bromo-3-methyl-5-isoxazolyl)-3-toluensulfonate

N-(4-bromo-3-methyl-5-aeoxisillin)-3-toluensulfonate was obtained from 5-amino-4-bromo-3-methylisoxazole and 3-toluensulfonate in accordance with the procedures described in Example 45. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 138-140oC, 63%.

EXAMPLE 71

3-chloro-2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

3-chloro-2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and 3-chloro-2,5 - dimethylbenzenesulfonamide in accordance with the procedures described in Example 45. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain a solid crystalline substance with a melting point 148-150oC, 71% yield.

EXAMPLE 72

2.5-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

2.5-debtor is lifelihood in accordance with the procedures described in Example 45. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain a solid crystalline substance with a melting point of 123-125oC, yield 62%.

EXAMPLE 73

2,3,4-trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

2,3,4-trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and 2,3,4-trichlorobenzaldehyde in accordance with the procedures described in Example 45. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain a solid crystalline substance with a melting point 110-113oC, 66%.

EXAMPLE 74

2,3-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

2,3-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and 2,3-dichlorobenzenesulfonyl in accordance with the procedures described in Example 45. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain a solid crystalline substance with a melting point 166-169oC, yield 75%.

EXAMPLE 75

2,5-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzolsulfonat the La and 2.5-dichlorobenzenesulfonate in accordance with the procedures described in Example 40b. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain a yellow powder with a melting point 148-150oC, yield 53%.

EXAMPLE 76

5-bromo-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

5-bromo-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and 5-bromo-2-methoxybenzenesulfonamide in accordance with the procedures described in Example 45. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain a solid crystalline substance with a melting point 192-195 (in Russian)oC, yield 61%.

EXAMPLE 77

2-bromo-N-(4-bromo-3-MathML-5-isoxazolyl)benzosulfimide

2-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and

2-bromobenzaldehyde in accordance with the procedures described in Example 45. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point of 84-86oC, 31%.

EXAMPLE 78

2-cyano-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

2-cyano-N-(4-b is melhorada in accordance with the procedures described in Example 45. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 152-155oC, yield 70%.

EXAMPLE 79

2,4,5-trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

2,4,5-trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and 2,4,5-trichlorobenzaldehyde in accordance with the procedures described in Example 45. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 179-182oC, yield 67%.

EXAMPLE 80

3,4-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

3,4-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and 3,4-dichlorobenzenesulfonate in accordance with the procedures described in Example 45. The crude product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain crystalline solid with a melting point 144-146oC, yield 60%.

EXAMPLE 81

3,4-dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide the Ola and 3,4 - dimethoxybenzenesulfonamide in accordance with the procedures described in Example 45. The resulting product was purified by recrystallization from a mixture of ethylacetat-hexane to obtain a crystalline substance, so pl. 136-138oC, yield 64%.

EXAMPLE 82

2,4-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide.

2,4-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and 2,4-dichlorobenzenesulfonyl in accordance with the procedure described in Example 45. The product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain a solid crystalline substance, so pl. 138-141oC, yield 46%.

EXAMPLE 83

N-(4-Iodine-5-methyl-3-isoxazolyl)benzosulfimide.

(a) 3-amino-4-iodine-5-methylisoxazol.

3-Amino-4-iodine-5 - methylisoxazol was obtained from 3-amino-5-methylisoxazole and N-iodosuccinimide as described in Example 50A, with 46% yield, and so pl. 115-117oC.

(b) N-(4-Iodine-5-methyl-3-isoxazolyl)benzosulfimide.

N-(4-iodine-5-methyl-3-isoxazolyl)benzosulfimide was obtained from 3-amino-4-iodine-5-methylisoxazole and benzosulfimide in accordance with the method described in Example 41b. The product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain a brown powder, so LASS="ptx2">

4-Nitro-N-(4-bromo-5-methyl-3-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and 4 - nitrobenzenesulfonamide in accordance with the procedure described in Example 40b. The product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain a light yellow-brown solid, so pl. 161-163oC, 55%.

EXAMPLE 85

3-Nitro-N-(4-bromo-5-methyl-3-isoxazolyl)benzosulfimide.

3-Nitro-N-(4-bromo-5-methyl-3-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and 3-nitrobenzenesulfonamide in accordance with the procedure described in Example 40b. The product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain a white powder, so pl. 137-139oC, yield 72%.

EXAMPLE 86

4-Trifluoromethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide.

4-Trifluoromethyl-N-(4-bromo-5-methyl-3-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and 4-triptime-diversalityjor in accordance with the procedure described in Example 45. The product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain a solid crystalline substance, so pl. 155-158oC, yield 72%.

the ω-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and 3-triptime-diversalityjor in accordance with the methodology described in Example 45. The product was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain a solid crystalline substance, so pl. 113-115oC, yield 83%.

EXAMPLE 88

2,5-Dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide.

2,5-Dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-methylisoxazole and 2.5-dimethoxybenzenesulfonamide in accordance with the procedure described in Example 45. The product was purified by recrystallization from a mixture of ethyl acetate - hexane to obtain a crystalline substance, so pl. 118-120oC, yield 58%.

EXAMPLE 89

N-(3,4-Dimethyl-5-isoxazolyl)-4-diphenylsulfone.

(a) 4-Diphenylsulfone.

4-Diphenylsulfone acid (3.0 g, 12.8 mm) was heated at 70oC with phosphorus oxychloride (1,30 ml, 14.0 M) for 2 h, the Excess phosphorus oxychloride was removed under reduced pressure. The residue was dissolved in ice water and was extracted with ethyl acetate. The extract was washed with 5% sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated to obtain 2.9 g of 4 - diphenylsulfone.

(b) N-(3,4-dimethyl-5-isoxazolyl)diphenylsulfone.

4-di is 4-(dimethyl) aminopyridine (5 mg) in dry pyridine (2 ml). This reaction mixture is stirred at room temperature for 4 h, the Pyridine was removed under reduced pressure, the residue was distributed between water and ethyl acetate. The organic layer is washed with 1N HCl (2 x 25 ml), a solution of salt (25 ml) and dried over anhydrous magnesium sulfate. After evaporation of the formed oily residue, which after purification using column chromatography on silica gel (1% methanol as additionally separated by) was obtained white solid in the amount of 337 mg (yield 45%). Upon recrystallization from a mixture of ethyl acetate-hexane obtained white crystalline substance, so pl. 154-155oC.

EXAMPLE 90

N-(4-Bromo-3-methyl-5-isoxazolyl)-4-diphenylsulfone.

(a) 5-Amino-4-bromo-3-methylisoxazole. 5-Amino-3-methylisoxazole (0,98 g, 10 mm) was dissolved in chloroform (15 ml) and cooled to 0oC. N-Bromosuccinimide (1.78 g, 10.0 mm) was added in small portions over 10 minutes In the next 10 min was continued stirring at 0oC. the Reaction mixture was diluted with chloroform (50 ml), washed with water (2 x 50 ml) and the organic layer was dried over magnesium sulfate. After removal of the solvent under reduced pressure got the product, which was purified by Colo the ω-3-methylisoxazole (1.55 g, yield 87%).

(b) N-(4-diphenylsulfone)-N-(4-bromo-3-methyl-5-isoxazolyl)- 4-diphenylsulfone.

5-Amino-4-bromo-3-methylisoxazole (0,179 g, 1.0 mm) was dissolved in dry pyridine (2 ml), 4-diphenylsulfone (0,509 g, 2.2 mm) was added under stirring at room temperature. Then was added N,N-dimethylaminopyridine (5 mg), and stirring was continued for 16 h at 50oC. This reaction mixture was diluted with dichloromethane (75 ml), washed with 1N HCl (2 x 50 ml), dried the organic phase over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain a product which after purification using column chromatography using a mixture of hexane-ethyl acetate (8:2) as additionally separated by, was obtained 0,390 g (60% yield) of N-(4-diphenylsulfone)-N-(4-bromo-3-methyl-5 - isoxazolyl)-4-diphenylsulfone.

(c) N-(4-Bromo-3-methyl-5-isoxazolyl)-4-diphenylsulfone.

N-(4-diphenylsulfone)-N-(4-bromo-3-methyl-5-isoxazolyl)-4 - diphenylsulfone (0,150 g, 0,233 mm) was dissolved in THF. Was added sodium hydroxide (0,120 g, 3.0 mm), the solution was heated to 45oC to dissolve the sodium hydroxide. Stirring was continued for 20 minutes THF was removed under reduced pressure. The remainder of restore is dried in vacuum to obtain N-(4-bromo-3-methyl-5-isoxazolyl)-4-diphenylsulfone (94% yield), which was further purified by recrystallization from a mixture of chloroform-hexane with so pl. 133-135oC.

EXAMPLE 91

N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-diphenylsulfone.

N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-diphenylsulfone was obtained in the same way as described in Example 90b of 5-amino-4-methyl-3-cryptomaterial and 4-diphenylacetonitrile with the release of 78%. Purification was achieved by recrystallization from methanol-water to obtain white solids, so pl. 139-140oC.

EXAMPLE 92

N-(4-Tridecyl-3-trifluoromethyl-5-isoxazolyl)-4-diphenylsulfone.

N-(4-Tridecyl-3-trifluoromethyl-5-isoxazolyl)-4-diphenylsulfone was obtained in the same way as described in Example 90b of 5-amino-4-tridecyl-3-cryptomaterial and 4-diphenylacetonitrile with the release of 81%. Purification was achieved by recrystallization from methanol-water to obtain not quite white solid substance, so pl. 115-116oC.

EXAMPLE 93

N-(3,4-Dimethyl-5-isoxazolyl)-2-dibenzofuransulfonate.

N-(3,4-Dimethyl-5-isoxazolyl)-2-dibenzofuransulfonate obtained in the same way as described in Example 89b of 5-amino-3,4-dimethylisoxazole and 2-benzofurazanyl with whom and cotton solids, so pl. 173-175oC (decomposition).

EXAMPLE 94

N-(4-Bromo-5-methyl-3-isoxazolyl)-4-diphenylsulfone,

(a) 3-Amino-4-bromo-5-methylisoxazol.

3-Amino-5-methylisoxazole (1,96 g, 20 mm) was dissolved in chloroform (10 ml) and cooled to 0oC. N-Bromosuccinimide (of 3.56 g, 20 mm) was added in small portions over 10 minutes Stirring continued next 15 min at 0oC. the Reaction mixture was diluted with chloroform (100 ml), washed with water (2 x 50 ml), the organic layer was dried over magnesium sulfate. After removal of the solvent under reduced pressure obtained semi-finished product, which was purified column chromatography, using as additionally separated by the mixture hexane-ethyl acetate (9: 1), to obtain 3-amino-4-bromo-5-methylisoxazole (1.4 g, yield 40%).

(b) N-[-(4-bromo-5-methyl-3-isoxazolyl)-4-diphenylsulfone.

N-(4-bromo-5-methyl-3-isoxazolyl)-4-diphenylsulfone was obtained using the method described in Example 89b, from 3-amino-4-bromo-5 - methylisoxazole and 4-diphenylacetonitrile with 5% yield. The product (so pl. 154-156oC) was isolated from 51% yield using column chromatography, recrystallization from a mixture of ethyl acetate-hexane. N-(4-diphenylsulfone)-N-(4-bromo-5-methyl-3 - isoxazolyl)-sulfonamide.

(a) 5-Amino-4-chloro-3-methylisoxazol.

Using the method described in example 90A, received 5-amino-4-chloro-3-methylisoxazol of 5-amino-3-methylisoxazole and N-chlorosuccinimide with 90% yield.

(b) N-(4-Chloro-3-methyl-5-isoxazolyl)-4-diphenylsulfone.

Suspended sodium hydride (188 mg, 4.4 mm) in dry THF (1 ml) and cooled to 0oC. With stirring was added a solution of 5-amino-4-chloro-3-methylisoxazol (mg mm) in dry THF (1 ml). After adding the whole, the mixture was heated to room temperature within 10 minutes Then the solution was again cooled to 0oC and added 4-diphenylsulfone (0,283 ml, 2.2 mm). Stirring is continued at 25oC for 2 h, the Excess sodium hydride was destroyed by adding methanol (0.4 ml) and then water (0.5 ml). THF was removed under reduced pressure, and the residue was dissolved in water (20 ml) and podslushivaet the addition of sodium hydroxide (pH 9-10). Neutral impurities were removed by extraction with ethyl acetate (2 x 10 ml). The aqueous layer was acidified to pH 2-3 using concentrated HCl, and was extracted with etilatsetatom (3 x 10 ml). The combined organic layers were dried over magnesium sulfate. After removal of the solvent was obtained N-(4-Chloro-3-methyl-5 - isoxazolyl)-4-given in the form of a white solid, so pl. 129-132oC.

EXAMPLE 96

4-tert-Butyl-N-(3,4-dimethyl-5-isoxazolyl)benzosulfimide.

4-tert-Butylbenzenesulfonamide (498 mg, 2,14 mm) and 4-(dimethyl)aminopyridine (5 mg) was added to a solution of 5-amino-3,4 - dimethylisoxazole (200 mg, 1,78 mm) in dry pyridine (2 ml). The reaction mixture was stirred at room temperature for 4 h, the Pyridine was removed under reduced pressure, and the residue was distributed between water and ethyl acetate. The organic layer is washed with 1 n HCl (2 x 25 ml), a solution of salt (25 ml) and dried over anhydrous magnesium sulfate. After removal of the solvent an oily residue remains, after purification column chromatography on silica gel using as additionally separated by 1% methanol in chloroform, was turned into a not-quite-white solid with a yield 320 mg (58%). Further purification was achieved by recrystallization from a mixture of ethyl acetate-hexane to obtain a white solid substance, so pl. 151-154oC.

EXAMPLE 97

An alternative method (see Example 90) to obtain N-(4-bromo-3 - methyl-5-isoxazolyl)-4-diphenylsulfone.

(a) N-(4-diphenylsulfone)-N-(4-bromo-3-methyl-5-isoxazolyl)-4 - diphenylsulfone.

5-Amino-4-bromo-3-methylisoxazole (0, ri room temperature. N,N- (Dimethyl)aminopyridine (5 mg) was added under stirring, and the stirring was continued for 16 hours at 50oC. the Reaction mixture was diluted with chloroform (75 ml), washed with 1 N. HCl (2 x 50 ml) and the organic layer was dried over magnesium sulfate. After removal of the solvent under reduced pressure obtained semi-finished product, which was purified by column chromatography using as additionally separated by the mixture hexane-ethyl acetate (8:2) to give N-(4-diphenylsulfone)-N-(4-bromo-3-methyl-5 - isoxazolyl)-4-diphenylsulfone (0,390 g, yield 60%).

(b) N-(4-Bromo-3-methyl-5-isoxazolyl)-4-diphenylsulfone.

N-(4-diphenylsulfone)-N-(4-bromo-3-methyl-5-isoxazolyl)-4 - diphenylsulfone (0,150 g, 0,233 mm) was dissolved in THF. Was added sodium hydroxide (0,120 g, 3.0 mm), the solution was heated to 45oC to dissolve the sodium hydroxide. Stirring was continued for 20 minutes THF was removed under reduced pressure. The residue was dissolved in water, cooled to 0oC and acidified to pH 3-4 with concentrated HCl. The solid precipitate was filtered and dried under vacuum to obtain N-(4-bromo-3-methyl-5-isoxazolyl)-4-diphenylsulfone (yield 94%) which was further purified by recrystallization from a mixture of chloroform-hexabenzocoronene.

N-(4,5,6,7-Tetrahydro-2,1-benzisoxazol-3-yl)benzosulfimide was obtained in the same way as described in Example 97, 3-amino-4,5,6,7-etrahydro-2,1-benzisoxazole and benzosulfimide with 55% yield. Purification was achieved by recrystallization from a mixture of ethyl acetate-hexane to obtain a white crystalline substance, so pl. 155-157oC.

EXAMPLE 99

N-(3,4-Dimethyl-5-isoxazolyl)-8-chinaincorporated.

N-(3,4-Dimethyl-5-isoxazolyl)-8-chinaincorporated was obtained as described for 4-tert-butyl-N-(3,4-dimethyl-5 - isoxazolyl)benzosulfimide (Example 96) with the release of 61%. Purification was achieved by column chromatography and recrystallization from a mixture of ethyl acetate-hexane to obtain a white solid crystalline substances, so pl. 176-178oC.

EXAMPLE 100

N-(4-Bromo-3-methyl-5-isoxazolyl)-8-chinaincorporated.

N-(4-Bromo-3-methyl-5-isoxazolyl)-8-chinaincorporated was obtained as described in Example 96 5-amino-4-bromo-3-methylisoxazole and 8-chinaincorporated with the release of 62%. Purification was achieved by recrystallization from a mixture of ethyl acetate-hexane to obtain a solid crystalline substance, so pl. 169-171oC.

EXAMPLE 101

N-(3,4-Dimethyl-5-isok is 49% yield as a white solid after column chromatography and recrystallization from a mixture of ethyl acetate-hexane, so pl. 135-137oC.

EXAMPLE 102

N-(3,4-Dimethyl-5-isoxazolyl)-(+)-10-camphorsulfonate.

This compound was obtained following the procedure described in Example 96 % yield as a white solid after column chromatography and recrystallization from a mixture of ethyl acetate-hexane, so pl. 137-139oC.

EXAMPLE 103

N-(3,4-Dimethyl-5-isoxazolyl)methanesulfonamide.

This compound was obtained following the procedure described in Example 96, 90% yield in the form of a solid after column chromatography, which was recrystallized from a mixture of ethyl acetate-hexane with the formation of colorless crystals, so pl. 125-127oC.

EXAMPLE 104

N-(3,4-Dimethyl-5-isoxazolyl)-TRANS-styrelseledamot.

This compound was obtained following the procedure described in Example 96, exit 48% in the form of a colorless crystalline solid substance after column chromatography and recrystallization from a mixture of ethyl acetate-hexane, so pl. 125-128oC.

EXAMPLE 105

2-Nitro-N-(3,4-dimethyl-5-isoxazolyl)- -- TRANS-styrelseledamot.

This compound was obtained following the procedure described in Example 96, exit 59% of 2-nitro-TRANS - storycontinued (see, n is isoxazole in the form of a colorless solid after column chromatography and recrystallization from a mixture of ethyl acetate - hexane, so pl. 108,5-111oC.

EXAMPLE 106

N-(5-Methyl-3-isoxazolyl)benzosulfimide.

3-Amino-5-methylisoxazole (0,196 g, 2.0 mm) was dissolved in dry pyridine (3 ml). Added benzosulphochloride (0,352 g, 2.0 mm), and the resulting solution was stirred at room temperature for 16 hours. The pyridine was removed under reduced pressure. The residue was dissolved in dichloromethane (75 ml) and washed with 1 n HCl (2 x 50 ml). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain N-(5-methyl-3-isoxazolyl) benzosulfimide (0.40 g, 84% yield). The product was purified by recrystallization from a mixture of ethyl acetate-hexane with the formation of a white solid substance, so pl. 107-108oC.

EXAMPLE 107

4 Benzylamino-N-(3,4-dimethyl-5-isoxazolyl)benzosulfimide.

To a mixture of 4-amino-N-(3,4-dimethyl-5-isoxazolyl)benzosulfimide (1.0 g, 3,74 mm) and sodium bicarbonate (310 mg, 4.48 mm), suspended in ethanol, was added benzylbromide (770 mg, 4.48 mm). After 10 min stirring at 70oC the mixture became homogeneous. The reaction mixture was stirred 2 h at 70oC, then the solvent and volatile components are evaporated under reduced pressure. The residue was dissolved in atratulus yellow viscous oil, which was subjected to chromatography on silica gel to obtain 960 mg of colorless oil (yield 72%). After further purification by HPLC was obtained a white solid substance, so pl. 47-48oC.

EXAMPLE 108

4-Dimethylamino-N-(3,4-dimethyl-5-isoxazolyl)benzosulfimide.

A solution containing 4-amino-N-(3,4-dimethyl-5-isoxazolyl) benzosulfimide (1.0 g, 3,74 mm), formic acid (1.1 mg, 22.4 mm) and a 37% solution of formaldehyde (0,65 ml, 8.97 mm) was heated at 40oC for 5 hours in an argon atmosphere. The reddish solution was cooled and neutralized with saturated sodium bicarbonate solution and was extracted with ethyl acetate (3 x 40 ml). The organic layer was washed with salt solution (2 x 20 ml). After drying over magnesium sulfate, evaporation of the solvent under reduced pressure and column chromatography on silica gel there was obtained a white solid substance, so pl. 152-154oC, 25%.

EXAMPLE 109

4 Ethylamino-N-(3,4-dimethyl-5-isoxazolyl)benzosulfimide.

Sodium borohydride (71 mg, 3.74 mm) was added to a solution of acetic acid (740 mg, 12 mm) in dry benzene (5 ml), keeping the temperature about 20oC. After stopped the release of hydrogen (about 5 min) was added 4-and what these lamps for 3 hours. The reaction mixture was cooled and shaken with saturated sodium bicarbonate solution. The organic layer was washed with salt solution (2 x 20 ml). After drying over magnesium sulfate, the solvent was evaporated, and the intermediate was purified column chromatography on silica gel using 1% solution of methanol in chloroform as additionally separated by obtaining 103 mg (19%) of colorless oil. After additional purification by HPLC was obtained a white solid substance so pl. 123oC.

EXAMPLE 110

4-Phenylethynyl-N-(3,4-dimethyl-5-isoxazolyl)benzosulfimide.

To a mixture of phenylacetylene (34.8 ml, 0.32 mm) and copper iodide (I) (0.25 mg) in diethylamine (2 ml), stir at room temperature was added 4-iodine-N-(3,4-dimethyl-5 - isoxazolyl)benzosulfimide (100 mg, 0.26 mm) and chloride bis(triphenylphosphine)palladium(11) (1.86 mg). The brown mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the yellow residue was extracted with 50 ml ethyl acetate. The organic extract was washed with a solution of 1 N HCl (2 x 20 ml) and salt (25 ml). After drying over magnesium sulfate, the solvent was evaporated and the resulting brown crystalline substance of chromatographically. By recrystallization from a mixture of ethyl acetate-hexane obtained white powder, so pl. 198-200oC (decomposition).

EXAMPLE 111

4-N'-(Ethoxycarbonylmethyl)ureido] -N-(3,4-dimethyl-5-isoxazolyl)- benzosulfimide.

4-Amino-N-(3,4-dimethyl-5-isoxazolyl)benzosulfimide (545 mg, 2.0 mm) was dissolved in dry dimethylformamide (10 ml). Added utilizationfocused (463 ml, 4.0 mm). The reaction mixture was stirred at room temperature for 3 h, and then further heated at 80oC for 8 hours. The dimethylformamide was removed under reduced pressure, the residue was recrystallized from a mixture of acetonitrile-water with getting 807 mg (yield 90%) of a brownish solid, so pl. 115-125oC.

EXAMPLE 112

4-[N-Cyclohexylamino] -N-(3,4-dimethyl-5-isoxazolyl)- benzosulfimide.

This compound was obtained from 4-amino-N-(3,4-dimethyl-5 - isoxazolyl)benzosulfimide and cyclohexylsulfamate in accordance with the procedure described in Example 110 with 75% yield. Further purification was achieved by preparative HPLC (yield 76%) to give the pure product as a white solid, so pl. 190 - 195oC.

EXAMPLE 113

4-(Dibenzosuberane)-N-(3,4-dimethyl-5-isoxazolyl) is ltname (545 mg, 2.0 mm) was dissolved in dry tetrahydrofuran (15 ml) and slowly added triethylamine (0.56 ml, 2.0 mm). The reaction mixture was stirred for 2 hours, the Solvent and volatile components were removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 N hydrochloric acid and dried over anhydrous magnesium sulfate. After removal of solvent the residue was recrystallized from methanol to obtain 610 mg (66% yield) yellow solid, so pl. 184oC.

EXAMPLE 114

4-(2,4-Dinitroaniline)-N-(3,4-dimethyl-5-isoxazolyl)- benzosulfimide.

2,4-Dinitrophenol (0.457 ml, 3.6 mm) and 4-amino-N-(3,4-dimethyl-5-isoxazolyl)benzosulfimide (818 mg, 3.0 mm) was dissolved in dry tetrahydrofuran (25 ml) and slowly added triethylamine (1.0 ml, 7.5 mm). The reaction mixture was stirred at room temperature for 48 hours, the Solvent and volatile components were removed under reduced pressure, the residue was distributed between 1N hydrochloric acid and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated, and the residue was recrystallized from methanol to obtain 1.1 g (yield 85%) of yellow solid, so pl. 187oC.

EXAMPLE 115

4-[(2,4-Diamino oxazolyl)- benzosulfimide (95 mg, 0.219 mm) was dissolved by heating in 60 ml of methanol. Was added 10% palladium on coal (8 mg), the mixture was hydrogenosomal at room temperature and pressure for 30 minutes, the Catalyst was removed by filtration through celite (Celite) and the filtrate was concentrated. The product was purified preparative HPLC to obtain 22 mg (yield 27%) of a white solid substance, so pl. 181-183oC.

EXAMPLE 116

N-13-Methyl-4-(4-methoxyphenoxy)-5-isoxazolyl]-benzosulfimide.

(a) 5-Amino-4-bromo-3-methylisoxazole.

5-Amino-3 - methylisoxazole (0.98 g, 10 mm) was dissolved in chloroform (15 ml) and cooled to 0oC. N-Bromosuccinimide (1.78, 10 mm) was added in small portions over 10 minutes, the Stirring was continued for 10 min at 0oC. the Reaction mixture was diluted with chloroform (50 ml), washed with water (2 x 50 ml) and the organic layer was dried over magnesium sulfate. After removal of the solvent under reduced pressure obtained semi-finished product, which was purified column chromatography, using as additionally separated by the mixture hexane-ethyl acetate (9: 1), to obtain 5-amino-4-bromo-3 - methylisoxazole (1.55 g, 87% yield).

(b) 5-Amino-4-(4-methoxyphenoxy)-3-methylisoxazol.

To a mixture of sodium hydride (60% dispersion in mineral is down at room temperature for 10 min was added 5-amino-4-bromo-3-methylisoxazole (0.2 g, 1.1 mm), and then bis(triphenylphosphine)palladium(II)chloride (79 mg, 0.11 mmol). The mixture was heated to 50oC for 2.5 h, then cooled to room temperature. The dark brown solution was treated with ethyl acetate and 5% NaOH. The organic layer was dried over magnesium sulfate, was filtered and was concentrated under reduced pressure. The residue was chromatographically on silica gel using 20% ethyl acetate in hexane, with the formation of 0.13 g (51% yield) of 5-amino-4-(4-methoxyphenoxy)- 3-methylisoxazole.

(c) N-[3-Methyl-4-(4-methoxyphenoxy)-5-isoxazolyl]-benzosulfimide.

This compound was obtained in accordance with the method described in Example 90, from benzosulfimide and 5-amino-4-(4 - methoxyphenyl)-3-methylisoxazole with the release of 94%. After column chromatography and recrystallization from a mixture of chloroform-hexane there was obtained a colorless solid, so pl. 128-130oC.

EXAMPLE 117

N-(4-Ethyl-3-trifluoromethyl-5-isoxazolyl)benzosulfimide.

N-(4-Ethyl-3-trifluoromethyl-5-isoxazolyl)benzosulfimide was obtained using the method described in example 90, from 5-amino-4-ethyl-3-cryptomaterial and benzosulfimide with the release of 72%. Purification was achieved by paracrystalline ethyl-3-trifluoromethyl-5-isoxazolyl)-1-naphthalenesulfonate.

N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-1-naphthalenesulfonate was obtained as described in Example 90 5-amino-4-methyl - 3-cryptomaterial and 1-naphthalenesulfonate with the release of 85%. Purification was achieved by recrystallization from methanol-water with the formation of white yarn with so pl. 154-155oC.

EXAMPLE 119

N-(4-Ethyl-3-trifluoromethyl-5-isoxazolyl)-1-naphthalenesulfonate.

N-(4-Ethyl-3-trifluoromethyl-5-isoxazolyl)-1-naphthalenesulfonate was obtained as described in Example 90, from 5-amino-4-ethyl-3 - cryptomaterial and 1-naphthalenesulfonate with the release of 70%. Purification was achieved by recrystallization from methanol-water with the formation of not-quite-white solid, so pl. 135-137oC.

EXAMPLE 120

N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-diphenylsulfone.

N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-diphenylsulfone was obtained as described in Example 90, from 5-amino-4-methyl-3-cryptomaterial and 4-diphenylacetonitrile with the release of 78%. Purification was achieved by recrystallization from a mixture of ethyl acetate-hexane with the formation of a white solid substance, so pl. 139-140oC.

EXAMPLE 121

N-(4-Hexyl-3-trifluoromethyl-5-isoxazolyl)benzols the Example 42, from 5-amino-4-hexyl-3 - cryptomaterial and benzosulfimide with yields of 80%. Purification was achieved by recrystallization of the intermediate product from a mixture of methanol-water with the formation of white yarn, so pl. 128.5-129oC.

EXAMPLE 122

N-(4-Nonyl-3-trifluoromethyl-5-isoxazolyl)benzosulfimide.

N-(4-Nonyl-3-trifluoromethyl-5-isoxazolyl)benzosulfimide was obtained as described in Example 42, from 5-amino-4-nonyl-3-methylisoxazole and benzosulfimide with the release of 87%. Purification was achieved by recrystallization from methanol-water with formation of a yellow solid, so pl. 101.5oC.

EXAMPLE 123

N-(4-Tridecyl-3-trifluoromethyl-5-isoxazolyl)benzosulfimide.

N-(4-Tridecyl-3-trifluoromethyl-5-isoxazolyl)benzosulfimide was obtained as described in Example 42 5-amino-4-tridecyl-3-methylisoxazole and benzosulfimide with 80% yield. Purification was achieved by recrystallization from methanol-water with formation of a yellow solid, so pl. 89oC.

EXAMPLE 124

N-(3-Cyclopropyl-4-methyl-5-isoxazolyl)benzosulfimide.

This compound was obtained as described in Example 42 5-amino-3-cyclopropyl-4-methylisoxazole and benzols izvetnogo oil.

EXAMPLE 125

N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)benzosulfimide.

This compound was obtained as described in Example 96, from 5-amino-4-methyl-3-cryptomaterial and benzosulfimide (see U.S. patent N 4,910,326 or the corresponding European patent A-0 220 947) yield 72%. Purification was achieved by recrystallization from a mixture of ethyl acetate-hexane to education is not quite white solid substance, so pl. 99.5-100oC.

EXAMPLE 126

N-(4-Ethyl-3-trifluoromethyl-5-isoxazolyl)benzosulfimide.

N-(4-Ethyl-3-trifluoromethyl-5-isoxazolyl)benzosulfimide was obtained as described in Example 42, from 5-amino-4-ethyl-3 - cryptomaterial and benzosulfimide with the release of 72%. Purification was achieved by recrystallization from a mixture of ethyl acetate-hexane with the formation of white fibers, so pl. 105-106.5oC.

EXAMPLE 127

N-(3-Ethyl-4-methyl-5-isoxazolyl)benzosulfimide.

N-(3-Ethyl-4 - methyl-5-isoxazolyl)benzosulfimide was obtained as described in Example 42, from 5-amino-3-ethyl-4-methylisoxazole and benzosulfimide with yield 68%. Purification was achieved by preparative HPLC with the formation of a white solid substance, so pl. 94-95oC.

EXAMPLE 128

Ospin)palladium (400 mg), Na2CO3(4 M, 80 ml, 320 mm) and phenylboric acid (3.81 g, 30.3 mm) in the form of a solution in ethanol (80 ml) was sequentially added to a solution of 2,3-dibromothiophene (7.33 g, 30,3 mm) in benzene (100 ml). The mixture was heated under reflux for 12 hours the Aqueous layer was removed, and the organic layer was diluted with ethyl ether (200 ml), washed with 1 N sodium hydroxide (2 x 150 ml), and dried over anhydrous magnesium sulfate, was filtered and the solvent was evaporated. The residue was chromatographically using hexane as additionally separated by, with the formation of 3-bromo-2 - forgiven in the form of a light oil (3.31 g, yield 47%).

Century 2-Phenylthiophene-3-sulforic.

n-Utility (2.38 M, 11.5 ml, 27.28 mm) was slowly added to a solution of 2-phenylthiophene (22.73 mm) in ether (50 ml) at 0oC. the Reaction mixture was stirred at this temperature for 1 h was Barbotirovany SO2through the mixture for 15 min at 0oC, after which was added NCS (3.95 g, 29.55 mm) in the form of a suspension in THF (20 ml). The intermediate was purified column chromatography (hexane) with the formation of 2-phenylthiophene-3-sulphonylchloride in the form of a white solid (1.23 g, yield 34%).

C. 2-Phenyl-N-(4-bromo-3-methyl-5-isoxazolyl)-3-thiophenesulfonyl.

2-Phenyl-N-(4-bromo-3-methyl-product was purified by HPLC with 77% yield as a reddish solid, so pl. 86-89oC.

EXAMPLE 129

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-pyridinesulfonamide.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2 - pyridinesulfonamide was obtained from pyridine-2-sulphonylchloride and 5-amino-4-bromo-3-methylisoxazole using the method of Example 1 (NaH/THF). Recrystallization from methanol gave a solid with a yield of 66%, and so pl. 184-189oC.

EXAMPLE 130

3 Phenoxy-N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide.

A. 3-Phenoxathiin.

The copper chloride (3.08 g, 31.1 mm) and phenol (8.78 g, 93.3 mm), was added to a solution of 3-bromothiophene (5.06 g, 31.1 mm) in pyridine (150 ml). Then slowly added sodium hydride (3.73 g, 93.9 mm, 60% dispersion in mineral oil). The reaction mixture was heated under reflux for 20 h in an argon atmosphere. The pyridine was removed under reduced pressure. The residue was diluted with ether (200 ml) and washed with 1 N NaOH (3 x 100 ml), 1 H HCl (2 x 150 ml) and 1 N NaOH (150 ml). The organic layer was dried over magnesium sulfate (MgSO4), was filtered, and the solvent was evaporated. The residue was chromatographically using hexane, to form a 3 - phenoxytoluene in the form of a clear oil (4.0 g, yield 74%).

Century 3-Phenoxathiin-2-sulphonylchloride.

Butelli the promo mixture was stirred at this temperature for 1 h Was barbotirovany S02through the mixture for 15 min at 0oC, after which was added NCS (3.95 g, 29.55 mm) in the form of a suspension in THF (20 ml). The mixture was gradually heated to 25oC and stirred at it for 2 more hours. The precipitate was filtered, the filtrate was concentrated and chromatographically (in hexane) with the formation of 3-phenoxathiin-2-sulphonylchloride in the form of a yellowish solid (1.03 g, yield 17%).

C. N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenoxathiin-2-sulfonamide.

N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenoxathiin-2 - sulfonamide was obtained from 3-phenoxathiin-2-sulphonylchloride and 5 - amino-4-bromo-3-methylisoxazole according to the method described in Example 1. The product was recrystallized from a mixture of acetonitrile-water with the formation of a solid substance, so pl. 121-123oC, yield 61%.

EXAMPLE 131

3-Phenylenecarbonyl-N-(3,4-dimethyl-5-isoxazolyl)pyridine-2 - sulfonamide.

Utility (1.8 ml, 2.34 M) was slowly added to a solution of N-(3,4-dimethyl-5-isoxazolyl)pyridine-2-sulfonamida (500 mg, 2.0 mm) in THF (14 ml) at -78oC. the Reaction mixture was stirred at this temperature for 1 h Then slowly added phenylisocyanate (3.55 mg, 2.9 mm), and the mixture was gradually heated to room temperature. The reaction of the Vali with ethyl acetate (2 x 50 ml). The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 (about 50 ml) and was extracted with ethanol (2 x 50 ml). The combined organic phases were dried over magnesium sulfate, was filtered and was evaporated with the formation of a yellow oil, which was purified by HPLC to yield 88%, so pl. 199-200oC.

EXAMPLE 132

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-isopropylphenyl) aminocarbonyl] thiophene-3-sulfonamide.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-isopropylphenyl) aminocarbonyl] thiophene-3-sulfonamide was obtained in the same way as described in Example 24 N-(4-bromo-3-methyl-5 - isoxazolyl)-2-(carboxy)thiophene-3-sulfonamida and 4 - isopropylaniline with 19% yield. The semi-product was passed through a column of silica gel, using ethyl acetate as additionally separated by. The substance was further purified by HPLC (5% to 100% acetonitrile over 30 min) with formation of a solid product.

EXAMPLE 133

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-sec - butylphenyl)aminocarbonyl] thiophene-3-sulfonamide.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-sec-butylphenyl) aminocarbonyl] thiophene-3-sulfonamide was obtained in the same way as described in Example 24 N-(4-bromo-3-methyl-5-isoxazolyl)-2- (carboxy)thiophene-3-sulfonamide is as additionally separated by. The substance was further purified by HPLC (5% to 100% acetonitrile over 30 min) with the formation of the solid product, so pl. 205-208oC.

EXAMPLE 134

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[-(4-tert-butylphenyl) aminocarbonyl] thiophene-3-sulfonamide.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-tert-butylphenyl) aminocarbonyl] thiophene-3-sulfonamide was obtained in the same way as described in Example 24 N-(4-bromo-3-methyl-5-isoxazolyl)-2- (carboxy)thiophene-3-sulfonamida and 4-tert-butylaniline with the release of 28%. The semi-product was passed through a column of silica gel, using ethyl acetate as additionally separated by. The substance was further purified by HPLC (5% to 100% acetonitrile over 30 min) with the formation of the solid product, so pl. 76-86oC.

EXAMPLE 135

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-butylphenyl) aminocarbonyl] thiophene-3-sulfonamide.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-butylphenyl) aminocarbonyl] thiophene-3-sulfonamide was obtained in the same way as described in Example 24 N-(4-bromo-3-methyl-5 - isoxazolyl)-2-(carboxy)thiophene-3-sulfonamida and 4-butylaniline with the release of 18%. The semi-product was passed through a column of silica gel, using ethyl acetate as additionally separated by. The substance was further purified BR>
N-(4-Bromo-3-methyl-5-isoxazolyl)-2-diphenylsulfone.

A. 2-diphenylsulfone.

2-Bromodiphenyl (2.33 g, 10 mm) was dissolved in ether (10 ml) and cooled to -78oC. n-Utility (2.5 M solution in hexane, 4.8 ml, 12 mm) was added dropwise under stirring and argon atmosphere. The resulting reaction mixture was stirred at a temperature of from -70 to -60oC for 1 h, the Reaction mixture was cooled to -78oC was added dropwise sulfurylchloride (0.88 ml, 11 mm). After the addition, the reaction mixture was gradually adopted to room temperature and stirred for another 1 h, the Reaction mixture was diluted with ethyl acetate (50 ml), washed with water, and the organic layer was dried over anhydrous magnesium sulfate. The removal of organic solvent under reduced pressure resulted in obtaining the intermediate product, which was purified by column chromatography, using hexane, then 5% ethyl acetate in hexane as additionally separated by, with the formation of 2-diphenylsulfone in the form of a solid (1.3 g, 51% yield).

Century T-(4-Bromo-3-methyl-5-isoxazolyl)-2-diphenylsulfone.

T-(4-Bromo-3-methyl-5-isoxazolyl)-2-diphenylsulfone was obtained in the same way as described in Example 2 from 5-AMI from a mixture of ethyl acetate-hexane to obtain a solid crystalline substance, so pl. 145-147oC.

EXAMPLE 137

T-(4-Chloro-3-methyl-5-isoxazolyl)-2-diphenylsulfone.

N-(4 - Chloro-3-methyl-5-isoxazolyl)-2-diphenylsulfone was obtained in the same way as described in Example 2 from 5-amino-4-chloro-3-methylisoxazole and 2-diphenylacetonitrile with yield 74%. Purification was achieved by recrystallization from a mixture of ethyl acetate-hexane to obtain a solid crystalline substance, so pl. 132-134oC.

EXAMPLE 138

N-(4-Bromo-3-methyl-5-isoxazolyl)-3-biphenylcarboxylic.

A. 3-Biphenylmethanol.

3-Bromodiphenyl (1.5 g, 6.4 mm) was dissolved in ether (15 ml) and cooled to -78oC. tert-Utility (1.7 M solution in hexane, 3.8 ml, 6.4 mm) was added dropwise under stirring and argon atmosphere. The resulting reaction mixture was stirred at a temperature of from -10 to -5oC for 6 hours, the Reaction mixture was cooled to -78oC and dropwise added sulfurylchloride (0.64 ml, 6.4 mm). After the reaction mixture was slowly taken at room temperature and stirred for another 1 h, the Reaction mixture was diluted with ethyl acetate (50 ml), washed with water, and the organic layer was dried over magnesium sulfate. After removal of the organic dissolved, the ATEM 5% ethyl acetate in hexane, to obtain 3-diphenylsulfone in the form of an oil (0.8 g, yield 49%).

C. N-(4-Bromo-3-methyl-5-isoxazolyl)-3-diphenylsulfone.

N-(4-Bromo-3-methyl-5-isoxazolyl)-3-diphenylsulfone was obtained in the same way as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 3-diphenylacetonitrile with the release of 22%. This substance was purified by HPLC (5% to 100% acetonitrile over 30 min) to obtain a solid substance, so pl. 78 -82oC.

EXAMPLE 139

N-(4-Chloro-3-methyl-5-isoxazolyl)-3-diphenylsulfone.

N-(4-Chloro-3-methyl-5-isoxazolyl)-3-diphenylsulfone was obtained in the same way as described in Example 2 from 5-amino-4-chloro-3 - methylisoxazole and 3-diphenylacetonitrile with the release of 63%. This substance was purified by HPLC (5% to 100% acetonitrile over 30 min) to obtain a solid substance, so pl. 84-86oC.

EXAMPLE 140

N-(4-Bromo-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide.

A. Thiazol-2-sulphonylchloride.

The thiazole (0.51 g, 6 mm) was dissolved in THF (5 ml) and cooled to -78oC in argon atmosphere. n-Utility (2.5 M solution in hexane, 2.4 ml, 6.0 mm) was added dropwise with constant stirring. Formed in the reactions is ing the mixture for 15 min at a temperature of -78oC. After the reaction mixture was slowly taken at room temperature and stirred for 30 minutes was Added NCS and continued stirring for 30 minutes the Reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (2 x 50 ml) and the combined organic phases were dried over magnesium sulfate. After removal of organic solvent under reduced pressure was obtained semi-finished product, which was purified column chromatography, using as additionally separated by hexane to obtain thiazol-2-sulphonylchloride liquid (0.6 g, yield 54%).

C. N-(4-Bromo-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide.

N-(4-Bromo-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide was obtained in the same way as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and thiazole-2-sulphonylchloride with the release of 57%. This substance was purified by HPLC (5% to 100% acetonitrile over 30 min) to obtain a solid substance, so pl. 175 - 177oC.

EXAMPLE 141

N-(4-Chloro-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide.

N-(4-Chloro-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide was obtained in the same way as described in Example 2 from 5-amino - 4-chloro-3-methylisoxazole and thiazole-2-sulphonylchloride with the release of 33%. This UP>oC.

EXAMPLE 142

N-(3,4-Dimethyl-5-isoxazolyl)thiazole-2-sulfonamide.

N-(3,4-Dimethyl-5-isoxazolyl)thiazole-2-sulfonamide was obtained in the same way as described in Example 14, from 5-amino-3,4 - dimethylisoxazole and thiazole-2-sulphonylchloride with the release of 37%. This substance was purified by HPLC (5% to 100% acetonitrile over 30 min) to obtain a solid substance, so pl. 118-120oC.

EXAMPLE 143

2-Benzyl-N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-5-sulfonamide.

A. 1-(2-Thienyl)benzyl alcohol.

2-benzoylthiophene (1.88 g, 10 mm) dissolved in methanol-THF (ratio 1: 10, 11 ml), was added sodium borohydride (0.37 g, 10 mm). Was stirred at room temperature for 10 hours, the Reaction mixture was decomposed by the addition of saturated solution of ammonium chloride (50 ml) and was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were dried over anhydrous magnesium sulfate. After removal of the solvent was obtained 1-(2-thienyl)benzyl alcohol in the form of a solid (1.75 g, yield 92%).

Century 2-Benzylthio.

Was added acetic anhydride (5 ml) to a solution of 1-(2-thienyl)benzyl alcohol in pyridine. The resulting solution was stirred at 70oC for 3 h Dobash 50 ml) and the combined organic layers were dried over anhydrous magnesium sulfate. After removal of the solvent obtained semi-finished product, which was purified by passing through silica gel, using as additionally separated by the mixture hexane-ethyl acetate (3:1), thus obtained 1-(2-thienyl)benzoylacetate.

A solution of 1-(2-thienyl)benzoylacetate in THF (5 ml) was carefully added to anhydrous liquid ammonia (100 ml). Metallic lithium was added in small portions to get a stable blue solution. The reaction mixture is stirred 30 min, the reaction was stopped by addition of solid ammonium chloride. After complete evaporation of the liquid ammonia the residue was dissolved in water (50 ml) and was extracted with methylene chloride (2 x 50 ml). The combined organic layers were dried over magnesium sulfate and filtered. After removal of the solvent was obtained semi-finished product, which was purified by column chromatography, using as additionally separated by hexane, to receive 2-benzoylthiophene (1.2 g, yield 68%).

C. 5-Benzylthio-2-sulphonylchloride.

To a solution of 2-benzoylthiophene (0.875 g, 5 mm) in chloroform (2 ml) was added at 0oC dropwise chlorosulfonic acid, the reaction mixture was stirred at 0oC 30 minutes the Reaction mixture was dissolved, pouring on ice chips (20 g). A mixture of ex is m pressure with the formation of 5-benzylthio-2 - sulfonic acid.

Pentachloride phosphorus (2.08 g, 40 mm) was added to a solution of 5-benzylthio-2-sulfonic acid in phosphorus oxychloride (6.0 g, 40 mm) at 0oC. the Reaction mixture was stirred at a temperature of 50oC 1 h, cooled to room temperature, then poured on ice chips (50 g) and extracted with ethyl acetate (2 x 30 ml). After removal of the solvent under reduced pressure was obtained semi-finished product, which was purified by column chromatography, using as additionally separated by 3% ethyl acetate in hexane, to receive 2-benzylthio-5-sulphonylchloride (0.6 g, yield 39%).

D. 5-Benzyl-N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide.

5-Benzyl-N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide was obtained in the same way as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-benzyl-2-thiophenesulfonyl with the release of 22%. The product was purified by HPLC (5% to 100% acetonitrile over 30 min) to obtain a solid substance, so pl. 49-50oC.

EXAMPLE 144

3-Phenethyl-N-(4-bromo-3-methyl-5-isoxazolyl)titsn-2-sulfonamide.

A. 1-(3-Thienyl)finitely alcohol. Benzylbromide (25.65 g, 150 mm) dissolved in ether (30 ml) was added dropwise over 8 h to a suspension of magnesium (3.6 g is in 30 min, and the resulting reaction mixture was stirred at room temperature for 6 hours Then it was cooled to 0oC, and was dissolved by adding 0.1 N hydrochloric acid. Separated ether layer, and the aqueous phase was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were dried over magnesium sulfate and filtered. After removal of the solvent was obtained 1-(3-thienyl)finitely alcohol (16 g, yield 78%).

C. 1-(3-Thienyl)ventilated.

1-(3-thienyl)finitely alcohol (10 g, 49 mm) was dissolved in 50 ml of a mixture of pyridine-acetic anhydride (2:1). The solution was stirred at 80oC 4 h Excess pyridine and acetic anhydride were removed under reduced pressure, and the residue was dissolved in water (100 ml). Were extracted with methylene chloride (3 x 75 ml) and the combined organic layers were dried over magnesium sulfate and was filtered. After removal of the solvent was obtained 1-(3-Thienyl)ventilated (10.2 g, yield 84%).

C. 3-Penetrtion.

1-(3-Thienyl)ventilated dissolved in THF (20 ml) was carefully added to anhydrous liquid ammonia (300 ml). Metallic lithium was added in small portions to get a stable blue solution. The reaction mixture is stirred 30 min, the reaction osteal in water (100 ml) and was extracted with methylene chloride (4 x 50 ml). The combined organic layers were dried over magnesium sulfate and filtered. After removal of the solvent was obtained semi-finished product, which was purified by column chromatography, using as additionally separated by hexane, and then a mixture of ethyl acetate with hexane, it was obtained 3-penetrtion (3.2 g, yield 34%) and 1-(3-thienyl)ventilated (starting material, 7 g).

D. 3-Penetrtion-2-sulphonylchloride and 4-penetrtion-2 - sulphonylchloride.

3-penetrtion (0.94 g, 5 mm) was dissolved in THF (12 ml) and cooled to -78oC in argon atmosphere. n-Utility (2.5 M solution in hexane, 4.4 ml, 5.5 mm) was added dropwise with constant stirring in an argon atmosphere. The resulting reaction mixture was stirred at a temperature of from -10 to 0oC for 3 h, cooled to -78oC, barbotirovany sulfur dioxide through the reaction mixture for 15 minutes then the reaction mixture was slowly taken at room temperature and stirred for 30 minutes was Added NCS (1 g) and continued stirring 1 h, the Reaction mixture was diluted with water (50 ml), extracted with methylene chloride (2 x 50 ml) and the combined organic phase was dried over anhydrous magnesium sulfate. After removal of the solvent under ponizhennye 0.2% ethyl acetate in hexane, with 3-phenethyl-2-thiophenesulfonyl (0.06 g, yield 4%) and 4-phenethyl-2-thiophenesulfonyl (0.72 g, yield 45%).

E. 3-Phenethyl-N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2 - sulfonamide.

3-Phenethyl-N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide was obtained in the same way as described in Example 2 from 5 - amino-4-bromo-3-methylisoxazole and 3-phenethyl-2 - thiophenesulfonyl with the release of 48%. This substance was purified by HPLC (5% to 100% acetonitrile over 30 min) to obtain a solid substance.

EXAMPLE 145

4-Phenethyl-N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide.

4-Phenethyl-N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide was obtained in the same way as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 4-phenethyl-2-thiophenesulfonyl with the release of 32%. This substance was purified by HPLC (5% to 100% acetonitrile over 30 min) to obtain the resinous substance.

EXAMPLE 146

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene-2 - sulfonamide.

A. 5-Bromothiophene-2-sulphonylchloride.

Was added dropwise chlorosulfonic acid over 20 min to a cooled to -78oC to a solution of 2-bromothiophene (16.3 g, 100 mm) in methylene the military took at room temperature (2 h), then it poured dropwise in an ice powder (1000 g), and extracted with methylene chloride (4 x 100 ml). The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure to obtain intermediate. It was purified by column chromatography, using as additionally separated by hexane, to obtain 5-bromo thiophene-sulphonylchloride (22 g, yield 75%).

C. N-(5-Bromothiophene-2-sulfonyl)pyrrole.

N-(5-Bromothiophene-2 - sulfonyl)pyrrole was obtained in the same way as described in Example 33a, from 5-bromothiophene-2-sulphonylchloride and pyrrole with the release of 88%. The substance was purified by recrystallization in a solvent of hexane-ethyl acetate.

C. 3-Methoxyflavone acid.

3-Methoxyflavone acid was obtained by the method described in Example 33B, 3-bromoanisole and triisopropylsilane with the release of 82%. This substance was used in the next stage without additional purification.

D. N-[5-(3-Methoxyphenyl)typei-2-sulfonyl]pyrrole.

N-[5-(3-Methoxyphenyl)thiophene-2-sulfonyl] pyrrole was obtained by the method described in Example 32C, 3 methoxyflavone acid and N-(5-bromothiophene-2-sulfonyl)of pyrrole with the release of 93%. This substance is xifei)thiophene-2-sulphonylchloride.

To a suspension of N-[5-(3-Methoxyphenyl)thiophene-2-sulfonyl]pyrrole (1.4 g, 4.5 mm) in ethanol (15 ml) was added 6 N sodium hydroxide solution (15 ml) was boiled under reflux for 14 hours. The reaction mixture was cooled to room temperature. The ethanol was removed under reduced pressure, the resulting residue was filtered and dried under vacuum (1.1 g, yield 91%).

Pentachloride phosphorus (2.08 g, 10 mm) was added to a suspension of sodium salt of sulfonic acid (0.62 g, 2.5 mm) obtained at the previous stage, in phosphoroxychloride (0.93 ml, 10 mm), and the resulting reaction mixture was stirred at room temperature for 3 hours the Reaction mixture was decomposed by adding ice chips, and were extracted with methylene chloride (2 x 50 ml). The combined organic layers were dried over magnesium sulfate and filtered. After removal of the solvent was obtained semi-finished product, which was purified by column chromatography, using as additionally separated by 2% ethyl acetate in hexane, to receive 5-(3-methoxyphenyl)thiophene - 2-sulphonylchloride (0.51 g, yield 75%).

EXAMPLE 147

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene-2 - sulfonamide.

N- (4-Bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene-2 - toxigenic)thiophene - 2 - sulphonylchloride with the release of 48%. After purification by HPLC (5% to 100% acetonitrile over 30 min) obtained solid substance.

EXAMPLE 148

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-2 - sulfonamide.

A. 4-Ethoxyphenylurea acid.

4-Ethoxyphenylurea acid was obtained by the method described in Example 33B, 4-bromoanisole and triisopropylsilane exit 69% of This substance was used in the next stage without additional purification.

C. N-[5-(4-Methoxyphenyl)thiophene-2-sulfonyl]pyrrole.

N-[5-(4-Methoxyphenyl)thiophene-2-sulfonyl] pyrrole was obtained by the method described in Example 32C from 4-ethoxyphenylurea acid and N-(5-bromothiophene-2-sulfonyl)of pyrrole with a quantitative yield. This substance was recrystallized from a mixture of hexane-ethyl acetate.

C. 5-(4-Methoxyphenyl)thiophene-2-sulphonylchloride

5-(4-Methoxyphenyl)thiophene-2-sulphonylchloride was obtained in the same way as described in Example A, from N-[5-(4 - methoxyphenyl)thiophene-2-sulfonyl]pyrrol exit 77%.

EXAMPLE 149

1,2-TRANS-dimethylstyrene(3,4-dimethyl-5-isoxazolyl)-2-sulfonamide.

1,2-TRANS-dimethylstyrene(3,4-dimethyl-5-isoxazolyl)-2-sulfonamide was obtained according to the method described in example 14, and is cromatografia (30% ethyl acetate in hexane) and recrystallization from a mixture of chloroform - hexane received 79 mg (yield 14%) of light yellow crystals, so pl. 164-166oC.

EXAMPLE 150

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-thienyl)thiophene-2-sulfonamide.

A. 3-Tithebarn acid.

To a solution of 3-bromothiophene (8.15 g, 50 mm) in THF (20 ml) at - 78oC in argon atmosphere was added dropwise n-utility (2.5 M solution in hexane, 20 ml, 50 mm), the resulting solution was stirred at a temperature of - 78oC for 45 minutes This solution was added to a solution of triisopropylsilane (9.4 g, 50 mm) in THF at -78oC for 30 min through a steel capillary. The resulting reaction mixture was stirred at room temperature for 12 h, and then decomposing the reaction mixture by addition of 100 ml of 1 N hydrochloric acid. The aqueous layer was extracted with ether (2 x 100 ml) and the combined organic layers were extracted with 1 M sodium hydroxide (3 x 30 ml), aqueous extracts were acidified with concentrated hydrochloric acid to pH 2 and extracted with ether (3 x 50 ml). The combined ether extracts once washed with water, dried over magnesium sulfate and filtered. After removal of the solvent was obtained 3-tienerporno acid as a solid (5.2 g, yield 80%).

C. N-[5-(3-Thienyl)thiophene-2-sulfonyl]pyrrole.

N-[5-(3-Thienyl)thiophene-2-sulfonyl]pyrrole was obtained JV is output. This substance was recrystallized from a mixture of hexane-ethyl acetate.

C. 5-(3-Thienyl)thiophene-2-sulphonylchloride.

5-(3-Thienyl)thiophene-2-sulphonylchloride was obtained according to the method described in Example A, from N-[5-(4-methoxyphenyl)thiophene-2-sulfonyl]pyrrole to yield 74%.

D. N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-thienyl)thiophene-2 - sulfonamide.

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-thienyl)thiophene - 2-sulfon-amide ball obtained by the method described in Example 2 from 5 - amino-4-bromo-3-methylisoxazole and 5-(3-thienyl)thiophene-2 - sulphonylchloride with the release of 40%. The substance was purified by HPLC (5% to 100% acetonitrile over 30 min) with the formation of solids.

EXAMPLE 151

1,2-CIS-Dimethylstyrene(3,4-dimethyl-5-isoxazolyl)-2-sulfonamide.

A. CIS - and TRANS - 1,2-Dimethylethanol-2-sulphonylchloride.

CIS - and TRANS-2-Bromo-1,2-dimethylethanol (2.61 g, 12.4 mm) was added to a mixture of magnesium (0.9 g, 37.1 mm) in dry ether (40 ml). The reaction mixture was stirred 18 hours at room temperature, then was passed through the reaction vessel and sulfur dioxide. The ether was removed by distillation, the resulting brown residue was stirred in 40 ml of methylene chloride, then was added NCS (1.82 g, 13.6 mm). The reaction mixture was stirred 1 h at s layer was dried over magnesium sulfate, was filtered and concentrated. Using high-speed chromatography (5% ethyl acetate in hexane) received 0.269 g (yield 9%) of the CIS isomer and 0.563 g (yield 20%) of TRANS-isomer.

C. 1,2-CIS-Dimethylstyrene(3,4-dimethyl-5-isoxazolyl)-2-sulfonamide

1,2-CIS-Dimethylstyrene(3,4-dimethyl-5-isoxazolyl)-2-sulfonamide was obtained according to the method described in example 14, from 3,4-dimethyl-5-aminoisoquinoline (0.105 g, 0.94 mm) and CIS-1,2-dimethylethanol-2-sulphonylchloride (0.26 g, 1.13 mm). Using high-speed chromatography (30% ethyl acetate in hexane) and recrystallization from a mixture of chloroform-hexane obtained 37 mg (yield 13%) of white crystals, so pl. 122.5-124oC.

EXAMPLE 152

1-Fenestral(3,4-dimethyl-5-isoxazolyl)-2-sulfonamide

A. 1,1-Diphenylether-2-sulphonylchloride.

1,1 Diphenylether (11.3 mm, 2 ml) was added to a solution of DMF (22.7 mm, 1.75 ml) and sulfurylchloride (19.3 mm, 1.55 ml) at 0o. The solution was heated at a temperature of 90oC 4 hours, then cooled to room temperature and poured into ice (500 ml). The aqueous phase was extracted with ethyl acetate (2 x 100 ml). Then the organic layer was dried over magnesium sulfate, filtered and concentrated. Using high-speed chromatography (5% ethyl acetate-hexane) was obtained 0.92 g (yield 29%) light gelter-5-isoxazolyl)-2-sulfonamide was obtained according to the method, described in Example 14, from 3,4-dimethyl-5 - aminoisoquinoline (0.168 g, 1.5 mm) and 1,1-diphenylether-2 - sulphonylchloride (0.502 g, 1.8 mm). Using high-speed chromatography (30% ethyl acetate-hexane) received 133 g of light brown crystals, so pl. 159.5-161oC.

EXAMPLE 153

A. 2.5-Dimethylfuran-3-sulphonylchloride.

Stirred DMF (2.2 ml, 28 mm) and sulfurylchloride (1.9 ml, 24 mm) at 0oC for 30 min, and then was slowly added 2.5-dimethylfuran (1.5 ml, 14 mm). The reaction mixture was heated to 60oC for 30 min, then cooled to room temperature and poured into ice water (200 ml). The aqueous layer was extracted with ethyl acetate (100 ml) then the organic layer was dried over magnesium sulfate., was filtered and concentrated, and collected 0.69 g of brown liquid. Using high-speed chromatography (5% ethyl acetate in hexane) received 0.607 g (yield 22%) of a yellow liquid.

Century Furan-2-sulphonylchloride.

Furan-2-sulphonylchloride was obtained according to the method described in Example 1 from 4-bromo-3-methyl-2-aminoethanethiol (0.354 g, 1.0 mm), sodium hydride (60 dispersion in oil) (200 g, 5.0 mm) and 2,5-dimethylfuran-3-sulphonylchloride (0.467 g, 2.4 mm). Using high-speed chromatography (5% methyl alcohol in chloroform) and perakis the

C. N-(4-Bromo-3-methyl-5-isoxazolyl)furan-2-sulfonamide.

N-(4-Bromo-3-methyl-5-isoxazolyl)furan-2-sulfonamide was obtained by the method described in example 1 from 4-bromo-3-methyl-2 - aminoethanethiol (0.266 g, 1.5 mm), sodium hydride (60% dispersion in oil) (0.15 g, 3.8 mm) and furan-2-sulphonylchloride (0.30 g, 1.8 mm). Using high-speed chromatography (50% ethyl acetate in hexane) and recrystallization from chloroform and hexane received 90 g (yield 20%) of light yellow crystals, so pl. 117-119oC.

EXAMPLE 154

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2-sulfonamide

A. 2-Phenylthiophene.

Added tert-utility (1.7 M, 10 ml, 1.7 mm) to a solution of furan (1.24 ml, 17 mm) in 20 ml of THF at -60oC. After 30 min was added through a capillary solution diphenyldisulfide (3.7 g, 17 mm) in 8 ml THF. The reaction mixture was aged at room temperature for 30 min, then was diluted with 150 ml of ether and was washed with 3% sodium hydroxide (3 x 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated, collected 2.92 g (yield 97%) of a light yellow liquid.

Century 5-Phenylthiophene-2-sulphonylchloride.

5-Phenylthiophene-2-sulphonylchloride was obtained according to the method described in example 34A, 5-phenylthiophene (who hexane) received 1.61 g (yield 69%) of an orange-yellow liquid.

C. N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2 - sulfonamide.

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2-sulfonamide was obtained according to the method described in example 1 from 4-bromo-3-methyl-2 - aminoethanethiol (0.354 g, 2.0 mm), sodium hydride (60% dispersion in oil) (0.20 g, 5.0 mm) and 5-phenylthiophene-2-sulphonylchloride (0.66 g, 2.4 mm). Using high-speed chromatography (50% ethyl acetate in hexane) and recrystallization from a mixture of chloroform and hexane were obtained 82 mg (yield 10%) of brownish crystals, so pl. 90-91.5oC.

