Biphenylenediisocyanate

 

(57) Abstract:

Describes new compounds of formula (I) or their pharmaceutically acceptable salts, where X Is O; Y Is N; J Is O, S, N - R15; K and L is C or N, provided that one of them; p = 0, 1; R is hydrogen, lower alkyl, the group Z4-NR6R7where Z4represents a group Z9COZ10and Z4, Z9, Z10each means a single bond; R6is hydrogen, alkyl; R7is hydrogen, R2is hydrogen or lower alkyl; R3and R4each is lower alkyl; R12, R13, R14each hydrogen; R15is hydrogen, alkyl, hydroxyethoxymethyl, methoxyethoxymethyl;11is hydrogen, hydroxyl, CO2R5where R5- alkyl, oxazolyl, alkenyl, substituted phenyl; Z4-NR6R7where Z4is Z9COZ10where Z9and Z10each represents a single bond; R6and R7defined above; alkyl substituted by a group Z2where Z2the hydroxyl group

< / BR>
where Z4- link, Z5group Z9COZ10, Z9COOZ10, Z9S(O)nZ10where Z9, Z10every single bond, Z11is hydrogen, alkyl, Z6is hydrogen, alkyl, phenyl, phenyl, R>
< / BR>
where Z4is a single bond; Z5group Z9COZ10where Z9and Z10is a single bond, Z9is hydrogen, Z8- alkyl, phenyl; Z11is hydrogen, alkyl. The compounds are antagonists endothelin. 14 C.p. f-crystals.

This application is a partial continuation of application N 08/487308, filed July 7, 1995, which, in turn, is a partial continuation of application N 08/368285, filed January 5, 1995, which in turn is a partial continuation of application N 08/297187, filed August 26, 1994. The contents of all these applications are included in this description for details.

This invention relates to endothelin antagonists, useful inter alia for the treatment of