EXAMPLE 155

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-phenylfuro-2-sulfonamide.

A. 2-Phenylfuro.

2 - Phenylfuro was obtained according to the method described in example 32C from 2-bromofuran (0.93 g, 6.3 mm), sodium carbonate (18 ml of 2 M aqueous solution), phenylboric acid (0.93 g, 7.6 mm) and tetrakis(triphenylphosphine)palladium (0) (0.36 g, 0.32 mm). Using high-speed chromatography in hexane received 0.79 g (yield 87%) as a colourless liquid.

Century 5-phenylfuro-2-sulphonylchloride.

5-Phenylfuro-2-sulphonylchloride was obtained by the method described in example 34A, from 2-phenylbutane (0.79 g, 5.5 mm), tert-utility (1.7 M, 6.0 mm, 3.6 ml) and NCS (0.73 g, 5.5 mm). Using high-speed chromatography (50% ethyl acetate in hexa-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-phenylfuro-2-sulfonamide was obtained by the method described in Example 1 from 4-bromo-3-methyl-2 - aminoethanethiol (0,354 g, 2.0 mm), NaH (60% dispersion in oil) (0.20 g, 5.0 mm), and 5-phenylfuro-2-sulphonylchloride (of 0.58 g, 2.4 mm). After high-speed chromatography (50% ethyl acetate in hexane) and recrystallization from a mixture of CHCl3- hexane got to 0.23 g (yield 29%) of light yellow crystals (so pl. 124-126oC).

EXAMPLE 156

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-isopropylphenyl)Thiophene-2 - sulfonamide.

A. 4-Isopropylaniline acid.

4-Isopropylaniline acid was obtained by the same method as described in Example 33B, from 1-bromo-4-ethylbenzene. Boric acid was isolated as a white powder in 63% yield, so pl. 133 - 135oC.

C. N-(Pyrrole)-5-(4-isopropylphenyl)tifa-2-sulfonamide.

N-(Pyrrole)-5-(4-isopropylphenyl)thiophene-2-sulfonamide was obtained by the method described in Example 33, 4 - isopropylaniline acid and N-(5-bronchiopulmonar)pyrrole. After purification using column chromatography using as additionally separated by 10% ethyl acetate in hexane got the pure sulfonamide as not quite white colored solid with waterfeel)thiophene was obtained by the method described in Example 33D. Hydrolysis of 526 mg (1.59 mm) of N-(pyrrole)-5-(4-isopropylthio)-2-sulfonamida with 6 N sodium hydroxide, followed by chlorination using phosphorus oxychloride and pentachloride phosphorus was obtained the crude sulphonylchloride in the form of a dark oil. Using high-speed chromatography on silica gel in 2% solution of ethyl acetate in hexane received 262 mg (55%) of pure sulphonylchloride in the form of a light brown oil.

D. N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-isopropylphenyl)thiophene - 2-sulfonamide.

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4 - isopropylphenyl)thiophene-2-sulfonamide was obtained according to the method described in example 2. The reaction of 5-chlorosulfonyl-2-(4 - isopropylphenyl)thiophene (260 mg, 0.87 mm) with 5-amino-4-bromo-3 - methylisoxazole (161 mg, 0.91 mm) led after high-speed chromatography in a 10% solution of methanol in chloroform to obtain 265 mg of a brown solid substance, which then was purified by HPLC with net education sulfonamida in the form of a light brown solid substance, so pl. 114-116oC.

EXAMPLE 157

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-propylphenyl)thiophene-2 - sulfonamide.

A. 1-Bromo-4-propylbenzoyl.

A solution of 1-bromopropane (1.32 to Etu, in order to maintain a light boil under reflux. The turbid suspension was kept at room temperature for another 30 min for the formation of gray solution, which was then added dropwise within 15 min to a mixture of 1-iodine-4 - bromine benzol (3.0 g, 10.6 mm) and tetrakis(triphenylphosphine)palladium (0) in 50 ml of dry benzene at room temperature. The mixture was stirred for 2 hours, diluted with 50 ml water, the organic layer was separated, and the aqueous layer was extracted with ether (2 x 50 ml). The combined organic extracts were dried, the solvent evaporated and got 1.69 g (80%) of a light brown oil, which was used in the next stage without additional purification.

Century 4-Propylaniline acid.

To a suspension of magnesium turnings (217 mg, 8.9 mm) in 3 ml of dry THF in an argon atmosphere with a solution of 4-bromopropylate (1.69 g, 8.5 mm) in 6 ml of THF were added crystals with such a rate as to maintain a light boil under reflux. The solution was boiled under reflux for another 0.5 h, cooled to room temperature and was added after 10 min parts to the solution trimethylborane (924 mg, 8.9 mm), pre-dissolved in 4 ml of dry ether at -78oC. After 30 min the solution was heated up to the l of 10% hydrochloric acid. THF was removed under reduced pressure, the residue was extracted with diethyl ether (3 x 25 ml). The combined ether extracts were extracted with 1 M sodium hydroxide solution (3 x 25 ml), and the resulting aqueous layer was acidified to pH 2.0 using 6 N hydrochloric acid, then was extracted with diethyl ether (3 x 25 ml). The combined organic layers were washed with water (I ml), a solution of salt (g ml) and dried over magnesium sulfate. After evaporation of the solvent remained brown solid substance was filtered through a small layer of silica gel, using an 11% solution of methanol in chloroform. After evaporation of solvent received 448 mg (32%) brown solid substance, so pl. 90 - 93oC.

C. N-(Pyrrole)-5-(4-propylphenyl)thiophene-2-sulfonamide.

N-(Pyrrole)-5-(4-propylphenyl)thiophene-2-sulfonamide was obtained by the method described in Example 33, 4-propylaniline acid and N-(5-bronchiopulmonar)pyrrole. After purification using column chromatography using as additionally separated by 10% ethyl acetate in hexane got the pure sulfonamide as a white solid with a 55% yield, so pl. 106-108oC.

D. 5-Chlorosulfonyl-2-(4-propylphenyl)thiophene.

5-Chlorallyl)-2-sulfonamida with 6 N sodium hydroxide, followed by chlorination using phosphorus oxychloride and pentachloride phosphorus was obtained the crude sulphonylchloride in the form of a greenish-brown oil. Using high-speed chromatography on silica gel in 2% solution of ethyl acetate in hexane received 83 mg (81%) of pure sulphonylchloride in the form of a light yellow oil.

E. N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-propylphenyl)thiophene - 2-sulfonamide.

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-propylphenyl)thiophene-2 - sulfonamide was obtained according to the method described in example 2. The reaction of 5-chlorosulfonyl-2-(4-isopropylphenyl)thiophene (260 mg, 0.87 mm) with 5-amino-4-bromo-3-methylisoxazole (161 mg, 0.91 mm) led after high-speed chromatography in a 10% solution of methanol in chloroform to obtain 76.1 mg brown solid substance, which then was purified by HPLC with net education sulfonamida in the form of a light brown oil.

EXAMPLE 158

Methods of identifying compounds that have the activity of the antagonist and/or agonist endothelin.

Compounds that are potential endothelin antagonists identified by their ability to compete with125I-labelled endothelin-1 binding is aktivnosti tested compound as an antagonist or agonist of the biological response of endothelin tissue can also be evaluated by measuring the effect on endothelin-induced contraction of isolated rings of thoracic aorta of the rat. The ability of compounds to act as antagonists or agonists ETBreceptors can be assessed by testing the ability of compounds, which should inhibit induced endothelin-1 secretion of prostacyclin from the culture of endothelial cells bovine aorta.

A. Inhibition of binding of endothelin-Test link # 1:

Inhibition of binding with ETA-receptors.

Cells are THOSE 671 (ATCC Catalog N HTB 139) Express ETA-receptors. These cells were grown to confluence in flasks T-175. Cells from multiple flasks were collected by scraping, were combined and centrifuged for 10 min at 190 g. Cells are again suspended in phosphate buffer (PBS) containing 10 mm EDTA, using a homogenizer Tenbroek. The suspension was centrifuged at 4oC and speed 57800 g for 15 min, the precipitate is again suspended in 5 ml of buffer A (5 mm HEPES buffer, pH 7.4 containing Aprotinin (100 KIU/ml) and then once frozen and thawed. Added 5 ml of buffer B (5 mm HEPES buffer, pH 7.4, containing 10 mm MnCl2and 0.001% deoxyribonuclease 1st Type), the suspension was mixed by inversion and then incubated at 37oC for 30 minutes the Mixture centrifusion HEPES-buffer, pH 7.4 containing Aprotinin (100 KIU/ml), and received the final concentration of protein in solution 2 mg/ml, which was stored at -70oC before use.

The membrane suspension was diluted with buffer, which examined the binding (30 mm HEPES, pH 7.4, containing 150 mm sodium chloride, 5 mm MgCl2, 0.5% bacitracin), to a concentration of 8 µg/50 µl. 125I-labeled Endothelin-1 (3000 cpm, 50 ml) was added to 50 μl of either (A) endothelin-1 (for nonspecific binding) to obtain the final concentration equal to 80 nm, or (C) "linking" of buffer (for total binding), or (C) of the investigated compounds (final concentration from 1 nm to 100 μm). To each of solutions (A), (B), (C) was added to the membrane suspension (50 μl) containing 8 μg of membrane protein. The mixture was stirred and incubated at 4oC for 16-18 hours, and then centrifuged at 4oC for 25 min at 2500g. The supernatant, containing unbound radioactivity, decantation, and the residue was placed in a counter - radiation. The degree of inhibition of binding (D) was calculated by the following formula:

D (%)= 100 - {[(C)-(A)] 100/(B)-(A)}

Each experiment was repeated three times.

C. Inhibition of binding of endothelin - Test link # 2:

Ingibiruet. Received cells that expressed human ETBthe receptor were grown to confluence in flasks T-150. Membranes were prepared as described above. The experiment of binding was performed as described above using preparation of membranes diluted "linking" buffer to a concentration of 1 μg/50 μl.

Briefly summarizing, COS7 cells, described above, which were infected with the DNA that encodes ETB-receptor and expressing human ETB-receptor on their surface, were grown to confluence in flasks T-175. Cells from all flasks were collected by scraping, combined and centrifuged for 10 min at 190g. Cells resuspendable in phosphate buffer (FB) containing 10 mm EDTA, using a homogenizer Tenbroek. The suspension was centrifuged at 4oC when 57800g for 15 min, the precipitate is re-suspended in 5 ml of buffer A (5 mm HEPES, pH 7.4 containing Aprotinin (100 KIU/ml), and once frozen and thawed. Added five ml of buffer B (5 mm HEPES, pH 7.4, containing 10 mm MnCl2and 0.001% dnaase 1st Type), the suspension was mixed by inverting, and then incubated at 37oC for 30 minutes the Mixture was centrifuged at 57800g, as described above, sieges is the group of final protein concentration of 2 mg/ml Experiment linking was performed as described above in paragraph(A), using the drug membranes diluted "linking" buffer to a concentration of 1 μg/50 μl.

C. Test for activity against induced by endothelin reduction of isolated rings of thoracic aorta of the rat.

The effectiveness of the compounds as antagonist or agonist response of endothelin biological tissue is assessed by measuring the actions induced by endothelin reduction of isolated rings of thoracic aorta in rats (see, for example, Borges and others, (1989) Eur. J. Pharmacol. 165: 223-230) or by measuring the ability of the fabric to shrink when it is added.

Compounds that must be analyzed are prepared in the form of samples of 100 μm. If you want to make a dilution, the connection is first dissolved in a minimal amount of DMSO and diluted with 150 mm sodium chloride. Because DMSO can cause relaxation of aortic rings, we study the control solutions containing various concentrations of DMSO.

Cut a piece of thoraxes from the aorta young rats, the endothelium was removed by gentle vyskrebyvanii, and then cut 3-mm ring segments. Segments suspend the seal gas mixture of 95% oxygen and 5% carbon dioxide (118 mm NaCl, 4.7 mM KCl, 1.2 mM MgSO41.2 mM KH2PO4, 25 mM NaHCO3, 2.5 CaCl2, 10 mM D-glucose). Changing the tension isometries are measured and recorded using the instrument Glass Polygraph connected to the force sensor. Endothelin is added to the bath for bodies, with the gradual accumulation of its content, and the action of these compounds is determined for endothelin-1 from the curve of the concentration-response. Connections are added 15 minutes before the addition of endothelin-1.

D. Method of identifying compounds that have the activity of the agonist and/or antagonist with respect to ETB-receptors.

1. Stimulirovanie excretion of prostacyclin.

Since endothelin-1 stimulates the release of prostacyclin from cultured endothelial cells, bovine aortic compounds that have agonist activity or antagonist identified by their ability to inhibit induced endothelin-1 secretion of prostacyclin from these endothelial cells by measuring 6-keto - PGF1as described in Filep and others (1991) Biochem. Biophys. Res. Commun. 177: 171-176. Cells of the aorta bull is obtained from the processed collagenase bovine aorta, seeded into cups for cultivation, grown in medium 199, leptomycin and Fungizone, and who cultivate at least 4 times. Cells are then subcultured on a plate with six cells in the same environment. For 8 hours prior to determination of activity after cells had reached confluence, the medium is removed. Then cells are incubated (a) only in the environment, (b) in a medium containing endothelin-1 (10 nm), (C) only in the test compound, and (d) in the studied connection+ endothelin-1 (10 nm).

After 15 min incubation medium is removed from each cell, and the concentration of 6-keto - PGF1measured direct immunological method. The secretion of prostacyclin is calculated as the difference between the amount of 6-keto - PGF1produced by cells in the presence of endothelin-1, and the amount produced similarly treated cells in the absence of endothelin. Those compounds that stimulate the release of 6-keto - PGF1possess agonist activity, and those that inhibit the activity of endothelin antagonist.

2. Inhibition of sarafotoxin 6s, causing contraction.

Sarafotoxin-6s is a specific ETB- antagonist, which causes contraction of the strips of spare rat stomach. The effectiveness of the compounds in the inhibition of this inducer the>
antagonist. Two such isolated strips suspendered under a load of 1 g in 10 ml bath for bodies filled with Krebs solution-Hensleit containing 10 μm cyclo(D - Asp-Pro-D-Val-Leu-D-Trp) (BQ-123; see U.S. patent N 5,114,918, Ishikawa and others), 5 μm indomethacin and saturated with a gas mixture of 95% oxygen and 5% carbon dioxide. Changes in tension are measured isometrically and are registered using the instrument Glass Polygraph connected to the force sensor. Sarafotoxin-6s gradually added to one strip, while the other strip is pre-incubated for 15 min with the test compound prior to adding the total dose of sarafotoxin-6s. We study the effect of these compounds on curves the concentration of sarafotoxin-6s - response.

E. Results.

We measured concentrations of the IC50for each of the compounds shown in the Examples, for ETAand ETB- receptors. Almost all connections are IC50less than 10 microns as for ETAand ETB-receptors. Many compounds have IC50less than 10 microns, others have IC50less than 1 micron, and some IC50less than 0.1 microns. A series of compounds has the IC50significantly less (10 to 100 times or more) for ETtexts are selective for ETB-receptors. As modifications will be obvious to experts, it is understood that this invention be limited only within the attached claims.

At the end of the text, see table. 12.

Thus, all benzosulfimide that have groups such as methyl, bromine, chlorine, nonyl, trifluoromethyl, tridecyl, ethyl, hexyl, isopropyl, butyl, propyl, benzyl, phenoxy, butadienyl, nitro, phenyl, butylene, benzyl, cyclohexylmethyl, methoxy, cyano, hydrogen, amido, phenylethyl, hydroxypropyl, cyclopropyl, methoxycarbonyl, carboxy, isothiocyante and hydroxyethyl, R1and R2find the activity of antagonists of the endothelium. In addition, the data show that these results can be extrapolated to other classes of sulfonamides included in the formula. Therefore, the entire set of R1and R2included in the formula, supported by experimental data.

EXAMPLE 159

N-(4-Bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide

A solution of 5-amino-4-bromo-3-methylisoxazole (177 mg, 1.0 mmol) in dry tetrahydrofuran (THF, 2 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 90 mg, 2.2 mmol) in dry THF (1 ml) at 0 - 5oC. h to complete the reaction. The reaction mixture was again cooled t 0oC, and thiophene-2-sulphonylchloride (200 mg, 1.1 mmol) dissolved in dry THF (2 ml) was added dropwise. The conditioning was continued for 1 h; during this period the reaction mixture was slowly reached room temperature. THF was removed under reduced pressure. The residue was dissolved in water (10 ml), the pH was brought to 10 to 11 by adding 5 N sodium hydroxide solution, the resulting solution was extracted using ethyl acetate (3 X 10 ml) to remove neutral impurities. The aqueous layer was acidified using concentrated HCl (pH 2 - 3) and extracted using methylene chloride (3 x 10 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain N-(4-bromo-3-methyl-5 - isoxazolyl)thiophene-2-sulfonamida. Pure product was obtained by recrystallization using a mixture of hexane/ethyl acetate (1 10 mg, 34% yield), so pl. 125-127oC.

EXAMPLE 160

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-isoxazolyl)thiophene-2 - sulfonamide

A solution of 5-amino-4-bromo-3-methylisoxazole (177 mg, 1.0 mmol) in dry THF (2 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil is mesh was heated to room temperature within 10 min to complete the reaction. The reaction mixture was again cooled to 0oC and slowly added 5-(3-isoxazolyl)thiophene-2 - sulphonylchloride (273 mg, 1.1 mmol) dissolved in dry THF (2 ml). The conditioning was continued for 1 h, during this period the temperature of the reaction mixture was slowly reached room temperature. THF was removed under reduced pressure. The residue was dissolved in water (10 ml), the pH was brought to 2 to 3 by adding concentrated HCl, and was extracted using methylene chloride (3 x 10 ml). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain N-(4-bromo-3-methyl-5 - isoxazolyl)-5-(3-isoxazolyl)thiophene-2-sulfonamida. Pure product was obtained by recrystallization using a mixture of hexane/ethyl acetate (160 mg, 41% yield), so pl. 120-123oC.

EXAMPLE 161

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-pyridyl)thiophene-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-pyridyl)thiophene-2 - sulfonamide was obtained as described in Example 2 from 5 - amino-4-bromo-3-methylisoxazole and 5-(2-pyridyl)thiophene-2 - sulphonylchloride with 40% yield. Clearance made by recrystallization from ethyl acetate to obtain crystalline solid vases is R>
N-(4-bromo-3-methyl-5-isoxazolyl)-4,5-dibromothiophene-2 - sulfonamide was obtained as described in Example 2 from 5 - amino-4-bromo-3-methylisoxazole and 4,5-dibromothiophene-2-sulfonyl chloride with 45% yield. Purification was achieved by piperacetazine from a mixture of ethyl acetate/hexane to obtain crystalline solid, so pl. 153 - 155oC.

EXAMPLE 163

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-chloro-3-methylbenzo[b] thiophene - 2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-chloro-3 - methylbenzo[b]thiophene-2-sulfonamide was obtained as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole, and 5-chloro-3 - methylbenzo[b]thiophene-2-sulfonyl chloride with 18% yield. Clearance made by recrystallization from a mixture of ethyl acetate/hexane to obtain crystalline solid, so pl. 153 to 155oC.

EXAMPLE 164

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-chlorobenzamido)thiophene - 2-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-chlorobenzamido)thiophene - 2-sulfonamide was obtained as described in Example 2 from 5-amino-4-bromo - 3-methylisoxazole and 5-(4-chlorobenzamido)thiophene-2 - sulphonylchloride with 27% yield. Technical product was passed through a column of silica gel using mixtures of hexane/e shall eat crystalline solid, so pl. 210oC.

EXAMPLE 165

N-(4-Bromo-3-megil-5-isoxazolyl)-4-(benzoylphenyl)thiophene - 2-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-4-(benzoylphenyl)thiophene-2 - sulfonamide was obtained as described in Example 2 from 5 - amino-4-bromo-3-methylisoxazole and 4-benzosulfimide-2 - sulphonylchloride with 26% yield. Clearance made by recrystallization from a mixture of ethyl acetate/hexane to obtain crystalline solid, so pl. 181 -184oC.

EXAMPLE 166

N-(4-Bromo-3-methyl-5-isoxazolyl)-4-bromo-5-chloro-thiophene-2 - sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-4-bromo-5-chloro-thiophene-2 - sulfonamide was obtained as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 4-bromo-5-chlorothiophene-2 - sulphonylchloride with 25% output. Clearance made by recrystallization from a mixture of ethyl acetate/hexane to obtain crystalline solid, so pl. 143 - 145oC.

EXAMPLE 167

N-(4-Bromo-3-methyl-5-isoxazolyl)-2.5-dichlorothiophene-3 - sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-2.5-dichlorothiophene-3 - sulfonamide was obtained as described in Example 2 from 5 - amino-4-bromo-3-methylisoxazole and 2.5-dichlorothiophene-3-sulfonyl chloride with 47% yield. Purification is carried out by paracrystal"ptx2">

EXAMPLE 168

N-(4-Bromo-3-methyl-5-isoxazolyl)-2.5-dimethylthiophene-3 - sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-2.5-dimethylthiophene-3 - sulfonamide was obtained as described in Example 1 from 5 - amino-4-bromo-3-methylisoxazole and 2.5-dimethylthiophene-3 - sulphonylchloride with 55% yield. Clearance made by recrystallization from a mixture of ethyl acetate/hexane to obtain crystalline solid, so pl. 77 - 80oC.

EXAMPLE 169

N-(4-Bromo-3-methyl-5-isoxazolyl)-4,5-dichlorothiophene-2 - sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-4,5-dichlorothiophene-2 - sulfonamide was obtained as described in Example 1 from 5 - amino-4-bromo-3-methylisoxazole and 4,5-dichlorothiophene-2-sulfonyl chloride with a 42% yield. Clearance made by recrystallization from a mixture of ethyl acetate/hexane to obtain crystalline solid, so pl. 135 - 138oC.

EXAMPLE 170

N-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dichloro-4-bromothiophene-3 - sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dichloro-4 - bromothiophene-3-sulfonamide was obtained as described in Example 1 from 5-amino-4-bromo-3-methylisoxazole and 4-bromo-2,5-dichlorothiophene - 3-sulfonyl chloride with 58% yield. Clearance made by recrystallization from a mixture of ethyl acetate/hexane with polycentric)-2-{3-[1-methyl-5-(trifter - methyl)pyrazolyl]}thiophene-5-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-{ 3-[1-methyl-5- (trifluoromethyl)-pyrazolyl] }thiophene-5-sulfonamide was obtained as described in Example 1 from 5-amino-4-bromo-3-methylisoxazole and 2- {3-[1-methyl-5-(trifluoromethyl)pyrazolyl] } thiophene-5-sulphonylchloride with 30% output. Clearance made by recrystallization from a mixture of ethyl acetate/hexane to obtain crystalline solid, so pl. 121 - 123oC.

EXAMPLE 172

N-(4-Bromo-5-methyl-3-isoxazolyl)thiophene-2-sulfonamide

Thiophene-2-sulfonyl chloride (183 mg, 1 mmol) was added to a solution of 3-amino-4-bromo-5-methylisoxazole (177 mg, 1 mmol) in dry pyridine (0.5 ml). The reaction mixture was stirred at room temperature for 3 hours, the Pyridine was removed under reduced pressure and the residue was divided between water and ethyl acetate. The organic layer was washed using 1 N HCl (3 X 10 ml), brine (10 ml) and dried over anhydrous magnesium sulfate. After evaporation of the solvent left an oily residue, which hardened at -20oC and then was purified by recrystallization from a mixture of ethyl acetate/hexane, to obtain the pure product (51% yield) as a solid substance, so pl. 156-158oC.

EXAMPLE 173

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(bestsolution as well as described in Example 2 from 5 - amino-4-bromo-3-methylisoxazole and 5-benzoylthiophene-2 - sulphonylchloride with 59% yield. Clearance made by recrystallization from a mixture of ethyl acetate/hexane to obtain crystalline solid, so pl. 139 - 142oC.

EXAMPLE 174

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3 - sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3 - sulfonamide was obtained as described in Example 2 from 5 - amino-4-bromo-3-methylisoxazole and 2-(carbomethoxy)thiophene-3 - sulphonylchloride with 73% yield. Clearance made by recrystallization from a mixture of ethyl acetate/hexane to obtain crystalline solid, so pl. 198-200oC.

EXAMPLE 175

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carboxy)thiophene-3 - sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3 - sulfonamide (Example 16) (1.5 g, 3.95 mmol) was dissolved in methanol (10 ml). Then added tablet of sodium hydroxide (1 g, 25 mmol) and few drops of water. The resulting solution was kept for 16 hours at room temperature. The methanol was removed under reduced pressure. The residue was diluted with water and extracted using ethyl acetate (2 x 10 ml). The aqueous layer is of cetate (2 x 60 ml). The combined organic layers was dried over anhydrous magnesium sulfate, and filtered. After removal of the solvent there was obtained N-(4 - bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide (1.2 g, 82% yield, which was purified using column chromatography on silica gel using ethyl acetate as eluent, so pl. 188-194oC.

EXAMPLE 176

N-(4-Bromo-3-mthyl-5-isoxazolyl)-2-(N-phenylenecarbonyl)thiophene - 3-sulfonamide

Aniline (0.093 g, 1 mmol) and 1-ethyl-3'[3-dimethylaminopropyl] carbodiimide (EDCI) (0.191 g, 1 mmol) were added to N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxy)thiophene-3-sulfonamide (0.368 g, 1 mmol), suspended in methylene chloride (5 ml) to obtain a transparent solution. The conditioning was continued for 1 h At room temperature. The reaction mixture was diluted with methylene chloride (50 ml) and washed with 3 N hydrochloric acid (3 x 50 ml). The combined organic layers was dried over anhydrous magnesium sulfate and filtered. After removal of the solvent under reduced pressure was obtained N- (4-bromo-3-methyl-5-isoxazolyl)-2-(N-phenylenecarbonyl)thiophene-3 - sulfonamide. Technical product, thus obtained, was purified column .)

EXAMPLE 177

N-(4-Bromo-3-methyl-5-isoxazolyl) 1-(4'-isopropylphenyl)pyrrol - 2-sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl) 1-(4'-isopropylphenyl)pyrrole-3-sulfonamide

A. 1-(4'-isopropylphenyl)pyrrol

Glacial acetic acid (100 ml) was added to a mixture of 4 - isopropylaniline (10 ml, 72.4 mmol) and 2,5-dimethoxytetrahydrofuran (9.6 ml, 72.4 mmol) and the resulting mixture was converted under reflux for 1.5 hours, the Reaction mixture was left cooled, and acetic acid was removed under reduced pressure. The resulting brown mass was dissolved in ethyl acetate (200 ml) and washed with water (2 x 200 ml). The organic layer was dried over magnesium sulfate and filtered. After removal of the solvent was obtained 1-(4'-isopropylphenyl)pyrrole (13.28 g, 99% yield) as a brown mass.

Century 1-(4'-isopropylphenyl)pyrrol-2-sulfonic acid

Chlorosulfonic acid (1.82 ml, 27.08 mmol) was slowly added to a solution of 1-(4'-isopropylphenyl)pyrrole (5.01 g, 27.08 mmol) in chloroform (100 ml) at 0oC. the Resulting solution was kept at 0oC for 1 h and additionally for 1 h at room temperature. The chloroform was removed under reduced pressure. The resulting brown liquid Bilam was acidified using concentrated hydrochloric acid (pH<1) and then was extracted with chloroform (2 x 150 ml). The combined organic layers was dried over magnesium sulfate and filtered. After removal of the solvent was obtained 1-(4'- isopropylphenyl)pyrrol-2-sulfonic acid as a brown mass (3 g, 42% yield).

C. 1-(4'-isopropylphenyl)pyrrol-2-sulphonylchloride and 1-(4'- isopropyl-phenyl)pyrrol-3-sulfonyl chloride

Pentachloride phosphorus (4.7 g, 22.64 mmol) was slowly added to a solution of 1-(4'-isopropylphenyl)pyrrol-2-sulfonic acid (3 g, 11.32 mmol) in phosphorus oxychloride (8.4 ml, 90.57 mmol). The resulting mixture was heated to 0oC for 10 h, the Reaction mixture was left to cool to room temperature, then carefully poured onto crushed ice (500 g) and extracted using chloroform (200 ml). The combined organic layers was dried over anhydrous magnesium sulfate. After profilirovaniya and removal of solvent received a mixture of 4:1 1-(4'- isopropylphenyl)pyrrol-2-sulphonylchloride and 1-[4'- isopropylphenyl)pyrrole-3-sulphonylchloride (2.5 g, 78%) as a brown oil.

D. N-(4-bromo-3-methyl-5-isoxazolyl) 1-(4'-isopropylphenyl)pyrrol - 2-sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl) 1-(4'- isopropylphenyl)pyrrole-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl) 1-(4'-isopropylphenyl)pyrrol-opisane in Example 2, from 5-amino-4-bromo-3-methylisoxazole and a mixture of 1-(4'-isopropylphenyl)pyrrol-2-sulfonyl chloride and 1-(4'- isopropylphenyl)pyrrole-3-sulfonyl chloride with the combined output of 65%. The mixture was subjected to preparative HPLC to obtain N-(4 - bromo-3-methyl-5-isoxazolyl)-1-(4'-isopropylphenyl)pyrrol-2 - sulfonamida (retention time 22.85 min, 5% to 95% acetonitrile in water with the use of 0.1% TFU within 30 minutes period, the analytical column C18and N-(4-bromo-3-methyl-5-isoxazolyl)- 1-(4'-isopropylphenyl)pyrrole-3-sulfonamida (retention time 24.56 min, 5% to 95% acetonitrile in water with the use of 0.1% TFU for 30 min, analytical column C18in the form of oils.

EXAMPLE 178

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide was obtained as described in Example 2 from 5-amino-4-bromo-3 - methylisoxazole and 5-bromothiophene-2-sulfonyl chloride with 30% output. Clearance made by recrystallization from a mixture of ethyl acetate/hexane to obtain crystalline solid, so pl. 240oC.

EXAMPLE 179

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-methoxyphenyl) aminocarbonyl)-thiophene-Z-sulfonamide

4-Methoxyaniline (0.246 g, 2 mmol), bromo-Tris-pyrrolidino - possessor)-2-(carboxyl)thiophene-3-sulfonamide (0:368 g 1 mmol), were suspended in methylene chloride (3 ml), to obtain a transparent solution. The conditioning was continued for 24 h at room temperature. The reaction mixture was diluted with use of methylene chloride (50 ml) and washed with the use of 3 N hydrochloric acid solution (3 x 50 ml) then a solution of 5% sodium carbonate (2 x 50 ml). The combined organic layers was dried over anhydrous magnesium sulfate and filtered. Removal of the solvent under reduced pressure resulted in the receipt of N-(4-bromo-3-methyl-5 - isoxazolyl)-2-[N-(4-methoxyphenyl)aminocarbonyl] thiophene-3 - sulfonamida. Technical product, thus obtained, was purified column chromatography using ethyl acetate as eluent. After recrystallization from a mixture of ethyl acetate/hexane there was obtained a crystalline solid, so pl. 202 - 205oC (0.08 g, 17% yield).

EXAMPLE 180

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl) aminocarbonyl]-thiophene-Z-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(3 - methoxyphenyl)aminocarbonyl]-thiophene-Z-sulfonamide was obtained as described in Example 21, N-(4-bromo-3-methyl-5-isoxazolyl)- 2-(carboxyl)thiophene-3-sulfonamida and 3-methoxyaniline with 23% yield.eluent. After recrystallization from a mixture of ethyl acetate/hexane received a crystalline solid, so pl. 200 - 202oC.

EXAMPLE 181

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(2-methoxyphenyl) aminocarbonyl]-thiophene-Z-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(2-methoxyphenyl) aminocarbonyl]-thiophene-Z-sulfonamide was obtained as described in Example 21, N-(4-bromo-3-methyl-5-isoxazolyl)- 2-(carboxyl)thiophene-3-sulfonamida and 2 - methoxyaniline with 26% yield. Technical product was purified by column chromatography using ethyl acetate as eluent. He was recrystallized from a mixture of ethyl acetate/hexane to obtain crystalline solid, so pl. 74 - 80oC.

EXAMPLE 182

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(N-benzylaminocarbonyl) thiophene-3-sulfonamide

Benzylamine (0.214 g, 2 mmol), benzotriazol-1-yl-oxy - Tris(dimethylamino)phosphonium hexaflurophosphate (BOP) (0.442 g, 1 mmol) and N, N'-diisopropylethylamine (0.15 ml) were added to N- (4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide (0.368 g, 1 mmol), which was suspended in methylene chloride (3 ml). The resulting solution was kept for 14 h at room temperature. It was diluted with application the I (2 x 50 ml). The combined organic layers were dried over anhydrous magnesium sulfate and filtered. Removal of the solvent under reduced pressure resulted in the receipt. N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N - benzylaminocarbonyl)thiophene-3-sulfonamida. Technical product was purified by column chromatography using ethyl acetate as eluent. Recrystallization from a mixture of ethyl acetate/hexane resulted in crystalline solids, so pl. 186 to 190oC (0.14 g, 30% yield).

EXAMPLE 183

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-ethylphenyl) aminocarbonyl]-thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4 - ethylphenyl)aminocarbonyl]thiophene-3-sulfonamide was obtained as described in Example 24 N-(4-bromo-3-methyl-5-isoxazolyl)-2- (carboxyl)thiophene-3-sulfonamida and 4-ethylaniline with 31% yield. Technical product was purified by column chromatography using ethyl acetate as eluent. He was recrystallized from a mixture of ethyl acetate/hexane to obtain crystalline solid, so pl. 187 - 190oC

EXAMPLE 184

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-biphenyl)aminocarbonyl] thiophene-Z-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[is isoxazolyl)-2- (carboxyl)thiophene-3-sulfonamida and 4-phenylaniline with 26% yield. Technical product was purified by column chromatography using ethyl acetate as eluent. He was recrystallized from a mixture of ethyl acetate/hexane to obtain crystalline solid, so pl. 205 -212oC.

EXAMPLE 185

N-(3,4-dimethyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3 - sulfonamide

2-Methoxycarbonylaminophenyl-C-sulphonylchloride (2.50 g, 10.05 mmol) was added to a solution of 5-amino-3,4-dimethylisoxazole (0.98 g, 8.75 mmol) in dry pyridine (5.0 ml). The reaction mixture was kept at room temperature for 16 hours, the Pyridine was removed under reduced pressure and the residue was separated between water and dichloromethane. The organic layer was washed using 1 N HCl (2 x 50 ml) and dried over anhydrous magnesium sulfate. After evaporation of the solvent left an oily residue, which, after purification column chromatography over silica gel (mixture of 1:1 hexane/ethyl acetate as eluent), has led to 2.20 mg (65%) of a brown solid. Further purification was produced by recrystallization from a mixture of ethyl acetate/hexane, to obtain the pure product as white solids, so pl. 113-116oC.

EXAMPLE 186

N-(3,4-dimethyl-5-pokazali)-2-(carbox described in Example 17, from N-(3,4-dimethyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3 - sulfonamida basic hydrolysis with 94% yield. Clearance made by recrystallization from a mixture of ethyl acetate/hexane to obtain crystalline solid, so pl. 202 - 203oC.

EXAMPLE 187

N-(3,4-dimethyl-5-isoxazolyl)-2-(N-phenylenecarbonyl)thiophene - 3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-(N-phenylenecarbonyl)thiophene - 3-sulfonamide was obtained as described in Example 18, N-(3,4-dimethyl-5-isoxazolyl)-2-(carboxy)thiophene-3-sulfonamida with 40% yield. Clearance made by recrystallization from a mixture of ethanol/water to obtain crystalline solid, so pl. 176 - 178oC.

EXAMPLE 188

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-thienyl)thiophene-2-sulfonamide

A. 5-bromo-2,2'-betoven

N-Bromosuccinimide (NBS, 1.12 g, 6.3 mmol) was added in small portions to a solution of 1.0 g (6.01 mmol) of 2,2'-bithiophene in 10 ml of glacial acetic acid and 10 ml of chloroform. After incubation for 1 h at room temperature, the mixture was poured into ice-water and extracted with chloroform (75 ml). The organic layer was washed using an aqueous solution of sodium bicarbonate, water and then dried over magnesium sulfate and viparea brown solid, so pl. 55 - 56oC

Century 5-Chlorosulfonyl-2,2'-betoven

A sustained solution of 5-bromo-2,2'-bithiophene (1.5 g, 6.1 mmol) in 10 ml dry ether was placed in an argon atmosphere, cooled to -78oC, and 4.3 ml of 1.7 N solution of t-utility was added over 20 minutes Maintaining continued at this temperature for an additional 20 minutes Then barbotirovany at -78oC gaseous sulfur dioxide until the formed yellow precipitate. The bubbling of the gaseous sulfur dioxide continued advanced for 3 minutes, then immediately added dropwise N-chlorosuccinimide (NCS, 902 mg, 6.76 mmol) dissolved in THF. The mixture was heated to room temperature, and maintaining continued optional for 1.5 hours the Mixture was concentrated and the residue was dissolved in ether. The organic layer was washed with water, brine and dried over magnesium sulfate. After evaporation of the solvent left a yellowish solid, which was recrystallized from hexane to obtain 700 mg (44%) yellow solid, so pl. 63-64oC.

C. N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-thienyl)thiophene-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-thienyl)thiophene-2 - sulfonamide was obtained as described in Example 2. Rea which resulted in the receipt, after flash chromatography using 10% MeOH/CHCl3, 430 mg (94%) brown solid, so pl. 210oC.

EXAMPLE 189

N-(4-Bromo-3-methyl-5-isoxazolyl)thiophene-3-sulfonamide

A. Thiophene-3-sulphonylchloride

A sustained solution of 3-bromothiophene (1.5 g, 9.2 mmol) in 10 ml dry ether was placed in an atmosphere of argon and cooled to -78oC. for 20 min, the solution was added tert-utility (5.6 ml, 1.7 M) and maintaining continued additionally for 20 minutes Then was barbotirovany gaseous sulfur dioxide at -78oC, and the solution was heated to 0oC, then NCS (1.47 g, 12 mmol) in 8 ml THF was added dropwise. After heating to room temperature, keeping continued additionally, within 1 hour, after which produced the evaporation of the solvent, resulting remained 1.55 g of brown oil. Flash chromatography over silica gel using hexane resulted in the receipt of 1.24 g (74%) of yellow oil which hardened on standing to a yellow crystalline solid, so pl. 38-39oC.

C. N-(4-Bromo-3-methyl-5-isoxazolyl)thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-3-sulfonamide was obtained as described in Example 2, from t the night chromatography using 10% MeOH/CHCl3as eluent resulted in a light brown oil.

EXAMPLE 190

N-(3,4-dimethyl-5-isoxazolyl)-5-phenylthiophene-2-sulfonamide

A. N-(3,4-dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide

A solution of 5-bromothiophene-2-sulphonylchloride (2.75 g, 10 mmol) and 5-amino-3,4-dimethylisoxazole (1.07 g, 9.57 mmol) in pyridine containing a catalytic amount of 4-dimethylaminopyridine, (DMAP, 10 mg) was kept at room temperature for 3 hours. The solution was heated at 50oC optional for 1.5 hours to bring the reaction to completion. The pyridine was removed under reduced pressure and the residue, after extraction with ethyl acetate, was washed using 1 N HCl (2 x 25 ml), water (1 x 25), brine (1 x 25 ml) and dried over magnesium sulfate. After evaporation of the solvent left a viscous brown resin, which was subjected to flash chromatography. Chromatography using 3% methanol in hexane resulted in the receipt of 246 mg (10%) net sulfonamida.

C. N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5 - bromothiophene-2-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (680 mg, 2 mmol) in dry THF (2 ml) was added to sodium hydride (121 mg, 60% dispersion in oil, 3 mmol) in dry THF (1 mkaplan a pipette. The solution was heated to room temperature, and maintaining continued throughout the night. After evaporation of the solvent left an oil which was extracted with ethyl acetate, washed using brine, dried over magnesium sulfate and evaporated. Flash chromatography of the residue on silica gel using 10-15% mixture of ethyl acetate/hexane resulted in the receipt of 480 mg (56%) of colorless oil.

C. N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5 - phenylthiophene-2-sulfonamide

Sodium carbonate (2 ml of 2 M aqueous solution), and then phenylboric acid (86 mg, 0.71 mmol), 2 million 95% ethanol were added to a solution of N-(methoxyethoxymethyl)-N-(b, l, 4-dimethyl-5 - isoxazolyl)-5-bromothiophene-2-sulfonamida (200 mg, 0.47 mmol) and tetrakis(triphenylphosphine) palladium (0) 23 mg, 0.02 mmol) in dry benzene (4 ml) in an argon atmosphere. The mixture was distilled for 12 h, diluted with 5 ml of water and extracted with ethyl acetate (3 x 25 ml). The combined organic extracts were washed with brine (1 x 25 ml), dried and evaporated. The residue was subjected to flash chromatography on silica gel using 25% mixture of ethyl acetate/hexane to obtain 123 mg (62%) sulfonamida in the form of a colourless resin.

D. N-(3,4-dimethyl-5-isoxazolyl)-5-phenylthiophene-xazole)-5-phenylthiophene - 2-sulfonamida (100 mg, 0.24 mmol) in 3 ml of 95% ethanol, and the resulting mixture was distilled for 6 hours the Mixture was then concentrated, diluted with 5 ml of water, neutralized using saturated aqueous sodium bicarbonate solution and acidified to pH 4 using glacial acetic acid. The mixture was extracted using ethyl acetate (2 x 25 ml) and the combined organic extracts were washed with brine (1 x 5 ml), dried and evaporated. Flash chromatography of the residue on silica gel using 2% MeOH/CHCl3and further purification of obremenitve HPLC led to 33.4 mg (42%) of pure sulfonamida in the form of a white powder, so pl. 176-178oC.

EXAMPLE 191

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl)thiophene-2 - sulfonamide

A. N-(5-bromothiophene-2-sulfonyl)-pyrrol

Sodium hydride (60% dispersion in oil, 191 mg, 4.78 mmol) was suspended in dry tetrahydrofuran (2 ml) and the resulting suspension was cooled to 0oC in an ice bath. Pyrrole (385 mg, 5.75 mmol) in dry tetrahydrofuran (2 ml) was added dropwise within 10 minutes the Ice bath was removed and the solution was kept at room temperature until until gas evolution ceased (15 min), followed by 5-bromothiophene-2-sores steel pipette. After incubation for 1 h at room temperature the mixture was filtered through a zeolite. Filter pad was rinsed tetrahydrofuran, and the filtrate was evaporated, and then remained light brown solid which was recrystallized from methanol to obtain sulfonamida (821 mg, 74% yield) as a white powder.

Century 4-Ethylvanillin acid

A solution of 1-bromo-4-ethylbenzene (2.0 g, 11 mmol) in dry ether (5 ml) was added dropwise to magnesium turnings, (311 mg, 13 mmol), suspended in dry ether. After complete addition, the suspension was distilled under reflux for 15 min, during this time, reacted almost all of the magnesium. Then the solution was added to trimethylborane (1.12 g, 11 mmol), previously dissolved in ether (5 ml) at -78oC, warmed to room temperature, and subjected to aging for 90 minutes the Reaction was stopped by adding 10% aqueous HCl (2 ml) and the solution was extracted using ether. Received the combined ether extracts were extracted using 1 M NaOH (2 x 20 ml), aqueous extracts were acidified using dilute HCl to pH 2 and extracted using ether (2 x 25 ml). The resulting joint afernoon), so pl. 138-140oC.

C. N-[5-(4-ethylphenyl)thiophene-2-sulfonyl]pyrrol

N-[5-(4-ethylphenyl)thiophene-2-sulfonyl] pyrrole was obtained as described in Example 32C from 4-ethylvanillin acid and N-(5-bronchiopulmonar)pyrrole. Purification via column chromatography using a 10% mixture of ethyl acetate/hexane resulted in the receipt of net sulfonamida as a gray solid with 81% yield.

D. 5-Chlorosulfonyl-2-(4-ethylphenyl)thiophene

A solution of N-[5-(4-ethylphenyl)thiophene-2-sulfonyl] pyrrole (100 mg, 0.32 mmol) and 6 N sodium hydroxide (1 ml) in methanol (1.5 ml) was distilled under reflux for about 6 hours. Evaporation of the solvent and drying under vacuum resulted in the oil. The phosphorus oxychloride (258 ml, 2.52 mmol) and pentachloride phosphorus (131 mg, 0.63 mmol) were added to the oil, and the resulting brown suspension was heated at 50oC for 3 hours, the Resulting light brown solution was carefully added to about 20 ml of crushed ice, and then extracted with ethyl acetate (CH ml). The combined organic layers was washed with brine (2x5 ml), dried (MgSO4) and evaporated to obtain an oily residue. Flash chromatography over silica gel with Apollo oil.

E. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl)thiophene-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl) thiophene-2 - sulfonamide was obtained as described in Example 2. The reaction of 5-chlorosulfonyl-2-(4-ethylphenyl) thiophene (47.1 mg, 11.16 mmol) with 5 - amino-4-bromo-3-methylisoxazole (29 mg, 0.16 mmol) resulted, after flash chromatography using 10% MeOH/CHCl3light brown solid (46 mg, 66% yield), so pl. 172-175oC.

EXAMPLE 192

N-(3,4-dimethyl-5-isoxazolyl)benzo[b]thiophene-2-sulfonamide

A. Benzo[b]thiophene-2-sulfonyl chloride

Benzo[b] thiophene (1.50 g, 11.2 mmol) kept at 0oC in 20 ml of THF. t-Utility (1.7 M, 16.8 mmol, 9.9 ml) was slowly added within 5 min After 15 min in the reaction vessel was barbotirovany SO2, and formed a white powder. The reaction mixture was stirred for 15 min at 0oC, and then was added NCS (1.64 g, 12.3 mmol). The reaction mixture was heated at 25oC and kept for 30 minutes She was then poured into ethyl acetate (150 ml) and washed with brine (CH ml). The organic phase was dried using MgSO4, filtered and concentrated to obtain 2.29 g of a brown oil. The brown oil was subjected to flash chromatogr is="ptx2">

C. N-(3,4-Dimethyl-5-isoxazolyl)benzo[b]thiophene-2-sulfonamide

3,4-Dimethyl-5-amino-isoxazol (0.224 g, 2.0 mmol) and 50 mg DMAP kept in 5 ml of pyridine at 25oC. was Added benzo[b]thiophene-2-sulphonylchloride (0.16 g, 2.6 mmol) and dark brown-yellow reaction mixture was stirred for 18 h at room temperature, poured into 100 ml of etilatsetata and washed with 2% HCl (g ml). The organic phase was dried MgSO4was filtered and concentrated, collected 0.61 g of a mixture of brown oil and solids. The brown mixture of oil and solids was subjected to flash chromatography (30% mixture of ethyl acetate-hexane) to obtain 0.37 g of light brown solid. It was kept in 10 ml of methanol and 0.5 g of NaOH. The methanol solution was heated, it was distilled under reflux for 1 h, then was cooled to 25oC and the methanol was removed in vacuum. The resulting residue was acidified to pH 1 with 2% HCl (100 ml) and extracted with ethyl acetate (CH ml) the Organic phase was dried MgSO4, filtered and concentrated to obtain 0.225 g of a yellow-orange solid. It was recrystallized from a mixture of CHCl3/hexane to obtain pale yellow solid (from 0.194 b g, 31% yield), so pl. 157-160
Benzo[b] furan-2-sulphonylchloride was obtained according to Example 34A of benzo[b] furan (1.61 g, 13.6 mmol), tert-BuLi (1.7 M, 17.7 mmol, 10.4 ml) and NCS (2.0 g,}5.0 mmol). After flash chromatography (5% atlapetes/hexane) received a brown solid (1.84 g, 62% yield).

C. N-(3,4-Dimethyl-5-isoxazolyl)benzo[b]furan-2-sulfonamide

N-(3,4-Dimethyl-5-isoxazolyl)benzo[b] furan-2-sulfonamide was obtained according to Example 34B, 3,4-dimethyl-5-aminoisoquinoline (78 mg, 0.70 mmol) and benzo[b] furan-2-sulfonyl chloride (0.46 g, 2.1 mmol). After flash chromatography (30% ethyl acetate/hexane) received 0.186 g of light yellow solid, which was treated 31 mg of NaOH in 10 ml of methanol at 25oC for 30 minutes Recrystallization from a mixture of CHCl3/hexane resulted in the receipt of a light grey solid (90 mg, 44% yield), so pl. 160.5-163oC.

EXAMPLE 193

N-(3,4-dimethyl-5-isoxazolyl)furan-2-sulfonamide

A. Furan-2-sulphonylchloride

Furan-2-sulfonyl chloride was obtained as in example 34A, furan (0.96 g, 14.2 mmol), t-BuLi (1.7 M, 17 mmol, 10 ml) and NCS (2.27 g, 17 mmol) using ether (30 ml) as solvent. Flash chromatography (5% ethyl acetate/hexane) yielded a yellow liquid (1.22 g, 52% yield the amide was obtained, as described in Example 34B, 3,4-dimethyl-5-amino isoxazol (0.122 g, 1.0 mmol), furan-2-sulphonylchloride (0.50 g, 3.0 mmol) and NaOH (64 mg). Flash chromatography (50% mixture of ethyl acetate/hexane) yielded 70 mg of yellow solid. Recrystallization from CHCl3/hexane resulted in a white solid (46 mg, 29% yield), t, pl. 107 - 110oC.

EXAMPLE 194

N-(3,4-Dimethyl-5-isoxazolyl)-3-methoxy-2-thiophene of the sulfonamide

A. 3-methoxy-2-thiophenesulfonyl

Chlorosulfonic acid (ClSO3H, 2.31 g, 19.62 mmol) was slowly added to a solution of 3-methoxythiophene (2.29 g, 19.62 mmol) in CHCl3(80 ml) at 0oC. the Resulting mixture was stirred at 0oC for 30 minutes the Solvent was evaporated under reduced pressure, at room temperature, the residue suspended in POCl3(15 ml, 156.96 mmol), was slowly added PCl5(8.2 g, 39.24 mmol). The reaction was conducted at 60oC for 18 h, then the reaction mixture was cooled to room temperature and poured onto crushed ice (200 g). The aqueous mixture was extracted with CHCl3(G ml) and the combined organic layers were dried (MgSO4). The solid was removed by filtration, and the filtrate was concentrated to obtain 3-isoxazolyl)-3-methoxy-2-thiophene of the sulfonamide

Sodium hydride (1.02 g, at 25.56 mmol, 60% dispersion in mineral oil) was slowly added to a solution of 3-methoxy-2 - thiophenesulfonyl chloride (1.18 g, 8.52 mmol) and 3,4-dimethyl-5 - aminoisoquinoline (1.05 g, 9.37 mmol) in THF (20 ml) at room temperature. The resulting mixture was distilled under reflux for 4 h THF was removed under reduced pressure. The residue was dissolved in water (10 ml), the pH was brought to 10 to 11 by adding 5 N sodium hydroxide solution, and spent extraction with ethyl acetate (3 x 10 ml) to remove neutral impurities. The aqueous layer was acidified with concentrated HCl (pH 2-3) and extracted with methylene chloride (3 x 10 ml). The combined organic layers were dried over anhydrous magnesium sulfate to obtain oil. Further purification of obremenitve HPLC resulted in a yellow oil (retention time 14.94 min, 5% to 95% acetonitrile in H2O using 0.1% TFU for 30 min, analytical column C18).

EXAMPLE 195

N-(4-Bromo-3-methyl-5-isoxazolyl)-3-phenyl-2-thiophenesulfonyl and N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenyl-2-thiophenesulfonyl

A. 3-phenyl-2-thiophenesulfonyl chloride and 4-phenyl-2 - thiophenesulfonyl

n-Utility (2.38 M, 17.2 ml, 41,03 mmol) was slowly to the ü kept at room temperature for 2 h, then was cooled to -30oC (CO2/acetone) and barbotirovany gaseous SO2through the reaction mixture for 20 min Then the solution was added NCS (6.06 g, 44.5 mmol) in THF (20 ml). The reaction mixture was warmed to room temperature and kept for 16 hours the Mixture was filtered, and the solid is washed with Et2O. the combined organic layers were concentrated, and the residue was subjected to chromatography (hexane/CHCl3) with 3-phenyl-2 - thiophenesulfonyl and 4-phenyl-2-thiophenesulfonyl as a mixture of composition 1:1 (1.46, 16.5%, solid).

C. N-(4-Bromo-3-methyl-5-isoxazolyl)-3-phenyl-2-thiophene of the sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenyl-2 - thiophenesulfonyl

N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenyl-2-thiophenesulfonyl and N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenyl-2 - thiophenesulfonyl were obtained as described in Example 1. The fraction of the mixture of products was purified HPLC to obtain N-(4-bromo-3 - methyl-5-isoxazolyl)-3-phenyl-2-thiophenesulfonyl (light brown solid, the retention time of 20.48 min, 5% to 95% acetonitrile in water with the use of 0.1% TFU for 30 min, analytical column C18so pl. 105-107oC) and N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenyl-2-thiophenesulfonyl
4-tert-Butyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

A solution of 5-amino-4-bromo-3-methylisoxazole (354 mg, 2.0 mmol) in dry THF (1 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 188 mg, 4.4 mmol) in dry THF (1 ml) at 0-5oC. After keeping at 0-5oC for 10 min, the reaction mixture was warmed to room temperature for 10 min to complete the reaction. The reaction mixture was again cooled t 0oC and slowly added 4-tert-butylbenzenesulfonyl chloride (512 mg, 2.2 mmol). The conditioning was continued for 20 minutes at 0-5oC. Excess sodium hydride was decomposed by addition of methanol (0.4 ml) and then water (0.5 ml). The mixture was acidified with hydrochloric acid and was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to get crude product, which was purified by recrystallization from a mixture of ethyl acetate/hexane to obtain white solids with 21% yield, so pl. 170oC (decomp.).

EXAMPLE 197

N-(3,4-Dimethyl-5-isoxazolyl)-2-methylbenzo[b]thiophene-3 - sulfonamide

A. 2-Methylbenzo[b]thiophene

tert-BuLi (1.7 M, 26 mmol, 15 ml) was added to a dignified solution BA t -30oC and was added podbean (26 mmol, 1.6 ml). After 10 min at -30oC the solution was heated a t room temperature and kept for an additional 30 min, then was diluted with ether (100 ml) and washed with brine (2 x 100 ml). The organic phase was dried (MgSO4), filtered and concentrated and was collected 2.48 g (98%) 2 - methylbenzo[b]thiophene as a pale yellow solid.

Century 2-Methylbenzo[b]thiophene-3-sulphonylchloride

Sulfurylchloride (9.5 mmol, 0.76 ml) was added to a dignified solution of dimethylformamide (DMF); 11.2 mmol, 0.87 ml) at 0oC, and the resulting yellow solution was kept for 20 min at 0oC. Then added 2-Methylbenzo[b] thiophene (5.6 mmol, 0.83 g), the reaction mixture was diluted with 2 ml DMF and then was heated to 85oC. After 2.5 h of incubation at 85oC brown reaction mixture was cooled to taboutroom temperature and added to ice (>100 ml). The aqueous phase was extracted with ethyl acetate (100 ml) and the organic phase was dried (MgSO4), filtered and concentrated, were collected arnuva-brown solid. Flash chromatography (4% ethyl acetate/hexane) resulted in the receipt of 0.89 g (64%) 2-methylbenzo[b]thiophene-3-sulphonylchloride in the form of a yellow solid is iophen-3-sulphonylchloride (1.7 mmol, 0.41 g) was added to a solution of 3,4-dimethyl-5-aminoisoquinoline (0.75 mmol, 84 mg), 4-dimethylamino-pyridine (DMAP, 50 mg) and pyridine (5 ml) at room temperature. After 24 h the reaction mixture was diluted with ethyl acetate (50 ml) and washed with 2% HCl (3 x 50 ml). The organic phase was dried (MgSO4), filtered and concentrated, gathered a brown-orange solid, which was dissolved in a solution of methanol (10 ml) and NaOH (60 mg). The solution was kept for 1 h at room temperature, and then methanol was evaporated and the resulting residue was diluted with 2% HCl (50 ml), and extracted with ethyl acetate (75 ml). The organic phase was dried (MgSO4), filtered and concentrated, were collected grey solid. Recrystallization from chloroform and hexane resulted in the receipt of 93 mg (38%) of N-(3,4 - dimethyl-5-isoxazolyl)-2-methylbenzo[b] thiophene-3-sulfonamida in the form of light yellow crystals, so pl. 174-176oC.

EXAMPLE 198

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-methylbenzo[b]thiophene-3 - sulfonamide

NaH (60% dispersion in oil, 2.5 mmol, 100 mg) was added to a solution of 4-bromo-Z-methyl-5-aminoisoquinoline (1.0 mmol, 0.177 g). THF (5 ml) was added 0oC, and the resulting reaction mixture was stirred for 10 min at 0oC. Added is UP>oC, then warmed up to room temperature for 1 hour, after which was added 2 ml of water. The mixture was diluted with ethyl acetate (100 ml) and washed with 2% HCl (2 x 50 ml), then brine (50 ml). The organic phase was dried (MgSO4), filtered and concentrated. Recrystallization of the crude reaction mixture resulted 0.24 r (63%) of N-(4-bromo-3-methyl-5 - isoxazolyl)-2-methylbenzo[b]thiophene-3-sulfonamida in the form of a white solid substance, so pl. 131-133oC.

EXAMPLE 199

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-ethylbenzo[b]thiophene-3 - sulfonamide

A. 2-Ethylbenzo[b]thiophene

2 Ethylbenzo[b] thiophene was obtained according to the method described in Example 40A, using benzo[b]thiophene (7.5 mmol, 1.0 g), t-BuLi (1.7 M, 8.9 mmol, 5.3 ml), iodata (8.9 mmol, 0.72 ml) and THF (20 ml). Was allocated to 1.2 g (99%) of a yellow liquid.

Century 2-Ethylbenzo[b]thiophene-3-sulphonylchloride

2 Ethylbenzo[b]thiophene-3-sulphonylchloride was obtained according to the method described in Example 40B with the use of dimethylformamide (DMF); 13.6 mmol, 1.1 ml), sulphonylchloride (11.5 mmol, 0.93 ml). Flash chromatography (2% ethyl acetate/hexane) yielded 1.34 g (76%) of light yellow solid.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-ethylbenzo[b]thiophene-3 - sulfonamide

N-(4-b is Itanium 4-bromo-3-methyl-5-aminoisoquinoline (1.0 mmol, 0.177 g), NaH (2.5 mmol, 100 mg), 2-ethyl-benzo[b] thiophene-3 - sulphonylchloride (1.2 mmol, 0.31 g) and THF (7 ml). Recrystallization from chloroform and hexane resulted in the receipt of 0.24 g (60%) of crystalline solid, so pl. 118.5-120oC.

EXAMPLE 200

N-(4-Bromo-3-methyl-5-isoxazolyl)-2 - bencivengo[b]thiophene-3-sulfonamide

A. 2-Bencivengo[b]thiophene

2 Bencivengo[b]thiophene was obtained according to the method described in Example 40A using benzo[b]thiophene (7.5 mmol, 1.0 g), tert - BuLi (1.7 M, 11.2 mmol, 6.6 ml), benzylbromide (10.2 mmol, 1.3 ml) and THF (20 ml). Flash chromatography (hexane) yielded 0.66 g (39%) yellow solid.

Century 2-Bencivengo[b]thiophene-3-sulphonylchloride

2 Bencivengo[b] thiophene-3-sulphonylchloride was obtained according to the method described in Example 40B, using DMF (5.4 mmol, 0.41 ml), sulfurylchloride (4.6 mmol. 0.37 ml) and 2 - bencivengo[b]thiophene. Flash chromatography (5% ethyl acetate/hexane) yielded 0.55 g (64%) of yellow solid.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-bencivengo[b]thiophene - 3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-bencivengo[b] thiophene-3 - sulfonamide was obtained according to the method described in Example 41, using 4-bromo-3-methyl-5-aminoisoquinoline (1.0 mmol who Oia (5% methanol/chloroform), and then recrystallization from chloroform and hexane resulted in the receipt of 0.11 g (24%) of crystalline solid, so pl. 120-123oC.

EXAMPLE 201

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-butylbenzo[b]thiophene-3 - sulfonamide

A. 2-Butylbenzo[b]thiophene

2-n-Butylbenzo[b]thiophene was obtained according to the method described in Example 40A, using benzo[b]thiophene (7.5 mmol, 1.0 g), t - BuLi (1.7 M, 9.7 mmol, 5.7 ml), 1-bromobutane (9.7 mmol, 1.0 ml), THF (20 ml). Was allocated 0.65 g (46%) of a yellow liquid.

Century 2-n-Butylbenzo[b]thiophene-3-sulfonyl chloride

2-n-Butylbenzo[b] thiophene-3-sulfonyl chloride was obtained by the method described in Example 40B using DMF (6.6 mmol, 0.51 ml), Sulfuryl chloride (5.6 mmol, 0.45 ml) and 2-n-butylbenzo[b]thiophene (3.3 mmol, 0.63 g). Flash chromatography (2% ethyl acetate/hexane) resulted in the receipt of 0.68 g (71%) of orange solid.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-butylbenzo[b]thiophene - 3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-butylbenzo[b] thiophene-3 - sulfonamide was obtained according to the method described in Example 41, using 4-bromo-3-methyl-5-aminoisoquinoline (1.0 mmol, 0.177 g), NaH (2.5 mmol, 100 mg), 2-n-butylbenzo[b] thiophene-3-sulphonylchloride (1.2 mmol, 0.35 g) and THF (6 ml). Recrystallization from etilize-(4-Bromo-3-methyl-5-isoxazolyl)-2-n-propellent[b]thiophene-3 - sulfonamide

A. 2-n-propellent[b]thiophene

2-n-Propellent[b] thiophene was obtained according to the method described in Example 40A, using benzo[b]thiophene (7.5 mmol, L g), t - BuLi (1.7 M, 9.7 mmol, 5.7 ml), n-bromopropane (9.7 mmol, 0.88 ml) and THF (20 ml). Was allocated 1.11 g (85%) of light yellow liquid.

Century 2-propellent[b]thiophene-3-sulphonylchloride

2 Propellent[b] thiophene-3-sulphonylchloride was obtained according to the method described in Example 40B, using DMF (3.6 mmol, 0.28 ml), sulfurylchloride (3.1 mmol, 0.25 ml) and 2 - propellent[b]thiophene (1.8 mmol, 0.32 g). Flash chromatography (3% ethyl acetate/hexane) yielded 0.28 g (56%) of yellow solid.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-propellent[b] thiophene-3 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-propellent[b]thiophene-3 - sulfonamide was obtained according to the method described in Example 41, using 4-bromo-3-methyl-5-aminoisoquinoline (0.68 mmol, 0.12 g), NaH (1.7 mmol, 6.8 mg), 2-n-propellent[b] thiophene-3-sulfonyl chloride (0.82 mmol, 0.23 g) and THF (3 ml). Recrystallization from chloroform and hexane resulted in the receipt of 0.19 g (67%) of a yellow crystalline solid, so pl. 136-138oC.

EXAMPLE 203

N-(4-Bromo-3-[cetyl-5-isoxazolyl)-2-isopropylbenzo[b] thiophene-3 - sulfonamide

ispolzovaniem benzo[b] thiophene (7.5 mmol, 1.0 g), t-BuLi (1.7 M, 11.2 mmol, 6.6 ml), 2-iodopropane (11.2 mmol, 1.12 ml) and THF (20 ml) keeping at room temperature for 24 hours. It was isolated as a yellow oil (1.11 g, 85% yield).

Century 2-isopropylbenzo[b]thiophene-3-sulfonyl chloride

2 isopropylbenzo[b]thiophene-3-sulphonylchloride was obtained according to the method described in Example 40B, using DMF (5.2 mmol, 0.40 ml), sulfurylchloride (4.2 mmol, 0.34 ml) and 2 - isopropylbenzo[b]thiophene (2.1 mmol, 0.37 g). Flash chromatography (1% ethyl acetate/hexane) yielded 0.17 g (29%) yellow solid.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-isopropylbenzo[b] thiophene - 3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-isopropylbenzo[b] thiophene-3 - sulfonamide was obtained according to the method described in Example 41, using 4-bromo-Z-methyl-5-aminoisoquinoline (0.55 mmol, 9.7 mg), NaH (1.4 mmol, 5.5 mg), 2-isopropylbenzo[b] thiophene-3 - sulphonylchloride (0.60 mmol, 0.17 g) and THF (2 ml). Recrystallization from chloroform and hexane resulted in the receipt of 89 mg (39%) of crystalline solid, so pl. 157.5-159oC.

EXAMPLE 204

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(4-active compounds)benzo[b] thiophene - 3-sulfonamide

- (2-benzo[b]thiophene)-4-ethylbenzylamine alcohol

- (2-Benzo[b] thiophene)-4-what r), T-BuLi (9.7 mmol, 1.7 M, 5.7 ml), 4 - ethylbenzaldehyde (8.9 mmol, 1.22 ml) and THF (20 ml). Flash chromatography (10% ethyl acetate/hexane) resulted in the receipt of 1.79 g (89%) of yellow solid.

Century 2-(4-active compounds)benzo[b]thiophene

To the solution - (2-benzo[b]thiophene)-4-ethylbenzylamine alcohol (4.0 mmol, 1.1 g), triethylsilane (4.4 mmol, 0.11 ml) and CH2Cl2(20 ml) at 0oC was added TFU (8.1 mmol, 0.62 ml). The solution was kept for 30 min at 0oC, then was diluted with ether (100 ml) and washed with saturated solution of NaHCO3(100 ml). The organic phase was dried (MgSO4), filtered and concentrated. Flash chromatography (2% ethyl acetate/hexane) resulted in the receipt of 0.69 g (68%) of a white solid.

C. 2-(4-active compounds)benzo[b]thiophene-3-sulfonyl chloride

2-(4-active compounds)benzo[b] thiophene-3-sulphonylchloride was obtained according to the method described in Example 40B, using DMF (5.4 mmol, 0.42 ml), sulfurylchloride (4.6 mmol, 0.37 ml) and 2-(4 - active compounds)benzo[b]thiophene (2.7 mmol, 0.69 g). Flash chromatography (2% ethyl acetate/hexane) yielded 0.43 g (45%) of orange solid.

D. N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-active compounds)benzo [b] thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-active compounds)benzisoxazole (1.0 mmol, 0.177 g), NaH (2.5 mmol, 100 mg), 2-(4-active compounds)benzo[b]thiophene-3-sulphonylchloride (1.2 mmol, 0.42 g) and THF (6 ml). Flash chromatography (50% ethyl acetate/hexane) followed by recrystallization from chloroform and hexane resulted in the receipt of 0.21 g (43%) of a solid substance, so pl. 128-130oC.

EXAMPLE 205

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)l - benzo[b] thiophene-3-sulfonamide

1 A. - (2-benzo[b]thienyl)-3,4-(methylenedioxy)benzyl alcohol

- (2-Benzo[b]thienyl)-3,4-(methylenedioxy)benzyl alcohol was obtained according to the method described in Example 40A, using benzo[b]thiophene (7.5 mmol, 1.0 g), t-BuLi (1.7 M, 9.7 mmol, 5.7 ml), piperonal (8.9 mmol, 1.0 g) and THF (20 ml). Flash chromatography (20% ethyl acetate/hexane) yielded 1.6 g (74%) of yellow solid.

Century 2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene

2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene was obtained according to the method described in Example 47B, using the 0oC - (2 - benzo[b]thienyl)-3,4-(methylenedioxy)benzyl alcohol (6.2 mmol, 1.8 g), triethylsilane (6.8 mmol, 1.1 ml) CH2Cl2(50 ml) and TFU (12.4 mmol, 0.95 ml). Recrystallization from hexane resulted in 1.2 g (73%) of a light orange solid.

C. 2-[3,4-(methylenedioxy)benzyl]benzo[b]t is described in Example 40B, using DMF (9.1 mmol, 0.70 ml), sulfurylchloride (7.7 mmol, 0.62 ml) and 2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene (4.6 mmol, 1.2 g). Flash chromatography (5% ethyl acetate/hexane) yielded 0.71 g (42%) of light yellow solid.

D. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy) benzyl] -benzo[b]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)- 2-[3,4-(methylenedioxy)benzyl]-benzo[b] thiophene-3-sulfonamide was obtained according to the method described in Example 41, using 4 - bromo-3-methyl-5-aminoisoquinoline (1.0 mmol, 0.177 g), NaH (2.5 mmol, 100 mg), 2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3 - sulphonylchloride (1.1 mmol, 0.40 g) and THF (7 ml). Flash chromatography (50% ethyl acetate/hexane, and then recrystallization from chloroform and hexane resulted in the receipt of 0.23 g (45%) of crystalline solid, so pl. 164-165oC.

EXAMPLE 206

N-(4-Bromo-3-methyl-5-isoxazolyl)benzo-2,1,3-thiadiazole-4 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)benzo-2,1,3-thiadiazole-4 - sulfonamide was obtained from 5-amino-4-bromo-3-methylisoxazole and 2,1,3-thiadiazole-4-sulphonylchloride in accordance with the procedure described in Example 39. Technical product was purified by recrystallization from a mixture of ethyl acetate/hexane to obtain cristalli-methylindol-2 - sulfonamide

A. 2-Methylindol-2-sulphonylchloride

2-Methylindol-2-sulphonylchloride was obtained according to the method described in Example 34, using 1-methylindole (7.8 mmol, 1.0 ml), t-BuLi (1.7 M, 9.4 mmol, 5.5 ml), sulfur dioxide, NCS (8.6 mmol, 1.2 g) and THF (15 ml). Flash chromatography (2% ethyl acetate/hexane) yielded 0.66 g (36%) yellow solid.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-1-methylindol-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-1-methylindol-2-sulfonamide was obtained according to the method described in Example 41, using 4-bromo-3-methyl-5-aminoisoquinoline (1.0 mmol, 0.18 g), NaH (2.5 mmol, 60 mg), 1-methylindol-2-sulphonylchloride (1.2 mmol, 0.26 g) and THF (7 ml). Recrystallization from chloroform and hexane resulted in the receipt of 0.28 g (77%) brown solid, so pl. 132 - 134oC.

EXAMPLE 208

N-(3,4-Dimethyl-5-isoxazolyl)-2-dibenzofuransulfonate

A. 2-Dibenzofuransulfonate

2-Dibenzofuransulfonate acid (12.8 mmol) was heated to 70oC with phosphorus oxychloride (1.30 ml, 14.0 mol) for 2 hours, the Excess phosphorus oxychloride was removed under reduced pressure. The residue was decomposed with ice water and extracted with ethyl acetate. The extract was washed with 5% sodium bicarbonate solution, missenard.

C. N-(3,4-Dimethyl-5-isoxazolyl)-2-dibenzofuransulfonate

2-Benzofurazanyl obtained at stage (a) was added to a solution of 5-amino-3.4-dimethylisoxazole (250 mg, 2.2 mmol) and 4-(dimethyl) aminopyridine (5 mg) in dry pyridine (2.0 ml). The reaction mixture was stirred at room temperature for 4 h, the Pyridine was removed under reduced pressure, and the residue was divided between water and ethyl acetate. The organic layer was washed with 1N HCl (2 x 25 ml), brine (25 ml) and dried over anhydrous magnesium sulfate. After evaporation of the solvent was obtained oily residue, after purification using column chromatography over silica gel (1% methanol in chloroform as eluent) yielded a white solid (32% yield). Clearance made by recrystallization from a mixture of chloroform/hexane to obtain a white hlopkopribor" solids, so pl. 173-175oC (decomp).

EXAMPLE 209

N-(4-chloro-3-methyl-5-isoxazolyl)-2-12-(3,4-methylenedioxy) phenyl] ethoxy-carbonyl-Z-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-(3,4-methylenedioxy) phenyl] ethoxy-carbonyl-Z-sulfonamide was obtained as described in Example 97 with the exception that 2-(3,4 - methylendioxy)phenylethanol was used is 500 mg, 25% yield).

EXAMPLE 210

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-phenylthiophene-3-sulfonamide

A. 3-Bromo-2-phenylthiophene

Tetrakis(triphenylphosphine)palladium (400 mg), Na2CO3(4 M, 80 ml, 320 mmol) and phenylboric acid (3.81 g, 30.3 mmol) in solution in ethanol (80 ml) were sequentially added to a solution of 2,3-dibromothiophene (7.33 g, 30.3 mmol) in benzene (100 ml). The mixture was heated under reflux for 12 hours. The aqueous layer was crude mixture was removed and the organic layer was diluted with Et2O (200 ml), washed 1 H NaOH (2 x 150 ml) and was dried (MgSO4), filtered, and the solvent was evaporated. The residue was chromatographia using hexane as eluent to obtain 3-bromo-2-phenylthiophene as a light oil (3.31 g, 47% yield).

Century 2-Phenylthiophene-3-sulphonylchloride

n-BuLi (2.38 M 1 1.5 ml, 27.28 mmol) was slowly added to a solution of 3-bromo-2-phenyl-thiophene (22.73 mmol) in ether (50 ml) at 0oC. the Reaction was conducted at 0oC for 1 h SO2was passed through the mixture for 15 min at 0oC, after which was added NCS (3.95 g, 29.55 mmol) in suspension in TTF (20 ml). Technical product was purified using column chromatography (hexane) to obtain 2-phenylthiophene-3-zolyl)-2-phenylthiophene-3 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-phenyl-thiophene-3-sulfonamide was obtained from 2-phenyl-3-thiophenesulfonyl using the method described in Example 1. The product was purified HPLC, with 77% yield, as a reddish solid, so pl. 86-89oC.

EXAMPLE 211

3 Phenoxy-N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide

A. 3-Phenoxathiin.

The copper chloride (3.08 g, 31.1 mmol) and finial (8.78 g, 93.3 mmol) were sequentially added to a solution of 3-bromothiophene (5.06 g, 31.1 mmol) in pyridine (150 ml). Then slowly added sodium hydride (3.73 g, 93.3 mmol, 60% dispersion in mineral oil). The reaction mixture was heated and was converted under reflux for 20 hours in an argon atmosphere. The pyridine was removed under reduced pressure. The residue was diluted with Et2O (200 ml) and washed with 1 N NaOH (3 x 100 ml), 1 H HCl (2 x 150 ml) and 1 N NaOH (150 ml). The organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was subjected to chromatography using hexane, to obtain 3-phenoxytoluene in the form of a light oil (4.0 g, 74% yield).

Century 3-Phenoxathiin-2-sulphonylchloride

BuLi (2.38 M, 11.5 ml, 27.28 mmol) was slowly added to a solution of 3-phenoxytoluene (4.0 g is through the mixture for 15 min at 0oC, after which was added NCS (3.95 g, 29.55 mmol) in suspension in THF (20 ml). The mixture was warmed to 25oC and was maintained for more than 2 hours. The precipitate was filtered, and the filtrate was concentrated and chromatographically (hexane) to obtain the C-phenoxathiin-2 - sulfonyl chloride as a yellowish solid (1.03 g, 17% yield).

C. N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenoxathiin-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenoxathiin-2 - sulfonamide was obtained from 3-phenoxathiin-2-sulphonylchloride and 5 - amino-4-bromo-3-methylisoxazole using the method described in Example 1. Product perekristalizovanny from a mixture of acetonitrile/H2O obtaining a solid substance with so pl. 121-123oC, 61% yield.

EXAMPLE 212

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-isopropylphenyl) aminocarbonyl] -thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4 - isopropylphenyl)aminocarbonyl] -thiophene-3-sulfonamide was obtained as described in Example 24 N-(4-bromo-3-methyl-5-isoxazolyl)- 2-(carboxyl)thiophene-3-sulfonamida and 4-isopropylaniline with 19% yield. Technical product was passed through a column Packed with silica gel, using ethyl acetate as eluent. receiving solids.

EXAMPLE 213

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-sec-butylphenyl)amino - carbonyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-sec - butylphenyl)aminocarbonyl] -thiophene-3-sulfonamide was obtained as described in Example 24 N-(4-bromo-3-methyl-5-isoxazolyl)-2- (carboxyl)thiophene-3-sulfonamida and 4-second-butylaniline with 25% output. Technical product was passed through a silica gel column using ethyl acetate as eluent. He was subjected to further purification using HPLC (5% CH3CN - 100% CH3CN over 30 min) to obtain a solid substance, so pl. 205 - 208oC.

EXAMPLE 214

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-tert-butylphenyl) aminocarbonyl] thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-tert-butylphenyl)- aminocarbonyl] thiophene-3-sulfonamide was obtained as described in Example 24 N-(4-bromo-3-methyl-5-isoxazolyl)-2- (carboxyl)thiophene-3-sulfonamida and 4-tertbutylamine with a 28% yield. Technical product was passed through a silica gel column using ethyl acetate as eluent. Further purification was carried out HPLC (5% CH3CN 100% CH3CN over 30 min) Were obtained solid substance, so pl. 76 - 86oC.

bromo-3-methyl-5-isoxazolyl)-2-[N-(4 - butylphenyl)aminocarbonyl]thiophene-3-sulfonamide was obtained as, as described in Example 24 N-(4-bromo-3-methyl-5-isoxazolyl)-2- (carboxyl)thiophene-3-sulfonamida and 4-butylaniline with 18% yield. Technical product was passed through a silica gel column using ethyl acetate as eluent. Further purification was carried out HPLC (5% CH3CN 100% CH3CN over 30 min ). There was obtained solid substance.

EXAMPLE 216

N-(4-bromo-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide

A. Thiazol-2-sulphonylchloride

The thiazole (0.51 g, 6 mmol) was dissolved in THF (5 ml) and cooled to -78oC in argon atmosphere. n-Utility (2.5 M solution in hexane, 2.4 ml, 6 mmol) was added dropwise with constant stirring. The resulting reaction mixture was stirred at -78oC for 40 min sulfur Dioxide was barbotirovany through the reaction mixture for 15 min at -78oC. the Reaction mixture was slowly warmed up to room temperature it was kept for 30 minutes After adding NCS maintaining continued for 30 minutes, the Reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (2 x 50 ml) and the combined organic layers were dried over anhydrous MgSO4. Removal of the solvent under reduced pressure resulted in the receipt of raw prodoljeniem the thiazole-2 - sulphonylchloride liquid (0.6 g, with a 4% yield).

C. N-(4-bromo-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide was obtained as described in Example 2 from 5-amino-4-bromo-3 - methylisoxazole and thiazole-2-sulphonylchloride with 57% yield. He was cleared HPLC (5% CH3CN 100% CH3CN over 30 min) to obtain a solid substance, so pl. 175 - 177oC.

EXAMPLE 217

N-(4-chloro-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide was obtained as described in Example 2 from 5-amino-4-chloro-3-methylisoxazole and thiazole-2-sulphonylchloride with 33% yield. He was cleared HPLC (5% CH3CN 100% CH3CN over 30 min) to obtain a solid substance, so pl. 171-173oC.

EXAMPLE 218

N-(3,4-dimethyl-5-isoxazolyl)thiazole-2-sulfonamide

N-(3,4 - methyl-5-isoxazolyl)thiazole-2-sulfonamide was obtained as described in Example 14, from 5-amino-3,4-dimethylisoxazole and thiazole-2-sulphonylchloride with a 37% yield. He was cleared HPLC (5% CH3CN 100% CH3CN over 30 min) to obtain a solid substance, so pl. 118-120oC.

EXAMPLE 219

5-benzyl-N-(4-Bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide

A. 1-(2-Thienyl)Benzino the methanol/TTF (ratio 1:10, 11 ml). The mixture was stirred at room temperature for 10 hours, the Reaction mixture was decomposed by the addition of saturated solution of ammonium chloride (50 ml), extracted with ethyl acetate (2 x 50 ml). The combined organic layers were dried over anhydrous MgSO4. After removal of the solvent was obtained 1-(2-thienyl)benzyl alcohol in the form of a solid (1.75 g, 92% yield).

Century 2-Benzylthio

To a solution of 1-(2-thienyl)benzyl alcohol in pyridine was added acetic anhydride (5 ml). The resulting solution was kept at 70oC for 3 hours and Then added water (50 ml) and the reaction mixture was stirred at room temperature for 2 hours, It was extracted with ethyl acetate (2 x 50 ml) and the combined organic layers were dried over anhydrous MgSO4. After removal of the solvent was obtained the crude product, which was purified by passing through silica gel, using a mixture 3:1 hexane/ethyl acetate. Received 1 -(2-thienyl)benzoylacetate.

A solution of 1-(2-thienyl)benzoylacetate in THF (5 ml) was carefully added to the dry liquid ammonia (100 ml). Metallic lithium was added in small portions until then, until the blue color. The resulting reaction after the complete evaporation of liquid ammonia was dissolved in water (50 ml) and was extracted with methylene chloride (2 x 30 ml). The combined organic layers were dried over MgSO4and filtered. After removal of the solvent was obtained the crude product, which was purified by column chromatography using hexane as eluent. There was obtained 2-benzoylthiophene (1.2, 68% yield).

C. 5-Benzylthio-2-sulfonyl chloride

To a solution of 2-benzoylthiophene (0.875 g, 5 mmol) in chloroform (2 ml) at 0oC was added dropwise chlorosulfonic acid, and the reaction was conducted at 0oC for 30 minutes the Reaction mixture was decomposed by pouring into crushed ice (20 g). The mixture was extracted with ethyl acetate, dried over MgSO4and filtered. The solvent was removed under reduced pressure to obtain 5 - benzylthio-2-sulfonic acid.

Pentachloride phosphorus (2.08 g, 40 mmol) was added to a solution of 5-benzylthio-2-sulfonic acid in phosphorus oxychloride (6.0 g, 40 mmol) at 0oC. the Reaction mixture was stirred at 50oC for 1 h, cooled to room temperature, then poured into crushed ice (50 g) and extracted with ethyl acetate (2 x 30 ml). Removal of the solvent under reduced pressure yielded the crude product, which was purified using levonelle (0.6 g, with 39% yield).

D. N-(4-bromo-3-methyl-5-isoxazolyl)-5-benzylthio-2 - sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-benzylthio-2-sulfonamide was obtained as described in Example 2 from 5-amino-4-bromo-3 - methylisoxazole and 5-benzyl-2-thiophenesulfonyl with 22% yield. The product was purified HPLC (5% CH3CN relative to 100% CH3CN over 30 min) to obtain a solid substance, so pl. 49 - 50oC.

EXAMPLE 220

N-(4-Bromo-3-methyl-5-isoxazolyl)-3-finaledition-2 - sulfonamide

A. 1-(3-Thienyl)phenethyl alcohol

Benzylbromide dissolved in ether (30 ml) (25.65 g, 150 mmol) was added dropwise over 8 h to a suspension of magnesium (3.6 g, 150 mmol) in ether (75 ml). The resulting mixture was cooled to - 10oC. Then was added 3-thiophenecarboxaldehyde in ether (45 ml) for 30 min, and the resulting reaction mixture was stirred at room temperature for 6 hours Then the reaction mixture was cooled to 0oC and decomposed by the addition of 0.1 N HCl. The ether layer was separated and the aqueous phase was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were dried over MgSO4and filtered. After removal of the solvent was obtained 1-(3 - thienyl)phenethyl alcohol (16 g, 78% yield). is si composition 2:1 (pyridine and acetic anhydride (50 ml). The resulting mixture was stirred at 80oC for 4 h the mixture of Excess pyridine and acetic anhydride were removed under reduced pressure, and the residue was dissolved in water (100 ml). It was extracted with methylene chloride (3 x 75 ml) and the combined organic layers were dried over MgSO4and filtered. After removal of the solvent was obtained 1-(3-thienyl)fenilatilamin (10.2 g, 84% yield).

C. 3-Finaledition

1-(3-thienyl)fenilatilamin dissolved in THF (20 ml) was carefully added to the dry liquid ammonia (300 ml). Then added in small portions metallic lithium as long until I installed blue color. The resulting reaction mixture was stirred for 30 min, and the reaction was stopped by addition of solid ammonium chloride. The residue after complete evaporation of liquid ammonia was dissolved in water (100 ml) and extracted with methylene chloride (4 x 50 ml). The combined organic layers was dried over MgSO4and filtered. After removal of the solvent was obtained the crude product, which was purified by column chromatography using hexane and then a mixture of ethyl acetate in hexane as eluent. Received 3-finaledition (3.2 g, 34% you-finaledition - 2-sulfonyl chloride

3-Finaledition (0.94 g, 5 mmol) was dissolved in THF (12 ml) and cooled to -78oC in an argon atmosphere, n-utility (2.5 M solution in hexane, 4.4 ml, 5.5 mmol) was added dropwise with constant keeping in argon atmosphere. The resulting reaction mixture is kept at -10oC - 0oC for 3 h, cooled to -78oC and barbotirovany sulfur dioxide through the reaction mixture for 15 minutes, the Temperature of the reaction mixture was slowly reached room temperature, and the curing was continued for 30 minutes was added NCS (1 g) and the curing was continued for 1 h, the Reaction mixture was diluted with water (50 ml), extracted methylene chloride (2 x 50 ml) and the combined organic layers were dried over anhydrous MgSO4. Removal of the solvent under reduced pressure yielded the crude product, which was purified by column chromatography, using a 0.2% ethyl acetate in hexane as eluent to obtain 3-phenylethyl-2 - thiophenesulfonyl (0.06 g, 4% yield) and 4-phenylethyl-2 - thiophenesulfonyl (0.72 g, 45% yield).

E. N-(4-bromo-3-methyl-5-isoxazolyl)-3-finaledition-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-3-geneletti-2 - thiophenesulfonyl with a 48% yield. He was cleared HPLC (5% CH3CN to 100% CH3CN over 30 min) to obtain a solid substance.

EXAMPLE 221

N-(4-Bromo-3-methyl-5-isoxazolyl)-4-finaledition-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-finaledition-2 - sulfonamide was obtained as described in Example 2 from 5 - amino-4-bromo-3-methylisoxazole and 4-phenylethyl-2 - thiophenesulfonyl with a 32% yield. He was cleared HPLC (5% CH3CN to 100% CH3CN over 30 min) to obtain the resin.

EXAMPLE 222

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene - 2-sulfonamide

A. 5-bromothiophene-2-sulphonylchloride

Chlorosulfonic acid was added dropwise over 20 min to a cold solution (-78oC) 2-bromothiophene (16.3 g, 100 mmol) in methylene chloride (50 ml). After complete addition of chlorosulfonic acid cold bath was removed. The reaction mixture was allowed to reach room temperature, after which it slowly (2 h), was added dropwise into crushed ice (1000 g) and was extracted with methylene chloride (4 x 100 ml). The combined organic layers was dried over MgSO4, filtered, and the solvent was removed under reduced pressure to get crude product. It was purified using g, with 75% yield).

C. N-(5-bromothiophene-2-sulfonyl)pyrrol

N-(5-bromothiophene-2-sulfonyl)pyrrole was obtained as described in Example 33A, from 5-bromothiophene-2-sulphonylchloride and pyrrole with 88% yield. It was purified by recrystallization using a mixture of hexane/ethyl acetate as solvent.

C. 3-Methoxyflavone acid

3-Methoxyflavone acid was obtained as described in Example 33B, 3-bromoanisole and triisopropylsilane with 82% yield. It was used in the next stage without any further purification.

D. N-[5-(3-methoxyphenyl)thiophene-2-sulfonyl]pyrrol

N-[5-(3-methoxyphenyl)thiophene-2-sulfonyl] pyrrole was obtained as described in Example 32C, 3 methoxyflavone acid and N-(5-bromothiophene-2-sulfonyl)of pyrrole with 93% yield. It was purified by recrystallization using a mixture of hexane/ethyl acetate as solvent.

E. 5-(3-Methoxyphenyl)thiophene-2-sulphonylchloride

To a suspension of N-[5-(3-methoxyphenyl)thiophene-2-sulfonyl]pyrrole (1.4 g, 4.5 mmol) in ethanol (15 ml) was added 6 N sodium hydroxide solution (15 ml) and the resulting reaction mixture was converted under reflux for 14 hours the Reaction mixture klaeden and dried under vacuum (1.1 g, 91% yield).

Pentachloride phosphorus (2.08 g, 10 mmol) was added to a suspension of sodium salt of sulfonic acid and 0.62 g, 2.5 mmol) (obtained in the previous stage) in phosphorus oxychloride (0.93 ml, 10 mmol) and the resulting reaction mixture was stirred at room temperature for 3 hours It was decomposed by adding crushed ice and the product was extracted using methylene chloride (2 x 50 ml). The combined organic layers were dried over MgSO4and filtered. After removal of solvent received a technical product, which was purified by column chromatography using 2% ethyl acetate in hexane to obtain 5-(3-methoxyphenyl)thiophene-2 - sulphonylchloride (0.51 g, 75%).

F. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene - 2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene-2 - sulfonamide was obtained as described in Example 2 from 5 - amino-4-bromo-3-methylisoxazole and 5-(3-methoxyphenyl)thiophene-2 - sulfonyl chloride with a 48% yield. It was purified using HPLC (5% CH3CN to 100% CH3CN over 30 min) to obtain a solid substance.

EXAMPLE 223

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-methylphenyl)thiophene - 2-su who was added dropwise at constant curing in nitrogen atmosphere to a solution of 2-methylfuran (1.0 g, 12 mmol) in THF (20 ml) at -78oC. the Solution was then warmed to -10oC, and curing was continued for 45 minutes the Solution was then added to a solution of zinc chloride (27 ml, 0.5 M solution in THF) at -30oC, and then heated to room temperature; curing was continued for 1 h Turned light yellow solution. The solution was then transferred under nitrogen atmosphere to a solution of N-(pyrrole)-5-bromothiophene-2-sulfonamida (Example 33A, 3.5 g, 12 mmol) and tetrakis(triphenylphosphine)palladium (0) (693 mg, 0.6 mmol) in THF (15 ml) at -78oC. the Solution was then warmed to room temperature and was maintained for 2 hours. Purification using column chromatography using 2% ethyl acetate resulted in the receipt of 680 mg of N-(pyrrole)-5-(2 - methylphenyl)thiophene-2-sulfonamida in the form of a yellow powder (19% yield).

Century 2-(2-methylphenyl)thiophene-5-sulphonylchloride

2-(2 - methylphenyl)thiophene-5-sulphonylchloride was obtained as described in Example 33D, of N-(pyrrole)-5-(2-methylphenyl)thiophene-2 - sulfonamida (300 mg, 1.02 mmol). Purification using column chromatography using 2% mixture of ethyl acetate/hexane resulted in the receipt of 145 mg (53%) of sulphonylchloride in the form of a yellow solid.

C. N-(4-bromo-3-methyl-5-and the sulfonamide was obtained in the same way, as described in Example 2. The reaction of 2-(2-methylphenyl)-thiophene-5-sulphonylchloride (55 mg, 0.21 mmol) with 5-amino-4-bromo-3-methylisoxazole (41 mg, 0.21 mmol), after purification using column chromatography using 10% MeOH/CHCl3led to obtain 45 mg of pure sulfonamida in the form of a brown semi-solid substance, with a 54% yield, so pl. 123-124oC.

EXAMPLE 224

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-2 - sulfonamide

A. N-15-(4-methoxyphenyl)thiophene-2-sulfonyl]pyrrol

N-[5-(4-methoxyphenyl)thiophene-2-sulfonyl] pyrrole was obtained as described in Example 32C from 4-ethoxyphenylurea acid and N-(5-bromothiophene-2-sulfonyl)pyrrole. Recrystallization using a mixture of hexane/ethyl acetate resulted in the formation of solid substances with a quantitative yield.

Century 5-chlorosulfonyl-2-(4-methoxyphenyl)thiophene

A solution of N-[5-(4-methoxyphenyl)thiophene-2-sulfonyl]pyrrole (1.4 g, 4.5 mmol) was suspended in ethanol (15 ml). Was added 6N solution of sodium hydroxide, and the resulting suspension was distilled under reflux for 14 hours to obtain a light solution. It was cooled to room temperature. The ethanol was removed under reduced pressure. When standing at commumon with getting a solid (1.2 g, 91%).

Solid (0.67 g, 2.5 mmol) was suspended in phosphorus oxychloride (0.92 ml, 10 mmol) was added pentachloride phosphorus (2.08 g, 10 mmol). The resulting mixture was stirred at room temperature for 3 hours the Reaction mixture was decomposed by pouring onto crushed ice (50 g). The mixture was extracted with methylene chloride (2 x 50 ml) and the combined organic layers was dried over MgSO4. After removal of the solvent under reduced pressure, the obtained crude product, which was purified by column chromatography using 2% EtOAc in hexane as solvent, to obtain 5-chlorosulfonyl-2-(4-methoxyphenyl)-thiophene (530 mg, 86%).

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene - 2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-2 - sulfonamide was obtained as described in Example 1. The reaction of 5-chlorosulfonyl-2-(4-methoxyphenyl)thiophene with 5-amino-4-bromo-3 - methylisoxazole led to N-(4-bromo-3-methyl-5 - isoxazolyl)-5-(4-methoxyphenyl)thiophene-2-sulfonamide with 50% output, so pl. 128-130oC.

EXAMPLE 225

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-thienyl)thiophene-2 - sulfonamide

A. 3-Tithebarn acid

n-Utility (2.5 M 8oC in argon atmosphere. The resulting solution was kept at -78oC for 45 min and then added to a solution of triisopropylsilane (9.4 g, 50 mmol) in THF at -78oC for 30 min through a steel funnel. The resulting reaction mixture was stirred at room temperature for 12 h and was dissolved by adding 100 ml of 1N HCl. The aqueous layer was extracted with ether (2 x 100 ml) and the combined organic layers were extracted 1 M NaOH (3 x 30 ml), the aqueous extract was acidified with concentrated HCl to pH 2, and extracted with ether (3 x 50 ml). The combined ether extracts were washed once with water, dried over MgSO4and filtered. After removal of solvent received 3-tienerporno acid as a solid (5.2 g, 80% yield).

C. N-[5-(3-thienyl)thiophene-2-sulfonyl]pyrrol

N-[5-(3-thienyl)thiophene-2-sulfonyl]pyrrole was obtained as described in Example 32C, 3 thienylboronic acid and N-(5 - bromothiophene-2-sulfonyl)of pyrrole with a quantitative yield. It was purified by recrystallization using a mixture of hexane/ethyl acetate as a solvent.

C. 5-(3-Thienyl)thiophene-2-sulphonylchloride

5-(3-thienyl)thiophene-2-sulphonylchloride was obtained as described in Example A, from N-[who yl)thiophene-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-thienyl)thiophene-2 - sulfonamide was obtained as described in Example 2 from 5 - amino-4-bromo-3-methylisoxazole and 5-(3-thienyl)thiophene-2 - sulphonylchloride with 40% yield. He was cleared HPLC (5% CH3CN to 100% CH3CN over 30 min) to obtain a solid substance.

EXAMPLE 226

N-(4-Bromo-3-methyl-5-isoxazolyl)furan-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)furan-2-sulfonamide was obtained according to the method described in Example 1, using 5-amino - 4-bromo-3-methylisoxazole (0.266 g, 1.5 mmol), NaH (60% dispersion in oil) (0.15 g, 3.8 mmol) and furan-2-sulphonylchloride (Example 36A) (0.30 mg, 1.8 mmol). Flash chromatography (50% EtOAc/hexane) and recrystallization from CHCl3and the hexane resulted in the receipt of 90 mg (20% yield) of light yellow crystals (so pl. 117-119oC).

EXAMPLE 227

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2 - sulfonamide

A. 2-(phenylthio)furan

t-BuLi (1.7 M, 10 ml, 1.7 mmol) was added to a solution of furan (1.24 ml, 17 mmol) in 20 ml of THF at -60oC. in thirty minutes was added through the funnel diphenyldisulfide (3.7 g, 17 mmol) in 8 ml THF. The reaction mixture was heated to room temperature for 30 min, then diluted with 150 ml of ether and washed with 3% NaOH (3 x 100 the Dom) light yellow liquid.

Century 5-phenylthiophene-2-sulphonylchloride

5-phenylthiophene-2-sulphonylchloride was obtained according to the method described in Example 34A, 5-phenylthiophene (1.5 g, 8.5 mmol), t-BuLi (1.2 M, 8.9 mmol, 5.3 ml) and NCS (1.14 g, 8.5 mmol). Flash chromatography (5% EtOAc/hexane) resulted in the receipt of 1.61 g (69% yield) of a yellow-orange liquid.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2 - sulfonamide was obtained according to the method described in Example 1, using 4-bromo-3-methyl-2 - aminoethanethiol (0.354 g, 2.0 mmol), NaH (60% dispersion in oil) (0.20 g, 5.0 mmol) and 5 - phenylthiophene-2-sulphonylchloride (0.66 g, 2.4 mmol). Flash chromatography (50% EtOAc/hexane) and recrystallization from a mixture of CHCl3/hexane resulted in the receipt of 82 mg (10% yield) of a gray solid (so pl. 90-91.5oC).

EXAMPLE 228

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-phenylfuro-2-sulfonamide

A. 2-Phenylfuro

2-phenylfuro was obtained according to the method described in Example 32C from 2-bromofuran (0.93 g, 6.3 mmol), sodium carbonate (18 ml of 2 M aqueous solution), phenylboric acid (0.93 g, 7.6 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.36 g, 0.32 mmol). Flash chromatography using hexane resulted in the receipt of 0.79 g Nellore was obtained according to the method, described in Example 34A, from 2-phenylbutane (0.79 g, 5.5 mmol), t-BuLi (1.7 M, 6.0 mmol, 3.6 ml) and NCS (0.73 g, 5.5 mmol). Flash chromatography (5% EtOAc/hexane) resulted in the receipt of 0.84 g (63% yield) of a light red solid.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-phenylfuro-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-phenylfuro-2-sulfonamide was obtained according to the method described in Example 1, using 4 - bromo-3-methyl-2-aminoethanethiol (0.354 g, 2.0 mmol), NaH (60% dispersion in oil) (0.20 g, 5.0 mmol) and 5-phenylfuro-2-sulfonyl chloride (0.58 g, 2.4 mmol). Flash chromatography (50% EtOAc/hexane) and recrystallization from a mixture of CHCl3/hexane resulted in the receipt of 0.23 g (29% yield) of light yellow crystals (so pl. 124-126oC).

EXAMPLE 229

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-isopropylphenyl)thiophene - 2-sulfonamide

A. 4-Isopropylaniline acid

4-Isopropylaniline acid was obtained as described in Example 33B, from 1-bromo-4-ethylbenzene. The acid was isolated as a white powder in 63% yield, so pl. 133-135oC.

C. N-[5-(4-isopropylphenyl)thiophene-2-sulfonyl]pyrrol

N-[5-(4-isopropylphenyl)thiophene-2-sulfonyl]pyrrole was obtained as described in Example 33, 4-isopropylphenyl% mixture of ethyl acetate/hexane, led to the production of clean sulfonamida in the form of a white colored solid in 84% yield, so pl. 112-114oC.

C. 5-chlorosulfonyl-2-(4-ethylphenyl)thiophene

5-chlorosulfonyl-2-(4-ethylphenyl)thiophene was obtained as described in Example 33D. Hydrolysis of 526 mg (1.59 mmol) of N-[5-(4 - isopropylthio)-2-sulfonyl] pyrrole using 6N sodium hydroxide followed by chlorination using phosphorus oxychloride and pentachloride phosphorus led to the crude sulphonylchloride in the form of a black oil. Flash column chromatography over silica gel using 2% mixture of ethyl acetate/hexane resulted in the receipt of 262 mg (55%) of pure sulphonylchloride in the form of a light brown oil.

D. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4 - isopropylphenyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-isopropylphenyl)thiophene - 2-sulfonamide was obtained as described in Example 2. The reaction of 5-chlorosulfonyl-2-(4-isopropyl)thiophene (260 mg, 0.87 mmol) with 5 - amino-4-bromo-3-methylisoxazole (161 mg, 0.91 mmol) yielded, after flash chromatography using 10% MeOH/CHCl3brown solid (265 mg), which was subjected to further purification using SS="ptx2">

EXAMPLE 230

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-propylphenyl)thiophene-2 - sulfonamide

A. 1-bromo-4-propylbenzoyl

A solution of 1-bromopropane (1.32 g, 0.6 mmol) was added dropwise at room temperature at a rate sufficient to maintain distillation under reflux to a suspension of magnesium (258 mg, 12 mmol) in dry tetrahydrofuran. The suspension is kept at room temperature additionally for 30 min with the aim of obtaining the gray solution, which was then added dropwise within 15 min to a mixture of 1-iodine-4-bromine benzol (3.0 g, 10.6 mmol) and tetrakis(triphenylphosphine)palladium (0) in 50 ml of dry benzene at room temperature. The mixture was stirred for 2 hours, diluted with 50 ml water, then the organic layer was separated, and the aqueous layer was extracted with ether (2 x 50 ml). The combined organic extracts were dried and evaporated. Received 1.69 g (80%) of a light brown oil, which was used in the next step with further purification.

Century 4-Propylaniline acid

To a suspension of sawdust magnesium (217 mg, 8.9 mmol) in 3 ml dry tetrahydrofuran in an argon atmosphere was added a crystal of iodine to a solution of 4-bromopropylate (1.69 g, 8.5 mmol) in 6 ml of tetrahydrofuran with such near the reflux for 0.5 h, was cooled to room temperature and was added in portions over 10 min to a previously prepared solution of triethylborane (924 mg, 8.9 mmol) in 4 ml of dry ether at -78oC. After 30 minutes the solution was warmed to room temperature, and the curing was continued for 90 minutes the Reaction was terminated by adding 2 ml of 10% hydrochloric acid. The tetrahydrofuran was removed under reduced pressure and the residue was extracted with diethyl ether (3 x 25 ml). The combined ether extracts were extracted 1 M NaOH (3 x 25 ml), and the resulting aqueous layer was acidified to pH 2.0 using 6N HCl, then extrahieren back into diethyl ether (3 x 25 ml). The combined organic layers were washed with water (1 x 25 ml), brine (1 x 25 ml) and dried over magnesium sulfate. Evaporation of the solvent led to a brown solid, which was filtered through a small layer of silica gel using 10% MeOH/CHCl3. After evaporation remained 448 mg (32%) brown solid, so pl. 90-93oC.

C. N-[5-(4-propylphenyl)thiophene-2-sulfonyl]pyrrol

N-[5-(4-propylphenyl)thiophene-2-sulfonyl] pyrrole was obtained as described in Example 33, 4-propylaniline sour is ylacetic/hexane resulted in the receipt of net sulfonamida in the form of a white solid with a 55% yield, so pl. 106-108oC.

D. 5-chlorosulfonyl-2-(4-propylphenyl)thiophene

5-chlorosulfonyl-2-(4-propylphenyl)thiophene was obtained as described in Example 33D. As a result of hydrolysis of 240 mg (0.73 mmol) of N-[5-(4-properposition)-2-sulfonyl] pyrrole using 6N NaOH followed by chlorination with phosphorus oxychloride and pentachloride phosphorus was obtained the crude sulphonylchloride in the form of a greenish-brown oil. Flash chromatography over silica gel using 2% mixture of ethyl acetate/hexane resulted in the receipt of 83 mg (81%) of pure sulphonylchloride in the form of a yellow oil.

E. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-propylphenyl)thiophene - 2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-propylphenyl)thiophene-2 - sulfonamide was obtained as described in Example 2, the Reaction of 5-chlorosulfonyl-2-(4-isopropyl)thiophene (260 mg, 0.87 mmol) with 5 - amino-4-bromo-3-methylisoxazole (161 mg, 0.91 mmol) led to a brown solid after flash chromatography using 10% MeOH/CHCl3. This substance (76.1 mg) was subjected to further purification using preparative HPLC to obtain pure sulfonamida in the form of a brownish oil.

EXAMPLE 231

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(3,4,5-Tr(2-benzo[b] thienyl)-3,4,5-trimethoxybenzylamine alcohol was obtained in the same way, as described in Example 40A. The reaction of benzo[b]thiophene (7.5 mmol, 1.0 g), t-BuLi (1.7 m, 9.7 mmol, 5.7 ml) and 3,4,5 - trimethoxybenzaldehyde (8.9 mmol, 1.8 g) in THF (20 ml) resulted, after flash chromatography using a mixture of 50% ethyl acetate/hexane, 2.4 g (97%) of a yellow-white solid.

Century 2-(3,4,5-trimethoxybenzyl)-benzo[b]thiophene

2-(3,4,5 - trimethoxybenzyl)-benzo[b]thiophene was obtained as described in Example 47B. Reaction - (2-benzo[b]thienyl)-3,4,5 - trimethoxybenzyl alcohol (4.5 mmol, 1.5 g), triethylsilane (5.0 mmol, 0.80 ml), CH2Cl2(50 ml) and TFA (9.1 mmol, 0.70 ml) resulted, after flash chromatography using a mixture of 20% ethyl acetate/hexane, 0.77 g (54%) of a white solid.

C. 2-(3,4,5-trimethoxybenzyl)-benzo[b] thiophene-3-sulphonylchloride 2-(3,4,5-trimethoxybenzyl)-benzo[b] thiophene-3-sulphonylchloride was obtained as described in Example 40B. The reaction of dimethylformamide, (DMF); 4.8 mmol, 0.40 ml), sulfurylchloride (4.1 mmol, 0.33 ml) and 2-(3,4,5-trimethoxybenzyl)-benzo[b] thiophene (2.4 mmol, 0.75 g) was yielded, after flash chromatography using a mixture of 20% ethyl acetate/hexane, 0.29 g (30%) of a yellow-orange oil.

D. N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4,5-trimethoxybenzyl)- benzo[b] thiophene-3-Sulak, as described in Example 41. The reaction of 4-bromo-3-methyl-5-aminoisoquinoline (0.55 mmol, 97 mg), NaH (1.4 mmol, 55 mg) and 2-(3,4,5-trimethoxybenzyl)-benzo[b]thiophene-3-sulphonylchloride (0.66 mmol, 0.27 g) in THF (2 ml) resulted, after flash chromatography using a 50% mixture of ethyl acetate/hexane and recrystallization from chloroform and hexane, 94 mg of a brown solid with so pl. 154-156oC.

EXAMPLE 232

N-(4-bromo-3-methyl-5-isoxazolyl) 2-ethyl-5-methylbenzo[b] thiophene - 3-sulfonamide

A. 2-ethyl-5-methylbenzo[b]thiophene

2-ethyl-5-methylbenzo[b] thiophene was obtained as described in Example 40A. The reaction of 5-methylbenzo[b]thiophene (3.4 mmol, 0.50 g), t-BuLi (1.7 M, 5.1 mmol, 3.0 ml) and ethyl iodide (6.8 mmol, 0.54 ml) in THF (10 ml) led to obtain 0.58 g (97%) of a light yellow liquid.

Century 2-ethyl-5-methylbenzo[b]thiophene-3-sulphonylchloride

2-ethyl-5-methylbenzo[b] thiophene-3-sulphonylchloride was obtained as described in Example 40B. The reaction DMF (6.5 mmol, 0.50 ml), sulfurylchloride (5.5 mmol, 0.44 ml) and 2-ethyl-5 - methylbenzo[b]thiophene (3.2 mmol, 0.57 g) was yielded, after flash chromatography, using a mixture of 2% ethyl acetate/hexane, 0.58 g (66%) of orange solid.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-ethyl-5-methylbenzo[b] Tiefenbach described in Example 41. The reaction of 4-bromo-3-methyl-5-aminoisoquinoline (1.0 mmol, 0.18 g), NaH (2.5 mmol, 0.10 g) and 2-ethyl-5-methylbenzo[b] thiophene-3 - sulphonylchloride (1.3 mmol, 0.36 g) in THF (6 ml) resulted in obtaining, after recrystallization from chloroform and hexane, 0.25 g (60%) of a light brown crystalline solid, so pl. 176-178oC.

EXAMPLE 233

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]- benzo[b] thiophene-3-sulfonamide

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy) benzyl]-benzo[b] thiophene-3-sulfonamide was obtained as described in Example 41. The reaction of 4-chloro-3-methyl-5 - aminoisoquinoline (0.61 mmol, 81 mg), NaH (1.5 mmol, 61 mg) and 2-[3,4-(methylenedioxy)benzyl] benzo[b]thiophene-3-sulphonylchloride (0.74 mmol, 0.27 g) in THF (4 ml) resulted, after flash chromatography using a 50% mixture of ethyl acetate/hexane followed by recrystallization from a mixture of ethyl acetate and hexane, 0.23 g (81%) of light brown solid, so pl. 178-181oC.

EXAMPLE 234

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxybenzyl)-benzo [b] thiophene-3-sulfonamide

A. - (2-benzo[b]thienyl)-3,4-dimethylbenzylamine alcohol

- (2-benzo[b] thienyl)-3,4-dimethylbenzylamine alcohol was obtained as described in Example 40A. The reaction of benzo[b]type the Oia, after flash chromatography using a mixture of 30% ethyl acetate/hexane, 2.25 g (> 100%) of a white solid "rubber-like" substances.

Century 2-(3,4-dimethoxybenzyl)benzo[b]thiophene

2-(3,4-dimethoxybenzyl)benzo[b] thiophene was obtained as described in Example 47B. Reaction - (2-benzo[b]thienyl)-3-4 - dimethoxybenzyl alcohol (7.5 mmol, 2.25 g), triethylsilane (8.2 mmol, 1.3 ml) and CH2Cl2(20 ml) TFU (15 mmol, 1.2 ml) resulted, after flash chromatography using a mixture of 10% ethyl acetate/hexane, 1.77 g (84%) of colorless oil.

C. 2-(3,4-dimethoxybenzyl)-benzo[b]thiophene-3-sulphonylchloride

2-(3,4-dimethoxybenzyl)-benzo[b]thiophene-3-sulphonylchloride was obtained as described in Example 40B. The reaction DMF (90 mmol, 7 ml) and 2-(3.4-dimethoxybenzyl)-benzo[b] thiophene (6.0 mmol, 1.7 g) was yielded, after flash chromatography using a mixture of 15% ethyl acetate/hexane, 1.24 g (54%) green oil.

D. N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxybenzyl)- benzo[b] thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxybenzyl)- benzo[b] thiophene-3-sulfonamide was obtained as described in Example 41. The reaction of 4-bromo-Z-methyl-5-aminoisoquinoline (1.0 mmol, 0.18 g), NaH (2.5 mmol, 60 mg) and 2-(3,4 - dimethoxybenzyl is a, led to obtain 0.42 g (80%) brown solid, so pl. 151-153oC.

EXAMPLE 235

N-(3,4-dimethyl-5-isoxazolyl)-2-(3,4-methylendioxy)benzo[b] thiophene-3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-(3,4-methylendioxy)benzo[b] thiophene-3-sulfonamide was obtained as described in Example 41. Reaction of 3,4-dimethyl-5-aminoisoquinoline (1.0 mmol, 0.11 g), NaH (2.5 mmol, 60 mg) and 2-[3,4-(methylenedioxy)benzyl] -benzo[b] thiophene-3 - sulphonylchloride (1.1 mmol, 0.40 g) in THF (6 ml) resulted, after flash chromatography using a 50% mixture of ethyl acetate/hexane, followed by recrystallization from chloroform and hexane, 0.35 g (79%) of a brownish solid, so pl. 135-137oC.

EXAMPLE 236

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(4-methoxybenzyl)benzo [b]thiophene-3-sulfonamide

A. - (2-benzo[b]thienyl)-4-methoxybenzyloxy alcohol

- (2-benzo[b]thienyl)-4-methoxybenzyloxy alcohol was obtained according to the method described in Example 40A, using benzo[b]thiophene (7.5 mmol. 1.0 g), t-BuLi (1.7 M, 10.4 mmol, 6.1 ml), 4-methoxybenzaldehyde (8.9 mmol, 1.1 ml) and THF (20 ml). Flash chromatography (20% mixture of ethyl acetate/hexane) yielded 1.75 g (87%) of a yellow solid.

Century 2-(4-methoxybenzyl)-benzo[b]thiophene

2-(4-IU the business of alcohol (1.9 mmol, 0.50 g), triethylsilane (2.0 mmol, 0.32 ml), CH2Cl2(20 ml) and TFU (3.7 mmol, 0.30 ml). Recrystallization using hexane and chloroform led to 0.40 (85%) of a pink solid.

C. 2-(4-methoxybenzyl)-benzo[b]thiophene-3-sulphonylchloride

2-(4-methoxybenzyl)-benzo[b]thiophene-3-sulphonylchloride was obtained according to the method described in Example 40B, using DMF (3.2 mmol, 0.24 ml), sulfurylchloride (2.7 mmol, 0.22 ml) and 2- (4-methoxybenzyl)-benzo[b]thiophene (1.6 mmol. 0.4 g). Flash chromatography using 2% mixture of ethyl acetate/hexane resulted in the receipt of 0.19 g (33%) of light yellow solid.

D. N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(4-methoxybenzyl) benzo[b] thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methoxybenzyl)- benzo[b] thiophene-3-sulfonamide was obtained according to the method described in Example 41 from 4-bromo-3-methyl-5-aminoisoquinoline (0.48 mmol, 85 mg), NaH (1.2 mmol, 48 mg), 2-(4-methoxybenzyl)-benzo[b]thiophene-3 - sulphonylchloride (0.53 mmol, 0.19 g) and THF (3 ml). Flash chromatography (mixture of 50% ethyl acetate/hexane) followed by recrystallization from methanol and water has led to 46 mg (20%) of white crystalline solid, so pl. 120-122oC.

EXAMPLE 237

N-(4-Bromo-3-methyl-5-R>
- (2-Benzo[b] thiophene)-2-methoxybenzyloxy alcohol was obtained according to the method described in Example 47A, benzo[b]thiophene (7.5 mmol, 1.0 g), t-BuLi (1.7 M, 9.7 mmol, 5.7 ml), 2-methoxybenzaldehyde (8.9 mmol, 1.1 ml) and THF (20 ml). Flash chromatography (mixture of 20% ethyl acetate/hexane) yielded 1.9 g (96%) of yellow oil.

Century 2-(2-Methoxybenzyl)-benzo[b]thiophene

2-(2-Methoxybenzyl)-benzo[b] thiophene was obtained according to the method described in Example 47B, (2-benzo[b]thiophene)-2-methoxybenzamido alcohol (7.1 mmol, 1.9 g), triethylsilane (7.9 mmol, 1.3 ml) and CH2Cl2(30 ml). At 0oC was added TFU (14.3 mmol, 1.1 ml). Flash chromatography (mixture of 2% ethyl acetate/hexane) yielded 1.31 g (72%) of yellow solid.

C. 2-(2-methoxybenzyl)-benzo[b]thiophene-3-sulfonyl chloride

2-(2-methoxybenzyl)-benzo[b] thiophene-3-sulfonyl chloride was obtained by the method described in Example 40B, using sulfurylchloride (8.4 mmol, 0.7 ml), DMF (9.8 mmol, 0.8 ml) and 2- (2-methoxybenzyl)-benzo[b]thiophene (4.9 mmol, 1.25 g). Flash chromatography (mixture of 2% ethyl acetate/hexane) resulted in the receipt of 0.94 g (54%) yellow solid.

D. N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2-methoxybenzyl)- benzo[b]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-itxas who eat 5-amino-4-bromo-3-methylisoxazole (1.0 mmol, 0.18 g), NaH (2.5 mmol, 100 mg), 2-(2-methoxybenzyl)- benzo[b]thiophene-3-sulphonylchloride (1.4 mmol, 0.49 g) and THF (7 ml). Flash chromatography (mixture of 50% ethyl acetate/hexane) followed by recrystallization from chloroform and hexane resulted in the receipt of 0.30 g (61%) brown solid, so pl. 80-84oC.

EXAMPLE 238

N-(3,4-dimethyl-5-isoxazolyl)-2-(4-chlorbenzyl)-benzo[b] thiophene - 3-sulfonamide

A. - (2-benzo[b]thienyl)-4-chlorbenzoyl alcohol

- (2-benzo[b]thienyl)-4-chlorbenzoyl alcohol was obtained according to the method described in Example 40A, using benzo[b]thiophene (7.5 mmol, 1.0 g), t-BuLi (1.7 M, 9.7 mmol, 5.7 ml), 4 - chlorobenzaldehyde (9.7 mmol, 1.4 g) and THF (20 ml). The crude material (2.45 g) was subjected to further purification.

Century 2-(4-chlorbenzyl)benzo[b]thiophene

2-(4 - chlorbenzyl)benzo[b] thiophene was obtained according to the method described in Example 47B, using - (2-benzo[b]thiophene)-4-Chlorobenzilate alcohol (8.9 mmol, 2.45 g), triethylsilane (9.8 mmol, 1.6 ml), CH2Cl2(40 ml) and TFU (13.4 mmol, 1.0 ml). Flash chromatography (mixture of 1% ethyl acetate/hexane) resulted in 1.3 g (67% - 2 stage) of a white solid.

C. 2-(4-chlorbenzyl)benzo[b]thiophene-3-sulphonylchloride

2-(4-chlorbenzyl)benzo[b] thiophene-3-sulphonylchloride was polarbear)- benzo[b]thiophene (4.6 mmol, 1.2 g). Flash chromatography (2% ethyl acetate/hexane) yielded 0.51 g (31%) of an orange-yellow oil.

D. N-(3,4-dimethyl-5-isoxazolyl)-2-(4-chlorbenzyl)- benzo[b] thiophene-3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-(4-chlorbenzyl)-benzo[b] thiophene - 3-sulfonamide was obtained according to the method described in Example 41, using 3,4-dimethyl-5-aminoisoquinoline (1.2 mmol, 1.4 g), NaH (3.0 mmol, 73 mg), 2-(4-chlorbenzyl)-benzo[b] thiophene-3-sulphonylchloride (1.4 mmol, 0.50 g) and THF (8 ml). Flash chromatography (mixture of 50% ethyl acetate/hexane) followed by recrystallization from methanol and water has led to 1.04 g (27%) yellow solid, so pl. 100-102oC.

EXAMPLE 239

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-dimethylaminobenzoyl)benzo [b]thiophene-Z-sulfonamide

A. - (2-benzo[b]thienyl)-4-dimethylaminobenzoyl alcohol

- (2-benzo[b]thienyl)-4-dimethylaminobenzoyl alcohol was obtained according to the method described in Example 40A, using benzo[b]thiophene (7.5 mmol, 1.0 g), t-BuLi (1.7 M, 8.9 mmol, 5.3 ml), 4-dimethylaminobenzaldehyde (8.9 mmol, 1.3 g) and THF (20 ml). Technical product (2.4 g) was subjected to further purification.

Century 2-(4-dimethylaminobenzoyl)benzo[b]thiophene

2-(4-dimethylaminobenzoyl)benzo[b]thiophene was obtained according to the method described 8 mmol, 1.3 ml), CH2Cl2(50 ml) and TFU (11.2 mmol, 0.9 ml). Flash chromatography (mixture of 10% ethyl acetate/hexane) resulted in 1.5 g (73% in two stages) of a white solid.

C. 2-(4-dimethylaminobenzoyl)-benzo[b]thiophene-3-sulphonylchloride

Chlorosulfonic acid (9.4 mmol, 0.6 ml) was added to 2-(4-dimethylaminobenzoyl)-benzo[b] thiophene (3.7 mmol, 1.0 g) in CH2Cl2(100 ml) at -78oC. the Solution is kept for 20 min at -78oC. phosphorus Oxychloride (11.2 mmol, 1.0 ml) and pentachloride phosphorus (11.2 mmol, 2.3 g) were added to the reaction mixture. The reaction mixture was heated to room temperature, and the curing was continued for additional 1.5 hours, after which the mixture was diluted with ice (> 200 ml), and extracted with ethyl acetate (200 ml). The organic layer was carefully washed with saturated solution of NaHCO3(3 x 100 ml), then dried (MgSO4), filtered and concentrated. Flash chromatography (mixture of 5% ethyl acetate/hexane) yielded 0.61 g (45%) yellow solid.

D. N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-dimethylaminobenzoyl)- benzo[b] thiophene-Z-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-dimethylaminobenzoyl)-benzo [b] thiophene-3-sulfonamide was obtained according to the method, openanalysis)-benzo[b] thiophene - 3-sulphonylchloride (0.58 mmol, 0.21 g) and THF (4 ml). Flash chromatography (mixture of 5% methanol/chloroform) yielded 0.16 g (66%) yellow rubbery solid substance, so pl. 105 - 110oC.

EXAMPLE 240

N-(4-bromo-3-methyl-5-isoxazolyl)-2.5-dimethylfuran-3 - sulfonamide

A. 2.5-dimethyl-furan-3-sulphonylchloride

2,5-dimethyl-furan-3-sulphonylchloride was obtained according to the method described in Example 40B, using DMF (28 mmol, 2.2 ml), sulfurylchloride (24 mmol, 1.9 ml) and 2,5-dimethylfuran (14 mmol, 1.5 ml). Flash chromatography (mixture of 5% ethyl acetate/hexane) yielded 0.61 g (22%) of a yellow liquid.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dimethyl-furan-3 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dimethyl-furan-3 - sulfonamide was obtained according to the method described in Example 41, using 4-bromo-3-methyl-5-amino-isoxazol (2.0 mmol, 0.35 g), NaH (5.0 mmol, 200 mg), 2,5-dimethyl-furan-3-sulphonylchloride (2.4 mmol, 0.47 g) and THF (9 ml). Flash chromatography (mixture of 5% methanol/chloroform) followed by recrystallization from chloroform and hexane resulted in the receipt of 0.21 g (31%) of light brown solid, so pl. 85.5-87oC.

EXAMPLE 241

N-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dimethyl-4-phenylthiophene - 3-sulfonamide

A. 2,5-dimethyl-3,4-dibromothiophene arrival at room temperature for 1.5 h, then was diluted with ether (50 ml) and washed with water (3 x 50 ml). The organic portion was dried (MgSO4), filtered and concentrated. Flash chromatography (hexane) resulted in 1.2 g (84%) of a white solid.

Century 2,5-dimethyl-3-bromo-4-phenylthiophene

Phenylboric acid (5.0 mmol, 0.61 g) was added to 2,5 - dimethyl-3,4-bromothiophene (4.5 mmol, 1.2 g), tetrakis(triphenylphosphine)palladium(0) (0.23 mmol, 0.26 g) and Na2CO3(2 M, 26 mmol, 13 ml) in benzene (20 ml). Two-phase reaction mixture was heated and was converted under reflux for 24 hours, then it was cooled to room temperature and was diluted with ether (100 ml), and washed with water (100 ml). The organic layer was dried (MgSO4), filtered and concentrated. After flash chromatography (hexane) was obtained 0.60 g (49%) yellow solid.

C. 2,5-dimethyl-4-phenyl-3-sulphonylchloride

t-BuLi (1.7 M, 2.7 mmol, 1.6 ml) was added to 2,5-dimethyl-3-bromo-4-phenyl the thiophene (2.2 mmol, 0.59 g) in THF (8 ml) at -30oC. the Solution was kept for 20 min at -30oC, then the reaction vessel was passed sulfur dioxide, and heated to -20oC, then added NCS (2.2 mmol, 0.30 g). The reaction mixture was heated to room temperature t4), filtered and concentrated. After flash chromatography (mixture of 2% ethyl acetate/hexane) was obtained 0.26 g (41%) of light yellow solid.

D. N-(4-bromo-3-methyl-5-isoxazol)-2,5-dimethyl-4-phenylthiophene - 3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazol)-2,5-dimethyl-4-phenylthiophene - 3-sulfonamide was obtained according to the method described in Example 41, using 4-bromo-3-methyl-5-aminoisoquinoline (0.79 mmol, 0.14 g), NaH (2.0 mmol, 80 mg), 2.5-dimethyl-4-phenylthiophene-3 - sulphonylchloride (0.91 mmol, 0.26 g) and THF (3 ml). After two recrystallization from chloroform and hexane was obtained 0.15 g (45%) of white crystalline solid, so pl. 166 - 168oC.

EXAMPLE 242

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(hydroxymethyl)thiophene-3 - sulfonamide

BH3THF (3.62 ml, 1 M in THF) was added to a solution of N-(4 - bromo-3-methyl-5-isoxazolyl)-2-carboxylate-3-sulfonamida (1.0 g, 2.72 mmol) in dry THF (15 ml) at room temperature. After keeping at room temperature for 10 min and the mixture was distilled under reflux for 1 h the Reaction mixture was cooled with an ice bath, was added 1N HCl (10 ml). The resulting mixture was concentrated. Then the aqueous residue was distributed between 1N HCl and EtOAc. Was organicsbrasil MeOH and concentrated again. The process was repeated 3 or more times to obtain N-(4-bromo-3-methyl-5-isoxazolyl)-2- (hydroxymethyl)thiophene-3-sulfonamida (680 mg, 71% yield), as a yellow oil.

EXAMPLE 243

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-1(3-methoxyphenyl)aminomethyl] thiophene-3-sulfonamide

BH3THF (15 ml, 1 M wthf) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl] thiophene-3-sulfonamida (Example 22) (1.0 g, 2.12 mmol) in dry THF (15 ml). The mixture was distilled under reflux for 8 hours and cooled. THF was evaporated on the rotor and MeOH was added to the residue. The resulting solution was concentrated. The final residue was purified HPLC to obtain N-(4-bromo-3-methyl-5 - isoxazolyl)-2-[(3-methoxyphenyl)aminomethyl] thiophene-3-sulfonamida (113 mg, 12% yield) as a gray powder, so pl. 70-73oC.

EXAMPLE 244

N-(4-bromo-3-methyl-5-isoxazolyl)-2-1N-(3 - carboxymethylaminomethyl]-thiophene-3-sulfonamide

Et3N (2.27 ml, 16. mmol), ethyl 3-aminobenzoate (836 ml, 5.44 mmol) and the trimer of phosphonitrilic (1.89 g, 5.44 mmol) were sequentially added to a solution of N-(4-bromo-3-methyl-5 - isoxazolyl)-2-(carbonyl)thiophene-3-sulfonamida (Example 17) (1 g, 2.27 mmol) in dry THF (20 ml). The reaction was conducted at room temp which was concentrated on a rotary evaporator. The residue was diluted with EtOAc and washed with 2N HCl (2 x 150 ml). The organic layer was dried (MgSO4). The solid was filtered, and the filtrate was concentrated. The residue was treated with 1H NaOH (200 ml) and was maintained at 0oC for 15 minutes the Mixture was then acidified with conc. HCl to pH 1. The resulting yellow precipitate was filtered and recrystallized from CH3CN/H2O obtaining N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3 - carboxyphenyl)aminocarbonyl] thiophene-3-sulfonamida (153 mg, 11.6%) as a yellowish powder, so pl. 183-185oC.

EXAMPLE 245

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(2-carboxyphenyl) aminocarbonyl] -thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(2 - carboxyphenyl)aminocarbonyl] thiophene-3-sulfonamide was obtained as described in Example 87, except that used ethyl-2-aminobenzoate instead of ethyl-3-aminobenzoate.

EXAMPLE 246

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(aminocarbonyl)thiophene-3 - sulfonamide

Carbonyldiimidazole (485 mg, 2.99 mmol) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylate-3 - sulfonamida (1 g, 2.72 mmol) in THF (10 ml) at room temperature. The mixture was stirred for 15 minutes Then added aqueous NH3(5 ml), the EN between EtOAc and 1N HCl. The organic layer was dried (MgSO4). The solid was filtered and the filtrate was concentrated. Oily residue was recrystallized from EtOAc to obtain N-(4-bromo-3-methyl-5-isoxazolyl)-2-(aminocarbonyl)thiophene - 3-sulfonamida (946 mg, 95% yield) as a white solid, so pl. 168-170oC.

EXAMPLE 247

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(5-dimethylamino-1 - naphthyl)sulfonyl-aminocarbonyl]thiophene-3-sulfonamide

Ancillary (90.2 mg, 0.328 mmol) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-(aminocarbonyl)thiophene-3 - sulfonamida (Example 89) (100 mg, 0.273 mmol) and NaH (43.7 mg, 60% dispersion in mineral oil, 1.10 mmol). The reaction was carried out at room temperature for 1 h, Water was added to stop the reaction, THF was evaporated on a rotary evaporator. The water balance was divided between 1N HCl and EtOAc. The organic layer was dried (MgSO4). The solid was filtered, and the filtrate concentrated. The residue was recrystallized from EtOAc to obtain N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(5-dimethylamino - 1-naphthyl)sulfonylmethane]thiophene-3-sulfonamida (55 mg, 34% yield) as a white powder (so pl. 184-186oC).

EXAMPLE 248

N-(4 isoxazolyl)-2-[(3,4 - methylenedioxyphenyl)aminocarbonyl] -thiophene-3-sulfonamide was obtained as, as described in Example 89, except that 3,4-methylenedioxyaniline was used instead of ammonium hydroxide. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4 - methylenedioxyphenyl)aminocarbonyl] thiophene-3-sulfonamide was purified HPLC, the Product was obtained with 15% yield as a dark gray powder, so pl. 138-140oC.

EXAMPLE 349

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy) phenoxycarbonyl] thiophene-3-sulfonamide

Carbodiimides (530 mg, 3.26 mmol) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylate-3-sulfonamida (Example 17) (1.0 r, of 2.72 mmol) in dry THF (10 ml). The mixture was stirred at room temperature for 15 minutes Sesamol (5.44 mmol) and imidazole (185 mg, 2.72 mmol) were added simultaneously. The resulting mixture was converted under reflux for 1 hour and was left to cool to room temperature. The solvent was evaporated. The remainder was divided between 1N Hcl and EtOAc. The organic layer was dried (MgSO4). The solid was filtered, and the filtrate is concentrated to obtain a yellow oil, which was recrystallized from a mixture of EtOAc/Et2O g/hexane. N-(4-bromo-3 - methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenoxycarbonyl] thiophene - 3-sulfonamide-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)benzoyl] thiophene-3-sulfonamide

A. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(N-methoxy-N-methyl) aminocarbonyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(N-methoxy-N-methyl) carboxamide]thiophene-3-sulfonamide was obtained as described in Example 89, except that instead of ammonium hydroxide used the N,O-dimethylhydroxylamine. The yield is 90%.

C. N-(4-Bromo-3-methyl-5-isoxazolyl)-2-1(3,4 - methylenedioxy)benzoyl]thiophene-3-sulfonamide

Their (3,4-methylendioxy)phenylboronic magnesium (1.28 g of (3,4 - methylenedioxy)bromine benzol and 172 mg Mg shavings) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(N-methoxy-N - methyl)aminocarbonyl]thiophene-3-sulfonamida (A) (652 mg, 1.59 mmol) in THF (10 ml) at room temperature. The resulting mixture was converted under reflux for 30 minutes the Mixture was left to cool to room temperature, and the reaction was stopped with 1N HCl (10 ml). Then THF was evaporated. The water balance was divided between 1N HCl and EtOAc. The organic layer was concentrated, and the residue was purified HPLC to obtain N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4 - methylenedioxy)benzoyl]thiophene-3-sulfonamida (90 mg, 12% yield) as a dark yellow powder, so pl. 47-49oC.

EXAMPLE 251

N-(4-Bromo-3-methyl shall hydroxyphenyl) aminocarbonyl] thiophene-3-sulfonamide was obtained as, as described in Example 89, except that instead of ammonium hydroxide used 3-aminophenol. The product was purified HPLC to obtain N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2-hydroxyphenyl)aminocarbonyl] thiophene-3-sulfonamida (50 mg, 18% yield) as a yellow solid, so pl. 42-44oC.

EXAMPLE 252

T-(3,4-dimethyl-5-isoxazolyl)-2[(3,4-methylenedioxy)phenoxy - carbonyl] thiophene-3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2[3,4-(methylendioxy) phenoxycarbonyl] thiophene-3-sulfonamide was obtained as described in example 92, except that N-(3,4 - dimethyl-5-isoxazolyl)-2-carboxylate-3-sulfonamide was used instead of N-(3-bromo-4-methyl-5-isoxazolyl)-2 - carboxylate-3-sulfonamida. N-(3,4-dimethyl-5-isoxazolyl)- 2[(3,4-methylenedioxy)phenoxycarbonyl] thiophene-3-sulfonamide was purified HPLC and was obtained as an orange oil (200 mg, 15% yield).

EXAMPLE 253

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-{ [(3,4-methylenedioxy)benzoyl] aminocarbonyl}thiophene-3-sulfonamide

Carbonyldiimidazole (213 mg, 1.31 mmol) was added to a solution of piperonylic acid (181.5 mg, 1.09 mmol) in dry TTF (10 ml) the Resulting mixture was stirred for 15 minutes. N- (4-bromo-3-methyl-5-isoxazolyl)-2-aminocarbonylmethyl. The mixture was stirred at room temperature for 8 hours. To destroy the excess NaH was added water. Then the solvent was evaporated and the residue was divided between 1N HCl and EtOAc. The organic layer was dried (MgSO4), the solid is filtered, and the filtrate concentrated. The residue was recrystallized from EtOAc to obtain N-(4-bromo-3-methyl-5 - isoxazolyl)-2-{ [(3,4-methylenedioxy)benzoyl] -aminocarbonyl}thiophene - 3-sulfonamida (20 mg, 3.6% yield) as a yellowish powder (so pl. 90-93oC).

EXAMPLE 254

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy) phenoxycarbonyl] -thiophene-3-sulfonamide

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy) phenoxycarbonyl] -thiophene-3-sulfonamide was obtained as described in Example 93, except that N-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylate-3-sulfonamide was used instead of N-(4-bromo-3-methyl-5-isoxazolyl)-2 - carboxylate-3-sulfonamida. N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[(3,4-methylenedioxy)phenoxycarbonyl]thiophene-3-sulfonamide was recrystallized from EtOAc (49% mg, 20% yield) as a white solid, so pl. 189-191oC.

EXAMPLE 255

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenyl - acetyl] thiophene-3-the Chan as well as described in Example 93, except that piperonylpiperazine was used instead of 3,4-methylene-dioxy)phenylmagnesium, and the reaction mixture was stirred overnight at room temperature instead of distillation under reflux for 30 minutes the Mixture was purified HPLC to obtain N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4- (methylendioxy)phenylacetyl]thiophene-3-sulfonamida (20 mg, 40% yield) as a yellow oil.

EXAMPLE 256

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy) phenoxycarbonylamino]thiophene-3-sulfonamide

The triethylamine (2.28 ml, 16.35 mmol) and diphenylphosphoryl (773 mg, 2.72 mmol) were sequentially added to a solution of N-(4-bromo-3 - methyl-5-isoxazolyl)-2-carboxylate-3-sulfonamida (Example 17) (1.0 g, 2.72 mmol) in dry THF (40 ml). The mixture was stirred for 8 hours. Added sesamol (1.54 g, 10.9 mmol) and the mixture was distilled under reflux for 2 hours the Mixture was left to cool to room temperature. The solvent was removed on a rotary evaporator, and the residue was separated between EtOAc and 1N HCl. The organic layer was dried (MgSO4), The solid was filtered and the filtrate concentrated. The residue was purified HPLC and was obtained N-(4-bromo - 3-IU the powder beige so pl. 39-43oC.

EXAMPLE 257

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy) phenylurea]-thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenylurea] thiophene-3-sulfonamide was obtained as described in example 99, except that 3,4-methylenedioxyaniline was used instead of sesamol. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4- (methylendioxy)phenylurea] thiophene-3-sulfonamide (157 mg, 12% yield) was obtained after HPLC purification as a brown-greenish powder, so pl. 62-65oC.

EXAMPLE 258

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy) benzyloxycarbonyl]thiophene-3-sulfonamide

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy) benzyloxycarbonyl]-thiophene-3-sulfonamide was obtained by the same method as described in Example 97, except that peperonity alcohol was used instead of sesamol. N-(4-chloro-3-methyl-5-isoxazolyl)-2- [(3,4-(methylendioxy)benzyloxycarbonyl] thiophene-3-sulfonamide (210 mg, 15% yield) was obtained after HPLC purification in the form of a yellowish powder, so pl. 35-38oC.

EXAMPLE 258

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy) phenylacetyl] -thiophene-Z-sulfonamide

N-(4-chloro-3-methyl-5-isoxa, with the exception that N-(4 - chloro-3-methyl-5-isoxazolyl)-2-carboxylate-3-sulfonamide was used instead of N-(4-bromo-3-methyl-5-isoxazolyl)-2 - carboxylate-3-sulfonamida. N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[(3,4-methylenedioxy)phenylacetyl] thiophene-3-sulfonamide (3 g, 50% yield) was obtained after HPLC purification as a yellow solid, so pl. 35-38oC.

EXAMPLE 259

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy) phenylethylene-carbonyl]thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy) phenylethyl-oxycarbonyl] thiophene-3-sulfonamide was obtained by the same method as described in Example 97 with the exception that (3,4 - methylenedioxy)phenethyl alcohol was used instead of sesamol. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy) generatelockkey]thiophene-3-sulfonamide (500 mg, 34% yield) was obtained after HPLC purification in the form of a yellowish oil.

EXAMPLE 260

N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[4-(3,4- methylenedioxybenzyl)piperazine-1-yl]carbonyl}thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[4-(3,4- methylenedioxybenzyl)piperazine-1-yl]carbonyl}thiophene-3-sulfonamide was obtained by the same method as described in Example 89, except that N-who yl)-2-carboxylate-3-sulfonamida, 1 - piperonylpiperazine was used instead of ammonium hydroxide. N- (4-chloro-3-methyl-5-isoxazolyl)-2-{ [4-(3,4- methylenedioxybenzyl)piperazine-1-yl]carbonyl} thiophene-3-sulfonamida (872 mg with 54% yield) was obtained after HPLC purification as a white powder, so pl. 221-223oC.

EXAMPLE 261

N-(4-chloro-3-methyl-5-isoxazolyl)-2-aminothiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-aminothiophene-3-sulfonamide was obtained by the same method as described in Example 99, except that the mixture was distilled under reflux with the addition of sesamol. N-(4-chloro-3-methyl-5-isoxazolyl)-2-aminothiophene-3-sulfonamide (298 mg, 31% yield) was obtained after HPLC purification as a yellow solid, so pl. 39-42oC.

EXAMPLE 262

N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ 1-cyano-1-1(3,4 - methylenedioxy)-phenyl]acetyl}thiophene-3-sulfonamide

Carbonyldiimidazole (603 mg, 3.72 mmol) was added to a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylate-3-sulfonamida (Example 17) (1.0 g, 3.1 mmol) in dry THF (40 ml). The mixture (1) was stirred at room temperature for 15 minutes

NaH (868 mg, 60% in mineral oil, 21.7 mmol) was added to a solution of (3,4-methylenedioxy)phenylacetonitrile in THF (100 ml). The mixture (II) re.

The mixture (1) was then introduced through the funnel into the mixture (II) under cooling in an ice bath, and the resulting mixture was left to warm to room temperature. Water was added to the decontamination of excess NaH. Then THF was removed on a rotary evaporator. The remainder was divided between 1H NaOH and Et2O. the Aqueous layer was acidified with concentrated HCl to pH 1 with cooling and extracted EtOAc. The organic layer was dried (MgSO4), the solid is filtered and the filtrate concentrated. The residue was purified HPLC to obtain N-(4-chloro-3-methyl-5 - isoxazolyl)-2-{1-cyano-1- [3,4- (methylenedioxy)phenyl]acetyl}thiophene-3-sulfonamida (277 mg, 19% yield) in the form of a yellowish powder, so pl. 142-142oC.

EXAMPLE 263

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(dimethylamino) phenoxycarbonyl]thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(dimethylamino) phenoxycarbonyl]-thiophene-3-sulfonamide was obtained by the same method as described in Example 97, with the exception that 3-dimethylaminophenol was used instead of sesamol. N-(4-chloro-3-methyl-5-isoxazolyl)-2- [3-(dimethylamino)phenoxycarbonyl]thiophene-3-sulfonamide (50 mg, 7.3% yield) was obtained after HPLC purification in the form of a dark brown oil.

EXAMPLE 265

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[b-hydroxy(3,4-methylendioxy)phenylethyl]thiophene-3-sulfonamide

LiBH4(36.6 mg, 1.68 mmol) was slowly added to a solution of N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[3,4-methylendioxy)phenylacetyl]thiophene-3-sulfonamida (Example 102) (74 mg, 0.168 mmol) in THF (10 ml). The resulting mixture was stirred for 8 hours. A saturated solution of NH4Cl (in water) was added to decompose the excess of LiBH4. The resulting mixture was concentrated on a rotary evaporator. The residue was separated between EtOAc and 1N HCl. The organic layer was dried (MgSO4), and the solid was filtered.

EXAMPLE 266

N,N'-bis{3-[(3,4-dimethyl-5-isoxazolyl)aminosulfonyl]Tien-2-yl} urea

The triethylamine (1.4 ml, 9.93 mmol) and diphenylphosphoryl (9.39 mg, 3.31 mmol) were sequentially added to a solution of N-(3,4 - dimethyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamida (Example 17) (1.0 g, 3.31 mmol) in TF (50 ml). P is rinicom for 1 hour. The mixture was left to cool to room temperature. THF was removed on a rotary evaporator. The residue was separated between EtOAc and 1N HCl. The organic layer was dried (MgSO4), the solid is filtered and the filtrate concentrated. N, N'-bis{ 3-[(3,4 - dimethyl-5-isoxazolyl)aminosulfonyl] Tien-2-yl} urea (140 mg, 14% yield) was obtained after HPLC purification in the form of a pale powder, so pl. 112-114oC.

EXAMPLE 267

N, N'-bis{3-1(4 - bromo-3-methyl-5-isoxazolyl)aminosulfonyl]Tien-2-yl}urea

N, N'-bis{3-[(4-bromo-3-methyl-5-isoxazolyl)aminosulfonyl]Tien-2 - yl}urea was obtained by the same method as described in Example 110, except that N-(4-bromo-3-methyl-5-isoxazolyl)-2 - carboxylate-3-sulfonamide was used instead of N-(3,4 - dimethyl-5-isoxazolyl)-2-carboxylate-3-sulfonamida. N,N'- bis{3-[(4-bromo-3-methyl-5-isoxazolyl)aminosulfonyl] Tien-2 - yl} urea (80 mg, 15.5% yield) was obtained after purification by HPLC in the form of a white solid substance, so pl. 127 - 129oC.

EXAMPLE 268

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(benzoyloxymethyl)thiophene-2 - sulfonamide

A. 2-(benzoyloxymethyl)thiophene

Sodium hydride (0.41 mg, 20 mmol) was added to a solution of 2-thiophenemethyl (2.0 g, 0.18 benzylbromide (3.6 g, 20 mmol). The solution was stirred at -40oC for 0.5 h, then at room temperature for 1 h THF was evaporated, and the residue was covered with ether (50 ml). The organic solution was washed with water (1 x 10 ml), brine (1 x 10 ml) and dried over MgSO4. After evaporation of the solvent left an oil which was purified by column chromatography using a mixture of 1% ether - hexane, to obtain 2.6 g of thiophene in the form of a pale yellow oil (78% yield).

Century 2-chlorosulfonyl-5-(benzoyloxymethyl)thiophene

2-chlorosulfonyl-5-(benzoyloxymethyl)thiophene was obtained as described in Example 132 2-(benzoyloxymethyl)thiophene (1.0 g, 5.25 mmol). Purification using column chromatography using 2.5% mixture of ethyl acetate/hexane resulted in the receipt of 520 mg of pure thiophene in the form of a brown oil (32% yield).

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzoyloxymethyl)thiophene - 2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzoyloxymethyl)thiophene-2 - sulfonamide was obtained as described in Example 2 from 2-chlorosulfonyl-5- (benzoyloxymethyl)thiophene (520 mg, 1.72 mmol) and 5-amino-4-bromo-3 - methylisoxazole (319 mg, 1.8 mmol). Purification using column chromatography using 10% MeOH/CHCl3the brown semi-solid substances (31% yield, so pl. 92oC).

EXAMPLE 269

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-ethylbenzo[b]furan-3 - sulfonamide

A. 2-Ethylbenzo[b]furan

2 Ethylbenzo[b] furan was obtained according to the method described in example 40A, using benzo[b]furan (7.3 mmol, 0.86 g) t-BuLi (1.7 M, 9.4 mmol) iodata (4 mmol, 0.9 ml) and THF (15 ml). Was allocated 1.0 g (95%) of a yellow liquid.

Century 2-Ethylbenzo[b]furan-3 - sulfonyl chloride

2 Ethylbenzo[b]furan-3-sulfonyl chloride was obtained by the method described in Example S. using 2 - ethylbenzo[b]furan (6.9 mmol, 1.0 g), chlorosulfonic acid (8.9 mmol, 0.6 ml), phosphorus oxychloride (21 mmol. 1.9 ml), pentachloride phosphorus (6.9 mmol, 1.4 g) and CH2Cl2(10 ml). Flash chromatography (mixture of 2% ethyl acetate/hexane) yielded 0.71 g (42%) of orange solid.

C. N-(4-chloro-3-methyl-5-isoxazolyl)-2-ethylbenzo[b]furan-3 - sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-ethylbenzo[b] furan-3 - sulfonamide was obtained according to the method described in Example 41, using 4-chloro-3-methyl-5-amino-isoxazol (1.0 mmol, 0.13 g), NaH (2.5 mmol, 60 mg), 2-ethylbenzo[b] furan-3-sulfonyl chloride (1.2 mmol, 0.28 g) and THF (7 ml). Flash chromatography (mixture of 20% ethyl acetate/hexane) followed by recrystallization from chlorofo>/BR>N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)benzyl] thiophene-3-sulfonamide

A. N-(2-carbomethoxyamino-3-sulfonyl)pyrrol

N-(2-carbomethoxyamino-3-sulfonyl)pyrrole was obtained as described in Example 33A, the reaction of 2-carbomethoxy-thiophene-3-sulfonyl chloride with pyrrole, with 50% output Century. N-[(2 - hydroxymethyl)thiophene-3-sulfonyl]pyrrol

To dignified solution of N-(2-carbomethoxyamino-3-sulfonyl) pyrrole (3.0 g, 11.02 mmol) in a mixture of THF and methanol (3:1 mixture, 40 ml) was added borohydride sodium (1.2 g) in six portions over 30 min (exothermic reaction) during curing. The solvent was removed under reduced pressure, and the residue was dissolved in a saturated solution of ammonium chloride (50 ml). Technical product was extracted with etiracetam, and the combined organic layers were dried over MgSO4and evaporated to obtain the crude product (2.4 g, 90%) which was used directly in the next stage.

C. N-[2-(methyl bromide)thiophene-3-sulfonyl]pyrrol

To the seasoned mixture of triphenylphosphine (3.1 g, 12 mmol) in methylene chloride (50 ml) was added bromine at 0oC in nitrogen atmosphere with stirring until then, until there was a stable yellow color. Several crystalinity)-3-sulfonyl]pyrrole, dissolved in methylene chloride (10 ml). The reaction was carried out at 0oC for 1 hour, and the mixture was concentrated to obtain the crude product. Technical product was purified flash chromatography on silica gel using a mixture of 10:1 hexane-ethyl acetate to obtain N-[2-(methyl bromide)thiophene-3-sulfonyl]pyrrole (2.7 g, 80% yield).

D. N-{2-[(3,4-methylenedioxy)benzyl]thiophene-3-sulfonyl]} pyrrol

N-{ 2-[(3,4-methylenedioxy)benzyl] thiophene-3-sulfonyl]}pyrrole was obtained as described in Example 32C, using N- [2-(methyl bromide)thiophene-3-sulfonyl]pyrrole and 3,4 - methylenedioxyaniline acid, with 53% yield.

E. 3-chlorosulfonyl-2-[(3,4-methylenedioxy)benzyl]thiophene

3-chlorosulfonyl - 2-(3,4-methylenedioxybenzyl)thiophene was obtained as described in Example A, from N-{2-[(3,4-methylenedioxy) benzyl]-3-sulfonyl} pyrrole by basic hydrolysis sulfonamida to sodium salts of sulfonic acid and the conversion of salts into the corresponding sulphonylchloride, with a 54% yield.

F. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4 - methylenedioxybenzyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)benzyl] thiophene-3-sulfonamide was obtained as described in Example 2,practical product was purified HPLC, with a 37% yield.

EXAMPLE 271

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-methoxyphenyl)thiophene-2 - sulfonamide

A. N-[5-(2-methoxyphenyl)thiophene-2-sulfonyl]pyrrol

N-[5-(2-methoxyphenyl)thiophene-2-sulfonyl] pyrrole was obtained as described in Example 32C using 2-methoxyflavone acid and N-(5-bronchiopulmonar)pyrrole, with 74% yield.

Century 5-chlorosulfonyl-2-(2-methoxyphenyl)thiophene

5-chlorosulfonyl-2-(2-methoxyphenyl)thiophene was obtained as described in Example A, from N-[5-(2-methoxyphenyl)thiophene-2 - sulfonyl]pyrrol by hydrolysis sulfonamida to the sodium salt of sulfonic acid (83%), followed by conversion of the salt to the corresponding sulphonylchloride, which was obtained from 24% yield.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methoxyphenyl)thiophene - 2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methoxyphenyl)thiophene - 2-sulfonamide was obtained as described in Example 1. The reaction of 2-chlorosulfonyl-5-(2 - methoxyphenyl)thiophene with 5-amino-4-bromo-3 - methylisoxazole led to N-(4-ROM-3-methyl-5 - isoxazolyl)-5-(2-methoxyphenyl)thiophene-2-sulfonamida with 32% yield, so pl. 114-117oC.

EXAMPLE 272

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-tolyl)thiophene-2-slot (0.294 g, 2.4 mmol) were added to a solution of 2-bromothiophene (0.542 g, 2 mmol) and tetrakis(triphenylphosphine)palladium (0) (100 mg) in toluene (5 ml) and ethanol (5 ml) under nitrogen atmosphere. The mixture was distilled under reflux for 2 hours, cooled to room temperature and was extracted using ethyl acetate (2 x 50 ml). The combined organic layers was dried over MgSO4and evaporated. The residue was subjected to flash chromatography on silica gel using hexane as eluent, there was obtained 1.2 g of 2-(2-tolyl)thiophene as a colorless resin.

Century 2-chlorosulfonyl-5-(2-tolyl)thiophene

To a cold (-5 - 0oC) solution of 2-(2-tolyl)thiophene (0.87 g, 5 mmol) was added chlorosulfonic acid (0.33 ml, 5 mmol) for 15 min during curing. After 10 min was added phosphorus oxychloride (2 ml) and pentachloride phosphorus. The reaction mixture was left to slowly reach room temperature and was stirred for 3 hours. The mixture is then poured on crushed ice (50 g) and extracted with ethyl acetate (2 x 50 ml). The combined organic layers was dried over MgSO4and evaporated. The residue was purified using flash column chromatography on silica gel using a mixture of 2% ethyl acetate in hexane with n the l)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-tolyl)thiophene-2 - sulfonamide was obtained as described in Example 2. The reaction of 5-chlorosulfonyl-2-(2-tolyl)-thiophene with 5-amino-4-bromo-3 - methylisoxazole led to the obtaining of a technical product, which was purified by column chromatography, giving the pure product (resin). The resin was dissolved in 5 ml of NH4OH, concentrated and dried under high vacuum to obtain ammonium salt of N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2 - tolyl)thiophene-2-sulfonamida with 67% yield, so pl. 180-184oC (g NH3+).

EXAMPLE 273

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-tolyl)thiophene-2-sulfonamide

A. 2-(3-tolyl)thiophene

2-(3-tolyl)thiophene was obtained as described in Example 117A, using a 2-bromothiophene and 3-methylphenylamine acid. Technical product was purified by flash chromatography on silica gel using hexane as eluent (86% yield).

Century 2-chlorosulfonyl-5-(3-tolyl)thiophene

2-chlorosulfonyl-5-(3-tolyl)thiophene was obtained as described in Example 117V, from 2-(3-tolyl)thiophene, with 22% yield.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-tolyl)thiophene-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-tolyl)-4-bromo-3 - methylisoxazole. To obtain the ammonium salt of the final product was used aqueous NH4OH (31% yield, hygroscopic).

EXAMPLE 274

N-(4-Bromo-3-methyl-5-isoxazolyl)-3-benzylthio-2-sulfonamide

A. C-benzylthio

3-benzylthio was obtained as described in Example 32C, using 3-thienylboronic acid and benzylbromide, with 74% yield.

Century 2-chlorosulfonyl-3-benzoylthiophene

2-chlorosulfonyl-3-benzoylthiophene was obtained as described in Example 117V, using 3-benzoylthiophene, with 78% yield.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-3-benzylthio-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-3-benzylthio-2 - sulfonamide was obtained as described in Example 2, by reaction of 2-chlorosulfonyl-3-benzoylthiophene with 5-amino-4 - bromo-3-methylisoxazole; the substance was obtained with a yield of 24%, so pl. 180-183oC.

EXAMPLE 275

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-methylphenyl)thiophene-2 - sulfonamide

A. N-[5-(2-methyl-5-furyl)thiophene-2-sulfonyl]pyrrol

m-BuLi (1.7 M solution in hexane, 7.9 ml, 14.6 mmol) was added dropwise while maintaining the nitrogen atmosphere, to a solution of 2-methylfuran (1.0 g, 12 mmol) in THF (20 ml) at -78oC. the Solution was then heated on the 7 ml of 0.5 M solution in THF) at -30oC, and then warmed to room temperature, at which stirring was continued for 1 hour to obtain a light yellow solution. The solution was then introduced through the steel funnel in a nitrogen atmosphere to a solution of N-(5-bromothiophene-2-sulfonyl)pyrrole (Example 33A, 3.5 g, 12 mmol) and tetrakis(triphenylphosphine)palladium (0) (693 mg, 0.6 mmol) in THF (15 ml) at -78oC. Then the solution was heated to room temperature and was stirred for 2 hours. Purification using column chromatography using 2% ethyl acetate resulted in the receipt of 680 mg of N-[5-(2 - methyl-5-furyl)thiophene-2-sulfonyl]pyrrole as a yellow powder (19% yield).

Century 2-(2-methyl-5-furyl)thiophene-5-sulfonyl chloride

2-(2-methyl-5-furyl)thiophene-5-sulfonyl chloride was obtained as described in Example 33D, from N-[5-(2-methyl-5 - furyl)thiophene-2-sulfonyl]pyrrole (300 mg, 1.02 mmol). Purification via column chromatography using a mixture of 2% ethyl acetate/hexane resulted in the receipt of 145 mg (53%) of sulphonylchloride in the form of a yellow solid.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyl-5-furyl)thiophene - 2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyl-5-furyl)thiophene-2 - sulfonamide was obtained as described in Example 2. Reacts the after purification using column chromatography using a mixture of 10% MeOH/CHCl3led to obtain 45 mg of pure sulfonamida in the form of a brown semi-solid materials (54% yield, so pl. 123-124oC).

EXAMPLE 276

N-Bromo-3-methyl-5-isoxazolyl-4-(phenylethyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(phenylethyl)thiophene-2 - sulfonamide was obtained as described in Example 2 using 5-amino-4-bromo-3-methylisoxazole (132.75 mg, 0.75 mmol) and 4-(phenylethyl)thiophene-2-sulfonyl chloride (Example 119D; 225.62 mg, 0.75 mmol). The product was purified (5-95% acetonitrile with 0.1% TFU within 30 minutes) to obtain N-(4-bromo-3-methyl-5 - isoxazolyl)-4-(phenylethyl)thiophene-2-sulfonamida in the form of a brownish oil (72.3 mg, 32% yield).

EXAMPLE 277

N-(3,4-dimethyl-5-isoxazolyl)-2-[(4-were)aminocarbonyl] thiophene-3-sulfonamide

The trimer of phosphonitrilic dissolved in THF (5 ml) was added to a suspension of N-(3,4-dimethyl-5-isoxazolyl)-2- (carboxyl)thiophene-3-sulfonamida (2.0 g, 6.6 mmol) (Example 28) in THF (5 ml) and Et3N when 0oC. the Cold bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (150 ml) and acidified to pH 2 with concentrated hydrochloric acid. The reaction mixture was extracted with methylene chloride (2 x 100 ml), the seat of obtaining the crude product. Technical product was dissolved in ether and left to stand at room temperature to obtain a precipitate, which was filtered and washed with cold ether to obtain N-(3,4 - dimethyl-5-isoxazolyl)-2-[(4-were)aminocarbonyl] thiophene-3 - sulfonamida (1.6 g, 61% yield).

EXAMPLE 278

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-[(4-tolyl)aminocarbonyl] thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-[(4-tolyl)aminocarbonyl] thiophene-2-sulfonamide was obtained as described in Example 24 N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-carboxybenzoyl)thiophene-2 - sulfonamide (Example 148), (110 mg, 0.25 mmol) and 4-methylaniline (53 mg, 0.49 mmol). Purification by recrystallization from methanol/water yielded 91 mg of pure sulfonamida in the form of a light brown powder (61% yield, so pl. 188oC).

EXAMPLE 279

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-tolyl)aminocarbonyl] thiophene-3-sulfonamide

A. N-(4-chloro-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3 - sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene - 3-sulfonamide was obtained as described in Example 17 using N-(4-chloro-3-methyl - 5-isoxazolyl)-2- (carbomethoxy)thiophene-3-sulfonamida (Example 123), with 78% yield.

In-[(4 - tolyl)aminocarbonyl] thiophene-3-sulfonamide was obtained as, as described in Example 122, using N-(4-chloro-3-methyl-5 - isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamida. Technical product was dissolved in a small amount of EtOAc (2 ml) was added ether (15 ml). The resulting precipitate was filtered and cold ether (50 ml) to give N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[(4-tolyl)aminocarbonyl]thiophene-3-sulfonamida with 53% output (so pl. 177-179oC).

EXAMPLE 280

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-1(N-methyl)-N - phenylenecarbonyl)-thiophene-3-sulfonamide

A solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl) thiophene-3-sulfonamida (183.6 mg, 0.5 mmol) in dry THF (1 ml) was added to a solution of N-methyl-4-methylaniline (0.066 ml, 0.6 mmol) in THF (0.5 ml). The triethylamine (0.63 ml, 4.2 mmol) was added to the mixture and after 10 min was added to the solution of the trimer of phosphonitrilic (210.7 mg, 0.6 mmol). The mixture was stirred for 1 hour at 50oC, cooled, neutralized with 10 ml 1N HCl (pH 3) and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to get crude product, which was purified HPLC (5-95% acetonitrile with 0.1% TFU for 30 min). There was obtained N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(N-methyl)-N - phenylenecarbonyl] thiophene-3-N-(4-Bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenyl] thiophene-2-sulfonamide

A. 3-Bromothiophene-2-sulfonyl chloride

Chlorosulfonic acid (20 ml, 300 mmol) was added to a solution of 3-bromothiophene (8.15 g, 50 mmol) in methylene chloride (50 ml) at -78oC for 20 minutes After adding the cold bath was removed and stirring continued at room temperature for 1 hour. The reaction mixture was carefully added dropwise, crushed ice (100 g). The mixture was extracted with methylene chloride (2 x 100 ml). The combined organic layer was dried over MgSO4and evaporated. Technical product was purified flash chromatography on silica gel using hexane as eluent to obtain 3-bromothiophene-2-sulfonyl chloride (4 g, 30% yield) and 4-bromothiophene-2-sulfonyl chloride (200 mg, 1%).

C. N-(3-bromothiophene-2-sulfonyl)pyrrol

N-(3-bromothiophene-2-sulfonyl)pyrrole was obtained as described in Example 33A, by reaction of 3-bromothiophene-2 - sulphonylchloride with pyrrole (for 16 hours. ). N-(3-bromothiophene-2 - sulfonyl)pyrrole was obtained from 54% yield.

C. N-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrol

N - {[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrole was obtained as described in Example 32C, using 3,4 - methylenedioxyaniline the th on silica gel using 2% EtOAc in hexane as eluent. There was obtained N-{[3-(3,4-methylenedioxy)phenyl] thiophene-2-sulfonyl}pyrrol 90% yield.

D. 2-chlorosulfonyl-3-[3,4-(methylenedioxy)phenyl]thiophene

2-chlorosulfonyl-3-[3,4-(methylenedioxy)phenyl]thiophenyl was obtained as described in Example 112 VDC, using N- {[3-(3,4-methylenedioxy)-phenyl]thiophene-2-sulfonyl}pyrrole, Sulfonamide was subjected to basic hydrolysis to sulfonate sodium (100% output), then made the conversion of the salt to the corresponding sulphonylchloride. The final product was obtained in 34% yield.

N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenyl] thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenyl] thiophene-2-sulfonamide was obtained as described in Example 1 by reaction of 2-chlorosulfonyl-3-[3,4-(methylenedioxy)phenyl] thiophene with 5-amino-4-bromo-3-methylisoxazole. The product was obtained in 60% yield, so pl. 183-186oC.

EXAMPLE 282

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(2-chloro-3,4 - methylendioxy)phenoxymethyl]thiophene-3-sulfonamide

A. N-{2-[(3,4-methylenedioxy)phenoxymethyl]thiophene-3-sulfonyl} pyrrol

Sodium hydride (100 mg, 5 mmol) was added to a dignified solution of 3;4 - methylenedioxyphenol (0.607 g, 4.5 mmol) in DMF (dry, 5 the stirring was continued for 1 h The reaction mixture was cooled to 0oC, and N-[(2 - methyl bromide)thiophene-3-sulfonyl]pyrrole was added. Stirring is continued at room temperature for 16 hours. The reaction mixture was diluted with water (100 ml), extracted with ethyl acetate (2 x 50 ml) and washed 1H NaOH (2 x 25 ml) to remove the derivative Fenella. The mixture was dried over MgSO4and concentrated. Turned out to be N-{2-[(3,4-methylenedioxy)phenoxymethyl]thiophene-3-sulfonyl} pyrrole, he was recrystallized from a mixture of hexane/EtOAc (1.0 g, 92% yield).

Century 3-Chlorosulfonyl-2-1(2-chloro-3,4-methylendioxy)phenoxymethyl] thiophene

3-chlorosulfonyl-2-[(2-chloro-3,4-methylendioxy)phenoxymethyl] thiophene was obtained as described in Example I, using N-{2-[(3,4-methylenedioxy)phenoxymethyl] thiophene-3-sulfonyl} pyrrole, through basic hydrolysis (using potassium hydroxide in isopropanol) to sulfonate potassium, and then made the conversion of the salt to the corresponding sulphonylchloride with a total yield of 50%.

C. N-(4-Ohm-3-methyl-5-isoxazolyl)-2-[(2-chloro-3,4 - methylendioxy)phenoxy-methyl]thiophene-3-sulfonamide

N-(4-bromo-3 - methyl-5-isoxazolyl)-2-[(2-chloro-3,4-methylenedioxyphenoxy)methyl]- thiophene-3-sulfonamide was obtained as OPI what militarisation, the output is 47%, so pl. 152-154oC.

EXAMPLE 283

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[TRANS-3,4-(methylendioxy) cinnamyl] -thiophene-3-sulfonamide

A. Diethyl-2-{3-[(N-pyrrolyl)sulfonyl]thienylmethyl}phosphonate

N-[2-methyl bromide)thiophene-3-sulfonyl] pyrrole (0.915 g, 3 mmol) was suspended in triethylphosphite (5 ml) and was heated to 140oC for 1 h under stirring in nitrogen atmosphere. The excess triethyl phosphate was removed under reduced pressure, and the residue was dried under vacuum to obtain 0.9 g, 83% yield diethyl 2-{3-[(N-pyrrolyl)sulfonyl]thienylmethyl}phosphonate.

C. N-{2-[TRANS-3,4-(methylendioxy)cinnamyl]thiophene-3-sulfonyl} pyrrol

Sodium hydride (200 mg, 60% dispersion) was added in two portions to a solution of diethyl 2-{3-[(N-pyrrolyl)sulfonyl]thienylmethyl] phosphonate (900 mg, 2.48 mmol) with stirring in dry THF (10 ml) at 0oC. the Mixture was stirred at room temperature for 1 h and Then added piperonal (600 mg). Stirring is continued for 12 hours. The mixture was diluted with water (100 ml) and Proektirovanie with methylene chloride (2 x 50 ml) the combined organic layers were dried over MgSO4evaporated and the residue was subjected to flash chromatography on silica gel using a mixture of 84% yield).

C. 3-chlorosulfonyl-2-[TRANS-3,4-(methylendioxy)cinnamyl]thiophene

3-chlorosulfonyl-2-[TRANS-3,4-(methylendioxy)cinnamyl] thiophene was obtained as described in Example A, from N-{2-[TRANS-3,4-(methylendioxy)-cinnamyl] thiophene-3-sulfonyl} pyrrole by basic hydrolysis (using isopropanol and potassium hydroxide) to the corresponding sulfonate potassium (100%) followed by conversion of the salt to the corresponding sulphonylchloride with a total yield of 31%.

D. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[TRANS-3,4-(methylendioxy) cinnamyl]-thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[TRANS-3,4-(methylendioxy) cinnamyl] -thiophene-3-sulfonamide was obtained as described in Example 1, the reaction of 3-chlorosulfonyl-2-[TRANS-3,4-(methylendioxy) cinnamyl]thiophene with 5-amino-4-bromo-3-methylisoxazole. Technical product was purified HPLC. The final product was obtained with a 33% yield, so pl. 147-149oC.

EXAMPLE 284

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)phenylethyl] thiophene-3-sulfonamide

A. N-{2-[3,4-(methylendioxy)phenylethyl]thiophene-3-sulfonyl}pyrrol

A solution of N-{2-[TRANS-3,4-(methylendioxy)cinnamyl]thiophene-3-sulfonyl} pyrrole in ethyl acetate (15 ml) (Example 127V, 0.6 g, 1.67 mmol) was subjected kata and the filtrate was concentrated. There was obtained N-{2-[3,4- (methylendioxy)phenylethyl]thiophene-3-sulfonyl} pyrrole (0.55 g, 91% yield).

Century 3-chlorosulfonyl-2-[3,4-(methylendioxy)phenylethyl]thiophene

3-chlorosulfonyl-2-[3,4-(methylendioxy)phenylethyl] thiophene was obtained as described in Example A, from N-{2-[3,4-(methylendioxy)phenylethyl]thiophene-3-sulfonyl}pyrrole, which was subjected to basic hydrolysis (using isopropanol and potassium hydroxide) to the potassium salt of sulfonic acid (93%), followed by conversion of the salt to the corresponding sulphonylchloride with 42% yield.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy) phenylethyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy) phenylethyl] thiophene-3-sulfonamide was obtained as described in Example 2. By reaction of 3-chlorosulfonyl-2-[3,4- (methylendioxy)phenylethyl]thiophene with 5-amino - 4-bromo-3 - methylisoxazole and cleaning product in HPLC, N-(4 - bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)phenylethyl] thiophene - 3-sulfonamide was obtained with 30% output, so pl. 180oC (decomp.).

EXAMPLE 285

N-(4-Bromo-3-methyl-5-isoxazolyl)-3-(phenylthio)thiophene-2 - sulfonamide

A. 3-pinitiative-2-sulphonylchloride

Mixed rectouterine (2.78 ml of a 2.3 M solution) was added over 20 min and stirring continued at this temperature additionally for 20 minutes Then gaseous sulfur dioxide was barbotirovany at -78oC for 30 min, which resulted in a yellow precipitate. This made immediately after adding dropwise N-chlorosuccinimide (764 mg, 5.72 mmol) dissolved in THF. The mixture was heated to room temperature, and stirring was continued additionally during 1.5 h the Mixture was then concentrated, and the residue was dissolved in ether. The organic layer was washed with water, brine and dried over magnesium sulfate. After evaporation of the solvent left a light brown oil, which was subjected to flash chromatography. Elution using a mixture of 1% ethyl acetate-hexane resulted in the receipt of 840 mg (56%) of pale yellow solid.

C. N-(4-bromo-3-methyl-6-isoxazolyl)-3-(phenylthio)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-6-isoxazolyl)-3-(phenylthio)thiophene-2 - sulfonamide was obtained as described in Example 2 using 5-amino-4-bromo-3-methylisoxazole (192 mg, 1.1 mmol) and 3-pinitiative-2-sulphonylchloride (300 mg, 1.0 mmol). Purification using column chromatography using 10% MeOH/CHCl3led to obtain 358 mg (83%) of pure sulfonamida in the form of a brown oil.

EXAMPLE 286

N-(3,4 dimethyl-5-itxas is 3,4-dimethyl-5 - isoxazolyl)thiophene-2-sulfonamide was obtained as, as described in Example 14, using thiophene-2-sulfonyl chloride and 3,4-dimethylbenzoxazole. Purification via column chromatography using a mixture of 3% MeOH/CHCl3led to a 48% N-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamida.

C. N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)thiophene - 2-sulfonamide

N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)thiophene - 2-sulfonamide was obtained as described in Example 32V, using N-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamida and methoxyethoxymethyl chloride, with 34% yield. HPLC analysis of the crude oil obtained after synthesis, showed that the purity of the oil was approximately 96%, and thus, it was used in a later stage without any further purification.

C. N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5 - trimethylsilyl)thiophene-2-sulfonamide

The mixed solution of N-(methoxyethoxymethyl)-N-(3,4 - dimethyl-5-isoxazolyl)thiophene-2-sulfonamid (300 mg, 0.87 mmol) in 5.0 ml of dry THF was placed in an argon atmosphere, and cooled to tabout- 78oC. for 20 min a solution of t-BuLi in hexane (461 ml of a 2.25 M solution) was added dropwise, and stirring is continued at this temperatureresponsive at -78oC for 15 min, then at room temperature for 1.5 hours TLC (1% CHCl3in MeOH) showed that the reaction of the starting materials was gone. Then the reaction was quenched by the addition of 2.0 ml of water. After evaporation of the solvent the residue was extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. Purification via column chromatography using a mixture of 20% ethyl acetate/hexane resulted in the receipt of net sulfonamida in the form of a clear oil (52% yield).

D. N-(methoxyethoxymethyl)-N-(3,4-dimethylisoxazole)-3- (phenylenecarbonyl)-5-(trimethylsilyl)thiophene-2-sulfonamide

The mixed solution of N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5 - isoxazolyl)-5-trimethylsilyl)thiophene-2-sulfonamida (180 mg, 0.43 mmol) in 4 ml of dry THF was placed in an atmosphere of argon and cooled to -78oC. At this temperature a solution of t-BuLi in hexane (215 ml 2.55 M solution) was added dropwise, and stirring continued at -78oC for 0.5 h to obtain a light yellow solution. Phenylisocyanate (77 ml 0.65 mmol) was added dropwise at -78oC, and the solution was left until they reach room temperature. Then the solution was processed as noted above in part C. Ochistki received 108 mg sulfonamida with a 54% yield.

E. N-(3,4 dimethyl-5-isoxazolyl)-3-(phenylenecarbonyl)thiophene - 2-sulfonamide

N-(3,4 dimethyl-5-isoxazolyl)-3-(phenylenecarbonyl)thiophene - 2-sulfonamide was obtained as described in Example 32D, using N-(methoxyethoxymethyl)-N-(3,4-dimethylisoxazole)-3- (N-phenylcarbamate-5-trimethylsilyl)thiophene-2-sulfonamide (108 mg, 0.23 mmol). Clearance made by recrystallization from a mixture of acetonitrile/water to obtain 62 mg (71% yield) of N-(3,4 dimethyl-5-isoxazolyl)-3-(phenylenecarbonyl)thiophene-2 - sulfonamida in the form of a brown powder, so pl. 152oC.

EXAMPLE 287

N-(3,4-dimethyl-5-isoxazolyl)-2-( - hydroxybenzyl)thiophene-3 - sulfonamide

A. Thiophene-3-sulphonylchloride

n-BuLi (2.38 M, 17 ml) was slowly added to a solution of 3-bromothiophene (6.5 g, 40 mmol) in ether (30 ml) at -78oC. the Reaction was conducted at -78oC for 45 minutes SO2was barbotirovany through the mixture for 15 min at -78oC, and then was added NCS (6.4 g, 48 mmol) in suspension in THF (40 ml). Technical product was purified by column chromatography using a 5% mixture of ethyl acetate/hexane. Received 3.92 g of thiophene-3-sulphonylchloride in the form of a pale yellow solid (54% yield).

C. N-(3,4-dimethy is described in Example 14, using thiophene-3-sulfonyl chloride and 3,4-dimethylbenzoxazole. The product obtained in 66% yield as a pale brown solid.

C. 2-[2-(trimethyl)ethoxymethyl]-N-(3,4-dimethyl-5 - isoxazolyl)thiophene-3-sulfonamide

N, N-diisopropylethylamine (222 ml, 128 mmol) was added to a solution of N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamida (300 mg, 1.16 mmol) in methylene chloride (5 ml), and the mixture was stirred at room temperature for 15 minutes Then the mixture was cooled to 0oC, and 2- (trimethylsilyl)ethoxymethylene (SEM-chloride) (226 ml, 1.28 mmol) was added dropwise via syringe, and the resulting yellow solution was stirred at room temperature for 5 hours. After evaporation of the solvent left an oil which was extracted into ethyl acetate, washed with water and brine and dried over magnesium sulfate. Flash chromatography of the residue using a mixture of 10% ethyl acetate/hexane resulted in the receipt of 321 mg of 2-[2-(trimethylsilyl)ethoxymethyl] -N-(3,4-dimethyl-5 - isoxazolyl)thiophene-3-sulfonamida as light colorless oil, which was hardened in white solid irop standing (71% yield).

D. 2-[2-(trimethylsilyl)ethoxymethyl] -N-(3,4-dimethyl-5 - isoxazolyl)-2-( - hydroxyben(3,4-dimethyl-5 - isoxazolyl)thiophene-3-sulfonamida (156 mg, 0.38 mmol) in THF at -78oC in nitrogen atmosphere. The reaction was conducted at -78oC for 45 min, then was added benzaldehyde (45 ml, 0.42 mmol) in one portion at -78oC and the solution was left until they reach room temperature. Stirring was continued for 1 h Clearance made column chromatography using a 10% mixture of ethyl acetate/hexane to obtain 179 mg of 2-[2-(trimethylsilyl) amoxicillin] -N- (3,4-dimethyl-5-isoxazolyl)-2--hydroxybenzyl)thiophene-3 - sulfonamida in the form of a yellow viscous oil (90% yield).

E. N-(3,4-dimethyl-5-isoxazolyl)-2-( -hydroxybenzyl) thiophene-3-sulfonamide

To a solution of 2-[2-(trimethylsilyl)ethoxymethyl] -N-(3,4-dimethyl - 5-isoxazolyl)-2 - hydroxybenzyl)thiophene-3-sulfonamida (70 mg, 0-14 mmol) in DMF (2 ml) was added cesium fluoride (26 mg, 0.17 mmol) in one portion. The resulting mixture was heated to 100oC for 10 hours. The solvent was removed by evaporation under vacuum and the remaining residue was extracted into ethyl acetate, washed with water, brine, and dried over MgSO4. Then the product was purified by chromatography using a mixture of 50-70% ethyl acetate/hexane. Received 26.2 mg of N-(3,4-dimethyl-5 - isoxazolyl)-2-( - hydroxybenzyl)thiophene-3-sulfonamida as Bel is enyl)thiophene-2 - sulfonamide

A. N-[5-(4-were)thiophene-2-sulfonyl]pyrrol

N-[5-(4-were)thiophene-2-sulfonyl] pyrrole was obtained as described in Example 32C from 4-methyl-phenylboric acid and N-(5-bronchiopulmonar)pyrrole. Purification via column chromatography using a mixture of 2% ethyl acetate/hexane resulted in the receipt of N-[5-(4-were)thiophene-2-sulfonyl] pyrrole as a pale yellow solid with 77% yield.

Century 2-chlorosulfonyl-5-(4-were)thiophene

2-chlorosulfonyl-5-(4-were)thiophene was obtained as described in Example 33D, using N-[5-(4-were)thiophene-2 - sulfonyl]pyrrole. Purification using column chromatography using 2% mixture of ethyl acetate/hexane led to a 2-chlorosulfonyl-5-(4-were)thiophene as a pale yellow powder (61% yield).

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-were)thiophene-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-were)thiophene-2 - sulfonamide was obtained as described in Example 2. The reaction of 2-chlorosulfonyl-5-(4-were)thiophene (100 mg, 0.37 mmol) with 5 - amino-4-bromo-3-methylisoxazole (65 mg, 0.37 mmol) yielded, after column chromatography using 10% MeOH/CHCl3, 96 mg Koh is 289

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-phenyl)thiophene-2 - sulfonamide

A. N-(pyrrole)-5-(4-phenyl)thiophene-2-sulfonamide

N-(pyrrole)-5-(4-phenyl)thiophene-2-sulfonamide was obtained as described in Example 32C, with the use of phenylboric acid and N- (5-bronchiopulmonar)pyrrole. Purification via column chromatography using a mixture of 2% ethyl acetate/hexane resulted in the receipt of net sulfonamida in the form of a yellow powder with a 67% yield.

Century 2-chlorosulfonyl-5-(4-phenyl)thiophene

C. 2-chlorosulfonyl-5-(4-phenyl)thiophene was obtained as in Example 33D, of N-(pyrrole)-5-(4-phenyl)thiophene-2-sulfonamida. Purification via column chromatography using a mixture of 2% atlacatl/hexane resulted in the obtaining of pure thiophene with 77% yield as a yellow powder.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-phenyl)thiophene-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-phenyl)thiophene-2 - sulfonamide was obtained as described in Example 2. The reaction of 2-chlorosulfonyl-5-(4-phenyl)thiophene (94 mg, 0.36 mmol) with 5-amino - 4-bromo-3-methyl-isoxazol (64 mg, 0.36 mmol) resulted, after column chromatography using 10% MeOH/CHCl3, 85 mg of N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4 - phenyl)thiophene-2-N-(4-bromo-3-methyl-5-isoxazolyl)-5-[4-(trifluoromethyl)phenyl] thiophene-2-sulfonamide

A. N-{5-[4-(trifluoromethyl)phenyl]titsn-2-sulfonyl}pyrrol

N-{ 5-[4-(trifluoromethyl)phenyl] thiophene-2-sulfonyl} pyrrole was obtained as described in Example 32C from 4-triftorperasin acid and N-(5-bronchiopulmonar)pyrrole. Purification via column chromatography using a mixture of 2% ethyl acetate/hexane resulted in the receipt of net sulfonamida in the form of a white powder with 75% yield.

Century 2-Chlorosulfonyl-5-[4-(trifluoromethyl)phenyl]thiophene

2-chlorosulfonyl-5-[4-(trifluoromethyl)phenyl] thiophene was obtained as in Example 33D, of N-{5-[4-(trifluoromethyl)phenyl]thiophene-2 - sulfonyl}pyrrole. Purification using column chromatography using 2% mixture of ethyl acetate/hexane resulted in the obtaining of pure thiophene as a white powder with a 41% yield.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-[4-(trifluoromethyl)phenyl] thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-[4-(trifluoromethyl)phenyl] thiophene-2-sulfonamide was obtained as described in Example 2, the Reaction of 2-chlorosulfonyl-5-[4-(trifluoromethyl)phenyl] thiophene (100 mg, 0.31 mmol) with 5-amino-4-bromo-3-methylisoxazole (54 mg, 0.31 mmol) resulted, after column chromatography, 39 mg of N-(4-bromo-3-methyl-5-isoxazolyl)-5-[4-(trifluoromethyl)FeNi is R>
N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-formylphenyl)thiophene-2 - sulfonamide

A. N-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide

N-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide was obtained as described in Example 14, from 5-bromothiophene-2 - sulphonylchloride and 5-amino-3-methyl isoxazol. Clearance made by extraction of the crude sulfonamida in aqueous 2N NaOH, washing the aqueous layer with ethyl acetate, and acidified with concentrated HCl to pH 2. After Stripping the ethyl acetate was performed leaching of organic material with water, brine and dried over magnesium sulfate. After evaporation of the solvent there was obtained a brownish solid, sufficiently pure for use in the next stage.

C. N-(3-methyl-5-isoxazolyl)-5-(2-formylphenyl)thiophene - 2-sulfonamide

N-(3-methyl-5-isoxazolyl)-5-(2-formylphenyl)thiophene-2 - sulfonamide was obtained as described in Example 32C from 2 - formylbenzeneboronic acid (281 mg, 1.87 mmol) and N-(3-methyl-5 - isoxazolyl)-5-bromothiophene-2-sulfonamida (550 mg, 1.7 mmol). Purification using column chromatography using 15% MeOH/CHCl3led to obtain 163 mg (28%) net sulfonamida in the form of a brown oil.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-what sapolil)-5-(2-formylphenyl)thiophene-2-sulfonamide (155 mg, 0.45 mmol) in CHCl3(5 ml). The resulting brownish solution was stirred at room temperature for 3 hours. The solvent was removed and the material was extracted into ethyl acetate and washed with brine. Evaporation of the solvent led to 85 mg of product (45% yield). Part of the obtained product was subjected to further purification using preparative HPLC. N-(4 - bromo-3-methyl-5-isoxazolyl)-5-(2-formylphenyl)thiophene-2-sulfonamide was isolated as a pale brown oil.

EXAMPLE 292

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-AMINOPHENYL)thiophene-2 - sulfonamide

A. N-(3-methyl-5-isoxazolyl)-5-(3-AMINOPHENYL)thiophene-2-sulfonamide

N-(3-methyl-5-isoxazolyl)-5-(3-AMINOPHENYL)thiophene-2-sulfonamide was obtained as described in Example 32C from 3-amino bezopornoe acid (256 mg, 1.87 mmol) and N-(3-methyl-5-isoxazolyl)-5 - bromothiophene-2-sulfonamida (55 mg, 1.7 mmol). Purification using column chromatography using 15% MeOH/CHCl3led to 318 mg (56%) of product.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-AMINOPHENYL)thiophene-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-AMINOPHENYL)thiophene-2 - sulfonamide was obtained as described in Example 30A, (without acetic acid) with the schedule. Further purification was performed using preparative HPLC was obtained N-(4-bromo-3-methyl-5 - isoxazolyl)-5-(3-AMINOPHENYL)thiophene-2-sulfonamide as a clear colorless oil.

EXAMPLE 293

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3,3-dimethylbutan-1-yl) thiophene-2-sulfonamide

A. N-[5-(3,3-dimethylbutan-1-yl)thiophene-2-sulfonyl]pyrrol

A mixture of N-(5-bromothiophene-2-sulfonyl)pyrrole (600 mg, 2.05 mmol), 3,3-dimethyl-1-butyne (338 mg, 4.1 mmol), copper iodide (39 mg, 0.21 mmol), Tetra(triphenylphosphine)palladium [Pd(PPh3)4] (118 mg, 0.1 mmol) and piperidine (5 ml) was stirred at room temperature for 24 hours under nitrogen atmosphere. The mixture was then diluted with water (10 ml) and extracted three (3 x 25 ml portions of ether. The combined ether extracts were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography using a mixture of 2% ethyl acetate/hexane and getting 423 mg of N-[5-(3,3-dimethylbutan-1 - yl)thiophene-2-sulfonyl]pyrrole as a yellow powder (70% yield).

Century 2-chlorosulfonyl-5-(3,3-dimethylbutan-1-yl)thiophene

2-chlorosulfonyl-5-(t-butylamine)thiophene was obtained as described in what ispolzovaniem 2% mixture of ethyl acetate/hexane resulted in the receipt of net sulfonamida with 33% yield.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3,3-dimethylbutan-1-yl) thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3,3-dimethylbutan-1-yl) thiophene-2 - sulfonamide was obtained as described in Example 2. The reaction of 2-chlorosulfonyl 5-(3,3-dimethylbutan-1-yl)thiophene (120 mg, 0.46 mmol) with 5-amino-4-bromo-3-methylisoxazole (85 mg, 0.48 mmol) resulted, after column chromatography using 10% MeOH/CHCl3, 116 mg of N-(4-bromo-3-methyl-5-isoxazolyl)-5- (3,3-dimethylbutan-1-yl)thiophene-2-sulfonamida in the form of a clear viscous oil (63%).

EXAMPLE 294

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-[3,5-bis(trifluoromethyl)phenyl] thiophene-2-sulfonamide

A. N-{5-[3,5-bis(trifluoromethyl)phenyl]thiophene-2-sulfonyl}pyrrol

N-{ 5-[3,5-bis(trifluoromethyl)phenyl]thiophene-2-sulfonyl (pyrrole was obtained as described in Example 32C from 3,5 - bis(trifluoromethyl)basavaraj acid (619 mg, 2.26 mmol) and N-[5 - bromothiophene-2-sulfonyl]pyrrole (60 mg, 2.05 mmol). Purification via column chromatography using a mixture of 2% ethyl acetate/hexane resulted in the receipt of net sulfonamida in the form of a white solid with a 93% yield.

Century 2-chlorosulfonyl-5-[3,5-bis(trifluoromethyl)phenyl]thiophene

2-chlorosulfonyl-5-[3,5-bis(trifluoromethyl)phenyl]thiophene was p what omashu column chromatography using a mixture of 2% ethyl acetate/hexane resulted in the obtaining of pure thiophene with 73% yield as light brown oil.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-[3,5 bis(trifluoromethyl) phenyl]thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-[3,5 bis(trifluoromethyl) phenyl] thiophene-2-sulfonamide was obtained as in Example 2. The reaction of 2-chlorosulfonyl-5-[3,5-bis(trifluoromethyl)phenyl]thiophene (250 mg, 0.63 mmol) with 5-amino-4-bromo-3-methylisoxazole (118 mg, 0.67 mmol) resulted, after column chromatography, using 5% MeOH/CHCl3, 115.2 mg of N-(4-bromo-3-methyl-5-isoxazolyl)-5-[3,5 bis(trifluoromethyl)phenyl] thiophene-2-sulfonamida in the form of a white powder (34% yield). Part of this substance was subjected to further purification using preparative HPLC, so pl. 140oC.

EXAMPLE 295

T-(4-Bromo-3-methyl-5-isoxazolyl)-5-(5-methyl-2-thienyl)thiophene - 2-sulfonamide

A. 2-methylthiophene-5-boric acid

n-BuLi (2.38 M, 16 ml) was slowly added to a solution of 2 - methylthiophene (3.0 g, 31 mmol) in THF (20 ml) at -78oC. the Solution was kept at -78oC for 10 min, then was heated to 0oC optional for 0.5 hours. Then the solution was transferred using a steel syringe under nitrogen atmosphere in a vessel containing triisopropylsilane (6.3 g, 33 mmol) in ether (15 ml) at -78oC. the Resulting milky white solution re the and by adding 10% aqueous HCl (5.0 ml), and the solution was extracted with ether. The combined ether extracts were extracted 10 M NaOH (2 x 30 ml), aqueous extracts were acidified with dilute HCl to pH 2 and extracted with ether (3 x 25 ml). The combined ether extracts were washed once with water (10 ml), once with brine (10 ml) and dried, then evaporated to obtain 3.91 g of 2-methylthiophene-5-boric acid as a light brown solid. It was used in the next stage without additional purification,

C. N-[5-(5-methyl-2-thienyl)thiophene-2-sulfonyl]pyrrol

N-[5-(5-methyl-2-thienyl)thiophene-2-sulfonyl]pyrrole was obtained as described in Example 32C from 2-methylthiophene-5-boric acid and N-(5-bromothiophene-2-sulfonyl)pyrrole. Purification of column chromatography using a mixture of 2% ether/hexane resulted in the receipt of net sulfonamida with 72% yield as a white solid.

C. 2-chlorosulfonyl-5-(5-methyl-2-thienyl)thiophene

2-chlorosulfonyl-5-(5-methyl-2-thienyl)thiophene was obtained as described in Example 33D, from N-[5-(5-methyl-2-thienyl)thiophene-2 - sulfonyl]pyrrole (570 mg, 1.84 mmol). Purification via column chromatography using a mixture of 2% ethyl acetate/hexane resulted in the receipt of 258 mg (50%) of sulphonylchloride as UNAMID

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-methyl-2-thienyl) thiophene-2-sulfonamide was obtained as described in Example 2. The reaction of 2-chlorosulfonyl-5-(5-methyl-2-thienyl)thiophene (200 mg, 0.72 mmol) with 5-amino-4-bromo-3-methylisoxazole (127 mg, 0.72 mmol) resulted in the receipt of 273 mg (90%) of the crude sulfonamida. After passing through the silica gel portion of the product was subjected to further purification preparative HPLC to obtain pure sulfonamida in the form of a white powder, so pl. 161 - 162oC.

EXAMPLE 296

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)thiophene-2 - sulfonamide

A. 2-ethylthiophen-5-boronic acid

2-ethylthiophen-5-boronic acid was obtained as described in Example 140A, 2-ethylthiophene (2.0 g, 18 mmol). Evaporation of the solvent after the reaction resulted in the receipt of 2.16 g (78%) 2 - ethylthiophen-5-boric acid as a white solid, which was used in the next stage without further purification.

C. N-[5-(5-ethyl-2-thienyl)thiophene-2-sulfonyl]pyrrol

N-[5-(5-ethyl-2-thienyl)thiophene-2-sulfonyl] pyrrole was obtained as described in Example 32C from 2-ethylthiophen-5-boric acid (411 mg, 2.64 mmol) and N-(5-bromothiophene-2-sulfonyl)pyrrole (700 mg, 2.39 mmol). Purification using column chromatography with espargaro substances (90% yield).

C. 2-chlorosulfonyl-5-(5-ethyl-2-thienyl)thiophene

2-chlorosulfonyl-5-(5-ethyl-2-thienyl)thiophene was obtained as described in Example 33D, of N-(pyrrole)-5-(5-ethyl-2-thienyl)thiophene-2 - sulfonamida (630 mg, 2.16 mmol). Purification via column chromatography using a mixture of 1% ethyl acetate/hexane resulted in 400.3 mg of pure sulphonylchloride in the form of a bright yellow solid (57% yield).

D. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)thiophene - 2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl) thiophene-2-sulfonamide was obtained as described in Example 2. Reaction. 2 - chlorosulfonyl-5-(5-ethyl-2-tenil)thiophene (200 mg, 0.68 mmol) with 5-amino-4-bromo-3-methyl-isoxazol (121 mg, 0.68 mmol) resulted in the receipt of 174 mg of N-(4-bromo-3-methyl-5-isoxazolyl)-5- (5-ethyl-2-thienyl)thiophene-2-sulfonamida (59% yield). After passing through silica gel using elution with 10% mixture of MeOH/CHCl3part of the product was subjected to further purification using preparative HPLC to obtain sulfonamida in the form of a light brown colored powder, so pl. 126oC.

EXAMPLE 297

N-(4-chloro-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)thiophene-2 - sulfonamide

N-(4-chlorine is sulfonyl-5-(5-ethyl-2 - thienyl)thiophene (Example 141C, 200 mg, 0.68 mmol) with 5-amino-4-chloro-3-methyl-isoxazol (91 mg, 0.68 mmol) resulted in the receipt of 188 mg of the final product (71% yield). A small portion of the product was subjected to further purification preparative HPLC to obtain pure sulfonamida in the form of a brown colored solid.

EXAMPLE 298

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(benzo[b] Tien-2-yl)thiophene-2 - sulfonamide

A. Benzo[b]thiophene-2-boric acid

Benzo[b] thiophene-2-boronic acid was obtained as described in Example 140A, benzo[b]thiophene, except that t-BuLi was used as the base instead of n-BuLi Was obtained brown solid with 78% yield.

C. N-[5-(benzo[b]Tien-2-yl)typei-2-sulfonyl]pyrrol

N-[5-(benzo[b] Tien-2-yl)thiophene-2-sulfonyl] pyrrole was obtained as described in Example 32C from benzo[b]thiophene-2-boronic acid (426 mg, 2.39 mmol) and N-(5-bromothiophene-2-sulfonyl)pyrrole (700 mg, 2.39 mmol). Purification via column chromatography using a mixture of 2% ethyl acetate/hexane resulted in the receipt of net sulfonamida with 68% yield as a brown-red solid.

C. 2-chlorosulfonyl-5-(benzo[b]Tien-2-yl)thiophene

2-chlorosulfonyl-5-(benzo 1.5 mmol) Purification by means of column chromatography using a mixture of 2% ethyl acetate/hexane resulted in the receipt of 153 mg (yield 32%) of pure sulphonylchloride in the form of a white solid.

D. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzo[b] Tien-2-yl) thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzo[b]Tien-2-yl)thiophene - 2-sulfonamide was obtained as in Example 2. The reaction of 2 - chlorosulfonyl-5-(benzo[b] Tiep-2-yl)thiophene (150 mg, 0.48 mmol) with 5-amino-4-bromo-3-methylisoxazole (84 mg, 0.48 mmol) resulted in the receipt of 97 mg of pure N-(4-bromo-3-methyl-5-isoxazolyl)-5- (benzo[b] Tien-2-yl)thiophene-2-sulfonamida in the form of a light brown powder (45% yield, so pl. 164oC).

EXAMPLE 299

N-(Bromo-3-methyl-5-isoxazolyl)-5-(1-pentenyl)thiophene-2 - sulfonamide

A. N-[5-(1-pentenyl)thiophene-2-sulfonyl)pyrrol

N-[5-(1-pentenyl)thiophene-2-sulfonyl)pyrrole was obtained as in Example A, from N-(5-bromothiophene-2-sulfonyl)pyrrole (600 mg, 2.05 mmol) and 1-pentenyl (280 mg, 4.1 mmol). Purification via column chromatography using a mixture of 2% ethyl acetate/hexane resulted in the receipt of 424 mg of pure sulfonamida in the form of a brown oil (74% yield).

Century 2-chlorosulfonyl-5-(1-pentenyl)thiophene

2-chlorosulfonyl-5-(1-pentenyl)thiophene was obtained as described in Example 33D, from N-[5-(1-pentenyl)thiophene-2-sulfonyl] pyrrole (420 mg, 1.5 mmol). Purification using column chromatography using cm is ASS="ptx2">

C. N-(bromo-3-methyl-5-isoxazolyl)-5-(1-pentenyl)thiophene-2 - sulfonamide

N-(bromo-3-methyl-5-isoxazolyl)-5-(1-pentenyl)thiophene-2 - sulfonamide was obtained as described in Example 2, the Reaction of 2 - chlorosulfonyl-5-(1-pentenyl)thiophene (55 mg, 0.22 mmol) using 5-amino-4-bromo-3 - methylisoxazole (43 mg, 0.22 mmol) resulted in 75 mg of N-(bromo-3 - methyl-5 - isoxazolyl)-5-(1-pentenyl)thiophene-2-sulfonamida (87% yield). Part of the product was subjected to further purification preparative HPLC to obtain pure sulfonamida in the form of a light brown oil.

EXAMPLE 300

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(1-naphthyl)thiophene-2 - sulfonamide

A. N-[5-(1-naphthyl)thiophene-2-sulfonyl]pyrrol

N-[5-(1-naphthyl)thiophene-2-sulfonyl]pyrrole was obtained as described in Example 32C from 1-naphthaleneboronic acid (353 mg, 2.05 mmol) and N-(5-bromo-thiophene-2-sulfonyl)pyrrole (600 mg, 2.05 mmol). Purification using column chromatography using 2% mixture of ethyl acetate/hexane resulted in the receipt of net sulfonamida with 87% yield as a transparent pale yellow oil.

Century 2-chlorosulfonyl-5-(1-naphthyl)thiophene

2-chlorosulfonyl-5-(1-naphthyl)thiophene was obtained as described in Example 33D, from N-[5-(1-naphthyl)thiophene-2-sulfonyl] an led to 376 mg of pure thiophene with 68% yield.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(1-naphthyl)thiophene - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(1-naphtyl)thiophene - sulfonamide was obtained as described in Example 2. The reaction of 2-chlorosulfonyl-5-(1 - naphthyl)thiophene (200 mg, 0.65 mmol) with 5 - amino-4-bromo-3-methylisoxazole (0.65 mmol) after purification by column chromatography using a mixture of 1% MeOH/CHCl3led to 65.3 mg of pure N-(4-bromo-3 - methyl-5-isoxazolyl)-5-(1-naphthyl)thiophenesulfonyl in the form of a brown solid (22% yield, so pl. 118oC).

EXAMPLE 301

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2 - sulfonamide

A. N-(3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfonamide

N-(3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfonamide was obtained as described in Example 32C, 3 nitrobenzoic acid (362 mg, 2.17 mmol) and N-(3-methyl-5-isoxazolyl)-5-bromothiophene - 2-sulfonamida (700 mg, 2.17 mmol) Purification by means of column chromatography using a mixture of 10% MeOH/CHCl3led to obtain 166 mg of pure sulfonamida (21% yield).

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2 - sulfonamide

N-(4-bromo-3-mepl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene - 2-sulfonamide (328 g, 0.90 mmol) with N-bromosuccinimide (160 mg, 0.90 mmol) led to the final product. Part of the obtained material was subjected to further purification preparative HPLC to obtain pure sulfonamida in the form of a brown solid, so pl. 132oC.

EXAMPLE 302

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-methy) thiophene-2-sulfonamide

A. 2-(4-ethoxycarbonylphenyl)thiophene

2-(4-ethoxycarbonylphenyl)thiophene was obtained as described in Example 32C, from thiophene-2-boronic acid (1.0 g, 7.81 mmol) and methyl-4-bromobenzoate (1.68 g, 7.81 mmol). Purification via column chromatography using a mixture of 2% ethyl acetate/hexane resulted in obtaining 1.1 g of 2-(4-ethoxycarbonylphenyl)thiophene as a white solid (65% yield).

Century 2-chlorosulfonyl-5-(4-ethoxycarbonylphenyl)thiophene

Chlorosulfonic acid (1.06 g, 9.16 mmol) was slowly added to the solution. 2-(4-ethoxycarbonylphenyl)thiophene (500 mg, 2.29 mmol) in CH2Cl2(10 ml) at -78oC. the Resulting solution was stirred at -78oC for 1 h, during this time, the sulfonic acid is completely reacted, as can be judged by TLC using a mixture of 10% ethyl acetate/hexane. Then before mmol). The resulting solution was stirred at -78oC for 0.5 h and then at room temperature for 25 minutes and Then the solution was carefully poured onto crushed ice (100 g) and extracted with diethyl ether (100 ml). The combined organic layers were washed with brine (1 x 25 ml), and dried over MgSO4. After filtration, removal of solvent left a light green solid, which was subjected to further purification using column chromatography, using a 2% mixture of ethyl acetate/hexane. Received 620 mg of pure 2-chlorosulfonyl - 5-(4-ethoxycarbonylphenyl)thiophene as a pale yellow solid (85% yield).

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-ethoxycarbonylphenyl) thiophene-2-sulfonamide

N-(4-ROM-3-methyl-5-isoxazolyl)-5-(4-ethoxycarbonylphenyl) thiophene-2-sulfonamide was obtained as described in Example 2 from 2-chlorosulfonyl-5-(4-ethoxycarbonylphenyl)thiophene (646 mg, 2.04 mmol) and 5-amino-4-bromo-3-methylisoxazole (361 mg, 2.04 mmol). Purification via column chromatography using a mixture of 10% MeOH/CHCl3led to obtain 384 mg of N-(4-bromo-3 - methyl-5-isoxazolyl)-5-(4-ethoxycarbonylphenyl)thiophene-2 - sulfonamida in the form of a brown oil (41% yield).

4. After evaporation remained 50 mg (yield 43%) of a pale yellow residue, which was subjected to further purification preparative HPLC) to obtain N-(4-bromo-3-methyl-5 - isoxazolyl)-5-(4-carboxyphenyl)thiophene-2-sulfonamida in the form of a white solid substance, so pl. 219-228oC

EXAMPLE 304

N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)- phenyl] aminocarbonyl}thiophene-3-sulfonamide

Carbonyldiimidazole (553 mg, 3.41 mmol) was added to a solution of N-(4-Chloro-3 - methyl-5-isoxazolyl)-2-carboxylate-3 - sulfonamida (1.0 g, 3.1 mmol) in dry DMF (10 ml). The mixture was stirred at room temperature for 15 min with a mixture (I).

NaH (60% dispersion in mineral is Matt (10 ml) at 0oC. the Mixture was stirred at 0oC for 15 min to obtain a mixture (II). Mixture (I) was slowly introduced with a syringe to the mixture (II) if 0oC. the Resulting mixture was stirred at 0oC for 4 hours. The reaction mixture was poured into 2 N HCl (water, 200 ml) and the resulting precipitate was filtered. The solid was washed with water (2x10 ml) and ethyl ether (2x10 ml) to give N-(4-chloro-3-methyl-5-isoxazolyl)2-{ [2-acetyl-4,5- (methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamida (730 mg, 49% yield) as a dull yellow powder, so pl. 191-193oC.

EXAMPLE 305

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4,5-dimethoxy - 2-methoxycarbonyl-phenyl)aminocarbonyl] thiophene-3-sulfonamide and N-(4 - chloro-3-methyl-5-isoxazolyl)2-{ [4,5-dimethoxy-2] 4,5-dimethoxy-2 - methoxycarbonyl)phenyl]-phenylenecarbonyl}thiophene-3-sulfonamide

Connections marked in the title of the example were obtained by the method previously described for N-(4-chloro-3-methyl-5-isoxazolyl)2- {[2-acetyl-4,5-(methylene-dioxy)phenyl] aminocarbonyl} thiophene-3 - sulfonamida (Example 148), except that methyl 2-amino - 4,5-dimethoxybenzoate was used instead of 2'-amino-4',5'- (methylendioxy)acetovanillone. Technical product was purified HPLC to obtain N-(4-chloro-3-methyl-5-of the(13% yield, so pl. 167-168oC) and N-(4 - chloro-3-methyl-5-isoxazolyl)2-{ [4,5-dimethoxy-2,4,5-dimethoxy-2 - methoxycarbonyl)phenyl]-phenylenecarbonyl} thiophene-3-sulfonamida as a dull yellow solid (yield 1%. so pl. 228-230oC).

EXAMPLE 306

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2 - methyl-1,3,4-thiadiazole-5-yl)aminocarbonyl]thiophene-3-sulfonamide

Carbonyldiimidazole (553 mg, 3.41 mmol) was added to a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxy-thiophene-3-sulfonamida (10 g, 3.1 mmol) in dry DMF (10 ml). The mixture was stirred at room temperature for 15 min, and then added 2-amino-5-methyl-1,3,4-thiadiazole (736 mg, 6.2 mmol) and pyridine (10 ml). The resulting mixture was stirred at room temperature overnight. Then the reaction mixture was poured into 1 N HCl (150 ml) and was extracted with EtOAc. The organic layer was dried (MgSO4), the solid was filtered and the filtrate was concentrated. The residue was purified HPLC to obtain N-(4 - chloro-3-methyl-5-isoxazolyl)-2-[(2-methyl-1,3,4-thiadiazole-5 - yl)aminocarbonyl] thiophene-3-sulfonamida in the form of a white powder (15% yield, so pl. 192-194oC).

EXAMPLE 307

N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-carboxy-4,5- (methylenedioxy)phenyl]aminocarbonyl}tafeltennis)aminocarbonyl] thiophene-3-sulfonamide (Example 149); 410 mg). The resulting suspension was stirred at room temperature overnight to obtain a clear solution. The mixture was acidified with concentrated HCl while cooling. The resulting precipitate was filtered, washed with water (I ml) and dried lyophilized to obtain N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-carboxy-4,5- (methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamida in the form of a yellow powder (87% yield, so pl. 192-195 (in Russian)oC).

EXAMPLE 308

N-(3,4-dimethyl-5-isoxazolyl)-2-{ [2-acetyl-4,5-(methylene - dioxy)phenyl] aminocarbonyl}thiophene-3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-{ [2-acetyl-4,5-(methylene - dioxy)phenyl] aminocarbonyl} thiophene-3-sulfonamide was obtained according to the method described for N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2 - acetyl-4,5-(methylene-dioxy)phenyl]aminocarbonyl)thiophene-3 - sulfonamida (Example 148), except N-(3,4-dimethyl - 5-isoxazolyl)-2-carboxylate-3-sulfonamide was used instead of N-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylate-3 - sulfonamida. N-(3,4-dimethyl-5-isoxazolyl)-2-{ [2-acetyl-4,5- (methylenedioxy)phenyl]aminocarbonyl} thiophene-3-sulfonamide was obtained as a yellow powder (8% output, so pl. 228-231oC).

EXAMPLE 309

N-(4-chloro-3-methyl-5-is(4-methoxy-2-were) aminocarbonyl] thiophene-3-sulfonamide was obtained according to the method, described for N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-methyl-1,3,4 - thiadiazole-5-yl)aminocarbonyl] thiophene-3-sulfonamida (Example 150), except that 4-methoxy-2-methylaniline was used instead of 2-amino-5-methyl-1,3,4-thiadiazole and that pyridine was not used. The connection specified in the header, was obtained by purification by HPLC as a dull yellow powder (66% yield, so pl. 58-62oC).

EXAMPLE 310

N-(4-chloro-3-methyl-5-isoxazolyl)-2-1(2-cyano-4,5-acid) aminocarbonyl]thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-cyano-4,5-acid) aminocarbonyl] thiophene-3-sulfonamide was obtained according to the method described for N-(4-chloro-3-methyl-5-isoxazolyl)2-{ [2-acetyl-4,5-(methylenedioxy) phenyl] aminocarbonyl} thiophene-3-sulfonamida (Example 148), except 2 - amino-4,5-dimethoxybenzonitrile was used instead of 2'-amino-4', 5'-(methylendioxy)acetovanillone. N-(4-chloro-3-methyl - 5-isoxazolyl)-2-[{2-cyano-4,5-acid)aminocarbonyl] thiophene - 3-sulfonamide was obtained via HPLC purification as a light brown powder (36% yield, so pl. 53-56oC).

EXAMPLE 311

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4-acid) aminocarbonyl] thiophene-3-sulfonamide

N-(4-hnim for N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4 - methoxy-2-were)aminocarbonyl] thiophene-3-sulfonamida (Example 153), except that 2,4-dimethoxyaniline was used instead of 4-methoxy-2-methylaniline N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[(2,4-acid)aminocarbonyl] thiophene-3-sulfonamide was obtained after recrystallization (CH3CN/H20in the form of yellow crystals (16% yield, so pl. 162-164oC).

EXAMPLE 312

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6-pyridyl) aminocarbonyl] thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6-pyridyl) aminocarbonyl] -thiophene-3-sulfonamide was obtained according to the method described for N-(4-chloro-3-methyl-5-isoxazolyl)2-{ [2-acetyl-4,5-(methylenedioxy) phenyl]aminocarbonyl}-thiophene-3-sulfonamida (Example 148), except 2-amino-5-picoline was used instead of 2'-amino-4',5'-(methylendioxy)acetovanillone; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[(3-methyl-6-pyridyl)aminocarbonyl]thiophene-3-sulfonamide was obtained by purification by HPLC of the crude reaction mixture, in the form of a bright yellow powder (17% yield, so pl. 158 - 160oC).

EXAMPLE 313

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-were)acetyl] thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-were)acetyl] thiophene-3-sulfonamide was obtained as described in Example V, the medium is a sulfonamide in THF (see Example 93A) at from -78oC to room temperature, resulting from 78% yield; so pl. 146-150oC.

EXAMPLE 314

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)(cinnamyl)] thiophene - 3-sulfonamide

A. N-[2-(4-methyl-TRANS-styryl)-3-sulfonyl}pyrrol

N-[2-(4-methyl-TRANS-styryl)-3-sulfonyl} pyrrole was obtained as described in Example 127V, using diethyl{3-[(N - pyrrolidinyl)Tien-2-[Il]methylphosphonate and 4-methylbenzaldehyde with 30% output.

Century 2-(4-methyl-TRANS-styryl)thiophene-3-sulphonylchloride

2-(4 - methyl-TRANS-styryl)thiophene-3-sulfonyl chloride was obtained as described in Example A, from N-[2-(4-methyl-TRANS-styryl)-3-sulfonyl}pyrrole by basic hydrolysis (using ethanol and sodium hydroxide), to the corresponding sulfonate sodium, followed by conversion to the corresponding sulphonylchloride, with 13% yield.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methyl-TRANS-styryl)thiophene - 3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methyl-TRANS - styryl)thiophene-3-sulfonamide was obtained as described in Example 2, by reaction of 2-(4-methyl-TRANS-styryl)thiophene-3 - sulphonylchloride, 5-amino-4-bromo-3-methylisoxazole. Technical product was purified is R 315

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenylethyl] thiophene - 3-sulfonamide

A. N-{2-[(4-methyl)phenylethyl]thiophene-3-sulfonyl}pyrrol

N-{2-[(4-methyl)phenylethyl]thiophene-3-sulfonyl}pyrrole was obtained as described in Example I by catalytic hydrogenation of N-[2-(4-methyl-TRANS-styryl)-3-sulfonyl} pyrrole with 80% output

C. 2-[(4-methyl)phenylethyl]thiophene-3-sulphonylchloride

2-[(4-methyl)phenylethyl] thiophene-3-sulphonylchloride was obtained as described in Example A, from N-{ 2-[(4-methyl)phenylethyl]thiophene-3-sulfonyl} pyrrole by basic hydrolysis (KOH/ethanol) sulfonamida. to potassium salt, followed by conversion of the salt to the corresponding sulphonylchloride with 51% yield.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-1(4-methyl)phenylethyl] thiophene - 3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenylethyl] l-3 - sulfonamide was obtained as described in Example 2 from 2-[(4-methyl)- phenylethyl] thiophene-3-sulphonylchloride and 5-amino-4-bromo-3-methylisoxazole, with 52% yield.

EXAMPLE 316

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl] thiophene-3-sulfonamide

A. N-{2-[(4-methylphenoxy)methyl]thiophene-3-sulfonyl}pyrrol

N-{ 2-[(4-methylphenoxy)methyl] thiophene-3-sulfonyl}pyrrole was obtained, ka is m output.

C. 2-[(4-methylphenoxy)methyl]thiophene-3-sulfonyl chloride

2-[(4-methylphenoxy)methyl] thiophene-3-sulfonyl chloride was obtained as described in Example I, using N-{2-[(4 - methylphenoxyacetic]thiophene-3-sulfonyl}pyrrole by basic hydrolysis (NaOH/EtOH), followed by conversion to the corresponding sulphonylchloride, with 46% yield.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl] thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl] thiophene-3-sulfonamide was obtained as described in Example 2, by reaction of 3-chlorosulfonyl-2-[(4 - methylphenoxy)methyl] thiophene with 5-amino-4-bromo-3-methyl-isoxazol. The product was obtained in 64% yield, so pl. 128-130oC.

EXAMPLE 317

N-(3,4-dimethyl-5-isoxazolyl)-2-(4-tolylacetylene)thiophene - 3-sulfonamide

A. N-(3,4-dimethyl-5-isoxazolyl)-2-[N-methoxy(methylaminomethyl) thiophene-3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-[N-methoxy (methylaminomethyl)thiophene-3-sulfonamide was obtained as described in Example 93A, by reaction of N-(3,4-dimethyl-5 - isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamida N-O - dimethylhydroxylamine, using triethylamine as base, and carbonyldiimidazole.the use of a mixture of 1:1 hexane/EtOAc as eluent.

C. N-(3,4-dimethyl-5-isoxazolyl)-2-(4-tolylacetic)thiophene - 3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-(4-tolylacetic)thiophene-3 - sulfonamide was obtained as described in Example V, by reaction of N-(3,4-dimethyl-5-isoxazolyl)-2-[N-methoxy(methylaminomethyl)] thiophene-3-sulfonamida 4-wellmanicured. The substance was obtained with 65% yield, so pl. 95-100oC.

EXAMPLE 318

N-(3,4-dimethyl-5-isoxazolyl)-2-[3,4-(methylendioxy)phenylacetyl] thiophene-3-sulfonamide

T-(3,4-dimethyl-5-isoxazolyl)-2-[3,4-(methylendioxy)phenylacetyl] thiophene-3-sulfonamide was obtained as described in Example V, by reaction of N-(3,4-dimethyl-5-isoxazolyl)-2-[N - methoxy(methylaminomethyl)]thiophene-3-sulfonamida with 3,4 - methylendioxy)phenylmagnesium. The substance was obtained with 65% yield, so pl. 95-100oC.

EXAMPLE 319

N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ [2-cyano-4,5-(methylenedioxy) phenyl] -aminocarbonyl}thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ [2-cyano-4,5-(methylenedioxy) phenyl] aminocarbonyl}thiophene-3-sulfonamide was obtained as described in Example 148, except that 2'-amino-4', 5'- (methylendioxy)benzonitrile was used instead of 2'-amino - 4',5'-(methylendioxy)of acetophenone. The substance was obtained Paymer 320

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6 - trimethyl)phenylenecarbonyl-3-thiophenesulfonyl

A. Methyl 3-amino-2,4,6-trimethylbenzoic

Methyl 3-amino-2,4,6-trimethylbenzoic was synthesized in the same way as (3,4-methylenedioxy)-6-methylaniline (see Example 177, below).

C. N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6 - trimethyl)phenylenecarbonyl-3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6 - trimethyl)phenylenecarbonyl-3-thiophenesulfonyl was synthesized as in Example 94, except that DMF was used instead of THF, and the reaction mixture was heated at 80oC for 5 hours. Technical product was purified using preparative HPLC to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6 - trimethyl)phenylenecarbonyl-3-thiophenesulfonyl in the form of a white powder (48 mg, 1% yield, so pl. 66-70oC).

EXAMPLE 321

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacetyl - 3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl) phenylacetyl-3-thiophenesulfonyl was synthesized as described in Example 102, 2,4,6-trimethylbenzaldehyde and N-(4-chloro-3-methyl - 5-isoxazolyl)-2-(N-methyl-N'-methoxy)link 1% methanol in CH2Cl2) to obtain N-(4-chloro-3-methyl-5-isoxazolyl)- 2-(2,4,6-trimethyl)phenylacetyl-3-thiophenesulfonyl in the form of a solid (31% yield, so pl. 42-46oC).

EXAMPLE 322

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl) phenylenecarbonyl-3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6 - trimethyl)phenylenecarbonyl-3-thiophenesulfonyl was obtained as described in Example 94. Technical product was purified preparative HPLC to obtain N-(4-chloro-3-methyl-5-isoxazolyl)- 2-(2,4,6-trimethyl)phenylenecarbonyl-3-thiophenesulfonyl in the form of a yellowish-brown powder (410 mg, 30% yield, so pl. 45-48oC).

EXAMPLE 323

N-(3,4-dimethyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3 - thiophene-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3 - thiophenesulfonyl was synthesized as described in Example 102, using 2,4-dimethylbenzylamine and N-(3,4-dimethyl-5 - isoxazolyl)-2-(N-methyl-N'-methoxy)aminocarbonyl-3 - thiophenesulfonyl. Technical product was purified flash column chromatography (eluent 1% methanol in CH2Cl2) and then preparative HPLC to obtain N-(3,4-dimethyl-5 - isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonyl in VI is)phenylacetyl-3 - thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3 - thiophenesulfonyl was obtained as described in Example 102, using 2,4-dimethylbenzyl chloride and N-(4-chloro-3-methyl-5 - isoxazolyl)- 2-(N-methyl-N'-methoxy)aminocarbonyl-3-thiophenesulfonyl. Technical product was purified flash column chromatography (eluent a mixture of 1% methanol in CH2Cl2) to obtain N-(4-chloro-3 - methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonyl in the form of a solid (52% yield, so pl. 48-54oC).

EXAMPLE 325

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3 - thiophenesulfonyl

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl - 3-thiophenesulfonyl was synthesized as described in Example 102, using 2,4-dimethylbenzyl chloride and N-(4 - bromo-3-methyl-5-isoxazolyl)-2-(N-methyl-N'-methoxy)aminocarbonyl - 3-thiophenesulfonyl. Technical product was purified flash column chromatography (eluent is a mixture of 1% methanol in CH2Cl2) and then preparative HPLC to obtain N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3 - thiophenesulfonyl in the form of a solid (28% yield, so pl. 58-63oC).

EXAMPLE 326

N-(4-chloro-3-methyl-5-isoxazolyl)-persulfonic was obtained in the same way as described in Example 102, using 3,5-dimethylbenzylamine and N-(4-chloro-3-methyl-5 - isoxazolyl)-2-(N-methyl-N'-methoxy)aminocarbonyl-3-thiophenesulfonyl. Technical product was purified flash column chromatography (eluent is a mixture of 2% methanol in CH2Cl2) to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,5-dimethyl)phenylacetyl-3 - thiophenesulfonyl in the form of a solid (57% yield, so pl. 45-50oC).

EXAMPLE 327

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,5-dimethyl)phenylacetyl - 3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,5-dimethyl)phenylacetyl - 3-thiophenesulfonyl was obtained as described in Example 102, using 2,5-dimethylbenzylamine and N-(4-chloro-3 - methyl-5-isoxazolyl)- 2-(N-methyl-N'-methoxy)aminocarbonyl-3 - thiophenesulfonyl. Technical product was purified flash column chromatography (eluent is a mixture of 2% methanol in CH2Cl2) to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,5-dimethyl) phenylacetyl-3-thiophenesulfonyl in the form of a solid (33% yield, so pl. 72-76oC).

EXAMPLE 328

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6- (2-acetoxyethyl)]phenylenecarbonyl-3-thiophenesulfonyl

A. 2-(3,4-methylenedioxy)phenyl-1-ethanol

To a solution of 2-(3,4-methylendioxy)Fe). The mixture was stirred at room temperature for 1 h and Then THF was evaporated on a rotary evaporator. The residue was treated with water, acidified and extracted with ether (2 x 100 ml). Removal of the solvent under reduced pressure resulted in 2-(3,4-methylenedioxy)phenyl-1-ethanol in the form of an oil (4.7 g, 98% yield).

Century 1-acetoxy-2-[(3,4-methylenedioxy)phenyl]ethane

To a solution of 2-(3,4-methylenedioxy)phenyl-1-ethanol (1.68 g, 10 mmol) in dry pyridine under stirring was added acetic anhydride, and the resulting reaction mixture was stirred at 80oC for 1 h, the Reaction mixture was poured into ice water and was extracted with ether (2 x 75 ml). The combined ether extracts were washed with water (2 x 50 ml), 5% HCl (2 x 50 ml) and then 5% NaHCO3(2 x 50 ml). The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to obtain 1-acetoxy-2-[(3,4-methylenedioxy)phenyl] ethane in the form of a solid (1.7 g, 81% yield).

C. 1-acetoxy-2-1(3,4-methylenedioxy)-6-nitrophenyl]ethane

To a solution of 1-acetoxy-2-[(3,4-methylenedioxy)-phenyl] ethane (1.7 g, 8.09 mmol) with stirring in acetic acid (10 ml) was added dropwise, concentrated HNO3(4.5 ml). Was stirred at trovano, washed with water and dried under high vacuum to obtain 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl]ethane (1.8 g, 88% yield).

D. 1-acetoxy-2-[(3,4-methylenedioxy)-6-AMINOPHENYL]ethane

A solution of 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl] ethane (0.8 g, 3.13 mmol) in ethyl acetate (25 ml) was subjected to catalytic hydrogenation using 10% palladium deposited on charcoal (100 mg) at 50 psi for 30 minutes the Catalyst was filtered, and the solvent was removed under reduced pressure to obtain 1-acetoxy-2-[(3,4 - methylenedioxy)-6-AMINOPHENYL]ethane in the form of a solid (0.69 g, 98%th output).

E. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6- (2-acetoxyethyl)]phenylenecarbonyl-3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6- (2-acetoxyethyl)]phenylenecarbonyl-3-thiophenesulfonyl was obtained as described in Example 87. Technical product was purified preparative HPLC to obtain N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethyl)] phenylenecarbonyl-3-thiophenesulfonyl in the form of a dull yellow powder (12% output, so pl. 78-82oC)

EXAMPLE 329

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6- (2-hidroxi is(2-acetoxyethyl)] phenylenecarbonyl-3 - thiophenesulfonyl (35 mg, 0.066 mmol) in methanol under stirring was added NaOH powder (40 mg) and stirring was carried out at room temperature for 30 minutes, HPLC Analysis showed complete consumption of the original substance. The reaction mixture was diluted with water and acidified to pH 2-3. It was extracted with ethyl acetate (2 x 25 ml). The combined organic layers were dried over magnesium sulfate, and the solvent removed under reduced pressure to obtain N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[3,4-(methylenedioxy)-6-(2-hydroxyethyl)] phenylenecarbonyl-3 - thiophenesulfonyl in the form of a solid (84% yield, so pl. 47-52oC).

EXAMPLE 330

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2 - acetoacetate)]phenylenecarbonyl-3-thiophenesulfonyl

A. Methyl 2-[3,4-(methylendioxy)phenoxy]acetate and 2-[3,4- (methylendioxy)phenoxy]acetic acid

A mixture of sesamol (13.8 g, 100 mmol, methylpropanoate (15.3 g, 100 mmol) and potassium carbonate in acetone (200 ml) was distilled under reflux for 24 h under stirring. The acetone was removed under reduced pressure. The residue was dissolved in water (200 ml) and was extracted with ether (2 x 100 ml). The combined organic layers were dried over magnesium sulfate, and the solvent 57% yield). The aqueous phase was neutralized to pH 2-3 with concentrated HCl, and the precipitated solid was filtered. The obtained 2-[3,4-(methylendioxy)phenoxy] acetic acid as a solid (6 g, 31% yield).

Century, 2-3,4-(methylendioxy)phenoxy-1-ethanol

2-(3,4-methylendioxy)phenoxy-1-ethanol was synthesized as described in Example 172(A), using 2-[3,4-(methylendioxy) phenoxy]acetic acid and complex BH3THF. The reaction was carried out for 12 hours at room temperature (98% yield).

C. 1-acetoxy-2-[3,4-(methylendioxy)phenoxy]ethane

1-acetoxy-2-[3,4-(methylendioxy)phenoxy] ethane was essentially as described in Example 172(C), by acetylation of 2-(3,4-methylendioxy)phenoxy-1-ethanol with acetic anhydride and pyridine (92% yield).

D. 1-acetoxy-2-[3,4-(methylenedioxy)-6-nitrophenoxy]ethane

1-acetoxy-2-[3,4-(methylenedioxy)-6-nitrophenoxy] ethane was synthesized as described in Example 172(C), the nitration of 1-acetoxy-2-[3,4-(methylendioxy)phenoxy]ethane. The reaction was carried out between 0oC and 5oC for 30 min (78% yield).

That is, 1-acetoxy-2-[3,4-(methylenedioxy)-6-aminophenoxy]ethane

1-acetoxy-2-[3,4-(methylenedi is ilevoxi)-6-nitrophenoxy]ethane (100% yield).

F. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)- 6-(2-acetoacetate)]phenylenecarbonyl-3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6- (2-acetoacetate)] -phenylenecarbonyl-3-thiophenesulfonyl was synthesized as described in Example 87, using 1-acetoxy-2-[3,4-(methylenedioxy)-6 - aminophenoxy]ethane and N-(4-chloro-3-methyl-5-isoxazolyl)-2 - carboxylate-3-sulfonamida. Technical product was purified using preparative HPLC to obtain N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoacetate)] phenylenecarbonyl-3-thiophenesulfonyl in the form of a dull yellow powder (21% yield, so pl. 117-119oC).

EXAMPLE 331

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6- (2-hydroxyethoxy)]phenylenecarbonyl-3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6- (2-hydroxyethoxy)]-phenylenecarbonyl-3-thiophenesulfonyl was obtained as described in Example 173, the basic hydrolysis of N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2 - acetoacetate)] phenylenecarbonyl-3-thiophene-sulfonamida (86% yield, so pl. 158-161oC).

EXAMPLE 332

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methoxycarbonyl-2,6 - DIMET XMLType-3-sulfonamide

To a mixture of N-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylate - 3-sulfonamida (3.23 g, 100 mmol) and diisopropylethylamine (3 ml) in ethyl acetate (20 ml) was added methoxyethoxymethyl and the resulting reaction mixture was stirred at room temperature Uchenie 12 hours. She was diluted with ethyl acetate (100 ml) and washed with 1 N HCl (2 x 50 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)- 2-(carbomethoxy)thiophene-3-sulfonamida as a light brown oil.

The crude N-(4-chloro-3-methyl-5-isoxazolyl)-N- (methoxyethoxymethyl)-2-(carbomethoxy)thiophene-3-sulfonamide was dissolved in methanol (50 ml) were added potassium hydroxide (5 g) and water (5 ml). The reaction mixture was stirred at room temperature for 12 hours and was extracted with ethyl acetate (2 x 50 ml). The aqueous phase was neutralized to pH 2-3 and was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were dried over magnesium sulfate, and the solvent was removed to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-N- (methoxyethoxymethyl)-2-carboxylate-3-sulfonamida in the form of a light brown solid (3.5 g, 85% vyhoda who mmol) in acetic acid (30 ml) was added dropwise fuming nitric acid(30 ml). After the addition, the reaction mixture was heated heat gun. It was stirred additionally for 2 hours, during this period was precipitated solid. The reaction mixture was diluted with water (200 ml) and was filtered. The solid is dried under reduced pressure. To the above solid matter was added 20 ml of oxalicacid and catalytic amount of DMF (2 drops). The mixture was stirred at room temperature for 3 hours, and during this period formed a clear solution. Excess oxalicacid was removed under reduced pressure to obtain a yellow solid.

To the yellow solid substance was added dry methanol (100 ml) and the mixture was stirred at room temperature for 1 hour. The excess methanol was removed under reduced pressure, and the residue was dissolved in ether (200 ml). It was washed with water (100 ml) and then with saturated solution of NaHCO3(100 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed, the result was obtained 4-carbomethoxy-2,6-dimethylnitrobenzene in the form of a yellow solid (5.8 g, 83% yield). 4 Carbomethoxy-2,6-dimethylnitrobenzene (2 g, 9.5 mmol) was dissolved in ethyl acetate (20 m the e 30 minutes The catalyst was filtered, and the solvent was removed to obtain 4-carbomethoxy-2,6-dimethylaniline in the form of a solid (1.7 g, 100% yield).

C. N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methoxycarbonyl-2,6 - dimethyl)phenylenecarbonyl-3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2 - carboxylate-3-sulfonamide (3.5 g, 8.5 mmol) (obtained in stage A) was dissolved in oxanilide (5 ml), and added a drop of DMF. It was stirred at room temperature for 6 hours. Excess oxalicacid was removed under reduced pressure, and the mixture was dried under high vacuum.

To a solution of 4-carbomethoxy-2,6-dimethylaniline (0.9 g) (obtained in stage C) and triethylamine (2 ml) in methylene chloride (20 ml) at 0oC was added the acid chloride in 10 ml of methylene chloride (2.4 r, 4.98 mmol), obtained at the previous stage. The reaction mixture is left until it reaches room temperature, after which it was diluted with methylene chloride (50 ml) and was washed with 1 N HCl and then with saturated solution of NaHCO3. The organic layer was dried over magnesium sulfate and the solvent removed to obtain technical product. It was purified by column chromatogram)-N-(methoxyethoxymethyl)2-(4-methoxycarbonyl-2,6 - dimethyl)phenylenecarbonyl-3-thiophenesulfonyl in the form of an oil (0.6 g, with 20% yield).

N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)2- (4-methoxycarbonyl-2,6-dimethyl)phenylenecarbonyl-3 - thiophenesulfonyl (0.6 g) was dissolved in a mixture of methanol (8 ml) and concentrated HCl (1.5 ml) and the resulting reaction mixture was converted under reflux with stirring for 8 hours. The excess methanol was removed under reduced pressure, and the residue was dissolved in ethyl acetate (50 ml). It was washed with a saturated solution of sodium chloride. The organic layer was dried over magnesium sulfate, and the solvent was removed to obtain N-(4 - chloro-3-methyl-5-isoxazolyl)-2-(4-methoxycarbonyl-2,6 - dimethyl)phenylenecarbonyl-3-thiophenesulfonyl, which was crystallized using methylene chloride and hexane (0.23 g, 47% yield, so pl. 152-154oC).

EXAMPLE 333

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methyl] phenylenecarbonyl-3-thiophenesulfonyl

A. (3,4-methylenedioxy)-6-methylaniline

To a solution of (3,4-methylenedioxy)toluene (5 ml) in acetic acid (20 ml), cooled in a bath of cold water, was added, dropwise, nitric acid (70%, 5 ml). The mixture was stirred for 45 minutes Then added water (100 ml) and the resulting yellow precipitate was tfilter arena in EtOAc (250 ml) and dried (MgSO4), and the solid was filtered. The filtrate was subjected to catalytic hydrogenation (10% Pd/C, 1 ATM) for 12 h and Then the reaction mixture was filtered (filtered initiator), and the filtrate was concentrated on a rotary evaporator to obtain (3,4-methylenedioxy)-6-methylaniline in the form of brownish-gray solid (5.49 g, 87% yield).

C. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methyl]phenylenecarbonyl-3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methyl] phenylenecarbonyl-3-thiophenesulfonyl was obtained as described in Example 94, using (3,4-methylenedioxy)-6 - methylaniline. Technical product was purified using preparative HPLC to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)-6-methyl] phenylenecarbonyl-3-thiophenesulfonyl in the form of a yellow solid (45% yield, so pl. 60-62oC).

EXAMPLE 334

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxy-6-amino - carbonyl)phenylenecarbonyl-3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxy-6-amino - carbonyl)phenylenecarbonyl-3-thiophenesulfonyl was obtained as described in Example 94, with Isolda (Example 151) and ammonium hydroxide. Technical product was purified using preparative HPLC to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxy-6 - aminocarbonyl)phenylenecarbonyl-3-thiophenesulfonyl in the form of a yellow powder (66% yield, so pl. 189-192oC).

EXAMPLE 335

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methyl]phenylacetyl-3-thiophenesulfonyl

A. (3,4-methylenedioxy)-6-methylbenzyl chloride

To a mixture of 1: 1 ethyl ether (100 ml) and conc. HCl (100 ml) at 0oC was added (3,4-methylenedioxy)toluene (10 ml). Then was added dropwise formaldehyde (20 ml, 37% in water). The reaction was carried out at 0oC for 2 hours and at room temperature for additional 10 hours. The reaction mixture was then diluted with ethyl ether (100 ml) and separated the two layers. The organic layer was dried (MgSO4), the solid was filtered and the filtrate was concentrated. The residue was then heated with hexane (200 ml) and nerastvorimaya substance was filtered from the hot solution. The filtrate was concentrated to obtain a mixture of (3,4-methylenedioxy)- 6-methylbenzyl chloride (9.4 g, 63% yield) and bis[(3,4-methylenedioxy)- 6-methyl]phenylmethane (3.6 g) as a white solid. The mixture used in SL]-phenylacetyl-3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methyl] phenylacetyl-3-thiophenesulfonyl was obtained as described in Example 102, using (3,4-methylenedioxy)-6-methylbenzylamine instead of (3,4 - methylenedioxy)benzylchloride. Technical product was purified using preparative HPLC to obtain N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylacetyl-3 - thiophenesulfonyl in the form of a yellow powder (71% yield, so pl. 42-45oC)

EXAMPLE 336

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methanesulfonylaminoethyl]phenylenecarbonyl-3-thiophenesulfonyl

A. N-(3,4-methylenedioxy)benzyl methanesulfonate

To a solution of piperidylamine (6.07 g, 38.95 mmol) and triethylamine (5.37 g, 53.12 mmol) in dichloromethane (100 ml) at 0oC was added methanesulfonamide (4.14 g, 35.41 mmol). The reaction was carried out at 0oC for 1 hour. The mixture then was diluted with dichloromethane (100 ml) and washed with 1 N HCl (2 x 100 ml). The organic layer was dried (MgSO4), the solid was filtered, and the filtrate was concentrated to obtain N-(3,4 - methylenedioxy)benzyl-methanesulfonamide as a gray solid (8.4 g, 92% yield).

C. N-[3,4-(methylenedioxy)-6-amino]benzyl-m is(3,4-methylenedioxy)-6-methylaniline (Example 177).

C. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)- 6-methanesulfonyl-aminomethyl]phenylenecarbonyl-3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)-6-methanesulfonylaminoethyl] phenylenecarbonyl-3 - thiophenesulfonyl was obtained as described in Example 94. Technical product was recrystallized from acetonitrile and water to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)-6-methanesulfonyl-aminomethyl] phenylenecarbonyl-3 - thiophenesulfonyl in the form of a white solid (13% yield, so pl. 147-150oC).

EXAMPLE 337

N-(4-chloro-3-methyl-5-isoxazolyl)-2-13,4-(methylenedioxy)-6 - cyanomethyl] -phenylenecarbonyl-3-thiophenesulfonyl

A. [3,4-(methylenedioxy)-6-amino]phenylacetonitrile

[3,4-(methylenedioxy)-6-amino] phenylacetonitrile was obtained as described for (3,4-methylenedioxy)-6-methylaniline (Example 177).

C. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - cyanomethyl]phenylenecarbonyl-3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - cyanomethyl] phenylenecarbonyl-3-thiophenesulfonyl was obtained as described in Example 94. Technical product was recrystallized from a mixture of acetonitrile/octonaria in the form of a red-brownish powder (15% yield, so pl. 190-193oC).

EXAMPLE 338

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(3 - hydroxypropyl)]phenylenecarbonyl-3-thiophenesulfonyl

A. 3-(3,4-methylenedioxy)phenyl-1-propanol

To a solution of 3-(3,4-methylendioxy)phenylpropane acid (5 g, 25.75 mmol) in anhydrous THF (20 ml) at 0oC was added BH3THF (51,5 ml, 1.0 M in THF, 51.5 mmol). The mixture was distilled under reflux for 1 hour. Then THF was evaporated on a rotary evaporator. The residue was treated with methanol (20 ml) and the solution was concentrated. This process was repeated 6 times to obtain 3-(3,4-methylenedioxy)phenyl-1-propanol in the form of an oil (4.7 g, 100% yield)

Century 3-[3,4-(methylenedioxy)-6-amino]phenyl-1-propanol

3-[3,4-(methylenedioxy)-6-amino] phenyl-1-propanol was obtained as described for (3,4-methylenedioxy)-6-methylaniline (Example 177).

C. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(3 - hydroxypropyl)]phenylenecarbonyl-3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(3 - hydroxypropyl)] phenylenecarbonyl-3-thiophenesulfonyl was obtained as described in Example 94. Technical product was purified preparative HPLC to obtain N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[3,4-(set aside by the Russian output, so pl. 66-69oC).

EXAMPLE 339

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - cyano] phenylacetyl-3-thiophenesulfonyl

A. Methyl (3,4-methylenedioxy)phenyl acetate

Methyl (3,4-methylendioxy)phenylacetate was obtained as described in the well-known methods (see, Rachele (1963) Journal. Organic Chemistry 28:2898).

C. Methyl 6-bromo-(3,4-methylenedioxy)phenyl acetate

To a solution of methyl (3,4-methylendioxy)phenylacetate (5 g, 25.8 mmol) in acetic acid (15 ml) was added, dropwise, bromine until then, until I installed red-brown color. After keeping at room temperature for 30 min, the reaction mixture was separated between water (200 ml) and ether (200 ml). The organic layer was washed with water (3 x 200 ml), dried (MgSO4), the solid was filtered, and the filtrate was concentrated to obtain methyl 6-bromo-(3,4-methylendioxy) phenylacetate as an oil (5.9 g, 84% yield).

C. Methyl (3,4-methylenedioxy)-6-cyanophenylacetic

Methyl (3,4-methylenedioxy)-6-cyanophenylacetic was obtained as described in L. Friedman and N. Shechter, Journal. Organic Chemistry 26:2522 (1961).

D. t-Butyl (3,4-methylenedioxy)-6-cyanophenylacetic

To a solution of methyl (3,4-methylenedioxy)-6-cyanophenylacetic (5 g, 18.32 mmol) in which l is then evaporated on a rotary evaporator. The aqueous residue was acidified with conc. HCl to pH1 and extracted with ethyl acetate. The organic layer was dried (MgSO4), the solid was filtered, and the filtrate was concentrated to obtain a solid substance. The solid was treated with thionyl chloride (50 ml) and the mixture was converted under reflux for 10 min, and then volatiles were removed on a rotary evaporator. The residue was dissolved in dichloromethane (15 ml) and the solution was added dropwise to the solution. 2-methyl-2-propanol (6.8 g, 91.6 mmol) and triethylamine (9.3 g, 91.6 mmol) in dichloromethane (100 ml) at 0oC. the Mixture was stirred at 0oC for 1 hour and at room temperature for 2 hours. The mixture is then washed with water (I ml). The organic layer was dried (MgSO4), the solid was filtered, and the filtrate was concentrated to obtain t-butyl (3,4-methylenedioxy)-6 - cyanophenylacetic in the form of a solid (335 mg, 7% yield).

E. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - cyano] phenylacetyl-3-thiophenesulfonyl

To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxyl-3 - thiophenesulfonyl (2.78 g, 8.63 mmol) in anhydrous DMF (30 ml) was added carbonyldiimidazole (1.40 g, 8.63 mmol). Magnesium (3,4-methylenedioxy)-6-cyanophenylacetic (1.5 g, 5.75 mmol) in anhydrous DMF (15 ml) was added NaH (1.2 r, 60% dispersion in mineral oil, 29.9 mmol) at 0oC. the Mixture was stirred at room temperature for 30 min with a mixture II. Mixture I was introduced via syringe to the mixture II at 0oC, and the resulting mixture was stirred at 0oC for 1 hour and at room temperature for 10 hours. The crude mixture was added to a mixture of 2:2:1 acetonitrile/water/conc. HCl, and the resulting mixture was heated at 40oC for 12 hours. Then acetonitrile was removed by rotary evaporator and the aqueous residue was separated between ethyl acetate (200 ml) and 1 N HCl (150 ml). The organic layer was washed with 1 N HCl (3 x 150 ml), and dried (MgSO4). The solid was filtered, and the filtrate was concentrated. The residue was purified preparative HPLC to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)-6-cyano] phenylacetyl-3-thiophenesulfonyl in the form of a light dull yellow powder (450 mg, 17% yield, so pl. 105-108oC).

EXAMPLE 340

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - dimethylaminocarbonylmethyl]phenylenecarbonyl-3-thiophenesulfonyl

A. N,N-dimethyl(3,4-methylendioxy)phenylacetamide

N, N-dimethyl(3,4-methylenedioxyphenylacetone

N, N-dimethyl(3,4-methylenedioxy)-6-aminophenylacetamido was obtained as (3,4-methylenedioxy)-6-methylaniline (see Example 177).

C. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - dimethylaminocarbonylmethyl]phenylenecarbonyl-3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - dimethylaminocarbonylmethyl] phenylenecarbonyl-32-thiophenesulfonyl was obtained as described in Example 94. Technical product was recrystallized from a mixture of acetonitrile/water to obtain N- (4-chloro-3-methyl - 5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - dimethylamino-carbonylmethyl] phenylenecarbonyl-3 - thiophenesulfonyl in the form of a grey powder (400 mg, 19% yield, so pl. 190-193oC).

EXAMPLE 341

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methyl]phenylhydroxylamine-3-thiophenesulfonyl

To N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methyl]phenylacetyl-3-thiophenesulfonyl (100 mg) was added NH2OHHCl (300 mg) and water (15 ml). After stirring for 5 min was added NaOH tablets (300 mg) and methanol (2 ml). The mixture was heated at 80oC for 20 min and was cooled to 0oC. It was then poured into dilute HCl solution (30 ml). The obtained white precipitate would be the oversulphated in the form of a white solid (72 mg, with 70% output, so pl. 154-156oC).

EXAMPLE 342

N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-acetoxy-2-CIS-[3,4- (methylenedioxy)-6-methyl]phenyl}vinyl-3-thiophenesulfonyl

To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)-6-methyl] phenylacetyl-3-thiophenesulfonyl (50 mg, 0.1] mmol) in anhydrous DMF (1 ml) was added NaH (11 mg, 60% dispersion in mineral oil, 0.275 mmol). After keeping at room temperature for 5 min was added acetic anhydride (16.8 mg, 0.165 mmol). After keeping at room temperature additionally for 10 min the mixture was poured into dilute HCl solution and the resulting precipitate was filtered to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-acetoxy-2-CIS-[3,4- (methylenedioxy)-6-methyl] phenyl}vinyl-3-thiophenesulfonyl in the form of a yellowish powder (40 mg, 73%, so pl. 55-58oC)

EXAMPLE 343

(4-chloro-3-methyl-5-isoxazolyl)-2-(1,2,3-trimetoksi-6 - cyano)phenylenecarbonyl-3-thiophenesulfonyl

A. 2-amino-3,4,5-trimethoxybenzoate

2-amino-3,4,5-trimethoxybenzoate was obtained as (3,4-methylenedioxy)-6-methylaniline (see Example 177), and technical product was recrystallized from methanol/water to obtain a yellow powder (13% yield).

EXAMPLE 344

N-(3,4-dimethyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methyl]phenylacetyl-3-thiophenesulfonyl

N-(3,4-dimethyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methyl]phenylacetyl-3-thiophenesulfonyl was obtained as described in Example 179. Technical product was purified preparative HPLC to obtain N-(3,4-dimethyl-5-isoxazolyl)-2- [3,4-(methylenedioxy)-6-methyl] phenylacetyl-3-thiophenesulfonyl in the form of a yellow powder (417 mg, 14% yield, so pl. 45-50oC).

EXAMPLE 345

N-(4-chloro-5-methyl-3-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methyl]phenylacetyl-3-thiophenesulfonyl

N-(4-chloro-5-methyl-3-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methyl]phenylacetyl-3-thiophenesulfonyl was obtained as described in Example 179. Technical product was purified using preparative HPLC to obtain N-(4-chloro-5-methyl-3-isoxazolyl)- 2-[3,4-(methylenedioxy)-6-methyl] phenylacetyl-3-thiophenesulfonyl in the form of a yellowish powder (330 mg, 16% yield, so pl. 46 - 50oC).

For example, these compounds include the following: N-(4-bromo - 3-methyl-5-isoxazolyl)-3-[2-methyl-4,5- (methylenedioxy)cinnamyl]thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5 - isoxazolyl)-3-[2-(hydroxymethyl)-4,5-(methylenedioxy)- cinnamyl] thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5 - isoxazolyl)-3-{ 2-[(tetrahydro-4H-Piran-2-yloxy)methyl] -4,5- (methylenedioxy)cinnamyl}thiophene-2-sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)-3- (2,4-dimethylcarbamyl)thiophene-2-sulfonamide was obtained as N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylendioxy)- TRANS-styryl] thiophene-2-sulfonamide. N-(4-bromo-3-methyl-5 - isoxazolyl)-3-[2-methyl-4,5-(methylenedioxy)-phenylethyl] thiophene-2 - sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4,6 - trimethylphenyl)thiophene-3-sulfonamide were p is m-3-methyl-5-isoxazolyl)-3- { [2-propyl-4,5-(methylene-dioxy)phenoxy] methyl}thiophene-2-sulfonamide was obtained as, as N-(4-bromo-3-methyl-5-isoxazolyl)-3-[(4 - methylphenoxy)methyl] thiophene-2-sulfonamide and N-(4-bromo-3-methyl-5 - isoxazolyl)-3-{[3,4-(methylendioxy)phenoxy]methyl}-thiophene-2 - sulfonamide. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5- (methylenedioxy)phenylethyl] thiophene-3-sulfonamide was obtained as N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4 - methylenedioxy)phenylethyl] thiophene-3-sulfonamide, Compounds such as N-(4-bromo-3-Meinl-5-isoxazolyl)-3-(2-tolyl)thiophene-2 - sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-tolyl)thiophene-2 - sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-tolyl)thiophene-2 - sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3 - methoxyphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5 - isoxazolyl)-3-(3-methoxyphenyl)thiophene-2-sulfonamide, N-(4-bromo-3 - methyl-5-isoxazolyl)-3-(2-methoxyphenyl)thiophene-2-sulfonamide, N- (4-bromo-3-methyl-5-isoxazolyl)-3-(4 - ethylphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)- 3-(4-propylphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5 - isoxazolyl)-3-(4-isopropylphenyl)thiophene-2-sulfonamide, N-(4-bromo - 3-methyl-5-isoxazolyl)-3-(4-butylphenyl)thiophene-2-sulfonamide, N-(4 - bromo-3-methyl-5-isoxazolyl)-3-(2,4-dimetilfenil)thiophene-2 - sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-ISO - butylphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)- 3-(4-ISO-pentyl is methyl-5-isoxazolyl)-3-(4-ISO-butyl-2-methylphenyl)thiophene-2 - sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-ISO-pentyl-2 - were)thiophene-2-sulfonamide was obtained as N-(4 - bromo-3-methyl-5-isoxazolyl)-3-[(3,4-methylene-dioxy)phenyl] thiophene-2 - sulfonamide (see Example 125). N-(4-bromo-3-methyl-5-isoxazolyl)-2- [2-methyl-4,5-(methylene-dioxy)phenylethyl]thiophene-3-sulfonamide was obtained as N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[3,4- (methylendioxy)phenylethyl]thiophene-3-sulfonamide (Example 128). N-(4 - bromo-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylene - dioxy)cinnamyl] thiophene-3-sulfonamide was obtained as N-(4 - bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)(cinnamyl)] thiophene-3 - sulfonamide (Example 158).

N-(4-bromo-3-methyl-5-isoxazolyl)-2-{[3,4-(methylendioxy)- phenoxy]methyl} thiophene-3-sulfonamide, N-(4-balm-3-methyl-5 - isoxazolyl)-2-[(2,4,6-trimethylphenol)methyl] thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-{ [4,5-(methylenedioxy)-2 - propylenoxide]methyl}thiophene-3-sulfonamide was obtained as N-(4-bromo-3-metl-5-isoxazolyl)-2-[(4 - methylphenoxy)methyl] thiophene-3-sulfonamide (Example 160). Any corresponding N-(4-halo-3-methyl-5-isoxazolyl), N-(4-halo-5 - matl-3-isoxazolyl), N-(3,4-dimethyl-5-isoxazolyl), N-(4-halo-5 - methyl-3-isoxazolyl), N-(4-halo-3-methyl-5-isoxazolyl), N-(4,5 - dimethyl-3-isoxazolyl)-derivative of each of these compounds or any connection disclosed here can also be obtained and used as described here.

EXAMPLE 347

Other compounds that can be obtained above the R-3-methyl-5-isoxazolyl)-2-(2,3,4-trimetoksi-6 - methylphenylimino-carbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl - 5-isoxazolyl)-2-(2,3,4-trimetoksi-6-acetylphenylalanine) thiophene-3-sulfonamide, N-(4-chloro-3-methyl - 5-isoxazolyl)-2-(2,3,4-trimetoksi-6-methoxycarbonyl - phenylenecarbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5 - isoxazolyl)-2-(2,3,4-trimetoksi-6 - carboxymethylaminomethyl)thiophene-3-sulfonamide, N-(4-chloro-3 - methyl-5-isoxazolyl)-2-(2,3,4-trimetoksi-6 - methanesulfonylaminoethyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimetoksi-6- (cyanomethyl)phenylenecarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimetoksi-6-(2 - hydroxyethyl)phenylenecarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-acetylphenylalanine]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-methoxycarbonylaminophenyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-carboxymethylaminomethyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-methanesulfonylaminoethyl]thiophene-3-soulfulhouse,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-cyanomethylation]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-(2-hydroxyethyl)phenylenecarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2,6 - dimethylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - acetyl-2-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methoxycarbonyl-2-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - carboxyl-2-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methoxy-2-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methanesulfonyl-2-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - cyano-2-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6- (cyanomethyl)-2-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedi the(methylendioxy)-2 - cyano-6-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methoxy-2-cyanobenzeneboronic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - acetyl-6-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methoxy-2-acetylphenylalanine]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyano-2,4,6 - trimethylphenylsulfonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxy-2,4,6 - trimethylphenylsulfonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6 - trimethylphenylsulfonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methanesulfonyl-2,4,6 - trimethylphenylsulfonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyanomethyl-2,4,6 - trimethylphenylsulfonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(2-hydroxyethyl)-2,4,6 - trimethylphenylsulfonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(carboxymethyl)-2,4,6 - trimethylphenylsulfonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-cyano-2,6 - dimethylaminoethyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4 is methyl)-2,6 - dimethylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(2-hydroxyethyl-2,6 - dimethylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(cyanomethyl)-2,6 - dimethylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(carboxymethyl)-2,6 - dimethylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methanesulfonyl-2,6 - dimethylaminoethyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimetoksi-6 - methylphenylacetic)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimetoksi-6 - acetylphenylalanine)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimetoksi-6 - methoxycarbonylbenzyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimetoksi-6 - carboxyphenylazo)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimetoksi-6 - methanesulfonylaminoethyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimetoksi-6- (cyanomethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimetoksi-6-(2 - hydroxyethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-methylphenylacetic]thiophene-3-sulamid,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-methoxycarbonylbenzyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-carboxyphenylazo]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy-2 - methoxy-6-methanesulfonyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-(cyano)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-(cyanomethylene]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-(2-hydroxyethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2,6 - dimethylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - acetyl-2-methylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methoxycarbonyl-2-methylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - carboxyl-2-methylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methoxy-2-methylphenylacetic]thiophene-3-sulfonamide,

/BR>N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - cyano-2-methylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6- (cyanomethyl)-2-methylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6- (2-hydroxyethyl)-2-methylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - cyano-6-methylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methoxy-2-cyanophenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - acetyl-6-methylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methoxy-2-acetylphenylalanine]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyano-2,4,6 - trimethylpentanediol)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxy-2,4,6 - trimethylpentanediol)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6 - trimethylpentanediol)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methanesulfonyl-2,4,6 - trimethylpentanediol)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(cyanomethyl)-2,4,6 - trimethylpentanediol]typename,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(carboxymethyl)-2,4,6 - trimethylpentanediol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-cyano-2,6 - dimethylphenylacetic)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-carboxyl-2,6 - dimethylphenylacetic)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-hydroxymethyl-2,6 - dimethylphenylacetic)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(2-hydroxyethyl-2,6- (dimethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-cyanomethyl-2,6- (dimethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(carboxymethyl)-2,6 - dimethylphenylacetic]thiophene-3-sulfonamide, and

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methanesulfonyl-2,6 - dimethylphenylacetic)thiophene-3-sulfonamide.

Example 348

Other compounds with activity mainly at concentrations IC5010 mM or significantly less in relation to ETA'or ETBreceptors, where Ar2contains a heterocyclic ring, such as thienyl-, furyl - and pyrrole-sulfonamides representing interest here, can be or have been obtained (see, for example, table 1), using methods similar to those described in the above examples. The same is l-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-oxocyclohexyl)oxycarbonyl] thiophene - 3-sulfonamide, 2-[3,4-(methylendioxy)phenylacetyl] thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-{2-[3,4-(methylenedioxy)phenyl]acetyl} thiophene - 3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-phenylbenzo[b] thiophenesulfonyl, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-tolyl) aminocarbonyl] -1-methylindol-3 - sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[(4-methoxyphenoxy)carbonyl]thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5 - isoxazolyl)-1-[3,4-(methylendioxy)benzyl] indol-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)carbonyl] thiophene-3 - sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxyphenyl)acetyl] - thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-6-methoxy-2-[3,4- (methylenedioxy)benzyl] benzo[b] thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5 - isoxazolyl)-3-[(4-methylphenoxy)methyl]thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl] thiophene-3 - sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl-TRANS-styryl)thiophene - 2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylphenylethyl)thiophene - 2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-were)acetyl] thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methoxyphenyl) acetyl]thiophene-3-is 4-(bromo-3-methyl-5-isoxazolyl)-3-(4-methylphenylethyl)(4-tolyl)thiophene-2 - sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylbenzyl)- 5-(4-tolyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)- 3-(4-methyl-TRANS-styryl)-5-(4-toll)thiophene-2-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[b, b-(Ethylenedioxy)-3,4- (methylendioxy)phenylethyl] thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[b-(dimethylamino)-3,4-(methylenedioxy)phenyl] thiophene-3 - sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ a-hydroxy-{ 3,4-(methylene - dioxy)phenyl]acetyl}thiophene-3-sulfonamide; N-(4-chloro-5-methyl-3-isoxazolyl)- 2-[3,4-(methylenedioxy)benzyl] benzo[b]thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-stilllife-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-sterilite-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(benzoylamine)thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(phenyl)methylaminomethyl] thiophene-3 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-(hydroxymethyl)furan-2 - sulfonamide; N-(4-bromo-3-until-5-isoxazolyl)-5-(carbomethoxy)furan-2 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2.5-dimethylfuran-3 - sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-(diisopropylaminoethyl) thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2- (diethylaminoethyl)thiophene-3-sulfonamide; N-(4-bromo-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl] - 5-(dimethylamino)benzo[b]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[3,4-(methylenedioxy)benzyl] -7-methoxybenzo[b] thiophene-3 - sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl] - 7-phenoxybenzyl[b]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl] -5 - methoxybenzo[b]-thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[3,4-(methylenedioxy)benzyl] -5-isobutylamino[b] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl] -5 - benzylamines[b] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[3,4-(methylendioxy)phenoxy]benzo[b]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)phenoxy] -5 - dimethylaminobenzoyl[b]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[(3,4-methylenedioxy)-phenyl] acetyl-5-dimethylaminobenzoyl[b] thiophene-3 - sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy) benzylcarbamoyl] -N-methylindol-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[3,4-(methylendioxy)phenoxycarbonyl] indole-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)phenoxycarbonyl]- N-methylindol-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylendioxy)phenoxycarbonyl] indole-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazol] indole-3 - sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy) benzyloxycarbonyl]-7-(N,N-dimethylamino)benzo[b] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl] -7-(N, N - dimethylamino)benzo[b]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[3,4-(methylenedioxy)benzoyl] -7-(N, N-dimethyl)amino)benzo[b] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-7-(N, N - dimethylamino)benzo[b]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 7-(methoxycarbonyl)benzo[b] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[3,4-(methylenedioxy)benzyl] -7-(methoxy)-benzo[b]thiophene-3 - sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-7-(methoxy)- benzo[b] thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methylphenylethyl)thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(TRANS-4-methylcinnamic)thiophene-3 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylphenylethyl)thiophene - 2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-methylphenylethyl)thiophene - 2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-methylphenylethyl)thiophene - 2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-(TRANS-4-methylcinnamic) thiophene-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-(TRANS-3 - methylcinnamic)thiophene-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)- 3-(TRANS-2-methylcinnamic)Tiefencastel)-3-[3,4-(methylendioxy)phenylethyl] thiophene - 2-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{(3,4-(dimethoxy)phenyl] acetyl} thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,5 - acid)acetyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[(3,4,5-trimethoxyphenyl)acetyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-benzylmethyl] thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylendioxy)benzylmorphine] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[3,4-(methylendioxy)benzylmorphine] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-(dimethylamino)-2-[3,4- (methylenedioxy)phenyl} ethylthiophen-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-{ 1-methylamino)-2-[3,4-(methylenedioxy)phenyl] ethyl}thiophene-3 - sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ 1-(methoxyimino)-2-[3,4- (methylenedioxy)phenyl] ethyl} thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-{ 1-(carboxy)-2-[3,4-(methylenedioxy)phenyl] ethyl}thiophene-3 - sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{2-(carboxyl)-1-[3,4- (methylenedioxy)benzyl] vinyl} thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ 3-[3,4-(methylenedioxy)phenyl] -1,2,4 - oxadiazol-5-yl}thiophene-3-sulfonamide; and N-(4-chloro-3-methyl-5-isoxazolyl- 2-{3-[3,4-(methylendioxy)-benzyl]-1,2,4-oxadiazol-5-yl}thiophene-3-sulfonamide.

Up)-4,5- (methylenedioxy)phenyl] aminocarbonyl} thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ [3,4-(methylenedioxy)-6 - carboxyphenyl] aminocarbonyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[4,5-(methylenedioxy)-2- (methoxycarbonyl] phenyl} aminocarbonyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ [2-cyano-4,5-(methylenedioxy)phenyl] aminocarbonyl}thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)- 2-{[4,5-(methylenedioxy)-2-hydroxymethyl)phenyl] aminocarbonylmethyl-3 - sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-acetyl-4 - were] aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-{[2-(methanesulphonyl)-4-were] aminocarbonyl} thiophene-3 - sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-carboxy-4 - were)aminocarbonyl] thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[(2-methoxycarbonyl-4-were)aminocarbonyl] thiophene-3 - sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-cyano-4-were) aminocarbonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-{[2-(hydroxymethyl)-4-were]aminocarbonyl} thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-dimethoxy-6-acetylphenyl) aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-{[2-(methanesulfonyl)-4,5-acid]aminocarbonyl} thiophene-3 - sulfonamide; N-(4-chloro-3-matilal)-2-[(4,5-dimethoxy-2-methoxycarbonyl) phenyl)aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[2-cyano(4,5-acid)aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4,5-dimethoxy-2-hydroxymethyl) phenylenecarbonyl-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-acetyl-4,5-(methylenedioxy)phenyl] acetyl} thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ [2- (methanesulfonyl)-4,5-(methylenedioxy)phenyl] acetyl} thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ [carboxy-4,5-(methylenedioxy)-2 - phenylacetamide-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-{ [4,5-(methylenedioxy)-2-ethoxycarbonylphenyl]acetylthiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{2-cyano-[4,5-(methylenedioxy)-phenyl] acetyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ 2 - hydroxymethyl[4,5-(methylenedioxy)-phenyl]acetyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4-dimethoxy)phenyl)aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2 - were)aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[(2,3-dimetilfenil)aminocarbonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4-dimetilfenil)aminocarbonyl] thiophene - 3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,5-dimetilfenil) aminocarbonyl] thiophene-3-sulfonato)-2-[(3,4-dimetilfenil)aminocarbonyl] thiophene - 3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,5-dimetilfenil) aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-(3,5-dimethyl)phenylenecarbonyl-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-methoxy-6-were)aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4,6 - trimetilfenil)aminocarbonyl] -thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[(4-methoxy-2-were)aminocarbonyl] -thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-ethyl-(4-methoxy)phenyl)aminocarbonyl) thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-isopropyl-4-methoxyphenyl) aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[(2-propyl-4-methoxy-phenyl)aminocarbonyl] -thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-biphenylmethanol] - thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ [3,4- (methylenedioxy)-6-were)acetyl] -thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ [3,4-(methylenedioxy)-6-ethylphenyl) acetyl} thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ [3,4- (methylenedioxy)-6-methoxyphenyl]acetyl}thiophene-3-sulfonamide.

Example 349

N-(3,4-Dimethyl-5-isoxazolyl)-4-biphenylcarboxylic

(a) 4-Biphenylmethanol

4-Biphenylol the current phosphorus oxychloride was removed under reduced pressure. The residue was decomposed with ice water and was extracted with ethyl acetate. The extract was washed with 5% sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. Yield 2.9 g of crude 4-biphenylmethanol.

(b) N-(3,4-Dimethyl-5-isoxazolyl)-4-biphenylcarboxylic

4-biphenylmethanol obtained at stage (a) was added to a solution of 5-amino-3,4-dimethylisoxazole (250 mg, 2.2 mmol) and 4-(dimethyl)aminopyridine (5 mg) in dry pyridine (2.0 ml). The reaction mixture was stirred at room temperature for 4 h, the Pyridine was removed under reduced pressure, and the residue was divided between water and ethyl acetate. The organic layer was washed with 1N HCl (2 x 25 ml), brine (25 ml) and dried over anhydrous magnesium sulfate. After evaporation of the solvent left an oily residue, which after purification using column chromatography over silica gel (1% methanol in chloroform as eluent) was obtained 337 mg (45%) of white solids. Using recrystallization from a mixture of ethyl acetate/hexane, it was possible to obtain white crystals, so pl. 154-155oC.

Example 350

N-(4-Bromo-3-methyl-5-isoxazolyl)-4-biphenylcarboxylic

(a) 5-Amino-4-bromo-3-methylisoxazol

5-Amino-3-IU the ol) was added in small portions over 10 minutes Stirring is continued for the other 10 min at 0oC. the Reaction mixture was diluted with chloroform (50 ml), washed with water (2 x 50 ml) and the organic layer was dried over magnesium sulfate. Removal of the solvent under reduced pressure resulted in the receipt of a technical product, which was purified by column chromatography using a mixture of 9:1 hexane/ethyl acetate as eluent to obtain 5-amino-4-bromo-3-methylisoxazole (1.55 g, 87% yield).

(b) N-(4-Biphenylmethanol)-N-(4-bromo-3-methyl-5-isoxazolyl)-4 - biphenylcarboxylic

5-Amino-4-bromo-3-methylisoxazole (0.179 g, 1.0 mmol) was dissolved in dry pyridine (2 ml). 4-Biphenylmethanol (0.509 g, 2.2 mmol) was added under stirring at room temperature. N,N-dimethylaminopyridine (5 mg) was added, and stirring continued at 50oC for 16 h, the Reaction mixture was diluted with dichloromethane (75 ml), washed 1N HCl (2 x 50 ml) and the organic phase was dried over magnesium sulfate. The solvent was removed under reduced pressure. Was obtained the crude product, which was purified by column chromatography using 8:2, hexane/ethyl acetate, obtaining 0.390 g (60% yield). N-(4-biphenylmethanol)-N-(4-bromo-3
N-(4-biphenylmethanol)-N-(4-bromo-3-methyl-5-isoxazolyl)-4 - biphenylcarboxylic (0.150 g, 0.233 mmol) was dissolved in tetrahydrofuran (THF). Added sodium hydroxide (0.120 g, 3.0 mmol) and the solution was heated to 45oC to dissolve the sodium hydroxide. Stirring is continued for 20 minutes, the Tetrahydrofuran was removed under reduced pressure. The residue was dissolved in water, cooled to 0oC and acidified to pH 3-4 with concentrated HCl. The solid precipitate was filtered, dried in vacuum to obtain N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylamine (94% yield), which was subjected to further purification by recrystallization from a mixture of chloroform/hexane, so pl. 133-135oC.

Example 351

N-(3,4-Dimethyl-6-isoxazolyl)-2-dibenzofuransulfonate

N-(3,4-Dimethyl-5-isoxazolyl)-2-dibenzofuransulfonate was obtained according to the method described in example 193b, from 5-amino-3,4-dimethylisoxazole and 2-benzofurazanyl, with a 32% yield. Clearance made by recrystallization from a mixture of chloroform/hexane to obtain a white hlopkopribor" solids, so pl. 173-175oC (decomp.).

Example 352

N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylcarboxylic

N-(4-Methyl-3-trifluoromethyl-5-the-isoxazol-and 4-biphenylmethanol with 78% yield. Clearance made by recrystallization from methanol/water to obtain white solids, so pl. 139-140oC.

Example 353

N-(4-Tridecyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylcarboxylic

N-(4-Tridecyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylcarboxylic was obtained as described in example 194b, from 5-amino-4-tridecyl-3-trifluoromethyl-isoxazol-and 4-biphenylmethanol, with 81% yield. Clearance made by recrystallization from methanol/water to obtain white solids, so pl. 115-116oC.

Example 354

N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylcarboxylic

N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylcarboxylic was obtained as described in example 194 5-amino-4-methyl-3-cryptomaterial and 4-biphenylmethanol with 78% yield. Clearance made by recrystallization from a mixture of ethyl acetate/hexane to obtain a white solid substance, so pl. 139-140oC.

Example 355

N-(4-Bromo-5-methyl-3-isoxazolyl)-4-biphenylcarboxylic

(a) 3-Amino-4-bromo-5-methylisoxazol

3-Amino-5-methylisoxazole (1.96 g, 20 mmol) was dissolved in chloroform (10 ml) and cooled to 0oC. N-bromosuccinimide (3.56 g, 20 mmol) was added, the sky is nnow mixture was diluted with chloroform (100 ml), washed with water (2 x 50 ml) and the organic layer was dried over magnesium sulfate. Removal of the solvent under reduced pressure resulted in the receipt of a technical product, which was purified by column chromatography, using a mixture of 9:1 hexane/ethyl acetate as eluent to obtain 3-amino-4-bromo-5-methylisoxazole (1.40 g, 40% yield).

(b) N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylcarboxylic

N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylcarboxylic was obtained, using the method described in example 193b, from 3-amino-4-bromo-5-methylisoxazole and 4-biphenylmethanol chloride, 5% yield. Technical product was purified using column chromatography. After recrystallization from a mixture of ethyl acetate/hexane, N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylcarboxylic (so pl. 154-156oC) was obtained from 51% yield.

Example 356

N-(4-chloro-3-methyl-5-isoxazolyl)-4-biphenylcarboxylic

(a) 5-Amino-4-chloro-3-methylisoxazol

Using the method described in example 194a, 5-amino-4-chloro-3-methylisoxazol was obtained from 5-amino-3-methylisoxazole and N-chloro-succinimide with 90% yield.

(b) N-(4-chloro-3-methyl-5-isoxazolyl)-4-biphenylcarboxylic

Sodium hydride (188 is (mg, mmol) in dry THF (1 ml) was added under stirring. After complete addition, the reaction mixture was heated at room temperature for 10 minutes the Solution was cooled to 0oC, and 4-biphenylmethanol chloride (0.283 ml, 2.2 mmol) was added. Stirring is continued at 25oC for 2 h, the Excess sodium hydride was decomposed by addition of methanol (0.4 ml) and then water (0.5 ml). THF was removed under reduced pressure, and the residue was dissolved in water (20 ml) with alkalinization by adding sodium hydroxide (pH 9 - 10). Neutral impurities were removed by extraction with ethyl acetate (2 x 10 ml). The aqueous layer was acidified to pH 2-3 with concentrated HCl, and extracted with ethyl acetate (3 x 10 ml). The combined organic layers were dried over magnesium sulfate. After removal of the solvent was obtained N-(4-chloro-3-methyl-5-isoxazolyl)-4-biphenylcarboxylic with 83% yield. The product was purified by recrystallization from a mixture of ethyl acetate/hexane and was obtained as a white solid, so pl. 129-132oC.

Example 357

2,5-Dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide

2,5-Dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide was obtained from 5-amino-4-bromo-3-motiliy product was purified by recrystallization from a mixture of ethyl acetate/hexane to obtain crystalline solid, so pl. 118-120oC, yield 58%.

Example 358

N-(4-bromo-3-methyl-5-isoxazolyl)-2-biphenylcarboxylic

A. 2-Biphenylmethanol chloride

2-Bromobiphenyl (2.33 g, 10 mmol) was dissolved in ether (10 ml) and was cooled to -78oC. n-Utility (2.5 M solution in hexane, 4.8 ml, 12 mmol) was added dropwise under stirring and argon atmosphere. The resulting reaction mixture was stirred at -70oC - -60oC for 1 h, the Reaction mixture was cooled to -78oC was added dropwise sulfurylchloride (0.88 ml, 11 mmol). After the addition, the reaction mixture was left to slow it reaches room temperature and was stirred for 1 h, the Reaction mixture was diluted with ethyl acetate (50 ml), washed with water, and the organic layer was dried over anhydrous MgSO4. Removal of the solvent under reduced pressure yielded the crude product, which was purified by column chromatography, using hexane and then a mixture of 5% ethyl acetate in hexane as eluent to obtain 2-beenincorporated in the form of a solid (1.3 g, 51% yield).

B. N-(4-bromo-3-methyl-5-isoxazolyl)-2-biphenylcarboxylic

N-(4-bromo-3-methyl-5-isoxazolyl)-2-bipheny is inflorida with 71% yield. Clearance made by recrystallization from a mixture of ethyl acetate/hexane to obtain crystalline solid, so pl. 145-147oC.

Example 359

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-biphenylcarboxylic

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-biphenylcarboxylic was obtained as described in example 202, from 5-amino-4-chloro-3-methylisoxazole and 2-biphenylmethanol with 74% yield. Clearance made by recrystallization from a mixture of ethyl acetate/hexane to obtain crystalline solid, so pl. 132-134oC.

Example 360

N-(4-Bromo-3-methyl-5-isoxazolyl)-3-biphenylcarboxylic

A. 3-Biphenylmethanol chloride 3-Bromobiphenyl (1.5 g, 6.4 mmol) was dissolved in ether (15 ml) and cooled to -78oC. t-Utility (1.7 M solution in hexane, 3.8 ml, 6.4 mmol) was added dropwise with constant stirring in an argon atmosphere. The resulting reaction mixture was stirred at a temperature of -10oC - -5oC for 6 hours, the Reaction mixture was cooled to -78oC and added dropwise to sulfurylchloride (0.64 ml, 6.4 mmol). After complete addition, the reaction mixture was left to slow it reaches room temperature, and was stirred for 1 h, the Reaction mixture RA is the solvent under reduced pressure yielded the crude product. The latter was purified by column chromatography, using hexane and then a mixture of 5% ethyl acetate in hexane as eluent to obtain 3-beenincorporated in the form of an oil (0.8 g, 49% yield).

B. N-(4-bromo-3-methyl-5-isoxazolyl)-3-biphenylcarboxylic

N-(4-bromo-3-methyl-5-isoxazolyl)-3-biphenylcarboxylic was obtained as described in example 200b, from 5-amino-4-bromo-3-methylisoxazole and 3-biphenylmethanol with 22% yield. It was purified by HPLC (5% CH3CN - 100% CH3CN over 30 min), to obtain a solid substance, so pl. 78-82oC.

Example 361

N-(4-chloro-3-methyl-5-isoxazolyl)-3-biphenylcarboxylic

N-(4-chloro-3-methyl-5-isoxazolyl)-3-biphenylcarboxylic was obtained as described in example 204, from 5-amino-4-chloro-3-methylisoxazole and 3-biphenylmethanol with 63% yield. It was purified by HPLC (5% CH3CN - 100% CH3CN within 30 minutes), with solids, so pl. 84-86oC.

Example 362

N-(3-methyl-5-isoxazolyl)-4-(4-were)benzosulfimide

(a) N-(3-methyl-5-isoxazolyl)-4-bromobenzaldehyde

4-bromobenzosulfonyl (solid) was added in five portions to a solution of 3-methyl-5-aminoazo the s 3 h, and the pyridine was removed under reduced pressure. The residue was dissolved in THF (300 ml), and added a 5% NaOH solution (100 ml). Stirring was continued for 1 h at room temperature. THF was removed under reduced pressure and the resulting residue was neutralized to pH 2 using concentrated hydrochloric acid. It was extracted with ethyl acetate (3 x 200 ml) and the combined organic layers were dried over MgSO4and concentrated. Technical product was recrystallized using a mixture of hexane/ethyl acetate to obtain N-(3-methyl-5-isoxazolyl)-4-bromobenzaldehyde (9.2 g, 72% yield).

b) N-(3-methyl-5-isoxazolyl)-4-(4-were)benzosulfimide

Nitrogen was barbotirovany through a two-phase mixture of ethanol (15 ml), toluene (15 ml) and 2M sodium carbonate solution (15 ml). Added N-(3-methyl-5-isoxazolyl)-4-bromobenzophenone (0.951 g, 3 mmol), 4-methylbenzamide acid (0.56 g, 4 mmol) and tetranitropentaerithrite (0) (300 mg). The reaction mixture was stirred at 80oC in an atmosphere of N2within 24 h with stirring and then diluted with water (50 ml) and was extracted with ether (50 ml) to remove neutral impurities and excess 4-methylbenzeneboronic acid. The aqueous phase was Nate who was dried under vacuum, and recrystallized using a mixture of hexane/ethyl acetate to obtain N-(3-methyl-5-isoxazolyl)-4-(4-were)benzosulfimide (1.0 g, 100% yield, so pl. 194-198oC).

Example 363

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(4-were)benzosulfimide

N-bromosuccinimide (NBS) (0.178 g, 1 mmol) in one portion was added with stirring to a suspension of N-(3-methyl-5-isoxazolyl)-4-(4 - were)benzosulfimide (0.327 g, 1 mmol, example 206b) in chloroform (12 ml). The reaction mixture was stirred for 10 min, then was diluted with dichloromethane (50 ml). It was washed with water (2 x 50 ml). The organic layer was dried over MgSO4and concentrated. Technical product was recrystallized using hexane/ethyl acetate to obtain N-(4-bromo-3-methyl-5-isoxazolyl)-4-(4-were)benzosulfimide (350 mg, 86% yield, so pl. 153-156oC).

Example 364

N-(4-chloro-3-methyl-5-isoxazolyl)-4-(4-were)benzosulfimide

N-chlorosuccinimide (0,266 g, 2 mmol) was added in one portion, with stirring, to a suspension of N-(3-methyl-5-isoxazolyl)-4-(4 - were)benzosulfimide (0.327 g, 1 mmol, example 206b) in chloroform (10 ml). The mixture was stirred at room temperature for 2 hours the Reaction with anantaraman. Technical product was purified by column chromatography using ethyl acetate as eluent, to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-4-(4-were)benzosulfimide [210 mg, 58% yield, so pl. 260oC].

Example 365

N-(3-methyl-5-isoxazolyl)-4-[(4-trifluoromethyl)phenyl]benzosulfimide

N-(3-methyl-5-isoxazolyl)-4-(4-triptoreline)benzosulfimide was obtained as described in example 206b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzaldehyde and 4-triftorperasin acid. The final product turned out with a 78% yield, so pl. 150-153oC. the Product was recrystallized from a mixture of acetonitrile and water.

Example 366

N-(4-bromo-3-methyl-5-isoxazolyl)-4-[(4-trifluoromethyl)phenyl] benzosulfimide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-[(4-trifluoromethyl)phenyl] benzosulfimide was obtained as described in example 207 using N-(3-methyl-5-isoxazolyl)-4-(4-triptoreline) benzosulfimide (example 209) and NBS (reaction time 30 min at room temperature). Technical product was purified by column chromatography on silica gel using ethyl acetate as eluent. The final product turned out with 56% yield, so pl. 113-117ooC. the Product was recrystallized from a mixture of hexane/ethyl acetate.

Example 368

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzosulfimide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzosulfimide was obtained as described in example 207 using N-(3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzosulfimide (example 211) and NBS (reaction time 30 min at room temperature). Technical product was purified by column chromatography on silica gel using ethyl acetate as eluent. The final product was obtained in 78% yield, so pl. 208oC (decomp). The product was recrystallized from a mixture of hexane/ethyl acetate.

Example 369

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzosulfimide

(a) N-(3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzosulfimide

N-(3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzosulfimide was obtained as described in example 206b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzaldehyde (example 206A) and 3-methoxybiphenyl)benzosulfimide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzosulfimide was obtained as described in example 207 using N-(3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzosulfimide and NBS (reaction time 30 min at room temperature). Technical product was purified by column chromatography on silica gel using ethyl acetate as eluent. The final product was obtained after recrystallization from a mixture of hexane/ethyl acetate, 75% yield, so pl. 140-144oC.

Example 370

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(2-methoxyphenyl)benzosulfimide

(a) N-(3-methyl-5-isoxazolyl)-4-(2-methoxyphenyl)benzosulfimide

N-(3-methyl-5-isoxazolyl)-4-(2-methoxyphenyl)benzosulfimide was obtained as described in example 206, using N-(3-methyl-5-isoxazolyl)-4-bromobenzaldehyde and 2-methoxybenzeneboronic acid. The final product was obtained with 81% yield.

(b) N-(4-bromo-3-methyl-5-isoxazolyl)-4-(2-methoxyphenyl)benzosulfimide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(2-methoxyphenyl)benzosulfimide was obtained as described in example 207 using N-(3-methyl-5-isoxazolyl)-4-(2-methoxyphenyl)benzosulfimide and NBS (reaction time 30 min at room is an ethyl acetate as eluent. The final product was obtained in 68% yield, so pl. 205-209oC.

Example 371

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl) benzosulfimide

(a) N-(3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl) benzosulfimide

N-(3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl)benzosulfimide was obtained as described in example 206b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzaldehyde and 3,4-methylenedioxyaniline acid. The final product was obtained with 67% yield.

(b) N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl) benzosulfimide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl) benzosulfimide was obtained as described in example 207 using N-(3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl) benzosulfimide and NBS in THF as solvent. The product was obtained in 35% yield. Technical product was purified HPLC, so pl. 172-174oC.

Example 372

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3-were)benzosulfimide

(a) N-(3-methyl-5-isoxazolyl)-4-(3-were)benzosulfimide

N-(3-methyl-5-isoxazolyl)-4-(3-were)benzosulfimide was obtained as described in example 206b, using N-(3-METI the output.

(b) N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3-were)benzosulfimide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3-were)benzosulfimide was obtained as described in example 207 using N-(3-methyl-5-isoxazolyl)-4-(3-were)benzosulfimide and NBS in THF as solvent (reaction time 30 min at room temperature). Technical product was purified HPLC. The yield of the final product amounted to 31%, so pl. 186-189oC.

Example 373

Methyl 2-(3-(3-(4-Chloro-3-methyl-5-isoxazolidinone)-2 - thienylboronic)-2,4,6-trimetilfenil)acetate

A. Methyl 3-Amino-2,4,6-trimethylaniline

To a solution of 3-cyanomethyl-2,4,6-trimethylaniline (see example 230, procedure C) (5 g, 28.7 mmol) in methanol (30 ml) under cooling was added concentrated sulfuric acid (30 ml). The resulting mixture was heated distillation under reflux for 8 h, then left to cool to room temperature and diluted with water (100 ml). From the mixture was removed methanol, and to the residue was added a base (sodium carbonate), then it was extracted with ethyl acetate. The organic layer was processed and concentrated as usual. There was obtained the desired compound in the form of oil (5.2 g, 88%).

B. Methyl 2-(3-(3 the R-3-methyl-5-isoxazolyl)-3-allfamilies-2 - carboxylic acid (1 g, 3.1 mmol) in anhydrous N,N-dimethylformamide (20 ml) was added 1,1'-carbonyldiimidazole (553 mg, 3.41 mmol). After gas evolution ceased, was added methyl 3-amino-2,4,6-trimethylaniline (3.1 g, 15 mmol) and the resulting mixture was heated at 80oC for 24 h the Mixture was left to cool to room temperature and poured into cold 0.5 M HCl (100 ml). The precipitate was filtered and then purified by HPLC to obtain the desired compound as a solid (so pl. 75-78oC, 238 mg, 15%).

Example 374

2-(3-(3-(4-chloro-3-methyl-5-isoxazolidinone)-2-tailormaking)- 2,4,6-trimetilfenil)acetic acid

A solution of methyl 2-(3-(3-(4-chloro-3-methyl-5-isoxazolidinone)-2 - thienylboronic)-2,4,6-trimetilfenil)acetate (100 mg, 0.195 mmol) (example 217) in 1N NaOH (50 ml) was stirred at room temperature for 4 h, then was acidified with concentrated HCl to pH 1.2. The obtained white precipitate was filtered and dried on a freeze dryer to obtain 2-(3-(3-(4-chloro-3-methyl-5-isoxazolidinone)- 2-thienylboronic)-2,4,6-trimetilfenil)acetic acid as a white solid (so pl. 110-113oC, 74 mg, 76%).

Example 375

N2-(3-dimethylaminomethyl-2,4,6-trimethyl-2,4,6-trimethylaniline

To a mixture of THF (20 ml) and dimethylamine (20 ml, 40 wt%. in water) at 0oC was added 2,4,6-trimethylbenzaldehyde (5 g, 29.64 mmol). The mixture was left to warm to room temperature and was stirred for 4 h before the THF was evaporated and the aqueous residue was extracted with ether. The organic layer was processed and concentrated as usual, obtaining 2,4,6-trimethylenetrinitramine with quantitative yield. The compound was then subjected to nitration, and the resulting nitrosoaniline restored to the corresponding aniline as it was demonstrated in example 230.

B. N3-(3-dimethylaminomethyl-2,4,6-trimetilfenil)-3-(4-chloro-3-methyl-5 - isoxazolidinone)-2-thiophencarboxylic triptorelin

N2-(3-dimethylaminomethyl-2,4,6-trimetilfenil)-3-(4-chloro-3 - methyl-5-isoxazolidinone)-2-thiophencarboxylic triptorelin was synthesized and purified as described in example 217, and obtained in powder form (i.e pl. 92-94oC, 18% yield).

Example 376

N2-(3-methanesulfonamido-2,4,6-trimethyl)phenyl-3-(4-chloro-3 - methyl-5-isoxazolyl)-2-thiophencarboxylic

A. 3-methanesulfonamido-2,4,6-trimethylaniline

To a solution of 2,4,6-trimethyl-1,3-phenylenediamine (of 5.82 g, 38.76 molmol) dropwise. The mixture was stirred over night. The precipitate was filtered, and the filtrate was concentrated. The obtained solid was recrystallized from MeOH to obtain the desired product (3 g, 50% yield).

B. N2-(3-Methanesulfonamido-2,4,6-trimethyl)phenyl-3-(4-chloro-3 - methyl-5-isoxazolyl)-2-thiophencarboxylic

N2-(3-Methanesulfonamido-2,4,6-trimethyl)phenyl-3-(4-chloro-3 - methyl-5-isoxazolyl)-2-thiophencarboxylic was synthesized and purified as described in example 217, in powder form (i.e pl. 130-133oC, 19% yield).

Example 377

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl-6 - aminocarbonylmethyl)thiophene-3-sulfonamide

A. 2-Cyano-4,6-dimethylaniline

To a solution of 2,4-dimethylaniline (9.80 g, 80.9 mmol) in dichloromethane (200 ml) at 0oC was slowly added N-bromosuccinimide (15.1 g, 84.9 mmol). The mixture was left to warm to room temperature and was stirred at room temperature overnight, then washed 1N NaOH. The organic layer was processed and concentrated as usual. The residue was dissolved in N,N-dimethylformamide (120 ml), then added copper cyanide (14.5 g, 161.8 mmol). The mixture was heated distillation under reflux in techsmith.com Ethylenediamine, and the precipitate was filtered, re-dissolved in ethyl acetate, dried over MgSO4and then concentrated to obtain the desired compound in the form of oil (6.7 g, 55%).

B. N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl-6 - aminocarbonylmethyl)thiophene-3-sulfonamide

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl-6 - aminocarbonylmethyl)thiophene-3-sulfonamide was synthesized and purified as described in example 230. The cyano group was hydrolyzed to the corresponding amido-group during unprotect the PTO group. N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl-6 - aminocarbonylmethyl)thiophene-3-sulfonamide was obtained as a solid (so pl. 40-43oC, 61%).

Example 378

N2-(3-Hydroxy-2,4,6-trimethyl)phenyl-3-(4-chloro-3-methyl-5 - isoxazolyl)sulfamoyl-2-thiophencarboxylic

A. 3-acetoxy-2,4,6-trimethylaniline

To a solution of 2,4,6-trimethylphenol (10 g, 73.5 mmol) and triethylamine (11.1 g, 110.3 mmol) in ethyl acetate (200 ml) was added acetylchloride (7.5 g, 95.6 mmol) dropwise at 0oC. the Mixture was stirred over night. The reaction was stopped by adding water, and the organic layer was washed with 1N HCl. The organic layer was dried and concentrated as usual. The remainder of broader C) to obtain 3-acetoxy-2,4,6-trimethylaniline.

B. N2-(3-Hydroxy-2,4,6-trimethyl)phenyl-3-(4-chloro-3-methyl - 5-isoxazolyl)sulfamoyl-2-thiophencarboxylic

N2-(3-Hydroxy-2,4,6-trimethyl)phenyl-3-(4-chloro-3-methyl-5 - isoxazolyl)sulfamoyl-2-thiophencarboxylic was synthesized and purified as described in example 230. Acetoxy group was hydrolyzed to the corresponding hydroxyl during unprotect the PTO group. N2-(3-hydroxy-2,4,6-trimethyl)phenyl-3-(4-chloro-3-methyl-5 - isoxazolyl)sulfamoyl-2-thiophencarboxylic was obtained as a solid (so pl. 75-78oC, 54%).

Example 379

3-(4-Chloro-3-methyl-5-isoxazolyl)sulfamoyl-N2-(3 - carboxy-2,4,6-trimetilfenil)-2-thiophencarboxylic

A. Allyl 3-amino-2,4,6-trimethylbenzoic

To a solution of 2,4,6-trimethylbenzoic acid (10 g, 61 mmol) in DMF (100 ml) were sequentially added potassium carbonate (17 g, 122 mmol) and allylbromide (11 g, 91.5 mmol). The mixture was stirred at room temperature overnight and then poured into water (1 liter). The precipitate was filtered and washed with water, then dried in vacuum to obtain allyl-2,4,6-trimethylbenzoic in the form of a solid (10.2 g, 82%) which was subjected to nitration, and then recovered as described in example 230 (procedures B and C) obtaining the l-2,4,6-trimetilfenil)-2-thiophencarboxylic

3-(4-Chloro-3-methyl-5-isoxazolyl)sulfamoyl-N2-(3 - carboxy-2,4,6-trimetilfenil)-2-thiophencarboxylic was synthesized and purified as described in example 230. Protection allyl group was removed in accordance with the methods described in the literature. 3-(4-Chloro-3-methyl-5-isoxazolyl)sulfamoyl-N2-(3-carboxy - 2,4,6-trimetilfenil)-2-thiophencarboxylic was obtained as a solid (so pl. 179-181oC, yield 24%).

Example 380

3-(4-Chloro-3-methyl-5-isoxazolyl)sulfamoyl-N2-(2-carboxy - 4,6-dimethyl)phenyl-2-thiophencarboxylic

3-(4-Chloro-3-methyl-5-isoxazolyl)sulfamoyl-N2-(2-carboxy - 4,6-dimethyl)phenyl-2-thiophencarboxylic was synthesized and purified as described in example 230, using 2-amino-3,4-dimethylbenzoic acid. 3-(4-Chloro-3-methyl-5-isoxazolyl)sulfamoyl-N2-(2 - carboxy-4,6-dimethyl)phenyl-2-thiophencarboxylic was obtained as a solid (so pl. 171-174oC, 66%).

Example 381

3-(4-Chloro-3-methyl-6-isoxazolyl)sulfamoyl-N2-(2-phenyl - 4,6-dimethyl)phenyl-2-thiophencarboxylic

A. 2-Amino-3,5-dimethylbiphenyl

2-Bromo-4,6-dimethylaniline was doubled with the use of phenylboric acid in the Suzuki conditions to obtain 2-amino-3,5-dimethylbiphenyl carboxamid

3-(4-chloro-3-methyl-5-isoxazolyl)sulfamoyl-N2-(2-phenyl - 4,6-dimethyl)phenyl-2-thiophencarboxylic was synthesized and purified as described in example 230. 3-(4-Chloro-3-methyl-5-isoxazolyl)sulfamoyl - N2-(2-phenyl-4,6-dimethyl)phenyl-2-thiophencarboxylic was obtained as a solid (so pl. 178-181oC, 59%).

Example 382

3-(4-chloro-3-methyl-5-isoxazolyl)sulfamoyl-N2-(3 - sulfamoyl-2,4,6-trimethyl)phenyl-2-thiophencarboxylic

A. 3-sulfamoyl-2,4,6-trimethylaniline

To a solution of mesitylenesulfonyl (5 g, 22.9 mmol) in THF (50 ml) at 0oC was added ammonium hydroxide (20 ml). The mixture was stirred at room temperature for 30 min, then boiled away all volatile substances. The remaining white solid was filtered from the water and subjected to nitration and recovered as described in example 230 (procedures B and C) with 3-sulfamoyl-2,4,6-trimethylaniline with 47% yield.

B. 3-(4-Chloro-3-methyl-5-isoxazolyl)sulfamoyl-N2-(3 - sulfamoyl-2,4,6-trimethyl)phenyl-2-thiophencarboxylic

3-(4-Chloro-3-methyl-5-isoxazolyl)sulfamoyl-N2-(3 - sulfamoyl-2,4,6-trimethyl)phenyl-2-thiophencarboxylic was synthesized and purified as in example 230. 3-(4-Chloro-3-methyl-5-isoxazole is a (so pl. 214-217oC, yield 69%).

Example 383

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(pentamethyldisiloxane) thiophene-3-sulfonamide

A. Pentamethylenebis

To a solution of pentamethylbenzene (5 g, 33.8 mmol) in dichloromethane (250 ml) at 0oC was rapidly added tetrafluoroborate nitronium (5 g). The mixture was stirred for 4 h, then the reaction was stopped with cold water. The organic layer was concentrated, and the residue was restored (example 230, procedure C) obtaining pentanitroaniline with 52% yield.

B. N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(pentamethyldisiloxane) thiophene-3-sulfonamide

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(pentamethyldisiloxane) thiophene-3-sulfonamide was synthesized and purified as described in example 230. N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(pentamethyldisiloxane) thiophene-3-sulfonamide was obtained as a solid (so pl. 196-198oC, 69%).

Example 384

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(2,4,6 - trimethylhexamethylenediamine)thiophene-3-sulfonamide

A. 2,4,6-Trimethylaniline

To a solution of 2,4,6-trimethylbenzaldehyde (5 g, 29.7 mmol) in DMSO (20 ml) was added sodium azide (2.9 g, 44.6 mmol). The mixture was heated at 60oC for 3 h, then it Osteen in wet THF (50 ml), then added triphenylphosphine (15.6 g, 59.4 mmol). The mixture was heated distillation under reflux for 3 h, and boiled away the volatile substances. The residue was added to 1N HCl (200 ml), and the solid was filtered. The filtrate was parselocale, and the precipitate was filtered, dried under vacuum to obtain 2,4,6-trimethylaniline (2.7 g, 61% yield).

B. N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(2,4,6 - trimethylhexamethylenediamine)thiophene-3-sulfonamide

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(2,4,6 - trimethylhexamethylenediamine)thiophene-3-sulfonamide was synthesized and purified as described in example 230. N-(4-Chloro-3-methyl-5 - isoxazolyl)-2-(2,4,6-trimethylhexamethylenediamine)thiophene-3-sulfonamide was obtained as a solid (so pl. 175-177oC, 73%).

Example 385

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(3-cyanomethyl-2,4,6 - trimethylhexamethylenediamine)thiophene-3-sulfonamide

A. 3-Cyanomethyl-2,4,6-trimethylbenzene

To a solution of 1,3-bis(chloromethyl)-2,4,6-trimethylbenzoyl (10 g, 46 mmol) in DMSO (30 ml) was added sodium cyanide (2.25 g, 46 mmol). The mixture was stirred at room temperature overnight, then added sodium azide (4.5 g, 69 mmol). The mixture was heated at 80oC for 3 shall ethyl-2,4,6-trimethylaniline, 1,3-bis(cyanomethyl)-2,4,6 - trimethylbenzene and 1,3-bis(azidomethyl)-2,4,6-trimethylbenzene. The mixture was separated, treated with triphenylphosphine (18 g, 69 mmol) in wet THF. The reaction was conducted and the reaction mixture was treated as described in example 228 (procedure A) only, except that the HCl solution was podslushivaet K2CO3up until was not observed gas evolution. The mixture was extracted with dichloromethane and concentrated to obtain only the desired 3-cyanomethyl-2,4,6-trimethylaniline (2 g, 25% yield).

B. N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(3-cyanomethyl-2,4,6 - trimethylhexamethylenediamine)thiophene-3-sulfonamide

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(3-cyanomethyl-2,4,6 - trimethylhexamethylenediamine)thiophene-3-sulfonamide was synthesized and purified as described in example 230. N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(3-cyanomethyl-2,4,6 - trimethylhexamethylenediamine)thiophene-3-sulfonamide was obtained as a solid (so pl. 76-79oC, 53%).

Example 386

N-(3-Cyanomethyl-2,4,6-trimetilfenil)-3-(4-chloro-3-methyl-5 - isoxazolidinone)-2-thiophencarboxylic, N-(sulfonamide), sodium salt.

A. 2,4,6-Trimethylphenylsulfonyl

To the mixture-chlorostyrene (5 g, 29.64 mmol) ivali until while the reaction mixture is not reached again at room temperature, then it was heated at 80oC for 30 minutes and Then the reaction mixture was poured into water (200 ml). The resulting white precipitate was filtered, washed with water, dried with getting 2,4,6-trimethylphenylsulfonyl in the form of a white powder (4.5 g, 95%).

B. 3-Cyanomethyl-1-nitro-2,4,6-trimethylbenzene

To a suspension of 2,4,6-trimethylphenylsulfonyl (4.5 g) in acetic acid (40 ml) at room temperature was added dropwise 70% HNO3(20 ml) and conc. H2SO4(5 ml). The brown reaction mixture was stirred for 1 h, poured into ice water (500 ml). The product was extracted with ethyl acetate, the extract was washed with water, dried over MgSO4and concentrated to obtain 3-cyanomethyl-1-nitro-2,4,6-trimethylbenzene in the form of an oil (5.8 g, quantitative yield).

C. 3-Cyanomethyl-2,4,6-trimethylaniline

To a solution of 3-cyanomethyl-1-nitro-2,4,6-trimethylbenzene (5.8 g in methanol (150 ml) were sequentially added ammonium chloride (6 g in 50 ml water), powdered zinc (6 g). The exothermic reaction mixture is vigorously stirred until such time as it again not adopted at room temperature (2 h). The crude mixture was filtered, and the remaining ve the acetate and 1N NaOH. The organic layer was dried over MgSO4and concentrated to obtain 3-cyanomethyl-2,4,6-trimethylaniline in the form of a light brown solid (3.4 g, yield 69%).

D. 5-Amino-4-chloro-3-methylisoxazol

To a solution of 5-Amino-3-methylisoxazole (9.8 g, 100 mmol) in methylene chloride (200 ml) was added N-chlorosuccinimide (14.7 g, 110 mmol) at 0oC for 20 minutes the Reaction mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated and divided between 1N NaOH (150 ml)/ethyl acetate (400 ml). The organic layer was washed with 1N NaOH, water, brine, dried over MgSO4then concentrated to obtain a brown solid. For purification the product was Presiden from a mixture of chloroform/hexane, then recrystallized from a mixture of ethyl acetate/hexane to obtain 5-amino-4-chloro-3-methylisoxazole in the form of a brownish solid (5.5 g, yield 41%).

E. 2-Carbomethoxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)thiophenesulfonyl

To 60% suspension of NaH in mineral oil (8.5 g, 0.21 mol) in THF (100 ml) at -20oC was added a solution of 5-amino-4-chloro-3 - methylisoxazole (12.4 g, 92.4 mmol) in anhydrous THF (65 ml) in nitrogen atmosphere for 20 min After 10 min stirring was added p is injecting the mixture was stirred for 10 min, then the reaction was stopped using H2O (5 ml) at the same temperature. Then the reaction mixture was poured into 4N HCl, and the product was extracted with ethyl acetate. The combined organic layers were washed with water, and then the connection was extracted polysystem solution of NaHCO3. Combined basic solutions were decolorized with activated charcoal, cooled to 0oC and acidified with 4N HCl. The product was separated by filtration, washed with water, dried to obtain 2-carbomethoxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)]thiophenesulfonyl in the form of a white powder (23.4 g, 75% yield).

F. 2-Carbomethoxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)-N - IOM]thiophenesulfonyl

To a solution of 2-carbomethoxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)] thiophenesulfonyl (3.3 g, 10.0 mmol) in THF (50 ml) was added diisopropylethylamine (1.9 g, 15.0 mmol) at 0oC, and then added bromatology ether (1.5 g, 12.0 mmol). The reaction mixture was stirred over night at room temperature. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4concentrated to obtain 2-carbomethoxy-3-[N-(4-chloro-3 - methylisoxazol-5-yl)-N-IOM] thiopental is] thiophenesulfonyl

2 Carbomethoxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)-N-IOM] thiophenesulfonyl (3.0 g, 7.8 mmol) in a mixture of THF (30 ml) and 1N NaOH (30 ml) was stirred for 3 h at room temperature. The reaction mixture was diluted with water (20 ml) and was extracted with ethyl acetate (5 ml). The aqueous solution was acidified using 1N HCl, then extracted with ethyl acetate. The organic portion was washed with water, brine, dried over MgSO4and concentrated to obtain 2-carboxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)-N-IOM] ] thiophenesulfonyl in the form of an oil (quantitative yield).

H. 3-[N-mom-N-(4-Chloro-3-methylisoxazol-5-yl)aminosulfonyl]thiophene - 2-carbonylchloride

To a solution of 2-carboxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)-N - IOM]thiophenesulfonyl (1.5 g, 4.1 mmol) in a mixture of THF (10 ml) and chloroform (5 ml) was added pyridine (1 drop) at 0oC, and then added a 2M solution of oxalicacid (4.5 ml, 9.0 mmol). The reaction mixture was stirred over night at room temperature. The reaction mixture was concentrated under reduced pressure to remove all volatile substances. The desired product was obtained as a viscous oil which hardened on standing.

I. 3-[N-mom-N-(4-Chloro-s-methylisoxazol-5-yl)aminosulfonyl]thiophene - 2-Carbonell (20 ml) under nitrogen atmosphere was added a solution of 3-[N-mom-N-(4-Chloro-3-methylisoxazol-5-yl)aminosulfonyl]thiophene-2 - carbonylchloride (1.3 mg, 3.3 mmol) in THF (10 ml) at 0oC. the Reaction mixture was left to warm to room temperature and was stirred for 2 hours, the Reaction mixture was poured in 0.05 N HCl, and the product was extracted with ethyl acetate. The organic portion was washed with 0.05 N HCl, water, polysystem solution of NaHCO3again with water, brine, then dried over MgSO4was concentrated. Purification by column chromatography (silica, a mixture of 40% ethyl acetate/hexane) yielded 3-[N-mom-N-(4-chloro-3 - methylisoxazol-5-yl)aminosulfonyl]thiophene-2-carboxylic acid, 3-cyanomethyl-2,4,6-trimethylaniline in the form of a light oil (1.3 g, 76%).

J. N-(3-Cyanomethyl-2,4,6-trimetilfenil)-3-(4-chloro-3-methyl-5 - isoxazolidinone)-2-thiophencarboxylic, N(sulfonamide)-Na-salt

A solution of 3-[N-mom-N-(4-chloro-3-methylisoxazol-5-yl)aminosulfonyl] thiophene-2-carboxylic acid, 3-cyanomethyl-2,4,6-trimethylaniline (500 mg, 0.95 mmol) in THF (4 ml) and conc. HCl (2 ml) was stirred at 65-72oC for 3.5 h, the Reaction mixture was cooled and poured into water (50 ml). The product was extracted with ethyl acetate. The extract was washed with water, brine, saturated NaHCO3, brine, dried over MgSO4concentrated and obtained in the form of oil. The oil was recrystallized PII)-2-thiophencarboxylic in the form of a white solid (410 mg, 91%). The product (300 mg, 0.63 mmol) was dissolved in ethyl acetate (70 ml). The solution was washed with saturated solution of NaHCO3, brine, dried over MgSO4concentrated under reduced pressure. Methylene chloride (10 ml) was added under stirring, and then added ether. Na-salt of N-(3-cyanomethyl-2,4,6-trimetilfenil)-3-(4-chloro-3-methyl-5 - isoxazolidinone)-2-thiophenecarboxylate was precipitated in the form of a white solid, which was isolated by filtration (292 mg, 92%).1H NMR (DMSO-d6): 1.99 (s, 3H); 2.13 (s, 3H); 2.21 (s, 3H), 2.33 (s, 3H); 3.90 (s, 2H); 7.03 (s, 1H); 7.43 (d, 2H); 7.72 (d, 1H), 11.15 (s, 1H). IR (KBr); 3445, 2977, 2258, 1602, 1417, 1292, 1132, 1090 cm-1. Elemental analysis, found: C, 44.68; H, 3.92, N, 10.18. C20H18ClN4NaO4S2THF in THF (63.8 ml, 63.8 mmol) at 0oC. the Reaction mixture was stirred over night at room temperature, cooled to 0oC and the reaction was extinguished with water. The product was extracted into ethyl acetate, the extract was washed with water, dried over MgSO4and concentrated to obtain 1-acetoxymethyl-3-nitro-2,4,6-trimethylbenzene in the form of a light yellow oil (6.3 g, 89%).

C. 3-Acetoxymethyl-2,4,6-trimethylaniline

To a solution of 1-acetoxymethyl-3-nitro-2,4,6-trimethylbenzene (6.0 g, 25.2 mmol) in methanol (100 ml) were posledovatelno was stirred until until she took a room temperature (2 h). The crude mixture was filtered, and the residue was washed with methanol. The methanol solutions were concentrated to a volume of 20 ml, then added 1N HCl (300 ml). Insoluble material was removed by filtration, the solution was padmalochan solid NaHCO3. Semi-crystalline residue was extracted with ethyl acetate. The extract was concentrated, and the remaining product is purified column chromatography (mixture of 25% ethyl acetate/hexane) to give 3-acetoxymethyl-2.4,6-trimethylaniline in the form of a pink oil (3.8 g, 75%).

D. 3-[N-mom-N-(4-Chloro-3-methylisoxazol-5-yl)aminosulfonyl] thiophene - 2-carboxylic acid, 3-acetoxymethyl-2,4,6-trimethylaniline

The compound was synthesized in the same way as 3-[N-mom-N-(4-chloro-3 - methylisoxazol-5-yl)aminosulfonyl] thiophene-2-carboxylic acid, 3-cyanomethyl-2,4,6-trimethylaniline.

E. 2-(3-Acetoxymethyl-2,4,6-trimetilfenil)-3-(4-chloro-3-methyl-5 - isoxazolidinone)-2-thiophencarboxylic, N(sulfonamide)-Na-salt

To a solution of 3-[N-mom-N-(4-chloro-5-methylisoxazol-3-yl)aminosulfonyl] thiophene-2-carboxylic acid, 3-acetoxymethyl (400 mg, 0.90 mmol) in acetic acid (4 ml) at 50oC, water (2 ml) and 2N H2SO4(2 drops) were dobule ml). The product was extracted with ethyl acetate. The extract was washed with water, brine, dried over MgSO4concentrated to obtain oil. Using column chromatography (mixture of 10% methanol/methylene chloride) followed by kneading the obtained oily material with a mixture of ethyl acetate/hexane there was obtained 2-(3-acetoxymethyl-2,4,6-trimetilfenil)- 3-(4-chloro-3-methyl-5-isoxazolidinone)-2-thiophencarboxylic in the form of a white powder (180 mg, 49%). This material (240 mg, 0.47 mmol) was dissolved in ethyl acetate (70 ml). The solution was washed with saturated solution of NaHCO3, brine, dried over MgSO4concentrated under reduced pressure. Added methylene chloride (10 ml) under stirring, and then the ether Na-salt of 2-(3-acetoxymethyl-2,4,6 - trimetilfenil)-3-(4-chloro-3-methyl-5-isoxazolidinone)-2 - thiophenecarboxylate was precipitated in the form of a white solid, which was allocated filtering (209 mg, 83%).1H NMR (DMSO-d6); 1.98 (s, 3H); 2.02 (s, 3H): 2.13 (s, 3H); 2.17 (s, 3H), 2.31 (s, 3H), 5.11 (s, 2H); 6.99 (s, 1H); 7.41 (d, 2H); 7.71 (d, 1H); 11.09 (s, 1H). IR (KBr): 3447, 2963, 1730, 1602, 1497, 1417, 1261, 1133, 1089 cm-1. Elemental analysis, found: C, 44.94; H, 4.20; N, 7.12. C21H21ClN3NaO6S21. The resulting yellow precipitate was filtered and recrystallized from CHoC.

Example 410

N-(4-Bromo-5-methyl-3-isoxazolyl)-5-(4-were)thiophene-2-sulfonamide

A. N-[5-(4-were)thiophene-2-sulfonyl]pyrrol

N-[5-(4-were)thiophene-2-sulfonyl] pyrrole was obtained as described in example 250C, 4-methyl-phenylboric acid and N-(5-bronchiopulmonar)pyrrole. Purification using column chromatography using 2% mixture of ethyl acetate/hexane resulted in the receipt of N-[5-(4-were)thiophene-2-sulfonyl] pyrrole in the form of a dull yellow solid, 77% yield.

B. 2-chlorosulfonyl-5-(4-were)thiophene

2-chlorosulfonyl-5-(4-were)thiophene was obtained as described in example 251D, using N-[5-(4-were)thiophene-2 - sulfonyl]pyrrole. Purification via column chromatography using a mixture of 2% ethyl acetate/hexane led to a 2-chlorosulfonyl-5-(4-were)of thiophene in the form of a dull yellow powder (61% yield).

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-were)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-were)thiophene-2-sulfonamide was obtained as described in example 247. The reaction of 2-chlorosulfonyl-5-(4-were)thiophene (100 mg, 0.37 mmol) with 5 the mixture of 10% MeOH/CHCl3, 96 mg of the final product in the form of a dull yellow solid (63% yield, so pl. 175oC).

Example 411

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(benzoyloxymethyl)thiophene-2-sulfonamide

A. 2-(benzoyloxymethyl)thiophene

Sodium hydride (0.41 mg, 20 mmol) was added to a solution of 2-thiophenemethyl (2.0 g, 0.18 mmol) in THF (20 ml) at -40oC. the Reaction was carried out at -40oC for 25 min, then benzylbromide (3.6 g, 20 mmol) was added via syringe. The solution was stirred at -40oC for 0.5 h, then at room temperature for 1 h THF was evaporated and the remaining residue was extracted with ether ( 50 ml). The organic solution was washed with water (1 x 10 ml), brine (1 x 10 ml) and dried over MgSO4. After evaporation of the solvent left an oil which was purified by column chromatography using a mixture of 1% ether-hexane to obtain 2.6 g of thiophene in the form of a turbid yellow oil (78% yield).

B. 2-chlorosulfonyl-5-(benzoyloxymethyl)thiophene

2-chlorosulfonyl-5-(benzoyloxymethyl)thiophene was obtained as described in example 254A of 2-(benzoyloxymethyl)thiophene (1.0 g, 5.25 mmol). Purification via column chromatography using a mixture of 2.5% ethyl acetate/g is m-3-methyl-5-isoxazolyl)-5-(benzoyloxymethyl)thiophene-2 - sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzoyloxymethyl)thiophene-2 - sulfonamide was obtained as described in example 247 2-chlorosulfonyl-5-(benzoyloxymethyl)thiophene (520 mg, 1.72 mmol) and 5-amino-4-bromo-3-methylisoxazole (319 mg, 1.8 mmol). Purification via column chromatography using a mixture of 10% MeOH/CHCl3led to 238 mg of pure N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzoyloxymethyl)thiophene-2-sulfonamida in the form of a brown semi-solid substances (31% yield, so pl. 92oC).

Example 412

N-(4-Bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenyl] thiophene - 2-sulfonamide

A. 3-bromothiophene-2-sulfonyl chloride

Chlorosulfonic acid (20 ml, 300 mmol) was added to a solution of 3-bromothiophene (8.15 g, 50 mmol) in methylene chloride (50 ml) at -78oC for 20 min After complete addition, the cold bath was removed and stirring continued at room temperature for 1 hour. The reaction mixture was carefully added, dropwise, to crushed ice (100 g). The mixture was extracted with methylene chloride (2 x 100 ml). The combined organic layers was dried over MgSO4and evaporated. Technical product was purified flash chromatography on silica gel using hexane as eluent. Were ">

B. N-(3-bromothiophene-2-sulfonyl)pyrrol

N-(3-bromothiophene-2-sulfonyl)pyrrole was obtained as described in example 251A, by reaction of 3-bromothiophene-2-sulphonylchloride with pyrrole (for 16 hours). N-(3-bromothiophene-2-sulfonyl)pyrrole was obtained from 54% yield.

C. N-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrol

N-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrole was obtained as described in example 250C, using 3,4-methylenedioxyaniline acid and N-(3-bromothiophene-2-sulfonyl)pyrrole. Technical product was purified on a flash column chromatography on silica gel using a mixture of 2% EtOAc in hexane as eluent. There was obtained N-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrole with 90% yield.

D. 2-chlorosulfonyl-3-[3,4-(methylenedioxy)phenyl]thiophene

2-chlorosulfonyl-3-[3,4-(methylenedioxy)phenyl] thiophene was obtained as described in example 255B, using N-{[3-(3,4-methylenedioxy)phenyl] thiophene-2-sulfonyl} pyrrole, the main hydrolysis sulfonamida to sulfonate sodium (100% output), and then converting the salt to the corresponding sulphonylchloride. The final product was obtained, with 34% yield.

E. N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(- 2-the sulfonamide was obtained in the same way, as described in example 246, through the reaction of 2-chlorosulfonyl-3-[3,4-(methylenedioxy)phenyl]thiophene with 5-amino-4-bromo-3-methylisoxazole. The product was obtained in 60% yield, so pl. 183-186oC.

Example 413

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(2-chloro-3,4-methylendioxy) phenoxymethyl]thiophene-3-sulfonamide

A. N-{2-[(3,4-methylenedioxy)phenoxymethyl]thiophene-3-sulfonyl}pyrrol

Sodium hydride (100 mg, 5 mmol) was added to a solution of 3,4-methylenedioxyphenol (0.607 g, 4.5 mmol) in DMF (dry, 5 ml) at 0oC under stirring in nitrogen atmosphere. The reaction mixture was left to reach room temperature and stirring was continued for 1 h, the Reaction mixture was cooled to 0oC and added N-[(2-methyl bromide)thiophene-3-sulfonyl]pyrrole. Stirring is continued at room temperature for 16 hours, the Reaction mixture was diluted with water (100 ml), extracted with ethyl acetate (2 x 50 ml) and washed 1N NaOH (2 x 25 ml) to remove phenol derivatives. The mixture was dried over MgSO4and concentrated. There was obtained N-{2-[(3,4-methylenedioxy)phenoxymethyl]thiophene-3-sulfonyl}pyrrole, which was recrystallized from a mixture of hexane/EtOAc (1.0 g, 92% yield).

B. 3-chlorosulfonyl-2-[(2-chloro-3,4-methylendioxy)fenoc the Sano in example 252E, using N-{2-[(3,4-methylenedioxy)phenoxymethyl] thiophene-3-sulfonyl} pyrrole by conducting basic hydrolysis (using potassium hydroxide in isopropanol) to the potassium sulfonate, followed by conversion of the salt to the corresponding sulphonylchloride with a total yield of 50%.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2-chloro-3,4 - methylendioxy)phenoxymethyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2-chloro-3,4-methylendioxy)methyl] thiophene-3-sulfonamide was obtained as described in example 246, through the reaction of 3-chlorosulfonyl-2-[(2-chloro-3,4-methylenedioxyphenoxy) methyl]thiophene with 5-amino-4-bromo-3-methylisoxazole, with 47% yield, so pl. 152-154oC.

Example 414

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[TRANS-3,4-(methylendioxy) cinnamyl] thiophene-3-sulfonamide

A. Diethyl-2-{3-[(N-pyrrolyl)sulfonyl]thienylmethyl}phosphonate

N-[2-methyl bromide)thiophene-3-sulfonyl] pyrrole (0.915 g, 3 mmol) was suspended in triethylphosphite (5 ml) and was heated to 140oC for 1 h under stirring in nitrogen atmosphere. The excess triethyl phosphate was removed under reduced pressure, and the residue was dried under vacuum. Diethyl 2-{3-[(N-pyrrolyl)sulfonyl]thienylmethyl}phosphonate was obtained in 83% yield, 0,9, RSE) was added to two portions of a solution of diethyl 2-{3-[(N-pyrrolyl)sulfonyl]thienylmethyl}phosphonate (900 mg, 2.48 mmol) in dry THF (10 ml) under stirring at 0oC. the Mixture was stirred at room temperature for 1 h, then was added piperonal (600 mg). Stirring is continued for 12 hours. The mixture was diluted with water (100 ml) and was extracted with methylene chloride (2 x 50 ml). The combined organic layers were dried over MgSO4evaporated and the residue was subjected to flash chromatography on silica gel using a mixture of 0.5% ethyl acetate in hexane. There was obtained N-{2-[TRANS-(3,4-methylendioxy)cinnamyl] thiophene-3-sulfonyl} pyrrole (750 mg, 84% yield).

C. 3-chlorosulfonyl-2-[TRANS-3,4-(methylendioxy)cinnamyl]thiophene

3-Chlorosulfonyl-2-[TRANS-3,4-(methylendioxy)cinnamyl] thiophene was obtained as described in example 252E, from N-{2-[TRANS-3,4-(methylendioxy)cinnamyl] thiophene-3-sulfonyl} pyrrole, basic hydrolysis (using isopropanol and potassium hydroxide) to the corresponding sulfonate potassium (100%) followed by conversion of the salt to the corresponding sulphonylchloride with a total yield of 31%.

D. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[TRANS-3,4-(methylendioxy) cinnamyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[TRANS-3,4-(methylendioxy) cinnamyl] thiophene-3-sulfonamide was obtained in the same way, Ino-4-bromo-3-methylisoxazole. Technical product was purified by HPLC. Pure product was obtained with a 33% yield, so pl. 147-149oC.

Example 415

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)phenylethyl] thiophene-3-sulfonamide

A. N-{2-[3,4-(methylendioxy)phenylethyl]thiophene-3-sulfonyl}pyrrol

A solution of N-{2-[TRANS-3,4-(methylendioxy)cinnamyl]thiophene-3 - sulfonyl}pyrrole in ethyl acetate (15 ml) (example 258B, 0.6 g, 1.67 mmol) was subjected to catalytic hydrogenation using 10% Pd-C (100 mg) at 55 psi for 14 hours the Catalyst was filtered, and the filtrate concentrated. Howled obtained N-{ 2-[3,4-(methylendioxy)phenylethyl]thiophene-3-sulfonyl}pyrrole (0.55 g, 91% yield).

B. 3-chlorosulfonyl-2-[3,4-(methylendioxy)phenylethyl]thiophene

1-chlorosulfonyl-2-[3,4-(methylendioxy)phenylethyl] thiophene was obtained as described in example 252E, using N-{2-[3,4-(methylendioxy)phenylethyl] thiophene-3-sulfonyl}pyrrole, through basic hydrolysis (isopropanol and potassium hydroxide) sulfonamida to the potassium salt of sulfonic acid (93%), followed by conversion of the salt to the corresponding sulphonylchloride with 42% yield.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy) phenylethyl]thiophene-3-sulfone is AK described in example 247. By reaction of 3-chlorosulfonyl-2-[3,4-(methylendioxy)phenylethyl]thiophene with 5-amino-4-bromo-3-methylisoxazole and cleaning technical product HPLC was obtained N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy) phenylethyl] thiophene-3-sulfonamide with 30% output, so pl. 180oC (decomp.).

Example 416

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)(cinnamyl)] thiophene - 3-sulfonamide

A. N-[2-(4-methyl-TRANS-styryl)-3-sulfonyl}pyrrol

N-[2-(4-methyl-TRANS-styryl)-3-sulfonyl} pyrrole was obtained as described in example 258B, using diethyl{ 3-[(N-pyrrolidinyl)Tien-2-[Il]methylphosphonate and 4-methylbenzaldehyde with 30% output.

B. 2-(4-methyl-TRANS-styryl)thiophene-3-sulphonylchloride

2-(4-methyl-TRANS-styryl)thiophene-3-sulphonylchloride was obtained as described in example 252E, from N-[2-(4-methyl-TRANS-styryl)-3 - sulfonyl}pyrrol basic hydrolysis (using ethanol and sodium hydroxide) to the corresponding sulfonate sodium followed by conversion to the corresponding sulphonylchloride with 13% yield.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methyl-TRANS-styryl)thiophene - 3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methyl-TRANS-styryl)thiophene - 3-sulfonamide was obtained tar-3-methylisoxazole. Technical product was purified by HPLC with subsequent crystallization. The product was obtained in 34% yield, so pl. 101-105oC.

Example 417

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenylethyl] thiophene - 3-sulfonamide

A. N-{2-[(4-methyl)phenylethyl]thiophene-3-sulfonyl}pyrrol

N-{ 2-[(4-methyl)phenylethyl] thiophene-3-sulfonyl} pyrrole was obtained as described in example 259A, catalytic hydrogenation of N-[2-(4-methyl-TRANS-Steril)-3-sulfonyl}pyrrole with 80% yield.

B. 2-[(4-methyl)phenylethyl]thiophene-3-sulphonylchloride

2-[(4-methyl)phenylethyl] thiophene-3-sulphonylchloride was obtained as described in example 252E, using N-{2-[(4-methyl)phenylethyl]thiophene - 3-sulfonyl} pyrrole, basic hydrolysis (KOH/ethanol) sulfonamida to potassium salt, followed by conversion of the salt to the corresponding sulphonylchloride with 51% yield.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenylethyl)thiophene - 3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenylethyl]thiophene-3 - sulfonamide was obtained as described in example 247, using 2-[(4-methyl)phenylethyl]thiophene-3-sulphonylchloride and 5-amino-4-bromo-3-methylisoxazole with 52% yield.

Example 418

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-meth is tolfanate)methyl] thiophene-3-sulfonyl}pyrrole was obtained, as described in example 257A, by reaction of N-[2-methyl bromide)thiophene-3-sulfonyl]pyrrole with metilfenidato with 81% yield.

B. 2-[(4-(methylphenoxy)methyl]thiophene-3-sulfonyl chloride

2-[(4-methylphenoxy)methyl] thiophene-3-sulphonylchloride was obtained as described in example 252E, using N-{2-[(4-methylphenoxyacetic]thiophene-3-sulfonyl} pyrrole, basic hydrolysis (NaOH/EtOH) followed by conversion to the corresponding sulphonylchloride with 46% yield.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl] thiophene - 3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl] thiophene - 3-sulfonamide was obtained as described in example 247, by reaction of 3-chlorosulfonyl-2-[(4-methylphenoxy)methyl] thiophene with 5-amino-4-bromo-3-methylisoxazole. The product was obtained in 64% yield, so pl. 128-130oC.

Example 419

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methyl] phenylenecarbonyl-3-thiophenesulfonyl

A. (3,4-methylenedioxy)-6-methylaniline

To a solution of (3,4-methylenedioxy)toluene (5 ml) in acetic acid (20 ml), cooled by a bath of cold water, was added, dropwise, nitric acid (70%, 5 ml). The mixture was stirred for 45 minutes was Added water (100 ml), and receive the m The yellow solid was dissolved in EtOAc (250 ml) and dried (MgSO4). The solid was filtered. The filtrate was subjected to catalytic hydrogenation (10% Pd/C, 1 ATM) for 12 hours. Then the reaction mixture was filtered, the catalyst, and the filtrate was concentrated on a rotary evaporator to obtain (3,4-methylenedioxy)-6-methylaniline in the form of brownish-gray solid (5.49 g, 87% yield).

B. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methyl]phenylenecarbonyl-3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methyl] phenylenecarbonyl-3-thiophenesulfonyl was obtained as described in example 241 using (3,4-methylenedioxy)-6-methylaniline. Technical product was purified preparative HPLC to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methyl]phenylenecarbonyl-3-thiophenesulfonyl in the form of a yellow solid (45% yield, so pl. 60-62oC).

Example 420

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6 - trimethyl)phenylenecarbonyl-3-thiophenesulfonyl

A. Methyl 3-amino-2,4,6-trimethylbenzoic

Methyl 3-amino-2,4,6-trimethylbenzoic was obtained as described in the Nile-2,4,6 - trimethyl)phenylenecarbonyl-3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazol)-2-(3-methoxycarbonyl-2,4,6 - trimethyl)phenylenecarbonyl-3-thiophenesulfonyl was obtained as described in example 241, except that DMF was used instead of THF, and the reaction mixture was heated at 80oC for 5 hours. Technical product was purified preparative HPLC to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl - 2,4,6-trimethyl)phenylenecarbonyl-3-thiophenesulfonyl in the form of a white powder (48 mg, 1% yield, so pl. 66-70oC).

Example 421

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacetyl - 3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacetyl - 3-thiophenesulfonyl was obtained as described in example 243, using 2,4,6-trimethylbenzaldehyde and N-(4-chloro-3-methyl-5 - isoxazolyl)-2-(N-methyl-N'-methoxy)aminocarbonyl-3-thiophenesulfonyl. Technical product was purified flash column chromatography (eluent of 1% methanol in CH2Cl2) to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacetyl-3 - thiophenesulfonyl in the form of a solid (31% yield, so pl. 42-46oC).

Example 422

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylenecarbonyl - 3-type is obtained as, as described in example 241. Technical product was purified preparative HPLC to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylenecarbonyl - 3-thiophenesulfonyl in the form of a yellow-brown powder (410 mg, 30% yield, so pl. 45-48oC).

Example 423

N-(3,4-dimethyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3 - thiophenesulfonyl

N-(3,4-dimethyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3 - thiophenesulfonyl was synthesized as described in example 243, using 2,4-dimethylbenzyl chloride and N-(3,4-dimethyl-5-isoxazolyl)-2-(N-methyl-N'-methoxy)aminocarbonyl-3 - thiophenesulfonyl. Technical product was purified flash column chromatography (eluent of 1% methanol in CH2Cl2) and then preparative HPLC to obtain N-(3,4-dimethyl-5-isoxazolyl)-2- (2,4-dimethyl)phenylacetyl-3-thiophenesulfonyl in the form of semi-solid substances (34% yield).

Example 424

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3 - thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3 - thiophenesulfonyl was obtained as described in example 243, using 2,4-dimethylbenzylamine and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-methyl-N'-methoxy)aminocarbonyl-3 - type2) to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl - 3-thiophenesulfonyl in the form of a solid (52% yield, so pl. 48-54oC).

Example 425

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3 - thiophenesulfonyl

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3 - thiophenesulfonyl was obtained as described in example 243, using 2,4-dimethylbenzyl chloride and N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-methyl-N'-methoxy)aminocarbonyl - 3-thiophenesulfonyl. Technical product was purified flash column chromatography (eluent of 1% methanol in CH2Cl2) and then preparative HPLC to obtain N-(4-bromo-3-methyl-5-isoxazolyl)-2- (2,4-dimethyl)phenylacetyl-3-thiophenesulfonyl in the form of a solid (28% yield, so pl. 58-63oC).

Example 426

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,5-dimethyl)phenylacetyl-3 - thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,5-dimethyl)phenylacetyl-3 - thiophenesulfonyl was obtained as described in example 243, using 3,5-dimethylbenzylamine and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-methyl-N'-methoxy)aminocarbonyl - 3-thiophenesulfonyl. Technical product was purified on a flash column of chromatography is thiophenesulfonyl in the form of a solid (57% yield, so pl. 45-50oC).

Example 427

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,5-dimethyl)phenylacetyl-3 - thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,5-dimethyl)phenylacetyl-3 - thiophenesulfonyl was obtained as described in example 243, using 2.5-dimethylbenzyl chloride and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-methyl-N'-methoxy)aminocarbonyl - 3-thiophenesulfonyl. Technical product was purified flash column chromatography (eluent of 2% methanol in CH2Cl2) to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,5-dimethyl)phenylacetyl - 3-thiophenesulfonyl in the form of a solid (33% yield, so pl. 72-76oC).

Example 428

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2 - acetoxyethyl)]phenylenecarbonyl-3-thiophenesulfonyl

A. 2-(3,4-methylenedioxy)phenyl-1-ethanol

To a solution of 2-(3,4-methylenedioxy)phenylacetic acid (5 g, 25.75 mmol) in anhydrous THF (20 ml) at 0oC was added BH3THF (40 ml, 1.0 M in THF). The mixture was stirred at room temperature for 1 h THF was evaporated on a rotary evaporator. The residue was treated with water (100 ml), acidified and extracted with ether (2 x 100 ml). Removal of the solvent under reduced pressure resulted in 2-(3,4-metalian

To a stirred solution of 2-(3,4-methylenedioxy)phenyl-1-ethanol (1.68 g, 10 mmol) in dry pyridine was added acetic anhydride, and the resulting reaction mixture was stirred at 80oC for 1 h, the Reaction mixture was poured into ice water and was extracted with ether (2 x 75 ml). The combined ether extracts were washed with water (2 x 50 ml), 5% HCl (2 x 50 ml) and then 5% NaHCO3(2 x 50 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain 1-acetoxy-2-[(3,4-methylenedioxy)phenyl] ethane in the form of a solid (1.7 g, 81% yield).

C. 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl]ethane

To a stirred solution of 1-acetoxy-2-[(3,4-methylenedioxy)phenyl]ethane (1.7 g, 8.09 mmol) in acetic acid (10 ml) was added, dropwise, concentrated HNO3(4.5 ml). The solution was stirred at room temperature for 30 minutes, the Reaction mixture was poured into water (100 ml). The precipitated solid was filtered, washed with water, dried under high vacuum to obtain 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl]ethane (1.8 g, 88% yield).

D. 1-acetoxy-2-[(3,4-methylenedioxy)-6-AMINOPHENYL]ethane

A solution of 1-acetoxy-2-[(3,4-methylendioxyphenyl 10% palladium on coal (100 mg) at 50 psi for 30 minutes The catalyst was filtered, and the solvent was removed under reduced pressure to obtain 1-acetoxy-2-[(3,4-methylenedioxy)-6-AMINOPHENYL]ethane in the form of a solid (0.69 g, 98% yield).

E. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)- 6-(2-acetoxyethyl)]phenylenecarbonyl-3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2 - acetoxyethyl)] phenylenecarbonyl-3-thiophenesulfonyl was obtained as described in example 253. Technical product was purified preparative HPLC to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)- 6-(2-acetoxyethyl)] phenylenecarbonyl-3-thiophenesulfonyl in the form of a dull yellow powder (12% output, so pl. 78-82oC).

Example 429

Other compounds, which were obtained above methods or routine modifications include, but are not limited to only these: N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxyphenoxy)carbonyl] thiophene - 3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy) carbonyl]thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-[(4 - methylphenoxy)methyl] thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)- 2-[(4-methylphenoxy)methyl] thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5 - isoxazol named, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-were)acetyl] thiophene-3 - sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-methoxyphenyl) acetyl]thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4 - methylphenylethyl)-5-(4-tolyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5 - isoxazolyl)-3-(4-methylbenzyl)-5-(4-tolyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl-TRANS-Motril)-5-(4 - tolyl)thiophene-2-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2- [3,4-(methylenedioxy)benzyl] thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[(5-methyl-3-isoxazolyl)aminocarbonyl]thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-hydroxyl-6-pyridazinyl) aminocarbonyl] thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)- 3-{[3,4-(methylendioxy)phenoxy] methyl} thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)(cinnamyl)] thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylendioxy)phenylethyl] thiophene - 2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylendioxy)- TRANS-styryl] thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)- 2-[(4-methyl)phenylethyl] thiophene-3-sulfonamide, N-(3,4-dimethyl-5-isoxazolyl)- 2-(4-tolylacetylene)thiophene-3-sulfonamide, N-(3,4-dimethyl-5-isoxazolyl)- 2-[3,4-(methylendioxy)phenylacetyl] thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-and the s in table 1, but not here in some examples.

For example, N-(4-bromo-3-methyl-5-isoxazolyl)-3-[2-methyl-4,5- (methylenedioxy)cinnamyl]thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5 - isoxazolyl)-3-[2-(hydroxymethyl)-4,5-(methylenedioxy)cinnamyl]thiophene - 2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-{2-[(tetrahydro - 4H-Piran-2-yloxy)methyl] -4,5-(methylenedioxy)cinnamyl} thiophene-2-sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4-dimethylcarbamyl)thiophene-2 - sulfonamide was obtained as N-(4-bromo-3-methyl-5-isoxazolyl)- 3-[3,4-(methylendioxy)-TRANS-styryl] thiophene-2-sulfonamide. N-(4-bromo-3-methyl-5-isoxazolyl)-3-[2-methyl-4,5-(methylenedioxy) phenylethyl] thiophene-2-sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)- 2-(2,4,6-trimethylphenyl)thiophene-3-sulfonamide was obtained as N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenylethyl]thiophene-3 - sulfonamide (see example 261). N-(4-bromo-3-methyl-5-isoxazolyl)-3-{[2 - propyl-4,5-(methylenedioxy)phenoxy] methyl} thiophene-2-sulfonamide was obtained as N-(4-bromo-3-methyl-5-isoxazolyl)-3-[(4 - methylphenoxy)methyl]thiophene-2-sulfonamide and N-(4-bromo-3-methyl-5 - isoxazolyl)-3-{[3,4-(methylendioxy)phenoxy] methyl} thiophene-2-sulfonamide. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy) phenylethyl] thiophene-3-sulfonamide was receiving the e as N-(4-bromo-3-methyl-5-isoxazolyl)- 3-(2-tolyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3- (3-tolyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2 - tolyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3 - methoxyphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)- 3-(3-methoxyphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)- 3-(2-methoxyphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)- 3-(4-ethylphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-propylphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-ISO-propylphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-butylphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4-dimetilfenil)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-ISO-butylphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-ISO-pentylphenol)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-methyl-4-propylphenyl)thiophene-2 - sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-ISO-butyl-2 - were)thiophene-2-sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)- 3-(4-ISO-pentyl-2-were)thiophene-2-sulfonamide was obtained as N-(4-bromo-3-methyl-5-isoxazolyl)-3-[(3,4-methylenedioxy)phenyl] thiophene-2-sulfonamide. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[2-methyl - 4,5-(methylenedioxy)phenylethyl] thiophene-3-sulfonamid 259). N-(4-bromo-3-methyl-5-isoxazolyl)- 2-[2-methyl-4,5-(methylenedioxy)cinnamyl] thiophene-3-sulfonamide was obtained as N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl) (cinnamyl)]thiophene-3-sulfonamide (example 260). N-(4-bromo-3-methyl-5 - isoxazolyl)-2-{[3,4-(methylendioxy)phenoxy]methyl}thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenol)methyl] thiophene - 3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-{[4,5-(methylenedioxy)- 2-propylenoxide] methyl} thiophene-3-sulfonamide was obtained as N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]thiophene-3 - sulfonamide (example 262). Any corresponding N-(4-halo-3-methyl-5-isoxazolyl) - N-(4-halo-5-methyl-3-isoxazolyl), N-(3,4-dimethyl-5-isoxazolyl), N-(4-halo-5-methyl-3-isoxazolyl), N-(4-halo-3-methyl-5-isoxazolyl), N-(4,5-dimethyl-3-isoxazolyl) derivatives of any of these compounds or any other connections, disclosed here may also be obtained and used as described herein. Pharmaceutically acceptable derivatives, including salts, especially sodium salts, as expected, suitable for compositions, as described herein.

Example 430

Other compounds that can be obtained by the above methods or routine modifications include, but are not ogranichivayas the d,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimetoksi-6 - acetylphenylalanine)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimetoksi-6 - methoxycarbonylaminophenyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimetoksi-6 - carboxymethylaminomethyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimetoksi-6 - methanesulfonylaminoethyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimetoksi-6- (cyanomethyl)phenylenecarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimetoksi-6-(2 - hydroxyethyl)phenylenecarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-acetylphenylalanine]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-methoxycarbonylaminophenyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-carboxymethylaminomethyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-methanesulfonylaminoethyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-cyanomethylation]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-(2-hydroxyethyl)phenylenecarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2,6 - dimethylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - acetyl-2-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methoxycarbonyl-2-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - carboxyl-2-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methoxy-2-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methanesulfonyl-2-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - cyano-2-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6- (cyanomethyl)-2-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedi the(methylendioxy)-2-cyano - 6-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methoxy-2-cyanobenzeneboronic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - acetyl-6-methylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methoxy-2-acetylphenylalanine]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyano-2,4,6 - trimethylphenylsulfonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxy-2,4,6 - trimethylphenylsulfonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6 - trimethylphenylsulfonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methanesulfonyl-2,4,6 - trimethylphenylsulfonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyanomethyl-2,4,6 - trimethylphenylsulfonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(2-hydroxyethyl)-2,4,6 - trimethylaminoethyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(carboxymethyl)-2,4,6 - trimethylphenylsulfonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-cyano-2,6 - dimethylaminoethyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4 is methyl)-2,6 - dimethylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(2-hydroxyethyl-2,6 - dimethylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(cyanomethyl)-2,6 - dimethylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(carboxymethyl)-2,6 - dimethylphenylcarbinol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methanesulfonyl-2,6 - dimethylaminoethyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimetoksi-6 - methylphenylacetic)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimetoksi-6 - acetylphenylalanine)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimetoksi-6 - methoxycarbonylbenzyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimetoksi-6 - carboxyphenylazo)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimetoksi-6 - methanesulfonylaminoethyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimetoksi-6- (cyanomethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimetoksi-6-(2 - hydroxyethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-methylphenylacetic]thiophene-3-sulamid,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-methoxycarbonylbenzyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-carboxyphenylazo]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy-2 - methoxy-6-methanesulfonyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-(cyano)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-(cyanomethylene]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - methoxy-6-(2-hydroxyethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2,6 - dimethylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - acetyl-2-methylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methoxycarbonyl-2-methylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - carboxyl-2-methylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methoxy-2-methylphenylacetic]thiophene-3-sulfonamide,

/BR>N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - cyano-2-methylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6- (cyanomethyl)-2-methylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2 - hydroxyethyl)-2-methylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - cyano-6-methylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methoxy-2-cyanophenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)-2 - acetyl-6-methylphenylacetic]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6 - methoxy-2-acetylphenylalanine]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyano-2,4,6 - trimethylpentanediol)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxy-2,4,6 - trimethylpentanediol)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6 - trimethylpentanediol)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methanesulfonyl-2,4,6 - trimethylpentanediol)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(cyanomethyl)-2,4,6 - trimethylpentanediol]typename,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(carboxymethyl)-2,4,6 - trimethylpentanediol]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-cyano-2,6 - dimethylphenylacetic)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-carboxyl-2,6 - dimethylphenylacetic)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-hydroxymethyl-2,6 - dimethylphenylacetic)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(2-hydroxyethyl-2,6- (dimethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-cyanomethyl-2,6- (dimethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(carboxymethyl)-2,6 - dimethylphenylacetic]thiophene-3-sulfonamide, and

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methanesulfonyl-2,6 - dimethylphenylacetic)thiophene-3-sulfonamide. Pharmaceutically acceptable derivatives, including salts, especially the sodium salt, can be expected to be used in the compositions.

Example 431

Other compounds with activity mainly at concentrations IC5010 mM or less, with respect to ETAor ETBreceptors, where Ar2contains a heterocyclic ring, such as thienyl-, furyl - and pyrrole-sulfonamides, can be or have been obtained (see who to include, but not limited to only these: N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxyl-1-methylindol-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-oxocyclohexyl)oxycarbonyl]thiophene - 3-sulfonamide, 2-[3,4-(methylendioxy)phenylacetyl] thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-{ 2-[3,4-(methylenedioxy)phenyl] acetyl} thiophene - 3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-phenylbenzo[b] thiophenesulfonyl, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4 - tolyl)aminocarbonyl] -1-methylindol-3-sulfonamide, N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[(4-methoxyphenoxy)carbonyl] thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-1-[3,4-(methylenedioxy)benzyl] indol-2 - sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)carbonyl] thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4 - methoxyphenyl)acetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)- 6-methoxy-2-[3,4-(methylenedioxy)benzyl] benzo[b]thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-[(4-methylphenoxy)methyl] thiophene-2 - sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl] thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl - TRANS-styryl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)- 3-(4-methylphenylethyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)- 2-[(4-methyl is N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ 1-hydroxy-1-[3,4-(methylenedioxy) benzyl] ethyl} thiophene-3-sulfonamide, N-4-(bromo-3-methyl-5-isoxazolyl)-3-(4-methylphenylethyl)(4-tolyl)thiophene - 2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylbenzyl)- 5-(4-tolyl)thiophene-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)- 3-(4-methyl-TRANS-styryl)-5-(4-tolyl)thiophene-2-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[b,b-(Ethylenedioxy)-3,4- (methylendioxy)phenylethyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[b-(dimethylamino)-3,4-(methylendioxy)phenylthio]thiophene-3 - sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ a-hydroxy-[3,4 - methylenedioxy)phenyl] acetyl}thiophene-3-sulfonamide; N-(4-chloro-5-methyl-3 - isoxazolyl)-2-[3,4-(methylenedioxy)benzyl] benzo[b] thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-stilllife-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-sterilite-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(benzoylamino)thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(phenyl)methylaminomethyl] thiophene - 3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-(hydroxymethyl)furan-2 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-(carbomethoxy)furan-2 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2.5-dimethylfuran-3 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(diisopropylaminoethyl) thiophene-3-sulfonamide; N-(4-Uran-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5 - stilllife-2-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)benzyl] -5-(dimethylamino)benzo[b]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-7 - methoxybenzo[b] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[3,4-(methylenedioxy)benzyl] -7-phenoxybenzyl[b]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-5 - methoxybenzo[b]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[3,4-(methylenedioxy)benzyl] -5-isobutylamino[b] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl] -5 - benzylamines[b] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[3,4-(methylendioxy)phenoxy] benzo[b] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)phenoxy] -5 - dimethylaminobenzoyl[b]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[(3,4-methylenedioxy)phenyl] acetyl-5-dimethylaminobenzoyl[b] thiophene-3 - sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy) benzylcarbamoyl] -N-methylindol-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[3,4-(methylendioxy)phenoxycarbonyl] indole-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazol)-2-[3,4-(methylendioxy)phenoxycarbonyl] - N-methylindol-3-sulfonamides)-2-[3,4-(methylenedioxy)benzyl] -N-methylindol-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]indol-3 - sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy) benzyloxycarbonyl] -7-(N, N-dimethylamino)benzo[b] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl] -7-(N, N - dimethylamino)benzo[b] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[3,4-(methylenedioxy)benzoyl] -7-(N,N-dimethyl)amino)benzo[b]thiophene-3 - sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-7-(N,N-dimethylamino) benzo[b]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-7- (methoxycarbonyl)benzo[b]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[3,4-(methylenedioxy)benzyl] -7-(methoxy)benzo[b] thiophene-3 - sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-7-(methoxy)benzo[b] thiophene-3 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methylphenylethyl)thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(TRANS-4-methylcinnamic)thiophene-3 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylphenylethyl)thiophene-2 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-methylphenylethyl)thiophene-2 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-methylphenylethyl)thiophene-2 - sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-(TRANS-4-methylcinnamic) thiophene-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-(TRANS-3 - methylcinnamic)type oxazolyl)-3-[(4-methylphenoxy)methyl] thiophene-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylendioxy)phenylethyl] thiophene-2 - sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ (3,4-(dimethoxy)phenyl] acetyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,5 - acid)acetyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[(3,4,5-trimethoxyphenyl)acetyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[3,4-(methylendioxy)benzylmethyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylendioxy)benzylmorphine] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylendioxy)benzylmorphine] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-{1-(dimethylamino)-2-[3,4-(methylenedioxy)phenyl} ethylthiophen - 3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-methylamino)-2- [3,4-(methylenedioxy)phenyl]ethyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-{1-(methoxyimino)-2-[3,4-(methylenedioxy)phenyl]ethyl)thiophene - 3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ 1-(carboxy)-2- [3,4-(methylenedioxy)phenyl]ethyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-{2-(carboxy)-1-[3,4-(methylenedioxy)benzyl]vinyl}thiophene - 3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ 3-[3,4-(methylenedioxy)phenyl] - 1,2,4-oxadiazol-5-yl}thiophene-3-sulfonamide; and N-(4-chloro-3-methyl-5 - isoxazolyl-2-{3-[hunger but not limited to: N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ [2-(methanesulfonyl)-4,5- (methylenedioxy)phenyl] aminocarbonyl} thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ [3,4-(methylenedioxy)-6 - carboxyphenyl] aminocarbonyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[4,5-(methylenedioxy)-2-(methoxy - carbonyl] phenyl} aminocarbonyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ [2-cyano-4,5-(methylenedioxy)phenyl] aminocarbonyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-{[4,5-(methylenedioxy)-2-hydroxymethyl)phenyl] aminocarbonylmethyl-3 - sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-acetyl-4-were] aminocarbonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-{ [2-(methanesulphonyl)-4-were]aminocarbonyl} thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-carboxy-4-were) aminocarbonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[(2-methoxycarbonyl-4-were)aminocarbonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-cyano-4-were)aminocarbonyl] thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ [2-(hydroxymethyl)- 4-were]aminocarbonyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[(3,4-dimethoxy-6-acetylphenyl)aminocarbonyl] lifeglobe; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[(4,5-dimethoxy-2-carboxylphenyl)aminocarbonyl] thiophene-3 - sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4,5-dimethoxy-2 - methoxycarbonyl)phenyl)aminocarbonyl] thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-cyano-(4,5-acid) aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-(4,5-dimethoxy-2-hydroxymethyl)phenylenecarbonyl-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ [2-acetyl-4,5-(methylenedioxy)phenyl] acetyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2- (methanesulfonyl)-4,5-(methylenedioxy)phenyl] acetyl} thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ [carboxy-4,5-(methylenedioxy)-2 - phenylacetamide-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-{ [4,5-(methylenedioxy)-2-ethoxycarbonylphenyl]acetylthiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ 2-cyano-[4,5-(methylenedioxy)phenyl] acetyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ 2 - hydroxymethyl-[4,5-(methylenedioxy)phenyl] acetyl} thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4-dimethoxy)phenyl)aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2 - were)aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[(2,3-dimetyl - 3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,5 - dimetilfenil)aminocarbonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[(2,6-dimetilfenil)aminocarbonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-dimetilfenil)aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,5 - dimetilfenil)aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-(3,5-dimethyl)phenylenecarbonyl-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-methoxy-6-were)aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4,6 - trimetilfenil)aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5 - isoxazolyl)-2-[(4-methoxy-2-were)aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-ethyl-(4-methoxyphenyl)aminocarbonyl) thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-isopropyl-4-methoxyphenyl) aminocarbonyl] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[(2-propyl-4-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-biphenylmethanol] thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4- (methylenedioxy)-6-were)acetyl] -thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-sulfonamide; N-(4-chloro-3-methyl-5-isone, including salts, especially the sodium salt, as you might expect, can be used in the formulations described herein.

Example 432

N-(2-Acetyl-4,6-dimetilfenil)-3-(((4-chloro-3-methyl-5-isoxazolyl) amino)sulfonyl)-2-thiophencarboxylic

A. 2'-Amino-3',5'-dimethylacetophenone

To a solution of BCl3in dichloromethane (1.0 M, 25 ml) at 0oC was slowly added 2,4-dimethylaniline (3.03 g, 25 mmol) in 1,2-dichloroethane (25 ml). Acetonitrile (25 ml) was then added dropwise at 0oC. the Mixture then was heated at a bath temperature of 100oC for 2 days with a slow and steady stream of nitrogen to remove low-boiling dichloromethane. The reaction mixture was cooled to 0oC, and the reaction was stopped 2N HCl (25 ml) and the mixture was heated at 80oC as long, until it formed a homogeneous solution (20 min). The mixture was left to cool to room temperature, and the two layers were separated. The aqueous layer was padmalochan bicarbonate sodium up until the evolution of gas has not become invisible, and has formed a lot of sediment. Then the mixture was extracted with chloroform (30 ml) and the organic layers were combined and concentrated. The residue was dissolved in ethyl acetate (50 ml) and washed with 1N NaOH (40 ml). Organization. Oily residue was dissolved in ethyl ether (5 ml) and left to stand at room temperature for 24 h, the Resulting yellow precipitate was filtered to obtain 2'-amino-3',5'-dimethylacetophenone (1.3 g, 30%).

B. N-(2-Acetyl-4,6-dimetilfenil)-3-(((4-chloro-3-methyl-5 - isoxazolyl)amino)sulfonyl)-2-thiophencarboxylic

To a solution of 2'-amino-3', 5'-dimethylacetophenone (1.9 g, 11.66 mmol) in dichloromethane (20 ml) at room temperature was added N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2-thiophencarboxylic chloride (example 288) (1 g, 2.86 mmol). The mixture was stirred for 10 h, and during this time has formed a lot of yellow precipitate. Then the reaction mixture was concentrated, and the residue was diluted with ethyl acetate (50 ml) and washed with 1N HCl (50 ml). The organic layer was concentrated, and the residue was dissolved in methanol (30 ml), then added concentrated HCl (15 ml). The mixture was then heated under reflux for 2 h, after which it was cooled to room temperature, diluted with ethyl acetate (200 ml) and washed with water (2 x 200 ml). The organic layer was separated, dried (MgSO4), the solid is filtered, and the filtrate concentrated. Then the residue was purified obremenitve (580 mg, 43%).

Example 433

3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4 - dimethyl-6-propionitrile)-2-thiophencarboxylic

A. 2'-Amino-3',5'-dimethylpropylene

2'-Amino-3', 5'-dimethylpropylene was synthesized as 2'-amino-3', 5'-dimethylacetophenone (example 276), except that instead of acetonitrile used propionitrile.

B. 3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4 - dimethyl-6-propionitrile)-2-thiophencarboxylic

3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4 - dimethyl-6-propionitrile)-2-thiophencarboxylic was synthesized as N-(2-acetyl-4,6-dimetilfenil)-3-(((4-chloro-3-methyl-5 - isoxazolyl)amino)sulfonyl)-2-thiophencarboxylic (example 276), except that 2'-amino-3', 5'-dimethylpropylene was used instead of 2-amino-3', 5'-dimethylacetophenone.

Example 434

3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2 - isobutyryl-4,6-dimetilfenil)-2-thiophencarboxylic

A. 2'-Amino-3',5'-dimethyl-2-methylpropiophenone

2'-Amino-3', 5'-dimethyl-2-methylpropiophenone was synthesized as 2'-amino-3', 5'-dimethylacetophenone (example 276), except that instead of acetonitrile was used isobutyronitrile.

B. 3-(((4--methyl-5-isoxazolyl)amino)sulfonyl)-N-(2 - isobutyryl-4,6-dimetilfenil)-2-thiophencarboxylic was synthesized as N-(2-acetyl-4,6-dimetilfenil)-3-(((4-chloro-3-methyl-5 - isoxazolyl)amino)sulfonyl)-2-thiophencarboxylic (example 276), except 2'-amino-3', 5 a-dimethyl-2-methylpropiophenone was used instead of 2'-amino-3',5'-dimethylacetophenone.

Example 435

3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2- (cyclohexylcarbonyl)-4,6-dimetilfenil)-2-thiophencarboxylic

A. Cyclohexyl 2-amino-3,5-dimethylphenylamine

Cyclohexyl-2-amino-3,5-dimethylacetophenone was synthesized as 2'-amino-3', 5'-dimethylacetophenone (example 276), except that instead of acetonitrile was used cyclohexylethane.

B. 3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2- (cyclohexylcarbonyl)-4,6-dimetilfenil)-2-thiophencarboxylic

3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2- (cyclohexylcarbonyl)-4,6-dimetilfenil)-2-thiophencarboxylic was obtained GAK same as N-(2-acetyl-4,6-dimetilfenil)-3-(((4-chloro-3 - methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophencarboxylic (example 276), except what cyclohexyl 2-amino-3,5-dimethylphenylacetic was used instead of 2'-amino-3',5'-dimethylacetophenone.

Example 436

3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2- (cyclopropanecarbonyl)-4,6-dimetilfenil)-2-thiophencarboxylic

A. Cyclopropyl 2-amino-3,5-dimethylphenylacetic

Cyclopropyl 2-amino-3,5-dimethylpent propellant was used instead of acetonitrile.

B. 3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2- (cyclopropanecarbonyl)-4,6-dimetilfenil)-2-thiophencarboxylic

3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2- (cyclopropanecarbonyl)-4,6-dimetilfenil)-2-thiophencarboxylic was synthesized as N-(2-acetyl-4,6-dimetilfenil)-3-(((4-chloro-3 - methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophencarboxylic (example 276), except that cyclopropyl 2-amino-3,5-dimethylphenylacetic was used instead of 2'-amino-3',5'-dimethylacetophenone.

Example 437

N-(2-Benzoyl-4,6-dimetilfenil)-3-(((4-chloro-3-methyl-5 - isoxazolyl)amino)sulfonyl)-2-thiophencarboxylic

A. 2-Amino-3,5-dimethylphenylacetate

2-Amino-3,5-dimethylphenylacetate was synthesized as 2'-amino-3', 5'-dimethylacetophenone (example 276), except that instead of acetonitrile was used benzonitrile.

B. N-(2-Benzoyl-4,6-dimetilfenil)-3-(((4-chloro-3-methyl-5 - isoxazolyl)amino)sulfonyl)-2-thiophencarboxylic

N-(2-Benzoyl-4,6-dimetilfenil)-3-(((4-chloro-3-methyl-5 - isoxazolyl)amino)sulfonyl)-2-thiophencarboxylic was synthesized as N-(2-acetyl-4,6-dimetilfenil)-3-(((4-chloro-3-methyl-5 - isoxazolyl)amino)sulfonyl)-2-thiophencarboxylic (example 276), with the exception that 2-is 438

N-(2-Acetyl-4,6-dimetilfenil)-3-(((4-chloro-3-methyl-5 - isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophencarboxylic

A. N-(4-Chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-5-methyl-2 - thiencarbazone acid

To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-2 - thiophencarboxylic acid (6 g, 18.60 mmol) in anhydrous tetrahydrofuran (240 ml) at -78oC and under nitrogen atmosphere was added nBuLi (2.5 M in hexane, 30 ml, 74.4 mmol). The mixture was stirred at this temperature for 2 h, then added podbean (6.6 g, 74.4 mmol). The mixture is then poured into crushed ice and left to stand until it reaches room temperature. After acidification with concentrated HCl to pH 1, the mixture was extracted with ethyl acetate (2 x 200 ml). The organic layers were combined, dried (MgSO4), the solid was filtered, and the filtrate was concentrated to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-5-methyl-2-thiophencarboxylic acid and the source material in the ratio of about 2:1 (8.5 g total weight).

B. N-(4-Chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-5-methyl-2 - thiencarbazone acid

To a solution of the product obtained in example 282A (8.5 g) in THF (150 ml) were sequentially added diisopropylethylamine (9.62 g, 74.4 mmol) and methyl bromide met is wyzwania excess methyl bromide methyl ester. The reaction was carried out in the next 30 min, then the mixture was diluted with ethyl acetate (150 ml) and washed 1N HCl (200 ml). The organic layer was dried (MgSO4), the solid was filtered, and the filtrate was concentrated. The residue was subjected to chromatography (mixture of 10% ethyl acetate in hexane) to obtain methoxymethyl N-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-5-methyl-2-thiophenecarboxylate. Carboxylate was then hydrolyzed with 1N NaOH to obtain the corresponding carboxylic acid (3.5 g).

C. N-(4-Chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3 - sulfamoyl-5-methyl-2-thiencarbazone acid chloride

N-(4-Chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-5 - methyl-2-thiophencarboxylic acid chloride was obtained in the same way as N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2 - thiophencarboxylic chloride (example 288), except that N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-5 - methyl-2-thiencarbazone acid was used instead of N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2 - thiophencarboxylic acid.

D. N-(2-Acetyl-4,6-dimetilfenil)-3-(((4-chloro-3-methyl-5 - isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophencarboxylic

N-(2-Acetyl-4,6-dimetilfenil)-3-(((4-chloro-3-methyphenyl)-3-(((4-chloro-3 - methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophencarboxylic (example 276), with the exception that N-(4-chloro-3-methyl-5-isoxazolyl)-N - methoxymethyl-3-sulfamoyl-5-methyl-2-thiophencarboxylic acid chloride was used instead of N-(4-chloro-3-methyl-5-isoxazolyl)-N - methoxymethyl-3-sulfamoyl-2-thiophencarboxylic acid chloride.

Example 439

3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2 - hydroxyethoxymethyl)-4,6-dimetilfenil)-2-thiophencarboxylic

To a solution of N-(2-acetyl-4,6-dimetilfenil)-3-(((4-chloro-3-methyl-5 - isoxazolyl)amino)sulfonyl)-2-thiophenecarboxylate (example 276) (50 mg, 0.11 m mol) in 2N NaOH (40 ml) and methanol (4 ml) was added hydroxylamine hydrochloride (4 g, 57.6 mmol). The mixture was heated at 60oC for 3 h, then was cooled to 0oC and acidified with concentrated HCl to pH 1-2. The resulting white precipitate was filtered, washed with diluted acid and dried by lyophilization to obtain 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2 - hydroxyethoxymethyl)-4,6-dimetilfenil)-2-thiophenecarboxylate (45 mg, 87%).

Example 440

3-(((3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2 - thienyl)carbonyl)amino)-2,4,6-trimethylpentyl carbonate

To a solution of N2-(4-chloro-3-methyl-5-isoxazolyl)-N-(3 - hydroxy-2,4,6-trimetilfenil)-3-sulfamoyl-2-thiophenecarboxylate (note the masiania mixture for 30 min at this temperature, added methylchloroform (99.2 mg, 1.05 mmol). The reaction mixture is poured into acid, diluted with ice and the resulting precipitate was collected and purified HPLC with obtaining 3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino) sulfonyl)-2-thienyl)carbonyl)amino)-2,4,6-trimethylsilylmethylamine (186 mg, 70%).

Example 441

3-(((3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2 - thienyl)carbonyl)amino)-2,4,6-trimethylaniline

To a solution of N2-(4-chloro-3-methyl-5-isoxazolyl)-N-(3 - hydroxy-2,4,6-trimetilfenil)-3-sulfamoyl-2-thiophenecarboxylate (example 289) (500 mg, 1.05 mmol) in anhydrous DMF at 0oC was added tert-piperonyl potassium (295 mg, 2.61 mmol). After stirring the mixture for 10 min at this temperature was added p-nitrophenylacetate (317 mg, 1.57 mmol). After about 1 min of stirring the mixture was treated with ammonium hydroxide (8 ml), and stirring was continued at room temperature for 2 hours, the Reaction mixture was poured into acid, diluted with ice and the resulting precipitate was collected and purified HPLC with obtaining 3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2 - thienyl)carbonyl)amino)-2,4,6-trimethylenediamine (213 mg, 42%).

Example 442

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6 - trimethylphenol N-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-2 - thiophenecarboxylate (5 g, 15.6 mmol) in POCl3(50 ml) was heated at 60oC for 3 hours the Reaction mixture was cooled to room temperature and poured into crushed ice (250 g). The mixture was shaken, stirred until then, until melted all the ice (2 hours). The mixture is extracted with ethyl acetate, and the organic layer was dried (MgSO4). The solid was filtered, and the filtrate was concentrated and dried under vacuum to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-2 - thiophenecarbonitrile (4.8 g, 100%).

B. 3-Methoxy-2,4,6-trimethylbenzoic 3-Methoxy-2,4,6-trimethylbenzaldehyde was synthesized as 5-chloromethyl-6-methylbenzo[d][1,3]dioxole (example 245), with the exception that 1-methoxy-2,4,6-trimethylbenzoyl was used instead of 5-methylbenzo[d][1,3]dioxole.

C. N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6 - trimetilfenil)acetyl)-3-thiophenesulfonyl

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6 - trimetilfenil)acetyl)-3-thiophenesulfonyl was synthesized in the same way as 4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d] [1,3] xol-5-yl)acetyl)-3 - thienylboronic)isoxazol (example 245), except N-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-2-thiophenecarbonitrile (example 286A) was used instead of N2-metoxy-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6 - trimetilfenil)acetyl)-3-thiophenesulfonyl

To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy - 2,4,6-trimetilfenil)acetyl)-3-thiophenesulfonyl (example 286) (50 mg, 0.107 mmol) in dichloromethane (20 ml) at 0oC was added BBr3(1 M in dichloromethane, 3 ml, 3.0 mmol). The resulting mixture was stirred at 0oC for 1 h and at room temperature for 8 h, then it was poured into crushed ice (100 g). Water the mixture is stirred until until all the ice is melted and was extracted with dichloromethane (2 x 100 ml). The organic layers were combined and concentrated, and the residue was purified HPLC to obtain N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy - 2,4,6-trimetilfenil)acetyl)-3-thiophenesulfonyl (47 mg, 85%).

Example 444

N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2 - thiophenecarboxylate

A. 5-Amino-4-chloro-3-methylisoxazol

To a solution of 5-amino-3-methylisoxazole (9.8 g, 100 mmol) in methylene chloride (200 ml) was added N-chlorosuccinimide (14.7 g, 110 mmol) at 0oC for 20 minutes the Reaction mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated and divided between 1N NaOH (150 ml) and ethyl acetate (400 ml). The organic layer was washed with 1N NaOH, water, brine, dried over MgSO4then scancenter recrystallized from a mixture of ethyl acetate/hexane to obtain 5-amino-4-chloro-3-methylisoxazole in the form of a brownish solid (55 g, 41%).

B. 2-Carbomethoxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)]thiophenesulfonyl

To a dispersion of 60% suspension in mineral oil NaH (8.5 g, 0.21 mol) in THF (100 ml) at -20oC was added a solution of 5-amino-4-chloro-3-methylisoxazole (12.4 g, 92.4 mmol) in anhydrous THF (65 ml) in nitrogen atmosphere for 20 min After 10 min stirring was added a solution of 2-carbomethoxy-3-thiophenesulfonyl (22.2 g, 92.4 mmol) in THF (65 ml) at -20oC for 15 minutes the Reaction mixture was stirred for 10 min, then the reaction was repaid by H2O (5 ml) at the same temperature. The reaction mixture was poured into 4N HCl, and the product was extracted with ethyl acetate. The combined organic portion was washed with water, and then the connection was extracted polysystem solution of NaHCO3. Combined basic solutions were decolorized using activated charcoal, cooled to 0oC and acidified with 4N HCl. The product was isolated by filtration, washed with water, dried to obtain 2-carbomethoxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)] thiophenesulfonyl in the form of a white powder (23.4 g, 75%).

C. 2-Carbomethoxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)-N - methoxymethyl] thiophenesulfonyl

To a solution of 2-carbomethoxy-3-[N-(4-chloro-3-methylisoxazol-5 - yl) - Rev. eat added bromatology ether (1.5 g, 12.0 mmol). The reaction mixture was stirred over night at room temperature. The reaction mixture was concentrated and divided between water and ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4concentrated to obtain 2-carbomethoxy-3-[N-(4-chloro-3 - methylisoxazol-5-yl)-N-methoxymethyl] thiophenesulfonyl in the form of a greenish oil (3.5 g, 90%).

D. 2-carboxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)-N - methoxymethyl]thiophenesulfonyl

2 Carbomethoxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)-N - methoxymethyl]thiophenesulfonyl (3.0 g, 7.8 mmol) in a mixture of THF (30 ml) and 1N NaOH (30 ml) was stirred for 3 hours at room temperature. The reaction mixture was diluted with water (20 ml) and was extracted with ethyl acetate (5 ml). The aqueous solution was acidified with 1N HCl, then was extracted with ethyl acetate. The organic portion was washed with water, brine, dried over MgSO4and concentrated to obtain 2-carboxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)-N - methoxymethyl]thiophenesulfonyl in the form of an oil (quantitative yield).

E. N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl - 2-thiophencarboxylic chloride

To a solution of 2-carboxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)-N - methoxymethyl] thiophenesulfonyl (is the target of oxalicacid (4.5 ml, 9.0 mmol). The reaction mixture was stirred over night at room temperature. Then the reaction mixture was concentrated under reduced pressure to remove all volatile substances. The desired product was obtained in the form of oil, which hardened on standing.

Example 445

N2-(4-Chloro-3-methyl-5-isoxazolyl)-N-(3-hydroxy-2,4,6 - trimetilfenil)-3-sulfamoyl-2-thiophencarboxylic

A. 3-Acetoxy-2,4,6-trimethylaniline

To a solution of 2,4,6-trimethylphenol (10 g, 73.5 mmol) and triethylamine (11.1 g, 110.3 mmol) in ethyl acetate (200 ml) was added acetylchloride (7.5 g, 95.6 mmol) dropwise at 0oC. the Mixture was stirred over night. The reaction is extinguished by water, and the organic layer was washed with 1N HCl. The organic layers were dried and concentrated as usual. The residue was subjected to nitration 70% HNO3and conc. H2SO4. The brown reaction mixture was stirred for 1 h, poured into ice-cold water. The product was extracted into ethyl acetate, the extract was washed with water, dried over MgSO4and concentrated to obtain the desired nitro compounds. This compound was recovered in the methanol sequential addition of ammonium chloride and zinc powder. Exothermic reaction of smea filtered and the solid residue was washed with methanol. The methanol solutions were concentrated, and the residue is divided between ethyl acetate and 1N NaOH. The organic layer was dried over MgSO4and concentrated to obtain 3-acetoxy - 2,4,6-trimethylaniline.

B. N2-(4-Chloro-3-methyl-5-isoxazolyl)-N-(3-hydroxy-2,4,6 - trimetilfenil)-3-sulfamoyl-2-thiophencarboxylic

N2-(4-Chloro-3-methyl-5-isoxazolyl)-N-(3-hydroxy-2,4,6 - trimetilfenil)-3-sulfamoyl-2-thiophencarboxylic was synthesized by the reaction of the above amine (example 289A) with the product from example 288 in THF at 0oC. the Reaction mixture was left to warm to room temperature and was stirred for 2 hours, the Reaction mixture was poured in 0.05 N HCl, and the product was extracted with ethyl acetate. The organic portion was washed with 0.05 N HCl, water, polysystem solution of NaHCO3, water, brine, dried over MgSO4and concentrated. Purification of column chromatography (silicon dioxide, a mixture of 40% ethyl acetate/hexane) resulted in the N2-(4-chloro-3-methyl-5-isoxazolyl)-N-(3-hydroxy-2,4,6 - trimetilfenil)-N-methoxymethyl-3-sulfamoyl-2-thiophencarboxylic. The solution of the carboxamide in THF and conc. HCl was stirred at 65-72oC for 3.5 hours the Reaction mixture was cooled and poured into water. P brine, dried over MgSO4and concentrated in the form of oil. Acetoxy group was hydrolyzed to the corresponding hydroxyl during unprotect the PTO group. N2-(4-chloro-3-methyl-5-isoxazolyl)- N-(3-hydroxy-2,4,6-trimetilfenil)-3-sulfamoyl-2-thiophencarboxylic was obtained as a solid (so pl. 75-78oC, yield 54%).

Data for additional sulfonamides

Below is the data for the compounds obtained in the above examples, and the data of in vitro tests, which demonstrate activity as antagonists of endothelin. As can be seen from these data that all compounds have utility.

Table 13 shows the data of the IC50obtained by testing in vitro inhibition of attachment of peptides endothelin to endothelin-A (ETA) and endothelin-B (ETB) receptors (see, for example, example 158 description of the application). Note that data marked "a" were obtained by keeping the 24oC and unlabeled data were obtained at 4oC. Curing at higher temperatures leads to about 2-10-fold decrease in the measured activity.

1. The sulfonamides of the formula I

< / BR>
or

< / BR>
where Ar2selected benzofuranyl, dibenzopyrenes, dibenzothiophenes, thiazolyl;

R1and R2represent (i), (ii) or (iii) as follows:

(i) R1and R2each independently selected from the group consisting of H, NH2, NO2, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, aminocarbonyl, haloalkyl, halodrol, alkoxycarbonyl, alkylsulphonyl, arylcarbamoyl, formyl, amido-, raidgroup, in which alkyl, alkeline and alkyline parts have a linear or branched chain containing from 1 to 10 or so values carbon atoms, and the aryl portion contains from 4 or so values up to 14 or so values of carbon atoms, except that when R2is not halogen, pseudohalogen or higher alkyl, or

(ii) R1and R2together form -(CH2)nwhere n = 3 to 6, or

(iii) R1and R2together form 1,3-butadienyl.

2. Connection on p. 1, having the formula X

< / BR>
or

< / BR>
where each of the radicals R8, R9, R10contains hydrogen and is preferably 20 or less, and each of these radicals independently selected from (i) or (ii) as follows:

(i) the radicals R8, R9and R10contain up to 20 carbon atoms, and each of them is independently selected from the group consisting of hydrogen, halogen, pseudohalide, alkyl, alkoxy, alkenyl, quinil, aryl, aryloxy, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, OH, CN, C(O)R18, CO2R18, SH, S(O)nR18where n = 0 to 2, HNOH, NR18R19, NO2N3, OR18, R19NCOR18and CONR19R18where R19selected from the group consisting of hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, C(O)R20, S(O)nR20where n = 0 to 2, R18and R20independently selected from the group consisting of hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aryloxy, cycloalkyl, cycloalkenyl, cycloalkenyl or ureido; any of the groups defined for R8, R9and R10is unsubstituted or substituted with any substituents set forth for Z, which represents halogen, pseudohalide, alkyl, alkoxy, alkenyl, quinil, aryl, who>1, SH, S(O)nR21where n = 0 to 2, NHOH, NR22R21, NO2N3, OR21, R22NCOR21and CONR22R21while R22selected from the group consisting of hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, C(O)R23and S(O)nR23where n = 0 to 2; R21and R23independently selected from the group consisting of hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl or cycloalkenyl, or

(ii) any two of the radicals R8, R9and R10form an aryl, aromatic cycle, heteroaromatic cycle, alicyclic or heterocyclic ring that is saturated or unsaturated, containing from about 3 or this value to 16 or around that level members, mainly from 3 to 10 or so values of the members, more predominantly from 5 to 7 members, which are unsubstituted or substituted by one or more substituents, each Deputy independently selected from Z, while the third of the radicals R8, R9and R10selected, as defined in (i), and

X represents O, S, N or NR11where R11allerod, and selected from the group consisting of hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, C(O)R15and S(O)nR15where n = 0 to 2; R15represents hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl; R11and R15are unsubstituted or substituted by one or more substituents, each independently selected from Z, which represents halogen, pseudohalide, alkyl, alkoxy, alkenyl, quinil, aryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, OH, CN, C(O)R16, CO2R16, SH, S(O)nR16where n = 0 to 2, NHOH, NR12R16, NO2N3, OR16, R12NCOR16and CONR12R16; R16represents hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl or cycloalkenyl; R12, which is independently selected from R11and Z is selected from hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, C(O)R17S(O)nR17where n = 0 to 2, R17preschooler or cycloalkenyl, each of R11, R12, R15and R16may be optionally substituted by any of the groups defined for z

3. Connection on p. 2, having the formula XI

< / BR>
< / BR>
< / BR>
< / BR>
4. Connection PP. 1 to 3, in which R1selected from the group consisting of alkyl, lower alkenyl, lower quinil, lower alkyl halide, halogen, pseudohalogen and H, with R2selected from the group consisting of lower alkyl, lower alkenyl, lower quinil, lower alkyl halide and h

5. Connection PP.1 to 4, in which Ar2is thiophenyl.

6. Connection PP.1 to 4, in which Ar2represents a furyl.

7. Connection PP.1 to 4, in which Ar2represents pyrrolyl.

8. Connection PP. 1 to 7, in which R1represents H, lower alkyl, halogen or pseudohalogen, and R2represents lower alkyl, lower alkenyl, lower quinil, lower alkyl halide or hydrogen.

9. Compounds according to any one of paragraphs.2 to 8, in which at least one of the radicals R8, R9and R10optionally substituted by one or more substituents selected from Z, which is selected from the group consisting of hydrogen, halogen, pseudohalogen, caller ID, CN, C(O)R16, CO2R16, SH, S(O)nR16where n = 0 to 2, NHOH, NR12R16, NO2N3, OR16, R12NCOR16and CONR12R16; R16selected from the group consisting of hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl and cycloalkyl; R12selected from the group consisting of hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, C(O)R17and S(O)nR17where n = 0 to 2; and R17selected from the group comprising hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl or cycloalkenyl.

10. Compounds according to any one of paragraphs.1 to 9, in which R11represents aryl.

11. Compounds according to any one of paragraphs.2 to 10, in which at least two of the radicals R8, R9and R10represent hydrogen, halogen or lower alkyl, and the third is selected from the group consisting of hydrogen, halogen, pseudohalide, alkyl, alkoxy, alkenyl, quinil, aryl, aryloxy, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, OH, CN, C(O)R18, CO2R18, SH, S(O)nR18where n = 0 to 2, NHOH, N by p. 11, in which R19represents hydrogen or lower alkyl; and R18represents a lower aryl.

13. Connection on p. 11 or 12, in which R18represents phenyl.

14. Connection PP.2 to 13, in which at least two of the radicals R8, R9and R10represent hydrogen, halogen or lower alkyl, and the third is selected from the group consisting of C(O)R18, CO2R18, NR18R19, R19NCOR18or CONR19R18.

15. Compounds according to any one of paragraphs.1 through 14, in which R1represents Br or Cl or alkyl, and R2represents lower alkyl, lower alkyl halide or hydrogen.

16. Compounds according to any one of paragraphs.1 - 15, in which all alkyl, alkeline, alkyline substituents contain from 1 to 12 carbon atoms, and aryl and heterocyclic substituents other than Ar2contain from 3 to 6 carbon atoms in the ring.

17. Compounds according to any one of paragraphs.1 - 16, representing thiophene-2-sulfonamide or thiophene-3-sulfonamide.

18. Connection on p. 1, selected from the group consisting of

N-(4-bromo-3-methyl-5-isoxazolyl)-[N-(4-were)aminocarbonyl] thiophene-3-sulfonamide;

N-(4-bromo-3-meth is bonyl]thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-phenylenecarbonyl)thiophene-3-sulfonamide;

N-(4-bromo-5-methyl-3-isoxazolyl)-2-(N-phenylenecarbonyl)thiophene-3-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-2-(N-phenylenecarbonyl)thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2.5-dimethylthiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide;

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-diphenyl)aminocarbonyl] thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(2-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-benzylaminocarbonyl)thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-ethylphenyl)aminocarbonyl]thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenylthiophene-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenylthiophene-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenoxathiin-2-sulfone is oxazolyl)-2-[N-(4-isopropylphenyl)aminocarbonyl] thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-tertbutylphenyl)aminocarbonyl] thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-butylphenyl)aminocarbonylmethyl-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-terbutaline)aminocarbonyl] thiophene-3-sulfonamide;

3-phenethyl-N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide;

4-phenethyl-N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-2-sulfonamide; and

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-thienyl)thiophene-2-sulfonamide.

19. Connection on p. 1, selected from the group consisting of

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzazolyl)thiophene-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-1-(4'-isopropylphenyl)pyrrol-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-1-(4'-isopropylphenyl)pyrrole-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-{3-[1-methyl-5-(trifluoromethyl)pyrazolyl]}thiophene-5-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-diphenyl)aminocarbonyl] thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-ethylphenyl)AMI the ω-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl)thiophene-2-sulfonamide.

20. Connection on p. 1, selected from the group consisting of

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(phenylenecarbonyl)thiophene-3-sulfonamide;

N-(4-chloro-3-methyl-5-isoxazolyl)-5-benzylthio-2-sulfonamide;

N-(4-chloro-3-methyl-5-isoxazolyl)-3-benzylthio-2-sulfonamide;

N-(4-chloro-3-methyl-5-isoxazolyl)-3-penetrtion-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-3-stilllife-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-sterilite-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-phenoxathiin-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(benzazolyl)thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-phenylthiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-aminothiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(benzoylamine)thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-3-benzylthio-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-3-penetrtion-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-5-benzylthio-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(N-phenyl)methylaminomethyl] thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-5-benzylphenol-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2.5-dimethylfuran-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-isopropylphenyl)thiophene-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-propylphenyl)thiophene-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-3-(phenylenecarbonyl)thiophene-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-benzylthio-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-phenylthiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(dimethylaminoethyl)thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(diisopropylaminoethyl)thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(diethylaminoethyl)thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-isobutylphenyl)furan-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-5-stillborn-2-sulfonamide; and N-(4-bromo-3-methyl-5-isoxazolyl)-5-stilllife-2-sulfonamide.

21. Connection on p. 1, selected from the group:

N-(4-bromo-3-methyl-5-isoxazolyl)-2-thiophenesulfonyl;

N-(4-bromo-3-methyl-5-isoxazolyl)-2.5-dimethylthiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-phenylenecarbonyl)thiophene-3-sulfonamide;

N-(4-bromo-5-methyl-3-ionyl)thiophene-3-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-2-(N-phenylenecarbonyl)thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-methoxyphenyl)aminocarbonyl] thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl] thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(2-methoxyphenyl)aminocarbonyl] thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-N-(benzylaminocarbonyl] thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-ethylphenyl)aminocarbonyl] thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-diphenyl)aminocarbonyl] thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenylthiophene-2-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-were)aminocarbonyl] thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-isopropylphenyl)aminocarbonyl] thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-tertbutylphenyl)aminocarbonyl]thiophene-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-n-butylphenyl)aminocarbonyl] thiophene-3-sulfonamide, and

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-terbutaline)aminocarbonyl] thiophene-3-sulfonamide.

22. Connection on p. 1, representing N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4 the rum-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl)thiophene-2-sulfonamide.

24. Connection on p. 1, representing N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-ethylphenyl)aminocarbonyl]thiophene-3-sulfonamide.

25. Connection on p. 1, representing N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide.

26. Connection on p. 1, representing N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide.

27. Connection on p. 1, representing N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide.

28. Connection on p. 1, representing N-(3,4-dimethyl-5-isoxazolyl)-2-(N-phenylenecarbonyl)thiophene-3-sulfonamide.

29. Connection on p. 1, representing N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-phenylenecarbonyl)thiophene-3-sulfonamide.

30. Connection on p. 1, representing N-(4-bromo-3-methyl-5-isoxazolyl)-2-thiophenesulfonyl.

31. Connection on p. 1, representing N-(4-bromo-3-methyl-5-isoxazolyl)-2.5-dimethylthiophene-3-sulfonamide.

32. Connection on p. 1, representing N-(4-bromo-3-methyl-5-isoxazolyl)-[N-(4-were)aminocarbonyl]thiophene-3-sulfonamide.

33. Connection on p. 1, representing N-(4-chloro-3-METI the battle of N-(4-chloro-3-methyl-5-isoxazolyl)-2-[N-(4-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide.

35. Connection on p. 1, where Ar2selected from the group consisting of benzofuran, thenafter, indolyl, dibenzofurans, dibenzopyrene, dibenzothiophenes, thiazolyl.

36. Connection on p. 1 or 35, in which R1selected from the group consisting of alkyl, lower alkenyl, lower quinil, lower haloalkyl, halogen, pseudohalogen and H, and R2selected from the group consisting of lower alkyl, lower alkenyl, lower quinil, lower haloalkyl and h

37. Compounds according to any one of paragraphs.1, 35 or 36, where R1represents halogen, alkyl or haloalkyl, and R2represents lower alkyl, lower haloalkyl or hydrogen.

38. Connection on p. 35, representing

N-(4-bromo-3-methyl-5-isoxazolyl)dibenzofuran-4-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)dibenzofuran-2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)dibenzofuran-3-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)dibenzofuran-3-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)dibenzothiophen-4-sulfonamide; or

N-(4-bromo-3-methyl-5-isoxazolyl)dibenzothiophen-4-sulfonamide.

39. Connection on p. 35, selected from the group consisting of

5-acetamido-4-methyl-N-(3,4-dimethyl-5-isoxazolyl)thiazole-2-sulfonamide;

5-acetamido-4BR>
N-(4-bromo-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide;

N-(4-chloro-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-4-benzofuranol;

N-(3,4-dimethyl-5-isoxazolyl)benzo-2,1,3-thiadiazole-4-sulfonamide;

5-chloro-1,3-dimethyl-N-(4-chloro-3-methyl-5-isoxazolyl)pyrazole-4-sulfonamide;

5-chloro-1,3-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)pyrazole-4-sulfonamide;

N-(4-bromo-3-methyl-5-isoxazolyl)benzo-2,1,3-thiadiazole-4-sulfonamide; or

3,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)isoxazol-4-sulfonamide;

40. Connection on p. 35, selected from the group consisting of

N-(4-bromo-3-methyl-5-isoxazolyl)benzo-2,1,3-thiadiazole-4-sulfonamide;

N-(4-bromo-5-methyl-3-isoxazolyl)benzo-2,1,3-thiadiazole-4-sulfonamide;

N-(4-chloro-3-methyl-5-isoxazolyl)benzo-2,1,3-thiadiazole-4-sulfonamide; N-(4-chloro-5-methyl-3-isoxazolyl)benzo-2,1,3-thiadiazole-4-sulfonamide.

41. The sulfonamides of the formula I

< / BR>
or

< / BR>
where R1and R2represent (i), (ii) or (iii) as follows:

(i) R1and R2independently selected from the group consisting of H, NH2, NO2, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, hydroxyalkyl, alkoxyalkyl, arylsulfonyl, haloalkyl, halodrol, alkoxycarbonyl, alkylsulphonyl, aminocarbonyl, arylcarbamoyl, formyl, substituted or unsubstituted of aminogroup, substituted or unsubstituted of raidgroup, where alkyl, alkeline and alkyline parts contain from 1 to 14, or about the value of carbon atoms and are linear or branched chains or are cyclic, and the aryl portion contains from 4 or so values up to 16 or so values of carbon atoms, provided that R2does not represent halogen or pseudohalogen, or

(ii) R1and R2together form -(CH2)nwhere n = 3 to 6, or

(iii) R1and R2together form 1,3-butadienyl, and Ar2represents a group having the formula

< / BR>
where n = 0 to 6, mainly 0 to 3, more mainly 0 - 1, except when Ar2does not represent phenyl, 2-diphenyl or naphthyl, if the connection is not a N-isoxazolidinone, substituted in position 4 isoxazoline group halogen or higher alkyl, mainly C9H19- C13H27;

R3, R4, R5, R6and R7selected from (i), (ii), (iii) or (iv) provided that: (a) when Ar and R7does not represent hydrogen, (b) when Ar1is a 4-halo-5-methyl-3-isoxazolyl, R3is not NH2or CH3and (c) when Ar2represents phenyl, naphthyl or 2-diphenyl, R1is a halide or higher alkyl:

(i) R3, R4, R5, R6and R7each independently selected from the group consisting of H, NHOH, NH2N3, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, halodrol, alkoxycarbonyl, alkylsulphonyl, arylcarbamoyl, formyl, substituted or unsubstituted of raidgroup, where alkyl, Alchemilla, Alchemilla parts have a linear or branched chain containing from 1 to 10 or so values of atoms of carbon, mainly from 1 to 5 or 6 carbon atoms, and the aryl portion contains from 3 to 10 or so values of carbon atoms, predominantly 6 carbon atoms, or an alternative,

(ii) R4and R7together represent a substituted or unsubstituted 1,3-butadienyl, 4-dimethylamino-1,3-butadiene, 1-chloro-1,3-butadiene, 1-Aza-1,3-butadiene, or alternative,

(iii) R7and R3together represent a substituted or unsubstituted 1,3-butadienyl, 4-dimethylamino-1,3-butadiene, 1-chloro-1,3-butadiene, 1-Aza-1,3-butadienyl or 2-Aza-1,3-butadienyl group, and R4, R5and R6are as defined in (i) above, or

(iv) R3, R5and R7represent H, R4and R6each independently selected from the group consisting of alkyl, alkoxy, halogen, aminoalkyl, dialkylaminoalkyl, where alkyl and alkoxygroup contain 1 to 10, preferably 1 to 6 carbon atoms and are linear or branched chains.

42. Connection on p. 41, having the formula II

< / BR>
or

< / BR>
moreover, the connection represents a naphthyl-, phenyl - or diphenylsulfone,

R2selected from the group consisting of H, NH2, NO2, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, aminocarbonyl, haloalkyl, halodrol, alkoxycarbonyl, alkylsulphonyl, arylcarbamoyl, formyl, substituted or unsubstituted of aminogroup, substituted or nezamedin which contains from 1 to 10 or so values carbon atoms, and the aryl portion contains from 4 or so values up to 14 or so values of carbon atoms, and

R1represents halogen, haloalkyl or alkyl, where alkyl contains from 1 to 14, or about the value of carbon atoms.

43. Connection on p. 41 or 42, where R2represents H, CH3, CF3C2H5; R1represents Cl, Br or CH3; n = 0 or 1, R3, R4, R5, R6, R7selected from (i), (ii), (iii) or (iv) as follows:

(i) R5and R6represent H; R4and R7each independently selected from H, halogen, NH2, CF3, Ph, CH3; R3selected from the group consisting of H, NHOH, NH2, EtNH2, (CH3)2NH, Ph-CH2NH, F, Cl, Br, I, CN, CH3, (CH3)3C, C5H11CH3O, n-C4H9O, CH2=CH, Ph-CH=CH, CHC, Ph-CC, Ph, 3-(ethoxycarbonylmethyl)ureido, and 3 cyclohexylurea, or

(ii) R4and R7together form 1,3-butadienyl, 4-chloro-1,3-butadienyl, 4-dimethylamino-1,3-butadienyl or 1-Aza-1,3-butadienyl, R3, R5and R6are as defined in (i) this option, perform, or

(iii) R7and R3together form 1,3-butadienyl, 3 the AK dened in (i) this option, perform, or

(iv) R3, R5and R7represent H as defined in (i), and R4and R6each independently selected from the group consisting of alkyl, alkoxy, halogen, aminoalkyl, acylaminoalkyl or dialkylaminoalkyl, where alkyl and alkoxygroup contain from 1 to 10, mostly from 1 to 6 carbon atoms and are linear or branched chains.

44. Connection PP.41 - 43, which represent a substituted or unsubstituted phenyl - or naphthylamide, and R1represents Br, Cl or I, with R2represents H, CH3C2H5, CF3C2F5the h3H7, cyclo-C3H5and C4H8and R3, R4, R5, R6and R7represent (i), (ii), (iii), (iv) or (v):

(i) R5, R6and R7represent H; n = 0, and R3selected from the group consisting of H, NH2CH3, CF3, halogen, C2H5NH or Ph, R4represents H, CF3, NH2, R7represents H or CF3and R5and R6represent H, or

(ii) R3, R5and R6represent H; n = 0, and R4and R7together form 1,3-butadienyl, 4-dimethylamino-1,3-butad is H; n = 0, and R7and R3together form 1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadiene, 1-Aza-1,3-butadienyl, or

(iv) R4represents H or NH2, R5and R6represent H; n = 1, and R3represents H, NH2and halogen; CH3, Br, Cl, F, CF3, NH2, R7represents H, CH3, Br, Cl, F, NH2or CF3while R5and R6represent H, or

(v) R3, R5and R7represent H as defined in (i); R4and R6each independently selected from alkyl groups containing 1 to 6 carbon atoms and having a linear or branched chain, lower alkoxygroup and halides.

45. Compounds according to any one of paragraphs.41 - 44, representing N-(4-(halogen)-substituted N-isoxazolecarboxylic or 4-(higher alkyl)substituted N-isoxazolidinone, where the alkyl groups contain 8 to 15, mainly 9 to 13 carbon atoms; R2represents H, CH3C2H5C2F5or CF3while R3, R4, R5, R6and R7represent (i) or (ii) as follows:

(i) R4, R5, R6and R7each independently selected from GRU2C2H5NH2, (CH3)2NH, Ph-CH2NH, F, Cl, Br, I, CN, CH3, (CH3)3C, C5H11CH3O, n-C4H9O, CH2=CH, Ph-CH=CH, CHC, Ph-CC, Ph, 3-(ethoxycarbonylmethyl)ureido, and 3 cyclohexylurea, or

(ii) R3, R5and R7are H, and R4and R6each represents an alkyl group containing from 1 to 3 carbon atoms having a linear or branched chain.

46. Compounds according to any one of paragraphs.41 - 44, where R1represents Br or Cl; R2represents CH3C2H5or CF3and R3, R4, R6and R7represent (i) or (ii) as follows:

(i) R3represents H, NH2CH3, CF3, halogen or C2H5NH; R4, R5and R6independently selected from the group consisting of H, CF3, halogen, especially Br, and Cl, and NH2and R7represents H, CH3CH2CH5, (CH3)CH, F, or CF3; or

(ii) R3, R5, R7, R4, R6each represent methyl or ethyl.

47. Connection on p. 41, where Ar2represents phenyl or diphenyl, and n = 0, having formula III

< / BR>
about (a) when a connection is vinylsulfonate, at least one of the radicals R3, R4, R5, R6and R7does not represent hydrogen, (b) when the compound is a N-(3-isoxazolyl)vinylsulfonate, R3is not NH2or CH3and (c) when a connection is a naphthyl-, 2-diphenyl-, or phenylsulfonyl, R1is a halide or higher alkyl:

(i) R3, R4, R5, R6and R7each independently selected from the group consisting of H, NHOH, NH2N3, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, halodrol, alkoxycarbonyl, alkylsulphonyl, arylcarbamoyl, formyl, substituted or unsubstituted of raidgroup, where alkyl, alkeline, alkyline parts have a linear or branched chain with from about 1 to about 10 carbon atoms, preferably with from 1 or about this value to around 5 or 6 carbon atoms, and the aryl portion contains from 3 to 10 or so values of carbon atoms, predominantly 6 carbon atoms, each independently selected as described above, or, Alta is separately selected from the group containing alkyl, alkoxy, halogen, aminoalkyl, diaminoalkyl, which are unsubstituted or substituted alkyl groups, and the alkyl and alkoxygroup contain from 1 to 10, mostly from 1 to 6 carbon atoms and are linear or branched chains.

48. Connection on p. 47, in which Ar2represents an unsubstituted or substituted diphenylene group of the formula VI

< / BR>
where each cycle contains one or more substituents, each of which is independently selected from R26and R13and:

(ii) R26and R13independently selected from the group consisting of H, OH, OHNH, NH2, NO2, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, halodrol, alkoxycarbonyl, carbonyl, alkylaryl, aminocarbonyl, arylcarbamoyl, formyl, substituted or unsubstituted of aminogroup, substituted or unsubstituted of raidgroup, where alkyl, alkeline and alkyline parts contain from 1 to 14 carbon atoms, predominantly from 1 to 6 atoms, and have a linear or rasvet is that value carbon atoms, mostly from 4 to 10 carbon atoms, or

(ii) R26and R13together represent-CH2-, -CH=CH-, O, S, NR11where R11represents hydrogen or contains up to 30 carbon atoms, and selected from the group consisting of hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, C(O)R15and S(O)nR15where n = 0 to 2; R15represents hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl; R11and R15is unsubstituted or substituted by one or more substituents, each independently selected from Z, which represents halogen, cyanide, cyanate, thiocyanate, selenocyanate, azide, alkyl, alkoxy, alkenyl, quinil, aryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, OH, CN, C(O)R16, CO2R16, SH, S(O)nR16in which n = 0 - 2, NHOH, NR12R16, NO2N3, OR16, R12NCOR16and CONR12R16; R16represents hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl or cycloalkenyl; R12that n is, a heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, C(O)R17and S(O)nR17where n = 0 to 2; R17represents hydrogen, alkyl, alkenyl, quinil, aryl, alkylaryl, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl or cycloalkenyl, and each of the radicals R11, R12, R15and R16can be further substituted by any of the groups defined for Z, and R11is a mainly H or alkyl, especially lower alkyl.

49. Connection on p. 48 of the formula VII

< / BR>
or

< / BR>
where R26and R13selected from the group consisting of H, lower alkyl, haloalkyl and halogen.

50. Connection on p. 49, representing diphenylsulfone, where R1is a halogen; R2selected from the group consisting of alkyl, lower alkenyl, lower quinil, lower haloalkyl and H, and R26and R13selected from the group consisting of H, lower alkyl, haloalkyl and halogen.

51. Connection on p. 49, representing diphenylsulfone, where R1represents Cl or Br, if the connection does not represent 4-diphenylsulfone, and in this case, R1also represents CH3or CF3; R2-C3H7; R26and R13each independently selected from the group consisting of H, halogen, NH2, CF3CH3, CN, CH3, (CH3)3C, C5H11CH3O, n-C4H9O and CH=CH.

52. Connection on p. 49, representing diphenylsulfone, where R2represents H, CH3C2H5or CF3; R26and R13independently selected from the group consisting of H, CH3C2H5, CF3and halogen; X is 0.

53. Compounds according to any one of paragraphs.47 - 53, which represents a 3 - or 4-diphenylsulfone.

54. Connection on p. 53, where R1selected from the group consisting of halogen, CH3C2H5, CF3C2F5n-C3H7and cyclo-C3H7mainly halogen or CH3and R2selected from the group consisting of H, CH3C2H5, CF3C2F5n-C3H7and ISO-C3H7while R26and R13each independently selected from the group consisting of H, halogen, NH2, CF3CH3, CN, CH3, (CH3)3C, C5H11CH3O, n-C4H9O and CH2=CH.

55. Connection on p. 53, where R1performance 3
; R26and R13independently selected from the group consisting of H, CH3C2H5, CF3and halogen.

56. Connection on p. 53, where R1represents halogen or methyl.

57. Connection on p. 56, where the substituent in position 2 Ar2represents hydrogen.

58. The sulfonamide representing N-(3,4-dimethyl-5-isoxazolyl)-4-diphenylsulfone.

59. Connection on p. 47, selected from the group consisting of N-(4-bromo-3-methyl-5-isoxazolyl)-2-diphenylsulfone or N-(4-chloro-3-methyl-5-isoxazolyl)-2-diphenylsulfone.

60. Connection on p. 47, selected from the group consisting of N-(4-bromo-3-methyl-5-isoxazolyl)-4-diphenylsulfone N-(4-bromo-5-methyl-3-isoxazolyl)-4-diphenylsulfone N-(4-chloro-3-methyl-5-isoxazolyl)-4-diphenylsulfone, and N-(4-chloro-5-methyl-3-isoxazolyl)-4-diphenylsulfone

61. Sulfonamides of formula IV

< / BR>
or

< / BR>
where R3, R5and R7each independently represents (a) hydrogen, except when at least one of the radicals R3, R5and R7does not represent hydrogen, (b) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl, anilox what I when one of the radicals R3, R5, R7is alkyl in position 4, at least one of the two other substituents R3, R5, R7is not hydrogen; (C) halogen; (d) hydroxyl; (e) cyano; (f) nitro, with the exception of those cases when one of the substituents R3, R5, R7is 4-NO2then at least one of the other two radicals R3, R5, R7is not hydrogen; (g) -C(O)H or-C(O)R27; (h) -CO2H or-CO2R27; (i) -SH, -S(O)nR27, -S(O)m-OH, -S(O)m-OR27, -O-S(O)m-OH, or-O-S(O)m-OR27; (j) -W4NR28R29with the exception of those cases when one of the substituents R3, R5, R7is 4-W4NR28R29then at least one of the other two radicals R3, R5, R7is not hydrogen; or (k) -W4N(R32)-W5NR30R31;

R1is halide or higher alkyl (containing in the chain more than 8 or so values up to 15 or so values of carbon atoms); R2selected from the following range: (a) hydrogen; (b) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl, aryloxy, Ara; f) -C(O)H or-C(O)R27; (g) CO2H or-CO2R27; (h) -SH, -S(O)nR27, -S(O)m-OH, -S(O)m-OR27, -O-S(O)m-R27, -O-S(O)mOH or-O-S(O)m-OR27; (i) -W4NR28R29, (j) -W4N(R32)-W5NR30R31;

R27is alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkylation, cycloalkenyl, cycloalkenyl, aryl, aralkyl, any of the groups may be substituted by W1, W2, W3;

R28is: (a) hydrogen, (b) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkylation, cycloalkenyl, cycloalkenyl, aryl, aralkyl, and any group may be substituted by W1, W2, W3; (c) cyano; (d) hydroxyl; (e) -C(O)H or-C(O)R27; (f) -CO2R27; (g) -SH, -S(O)nR27, -S(O)m-OH, -S(O)m-OR27, -O-S(O)m-R27, -O-S(O)mOH or-O-S(O)m-OR27; except for the case when W4is S(O)n-;

R29is: (a) hydrogen; (b) -C(O)H or-C(O)R27; except in those cases when W4is-C(O)-, and R28is-C(O)H, -C(O)R27or-C(O)2R27; (c) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, zameena W1, W2, W3;

R28and R29together form alkylene or albaniles (each of which may be substituted by W1, W2, W3), ranging from 3 - to 8-membered saturated, unsaturated or aromatic ring with the nitrogen atom to which they are attached;

R30is: (a) hydrogen; (b) hydroxyl; (c) -C(O)H or-C(O)R27; (d) CO2R27; (e) -SH, -S(O)nR27, -S(O)m-OH, -S(O)m-OR27, -O-S(O)m-R27, -O-S(O)m-R27, -O-S(O)mOH or-O-S(O)m-OR27; (f) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkylation, cycloalkenyl, cycloalkenyl, aryl, or aralkyl, and any group may be substituted by W1, W2, W3;

R31is: (a) hydrogen; (b) -C(O)H or-C(O)R27except when W5is-C(O)-, and R30is-C(O)H, -C(O)R27or-C(O)2R27or (c) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkylation, cycloalkenyl, cycloalkenyl, aryl, aralkyl, any of the groups may be substituted by W1, W2, W3;

R32is: (a) hydrogen; (b) hydroxyl; (c) -C(O)H, -C(O)R27or-C(O)2R27or (d) alkyl, what aralkyl, any group may be substituted by W1, W2, W3;

or any two of R30, R31, R32together form alkylene or albaniles (each of which may be substituted by W1, W2, W3), forming a 3 - to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached;

W1, W2, W3independently are: (a) hydrogen; b) halogen; (c) hydroxyl; (d) alkyl; (e) alkenyl; (f) aralkyl; (g) alkoxy; (h) aryloxy; (i) arakaki; (j) -SH, -S(O)nW6, -S(O)m-OH, -S(O)m-OW6, -O-S(O)m-OH, -O-S(O)m-W6or-O-S(O)m-OW6; (k) oxo; (l) nitro; (m) cyano; (n) -C(O)H, -C(O)W6; (o) -C(O)2H or-C(O)2W6;

(p) -W4NW7W8; (q) -W4-N(W11)-W5-W6; or (r) -W4-N(W11)-W5NW7W8; W4and W5independently are: (a) a simple relationship; (b) -W9-S(O)n-W10-; (c) -W9-C(O)-W10-; (d) -W9-C(S)-W10-; (e) -W9-O-W10-; (f) -W9-S-W10-; or (g) -W9-O-C(O)-W10-;

W6, W7, W8each independently selected from a number of: hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, cycloalkenyl, the UYa 3-8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached;

W9and W10independently selected from simple communication, alkylene, Alcanena, or akinlana;

W11is: (a) hydrogen; (b) hydroxyl; (C) -C(O)H, -C(O)W6or-C(O)2W6, (d) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkylation, cycloalkenyl, cycloalkenyl, aryl, aralkyl;

or any two groups of W7, W8, W11together form alkylene or albaniles, form a 3-8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached;

m = 1 or 2;

n = 0, 1, or 2.

62. Connection p. 61, in which one of the substituents R3, R5or R7is phenyl or phenoxy.

63. Connection p. 61, in which one of the substituents R3, R5or R7is hydrogen, and one of the two other substituents R3, R5or R7is in position 2 and is not hydrogen, and the other of R3, R5or R7is in position 5; R1is a halogen; R2is lower alkyl or hydrogen.

64. Compounds according to any one of p. 47, Connection on p. 42, in which Ar2has the formula V

< / BR>
where R1is halide or higher alkyl having a linear or branched chain and contains from 8 to 15 carbon, preferably from 9 to 13 carbons in the chain;

R2independently selected from alkyl, lower alkenyl, lower quinil, lower haloalkyl and hydrogen; R3, R4, R5, R6and R7selected from either (i) or (ii) as follows:

(i) R4, R5, R6and R7selected independently from H, lower alkyl, NH2, NO2, halogen, pseudohalogen; R3chosen from a number of: H, NHOH, NH2N3, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, halodrol, alkoxycarbonyl, alkylsulphonyl, arylcarbamoyl, formyl, substituted or unsubstituted, ureido group, where the alkyl, alkenyl, quinil are linear or branched chain containing from 1 to 5-6 carbons, and aryl contains from 4 to 14 carbons; or

(ii) R3, R5and R7are H, and R4, R6each independently selected from a number of: alkyl, alkoxy, halogen, aminoalkyl is coxi groups contain from 1 to 6 carbons and have a linear or branched chain.

66. Connection PP.41, 42 or 65, in which R1is Cl or Br, or C9H19- C13H27; R2selected from H, CH3C2H5, CF3C2F5n-C3H7ISO-C3H7, cyclo-C3H7; R3, R4, R5, R6and R7selected from either (i) or (ii) as follows:

R4, R5, R6and R7selected each independently from a number of: H, halogen, NH2, CF3C6H5CH3; R3chosen from a number of: H, NHOH, NH2C2H5NH2, (CH3)2NH, C6H5CH2NH, NO2, F, Cl, Br, I, CN, CH3, (CH3)3C, C5H11CH3O, n-C4H9O, CH2=CH, PhCH=CH, CHC, C6H5CC, C6H5(ethoxycarbonylmethyl)ureido - and 3-cyclohexylurea-, or

(ii) R3, R5and R7is hydrogen; R4and R6each independently selected from alkyl and aminoalkyl, in which the alkyl groups have from 1 to 6 carbons and contain linear or branched chain.

67. Connection PP.41, 42, 65 or 66, in which R1is Br, Cl or C9H19- C13H27; R2is H, CH3C2H5or CF3; and R32
CH3, CF3, halogen or C2H5NH; R4, R5and R6independently selected from H, CH3C2H5, (CH3)2CH, CF3, halogen, preferably Br or Cl; NH2and R7is H, CH3CH2CH5, (CH3)CH, F, or CF3; or

(ii) R3, R5and R7are H; and R4and R6selected each independently from alkyl groups that contain from 1 to 3 carbons and have a linear or branched chain.

68. Compounds according to any one of paragraphs.41, 42 or 65 - 67, in which R3, R5and R7are hydrogen.

69. Compounds according to any one of paragraphs.41, 42 or 65 - 68, in which R3, R4, R5, R6and R7selected independently from lower alkyl, methyl, ethyl, propyl, halogen, amino, dimethylamino, methylamino and metoxygroup.

70. Connection on p. 41, selected from the series:

N-(4-bromo-5-methyl-3-isoxazolyl)benzosulfimide;

2-chloro-4-fluoro-N-(5-methyl-3-isoxazolyl)benzosulfimide;

N-(4-bromo-5-tert-butyl-3-isoxazolyl)benzosulfimide;

N-(4-chloro-5-methyl-3-isoxazolyl)benzosulfimide;

N-(4-iodine-5-methyl-3-isoxazolyl)benzosulfimide;

3-nitro-N-(4-bromo-5-methyl-3-isoxazolyl)benzolsulfonate;

N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

N-(4-bromo-3-tert-butyl-5-isoxazolyl)benzosulfimide;

4-isopropyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-nitro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-iodine-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

N-(4-bromo-3-ethyl-5-isoxazolyl)benzosulfimide;

4-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)-4-benzosulfimide;

2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dimethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2,4,6-trimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-iodine-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3,4-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,4-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzene is poured)benzosulfimide;

2,5-dimethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

4 butoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-chloro-2-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-chloro-2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,6-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2.5-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,3,4-trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,3-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-bromo-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-ethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-bromo-2-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-diethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-cyano-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,4,5-trichloro-N-(4-bromo-3-methyl-5-isocetyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-trifluoromethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-chloro-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

N-(4-bromo-3-trifluoromethyl-5-isoxazolyl)benzosulfimide;

N-(4-isothiocyanato-3-methyl-5-isoxazolyl)benzosulfimide;

2-carboxyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3,5-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-chloro-5-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3,5-di(trifluoromethyl)-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2.5-debtor-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-chloro-5-methyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-chloro-4-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2.5-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-chloro-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-amino-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-dimethylamino-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-are the amide;

2 phenoxy-5-nitro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dibromo-3,6-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2 triptoreline-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-butyl-5-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-butyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2.5-dipropyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-dimethylamino-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methylamino-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methylamino-5-methyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-dimethylamino-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-ethyl-5-dimethylamino-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-azido-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,4-diethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2,4-diethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-butyl-5-bromo-N-(4-chloram-5-butyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-propyl-5-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide; or

2-propyl-5-bromo-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide.

71. Connection on p. 41 or 61, chosen from a number of: N-(4-nonyl-3-trifluoromethyl-5-isoxazolyl)benzosulfimide; N-(4-tridecyl-3-trifluoromethyl-5-isoxazolyl)benzosulfimide.

72. Connection on p. 70, selected from the series:

N-(4-bromo-5-methyl-3-isoxazolyl)benzosulfimide;

2-chloro-4-fluoro-N-(5-methyl-3-isoxazolyl)benzosulfimide;

N-(4-chloro-5-methyl-3-isoxazolyl)benzosulfimide;

N-(4-iodine-5-methyl-3-isoxazolyl)benzosulfimide;

N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

4-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-nitro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-iodine-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

N-(4-bromo-3-ethyl-5-isoxazolyl)benzosulfimide;

4-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-fluoro-N-(4-bromo-3-methyl-5-Isler-3-methyl-5-isoxazolyl)benzosulfimide;

4-acetamido-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,4,6-trimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-iodine-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3,4-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,4-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4 butoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-chloro-2-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-chloro-2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,6-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2.5-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,3,4-trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,3-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-bromo-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzolamide oxazolyl)benzosulfimide;

2-bromo-5-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-bromo-2-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-diethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-cyano-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,4,5-trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3,4-dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-trifluoromethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-chloro-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

N-(4-bromo-3-trifluoromethyl-5-isoxazolyl)benzosulfimide;

N-(4-isothiocyante-3-methyl-5-isoxazolyl)benzosulfimide;

2-carboxyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3,5-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-chloro-5-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3,5-di(trifluoromethyl)-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2.5-debtor-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-chloro-5-methyl-N-(4-chloro-3-methyl-5-the top-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2.5-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-chloro-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-amino-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-dimethylamino-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-acetamido-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2 phenoxy-5-nitro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dibromo-3,6-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2 triptoreline-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-butyl-5-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-butyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2.5-dipropyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-dimethylamino-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methylamino-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methylamino-5-methyl-N-(4-chloro-3-methyl-5-from the 2-ethyl-5-dimethylamino-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-azido-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,4-diethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2,4-diethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-butyl-5-bromo-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-butyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-propyl-5-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide; and

2-propyl-5-bromo-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide.

73. Connection on p. 70, selected from the series:

N-(4-bromo-5-methyl-3-isoxazolyl)benzosulfimide;

2-chloro-4-fluoro-N-(5-methyl-3-isoxazolyl)benzosulfimide;

N-(4-chloro-5-methyl-3-isoxazolyl)benzosulfimide;

N-(4-iodine-5-methyl-3-isoxazolyl)benzosulfimide;

N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

4-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

N-(4-bromo-3-ethyl-5-isoxazolyl)benzosulfimide;

4-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzensulphochloramide;

4-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3,4-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-chloro-2-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-chloro-2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,6-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2.5-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,3,4-trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,3-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-bromo-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-ethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-bromo-2-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-diethyl-N-(4-bromo-3-methyl-5-isoxazolyl)Ben is sapolil)benzosulfimide;

2,4,5-trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3,4-dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-trifluoromethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-chloro-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

N-(4-bromo-3-trifluoromethyl-5-isoxazolyl)benzosulfimide;

N-(4-isothiocyanato-3-methyl-5-isoxazolyl)benzosulfimide;

2-carboxyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3,5-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-chloro-5-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3,5-di(trifluoromethyl)-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2.5-debtor-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-chloro-5-methyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2.5-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-amino-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-dimethylamino-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-ACET the MFA;

2 phenoxy-5-nitro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dibromo-3,6-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2 triptoreline-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-butyl-5-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-butyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2.5-dipropyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methylamino-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methylamino-5-methyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-dimethylamino-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-ethyl-5-dimethylamino-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-azido-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,4-diethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2,4-diethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-butyl-5-bromo-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-N-(4-chloro-3-methyl-5-isaccea-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide; or

2-propyl-5-bromo-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide.

74. Connection on p. 70, selected from the series:

N-(4-bromo-5-methyl-3-isoxazolyl)benzosulfimide;

2-chloro-4-fluoro-N-(5-methyl-3-isoxazolyl)benzosulfimide;

N-(4-chloro-5-methyl-3-isoxazolyl)benzosulfimide;

N-(4-iodine-5-methyl-3-isoxazolyl)benzosulfimide;

N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

N-(4-bromo-3-ethyl-5-isoxazolyl)benzosulfimide;

2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dimethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3,4-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-chloro-2-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-chloro-2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,6-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzolsulfonat the l)benzosulfimide;

5-bromo-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-ethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-bromo-2-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-diethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-cyano-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3,4-dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-chloro-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

N-(4-bromo-3-trifluoromethyl-5-isoxazolyl)benzosulfimide;

N-(4-isothiocyanato-3-methyl-5-isoxazolyl)benzosulfimide;

2-carboxyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3,5-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-chloro-5-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3,5-di(trifluoromethyl)-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2.5-debtor-N-(4-chloro-3-meth is,5-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2.5-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-amino-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-dimethylamino-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-acetamido-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2 phenoxy-5-nitro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dibromo-3,6-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2 triptoreline-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-butyl-5-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2.5-dipropyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methylamino-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methylamino-5-methyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-methylamino-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-ethyl-5-dimethylamino-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-azido-N-(4-bromo-3-METI is l-5-bromo-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-propyl-5-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-propyl-5-bromo-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide.

75. Connection on p. 70, selected from the series:

N-(4-bromo-5-methyl-3-isoxazolyl)benzosulfimide;

2-chloro-4-fluoro-N-(5-methyl-3-isoxazolyl)benzosulfimide;

N-(4-chloro-5-methyl-3-isoxazolyl)benzosulfimide;

N-(4-iodine-5-methyl-3-isoxazolyl)benzosulfimide;

N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-bromo-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-ethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-bromo-2-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-diethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3,5-dichloro-N-(4-bromo-3-methyl-5-isoxa is timetake-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-butyl-5-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methylamino-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methylamino-5-methyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-butyl-5-bromo-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-propyl-5-bromo-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-propyl-5-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide.

76. Connection on p. 70, selected from the series:

5-bromo-2-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-diethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methylamino-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methylamino-5-methyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-propyl-5-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-propyl-5-bromo-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide.

77. Connection on p. 41, selected from the series:

4-isopropyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-fluoro-N-(4-brar-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)-4-benzosulfimide;

2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-iodine-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3,4-dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4 butoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-chloro-2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,3,4-trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-bromo-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-ethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-bromo-2-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-diethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-trifluoromethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-chloro-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-carboxyl-N-(4-bromo-3-METI the amido-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dibromo-3,6-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-butyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-butyl-5-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2.5-dipropyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-dimethylamino-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methylamino-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methylamino-5-methyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-azido-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,4-diethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2,4-diethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-butyl-5-bromo-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-butyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-propyl-5-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-propyl-5-bromo-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide.

78. Connection p. 77, selected from the series:

4-iodine-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)-4-benzosulfimide;

4-iodine-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4 butoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-bromo-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-ethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

5-bromo-2-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-diethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-trifluoromethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

3-acetamido-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2,5-dibromo-3,6-debtor-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-bromo-5-butyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-dimethylamino-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methylamino-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

2-methylamino-5-methyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzosulfimide;

2-methyl-5-azido-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

79. Connection p. 77, selected from the series:

4-isopropyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-iodine-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-iodine-N-(4-bromo-5-methyl-3-isoxazolyl)benzosulfimide;

4-dimethylamino-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide;

4-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide; or

2-methylamino-5-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzosulfimide.

80. Compounds according to any one of paragraphs.41 or 63 - 69, in which R1is nonilon or tridesilon, and R2is stands, ethyl, trihalomethyl or hydrogen.

81. The sulfonamides of the formula I

< / BR>
or

< / BR>
in which R1and R2represent (i), (ii) or (iii) as follows:

(i) R1and R2independently selected from the group consisting of H, NH2, NO2, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, hydroxyalkyl, alkoxyalkyl, alkylthio, haloalkoxy, haloalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, haloacyl, alkoxycarbonyl, alkylsulphonyl, aminocarbonyl, arylcarbamoyl, formyl, substituted and kinyinya parts contain from 1 to 14 carbon atoms, have straight or branched chains or are cyclic, and the aryl portion contains from 4 to 16 carbon atoms, provided that R2does not represent halogen or pseudohalide; or

(ii) R1and R2together form -(CH2)nwhere n = 3 to 6; or

(iii) R1and R2together form 1,3-butadienyl; and Ar2represents a group having the formula

< / BR>
where n = 1 to 10; except that Ar2is not phenyl, 2-biphenyl, or naphthyl, if the connection is not a N-isoxazolecarboxylic substituted by halogen or higher alkyl in position 4 relative to isoxazoline group;

R3, R4, R5, R6and R7selected from (i), (ii), (iii) or (iv) provided that: (a) when Ar2is phenyl, other than a biphenyl, at least one of R3, R4, R5, R6and R7is not hydrogen, (b) when Ar1is a 4-halo-5-methyl-3-isoxazolyl, R3is not NH2or CH3and (c) when Ar2is phenyl, naphthyl or 2-biphenyl, R1is a halide or higher alkyl;

(i) R3, R4, R5, R6and R7each independently selected from the group with whom cocci, alkylamino, alkylthio, alkoxyalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, haloacyl, alkoxycarbonyl, alkylsulphonyl, arylcarbamoyl, formyl, substituted or unsubstituted of aminogroup, substituted or unsubstituted of raidgroup, where alkyl, alkeline, alkyline parts have straight or branched chains containing from 1 to 10 carbon atoms, and the aryl portion contains from 3 to 10 or so values carbon atoms, or an alternative,

(ii) R4and R7together represent a substituted or unsubstituted group, 1,3-butadienyl, 4-dimethylamino-1,3-butadiene, 1-chloro-1,3-butadiene, 1-Aza-1,3-butadienyl or 2-Aza-1,3-butadienyl; R3, R5and R6are as defined above in (i), or alternative,

(iii) R7and R3together represent a substituted or unsubstituted group, 1,3-butadienyl, 4-dimethylamino-1,3-butadiene, 1-chloro-1,3-butadiene, 1-Aza-1,3-butadienyl or 2-Aza-1,3-butadienyl; R4, R5and R6are as defined above in (i), or

(iv) R3, R5and R7represent H; R4and R6each independently selected from the group consisting of alkyl, alkoxy, halogen, aminoalkyl, dialkyl the chain.

82. Connection p. 81, in which the aryl part Ar2is a phenyl or biphenyl.

83. Connection p. 81 or 82, in which R2is H, CH3C2H5, CF3C2F5n-C3H7, cyclo-C3H7C4H8, R1is Br, Cl, CH3or tertiary alkyl carbon chain which is linear or branched and contains from 8 to 15 carbons, n = 1 to 3; R3, R4, R5, R6and R7selected from (i), (ii), (iii) or (iv) as follows:

(i) R5and R6are H; R4and R7each independently selected from H, halogen, NH2, CF3C6H5CH3; and R3selected from H, NHOH, NH2C2H5NH2, (CH3)2NH, C6H5CH2NH, NO2, F, Cl, Br, I, CN, CH3, (CH3)3C, C5H11CH3O, n-C4H9O, CH2= CH, C6H5CH= CH, CHC, C6H5CC, C6H5, 3-(ethoxycarbonylmethyl)ureido, 3 cyclohexylurea; or

(ii) R4and R7together form 1,3-butadienyl, 4-chloro-1,3-butadienyl, 4-dimethylamino-1,3-butadienyl or 1-Aza-1,3-butadienyl; R3, R5and R6selected as described in (i); or

(iii) R7and R4, R5and R6are as defined in (i); or

(iv) R3, R5and R7are hydrogen, as defined in (i); and R4and R6each independently selected from alkyl, alkoxy, halogen, aminoalkyl, acylaminoalkyl or dialkylaminoalkyl, which are unsubstituted or substituted alkyl group, where alkyl and alkoxygroup contain from 1 to 10, preferably from 1 to 6 carbons and have a linear or branched chain.

84. Connection p. 83, in which R1is Br, Cl, I, CH3or C9H19- C13H27; R2is H, CH3C2H5, CF3C2F5n-C3H7, cyclo-C3H7C4H8while R3, R4, R5, R6, R7are either (i), (ii), (iii), (iv) or (v) according to the following:

(i) R5, R6, R7are H; and R3is H, NH2CH3, CF3, halogen, C2H5NH or C6H5; R4is H, NH2, CF3, R7is H or CF3and R5and R6are H; or

(ii) R3, R5and R6are H; R4and R7together form 1,3-butadienyl, 1-chloro-1,3-butadienyl, 4-dimethylamine>together form 1,3-butadienyl, 1-chloro-1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, or 1-Aza-1,3-butadienyl; or

(iv) R4is H or NH2; R5and R6are H, R3is H, NH2or halogen, F, Cl, Br, CH3, CF3, NH2; R7is H, F, Cl, Br, CH3, CF3, NH2; R5and R6are H; or

(v) R3, R5and R7are hydrogen, as defined in (i); and R4and R6independently selected from alkyl groups that contain from 1 to 6 carbons and contain linear or branched chain.

85. Connection p. 81, in which R1is a halogen; R2is H, CH3C2H5, CF3C2F5; and R3, R4, R5, R6and R7represent (i) or (ii) as follows:

(i) R4, R5, R6and R7each independently selected from a number of: H, halogen, NH2CH3, CF3or C6H5; R3selected from H, NHOH, NH2C2H5NH2, (CH3)2NH, C6H5CH2NH, NO2, F, Cl, Br, I, CN, CH3, (CH3)3C, C5H11CH3O, n-C4H9O, CH2=CH, C6H5CH= CH, CHC, C6H5CC, C4and R6each are alkyl groups which contain from 1 to 3 carbons and contain linear or branched chain.

86. Connection p. 81, in which n = 1; R1is Br, Cl or CH3; R2is CH3C2H5or CF3; and R3, R4, R6and R7are either (i) or (ii) as follows:

(i) R3is H, NH2CH3, CF3, halogen or C2H5NH; R4, R5and R6chosen independently from the set: H, CF3, Br, Cl, NH2and R7is H, CH3CH2CH5, (CH3)CH, F, or CF3; or

(ii) R3, R4, R5, R6and R7independently selected from nitro, hydrogen, methyl or ethyl.

87. Connection p. 81, selected from N-(3,4-dimethyl-5-isoxazolyl)--toluensulfonate and 2-nitro-N-(3,4-dimethyl-5-isoxazolyl)--toluensulfonate.

88. Connection on p. 41, in which Ar2is naphthyl.

89. Sulfonamides that have formula VIII

< / BR>
or

< / BR>
where R2is H, CH3C2H5, CF3C2F5n-C3H7ISO-C3H7C4H8, R1is halogen or higher/SUP>, R4, R5, R6and R7selected from (i) or (ii) as follows:

(i) R4and R7together form a substituted or unsubstituted 1,3-butadienyl, 1-chloro-1,3-butadiene, 4-dimethylamino-1,3-butadiene, 1-Aza-1,3-butadienyl or 2-Aza-1,3-butadienyl; R3, R5and R6selected each independently from a number of: H, NHOH, NH2, NO2N3, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, halodrol, alkoxycarbonyl, alkylsulphonyl, arylcarbamoyl, formyl, substituted or unsubstituted, aminogroup, substituted or unsubstituted, raidgroup, where the alkyl, alkenyl, quinil contain linear or branched chain containing from 1 or about this value to 10 or so values carbons, preferably 1 to 5 6 or so values of carbon, and the aryl portion contains from 3 to 10 or so values carbons, preferably 6 carbons; or an alternative,

(ii) R7and R3together form a substituted or unsubstituted 1,3-butadienyl, 1-chloro-1,3-butadiene, 4-dimethylamino-1,3-butadiene, 1-Aza-1,3-butadienyl and the , N3, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, halodrol, alkoxycarbonyl, alkylsulphonyl, arylcarbamoyl, formyl, substituted or unsubstituted, aminogroup, substituted or unsubstituted, raidgroup, where alkyl, alkeline, alkyline parts contain linear or branched chain containing from 1 or about this value to 10 or so values carbons, preferably 1 to 5 6 or about

this value of carbons and the aryl portion contains from 3 to 10 or so values carbons, preferably 6 carbons.

90. Sulfonamides that have formula IX

< / BR>
or

< / BR>
which are substituted by groups R4, R5and R6that are independently selected, provided that at least one of the groups R4, R5and R6is not hydrogen, from the following range: (a) hydrogen; (b) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of these groups may be substituted by W1, W2and W3; (C) halogen;(O)m-OH, -S(O)m-OR27, -O-S(O)m-R27, -O-S(O)m-OH, or-O-S(O)m-OR27; (j) -W4-NR28R29or (k) -W4-N(R32)-W5-NR30R31; R1is halide or higher alkyl (containing in the chain from 8 to 15 or so values of carbon atoms);

R2selected from the following range: (a) hydrogen; (b) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of the groups may be substituted by W1, W2and W3; (C) hydroxyl; (d) cyano; e) nitro; (f) -C(O)H or-C(O)R27; (g) CO2H or-CO2R27; (h) -SH, -S(O)nR27, -S(O)m-OH, -S(O)m-OR27, -O-S(O)m-R27, -O-S(O)m-OH, or-O-S(O)m-OR27; (i) -W4NR28R27or (k) -W4N(R32)-W6NR30R31;

R27is alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkylation, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of the groups may be substituted by W1, W2, W3;

R28is: (a) hydrogen; (b) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkylation, cycloalkenyl, cycloalkenyl, aryl, ar27; (f) -CO2H or-CO2R27; (g) -SH, -S(O)nR27, -S(O)m-OH, -S(O)m-OR27, -O-S(O)m-R27, -O-S(O)m-OH, or-O-S(O)m-OR27; except for the case when W4is-S(O)n-;

R29is: (a) hydrogen; (b) -C(O)H or-C(O)R27; except in those cases when W4is-C(O)-, and R28is-C(O)H, -C(O)R27, CO2H or-CO2R27; (C) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkylation, cycloalkenyl, cycloalkenyl, aryl or aralkyl, and any of these groups may be substituted by W1, W2, W3; or

R28and R29together form alkylene or albaniles (each of which may be substituted by W1, W2, W3); ranging from 3 - to 8-membered saturated, unsaturated or aromatic ring with the nitrogen atom to which they are attached;

R30is: (a) hydrogen; (b) hydroxyl; (C) -C(O)H or-C(O)R27; (d) CO2H or-CO2R27; (e) -SH, -S(O)nR27, -S(O)m-OH, -S(O)m-OR27, -O-S(O)m-OH, -O-S(O)m-R27or-O-S(O)m-OR27; (f) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkylation, cyclea the W2, W3;

R31is: (a) hydrogen; (b) -C(O)H or-C(O)R27except when W6is-C(O)-, and R30is-C(O)H, -C(O)R27, -CO2H or-CO2R27(c) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkylation, cycloalkenyl, cycloalkenyl, aryl, or aralkyl, and any of these groups may be substituted by W1, W2, W3;

R32is: (a) hydrogen; (b) hydroxyl, CO2R27or CO2H, except for those cases when one of the substituents R30and R31are hydroxyl, CO2R27or CO2H; (c) -C(O)H or-C(O)R27; or (d) alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkylation, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of the groups may be substituted by W1, W2, W3;

or any two of R30, R31, R32together form alkylene or albaniles (each group may be substituted (W1, W2, W3), or forming a 3 - to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached;

W1, W2, W3independently are: (a) hydrogen; (b) halo)m-W6or-O-S(O)m-OW6; (f) oxo; (g) nitro; (h) cyano; (i) -C(O)H or-C(O)W6; (j) -CO2H or-CO2W6; or (k) NW7W8, -C(O)NW7W8or-S(O)nW7W8;

W4and W5each independently are: (a) a simple relationship; (b) -S(O)n-; (c) -C(O)-; (d) -C(S)-; or (e) alkyl, alkenyl, quinil, cycloalkyl, cycloalkylation, cycloalkenyl, cycloalkenyl, aryl, or aralkyl, and any of these groups may be substituted by W1, W2, W3;

W6, W7, W8independently selected from a number of: hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, or W7and W8together are alkylene or Alcanena, forming a 3 - to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached;

m = 1 or 2;

n = 0, 1, or 2.

91. Connection p. 89 or 90, which represents a 1 - or 2-naphthalenesulfonate, which are unsubstituted or substituted in position 5 di(lower alkyl)amino or (lower alkyl)amino group.

92. Connection p. 89 or 90, selected from the following range:

N-(4-bromo-3-methyl-5-ISOC-isoxazolyl)-1-naphthalenesulfonate;

N-(4-bromo-3-methyl-5-isoxazolyl)-1-naphthalenesulfonate;

5-dimethylamino-N-(4-bromo-3-methyl-isoxazolyl)-1-naphthalenesulfonate;

5-dimethylamino-N-(4-bromo-5-methyl-3-isoxazolyl)-1-naphthalenesulfonate.

93. Connection p. 89 or 90, selected from the series:

N-(4-halogen-3-methyl-5-isoxazolyl)-1-naphthalenesulfonate;

N-(4-halogen-5-methyl-3-isoxazolyl)-1-naphthalenesulfonate;

5-dimethylamino-N-(4-halogen-3-methyl-5-isoxazolyl)-1-naphthalenesulfonate;

5-dimethylamino-N-(4-halogen-5-methyl-3-isoxazolyl)-1-naphthalenesulfonate,

moreover, the halogen is Br or Cl.

94. Connection p. 93, which are 5-dimethylamino-N-(4-bromo-3-methyl-5-isoxazolyl)-1-naphthalenesulfonate or 5-dimethylamino-N-(4-bromo-5-methyl-3-isoxazolyl)-1-naphthalenesulfonate.

95. Connection on p. 41, in which Ar2is financila or AstraZeneca, which ring may be substituted by one or more substituents, each selected from R26who is H, lower alkyl, haloalkyl or halogen; R1is halogen, stands or higher alkyl, which is linear or branched chain and contains from 8 to 15 carbons; R2selected from alkyl, lower alkenyl, lower UP> is stands, ethyl or hydrogen; R26is H, CH3C2H5, CF3and halogen.

97. Connection p. 95, chosen from a number of: N-(4-bromo-3-methyl-5-isoxazolyl)phenanthrene-3-sulfonamide; N-(4-bromo-5-methyl-3-isoxazolyl)phenanthrene-3-sulfonamide; N-(3,4-dimethyl-5-isoxazolyl)phenanthrene-3-sulfonamide.

98. Compounds according to any one of paragraphs.41 - 97, in which R1selected from alkyl, lower alkenyl, lower quinil, lower haloalkyl, halogen, pseudohalogen and hydrogen; and R2selected from lower alkyl, lower alkenyl, lower quinil, lower haloalkyl and h

99. Sulfonamides having the formula I

< / BR>
or

< / BR>
where R1and R2are (i), (ii) or (iii) as follows:

(i) R1and R2independently selected from the series: H, NH2, NO2, halogen, pseudohalide, alkyl, alkenyl, quinil, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, hydroxyalkyl, alkoxyalkyl, alkylthio, haloalkoxy, haloalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, halodrol, alkoxycarbonyl, alkylsulphonyl, aminocarbonyl, arylcarbamoyl, formyl, substituted or unsubstituted, aminogroup, replace the mi or cyclic, containing from 1 to 15 or so values of carbons and the aryl portion contains from 4 or so values up to 16 or so values of carbon, provided that R2neither halogen nor pseudohalide; or

(ii) R1and R2together form -(CH2)n-, where n = 3 to 6; or

(iii) R1and R2together form 1,3-butadienyl; and Ar2is a six-membered heterocycle with one heteroatom selected from S, O, N, or NR11which is substituted by one or more substituents, each of which is independently selected from R26who is H, OH, NHOH, NH2, NO2, halogen, pseudohalogen, alkyl, alkenyl, quinil, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, calidarium, alkoxycarbonyl, carbonyl, alkylcarboxylic, aminocarbonyl, arylcarbamoyl, formyl, substituted or unsubstituted aminogroups, substituted or unsubstituted raidgroups, where the alkyl, alkenyl, quinil have a linear or branched chain, or are cyclic, containing from 1 to 14 or ecologo value to 16 or so values of carbon, preferably from 4 to 10 carbons.

100. Connection p. 99, in which R1selected from alkyl, lower alkenyl, lower quinil, lower haloalkyl, halogen, pseudohalogen and H; and R2selected from lower alkyl, lower alkenyl, lower quinil, lower haloalkyl and h

101. Connection p. 99 or 100, in which R26is H, alkyl, haloalkyl, halogen or amino group.

102. Compounds according to any one of paragraphs.99 - 101, in which R1is halogen, alkyl, haloalkyl; and R2is lower alkyl, lower haloalkyl or hydrogen.

103. Compounds according to any one of paragraphs.99 - 102, in which Ar2is pyridium.

104. Connection p. 103, selected from the series:

N-(4-bromo-3-methyl-5-isoxazolyl)pyridine-2-sulfonamide;

N-(4-bromo-5-methyl-3-isoxazolyl)pyridine-2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-2-pyridine-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)pyridine-2-sulfonamide;

3-methoxycarbonyl-N-(4-bromo-5-methyl-3-isoxazolyl)pyridine-2-sulfonamide;

3-methoxycarbonyl-N-(4-bromo-3-methyl-5-isoxazolyl)pyridine-2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-3-(N-phenylenecarbonyl)pyridine-2-sulfonamide;

N-(4-bromo-5-methyl-3-isomil)pyridine-2-sulfonamide.

105. Connection p. 99, in which Ar2is a heterocycle containing two or more heteroatoms selected from O, S, N and NR11where the heterocycle is substituted by one or more substituents selected from R26who are H, OH, NHOH, NH2, NO2, halogen, pseudohalogen, alkyl, alkenyl, quinil, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, calidarium, alkoxycarbonyl, carbonyl, alkylcarboxylic, aminocarbonyl, arylcarbamoyl, formyl, substituted or unsubstituted aminogroups, substituted or unsubstituted raidgroups, where the alkyl, alkenyl, quinil have a linear or branched chains or cycles, contain from 1 to 14 or so values of carbon, preferably from 1 to 6 atoms and the aryl portion contains from 4 or so values up to 16 or so values carbons, preferably 4 to 10 carbons.

106. The sulfonamides of the formula I

< / BR>
or

< / BR>
where R1and R2are (i), (ii) or (iii) as follows: (i) R1and R2independently selected shall Eroare, alkoxy, alkylamino, hydroxyalkyl, alkoxyalkyl, alkylthio, haloalkoxy, haloalkyl, alkylsulfonyl, alkylsulfonyl, aryloxy, arylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, halodrol, alkoxycarbonyl, alkylsulphonyl, aminocarbonyl, arylcarbamoyl, formyl, substituted or unsubstituted aminogroup, substituted or unsubstituted raidgroup, where the alkyl, alkenyl, quinil contain linear or branched chains or cycles containing from 1 to 14, or about the value of carbon atoms and the aryl portion contains from 4 or so values up to 16 or so values of carbon, provided what R2neither halogen nor pseudohalide; or

(ii) R1and R2together form -(CH2)n-, where n = 3 to 6; or

(iii) R1and R2together form 1,3-butadienyl; and Ar2is a heterocycle with one heteroatom and two condensed rings, where the heteroatoms are O, S or NR11and the rings may be replaced by one or more substituents, each of which is independently selected from R26who is H, OH, NHOH, NH2, NO2, halogen, pseudohalogen, alkyl, alkenyl, quinil, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, aaltio, arylsulfonyl, arylsulfonyl, haloalkyl, calidarium, alkoxycarbonyl, carbonyl, alkylcarboxylic, aminocarbonyl, arylcarbamoyl, formyl, substituted or unsubstituted aminogroups, substituted or unsubstituted raidgroups, where the alkyl, alkenyl, quinil have a linear or branched chains or cycles, contain from 1 to 14 or so values carbons, preferably from 1 to 6 carbon atoms, and the aryl portion contains from 4 or so values up to 16 or so values carbons, preferably 4 to 10 carbons.

107. Connection p. 106, in which R26is H, alkyl, haloalkyl, halogen and amino.

108. Connection p. 106 or 107, in which Ar2is chinaillon, ethanolism, dibenzofuran, dibenzothiophene, dibenzobarrelenes or carbazolyl.

109. Compounds according to any one of paragraphs.106 - 108, in which R1is hydrogen, halogen, alkyl, or haloalkyl, and R2is lower alkyl, lower haloalkyl or hydrogen.

110. Compounds according to any one of paragraphs.106 - 108, in which Ar2is chinaillon or ethanolism.

111. Connection p. 106, which is N-(4-bromo-3-methyl-5-isoxa the-5-isoxazolyl)quinoline-5-sulfonamide.

112. Compounds according to any one of paragraphs.106 - 110, in which R26selected from H, CH3, CF3C2H5and halogen.

113. Sulfonamides, which have the formula I

< / BR>
or

< / BR>
where Ar2is CH3-(CH2)mwhere m = 5 - 10; or Ar2is

< / BR>
or isomers or their substituted derivatives,

Ar2is unsubstituted or substituted by one or more substituents selected from halogen, amino, carbonyl, nitro and hydrogen;

R1selected from alkyl, lower alkenyl, lower quinil, lower haloalkyl, halogen, pseudohalogen and hydrogen;

R2selected from lower alkyl, lower alkenyl, lower quinil, lower haloalkyl and h

114. Connection p. 113, in which R1is hydrogen, halogen, alkyl or haloalkyl; and R2is lower alkyl, lower haloalkyl or hydrogen.

115. Connection p. 113 or 114, which is selected from the following range:

N-(3,4-dimethyl-5-isoxazolyl)-(-)-10-camphorsulfonate;

N-(3,4-dimethyl-5-isoxazolyl)methanesulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-(+)-10-camphorsulfonate;

N-(4-tridecyl-3-trifluoromethyl-5-isoxazolyl)methanesulfonamide; the

where R1selected from alkyl, lower alkenyl, lower quinil, lower haloalkyl, halogen, pseudohalogen and hydrogen;

R2selected from lower alkyl, lower alkenyl, lower quinil, lower haloalkyl and H;

R3, R4, R5, R6, R7independently selected from (i), (ii), (iii) or (iv) as follows:

(i) R4and R7independently selected from H, halogen, NH2, CF3C6H5CH3;

R3selected from H, NHOH, NH2C2H5NH2, (CH3)2NH, C6H5CH2NH, NO2, F, Cl, Br, I, CN, CH3, (CH3)3C, C5H11CH3O, n-C4H9O, CH2=CH, C6H5CH=CH, CHC, C6H5CC, C6H5, 3-(ethoxycarbonylmethyl)ureido, 3 cyclohexylurea; and

R5and R6are hydrogen; or

(ii) R4and R7together form 1,3-butadienyl, 4-chloro-1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-Aza-1,3-butadienyl; and R3, R5and R6determined as specified in (i) this option execution; or

(iii) R7and R3together form 1,3-butadienyl, 3-chloro-1,3-butadienyl, 4-dimethylamino-1,3-butadienyl or 1-Aza-1,3-butadienyl; and R4, R5SUP>7are hydrogen, as defined in (i); R4and R6each independently selected from alkyl, alkoxy, halogen, aminoalkyl, acylaminoalkyl or dialkylaminoalkyl, where alkyl and alkoxygroup contain from 1 to 10, preferably from 1 to 6 carbons and have a linear or branched chain;

R8and R9which each contain hydrogen or up to about 20 or this value or less carbon atoms, preferably less than 10, each independently selected from a number of: hydrogen, halogen, pseudohalide, alkyl, alkoxy, alkenyl, quinil, aryl, aryloxy, heterocycle, aralkyl, Alcoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, OH, CN, NH2SH, NHOH, NR18R19, NO2N3, OR18, R19NCOR18and CONR19R18where R18and R19independently selected from hydrogen, lower alkyl, lower haloalkyl, low alkoxygroup and halogen.

117. Connection on p. 116, where R8and R9independently selected from hydrogen, halogen, lower alkyl, pseudohalide, low alkoxygroup.

118. Connection on p. 116 or 117, where R2is H, CH3C2H5, CF3; R1is Cl, Br, CH3or CF3.

119. Connection on p. 116, UB>5n-C3H7, cyclo-C3H5C4H8; and R3, R4, R5, R6and R7are either (i) or (ii) as follows:

(i) R3is H, NH2CH3, CF3, halogen, C2H5NH or C6H5; R4is H, NH2, CF3, R7is H or CF3and R5and R6are hydrogen; or

(ii) R4is H or NH2, R5and R6are H; R7is H or CF3and R3is H, NH2or halogen.

120. Connection on p. 116, selected from the series:

N-(3,4-dimethyl-5-isoxazolyl)--TRANS-styrelseledamot;

N-(4-bromo-3-methyl-5-isoxazolyl)--TRANS-styrelseledamot;

N-(4-bromo-5-methyl-3-isoxazolyl)--TRANS-styrelseledamot;

2-nitro-N-(3,4-dimethyl-5-isoxazolyl)styrelseledamot;

2-nitro-N-(4-bromo-3-methyl-5-isoxazolyl)styrelseledamot;

2-nitro-N-(4-bromo-5-methyl-3-isoxazolyl)styrelseledamot;

1,2-TRANS-dimethyl-N-(3,4-dimethyl-5-isoxazolyl)styrene-1-sulfonamide;

1,2-TRANS-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)styrene-1-sulfonamide;

1,2-TRANS-dimethyl-N-(4-bromo-5-methyl-3-isoxazolyl)styrene-1-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-2-fenestral-1-is)-2-fenestral-1-sulfonamide;

1,2-CIS-dimethyl-N-(3,4-dimethyl-5-isoxazolyl)styrene-1-sulfonamide;

1,2-CIS-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)styrene-1-sulfonamide;

1,2-CIS-dimethyl-N-(4-bromo-5-methyl-3-isoxazolyl)styrene-1-sulfonamide.

121. Pharmaceutical composition containing 0.01 to 2000 mg sulfonamida according to any one of paragraphs.1 - 120 together with a pharmaceutically acceptable carrier.

122. A method of treating endothelin-dependent diseases, comprising applying an effective amount of one or more compounds according to any PP.1 - 120, where an effective amount is an amount sufficient to reduce one or more symptoms of the disease.

123. The method according to p. 122, in which the disease is selected from the group comprising the following diseases: hypertension, cardiovascular systems, asthma, pulmonary hypertension, inflammatory, ophthalmic diseases, increased eye pressure, glaucoma, menstrual disorders, obstetrics, injuries, gastrointestinal disease, renal failure, caused by immunosuppressants, reduction of renal blood vessels caused by endothelin contraction of blood vessels, ischemia, pulmonary hypertension, anaphylactic shock and hemorragia hypertension, cardiovascular disease, pulmonary hypertension, caused by endothelin reduction vessels, endotoxin shock, pulmonary hypertension, anaphylactic shock and hemorrhagic shock.

125. The method according to any of paragraphs.122 - 124, in which the disease is selected from the group comprising asthma and inflammatory processes.

126. Method of inhibiting the binding endothelioma peptide with endothelinA-(ETA) or endothelinB-(ETB) receptors, comprising contacting the receptors endothelioma peptide and one or more compounds according to any one of paragraphs. 1 - 120, the latter contacting is carried out before, simultaneously with or after contacting the receptors with endothelium peptide.

127. How to change the called endothelium receptor activity, comprising contacting endothelina receptor with a compound according to any one of paragraphs.1 - 120.

Priority points:

20.05.93 on PP.41 - 57, 59, 60 - 80, 88, 95 - 97, 121, 122 - 127;

30.07.93 on PP.1 - 40, 81 - 87, 89 - 94, 121, 122 - 127;

21.10.93 on PP.106 - 120, 121, 122 - 127;

05.04.94 on PP.99 - 105, 121, 122 - 127.

 

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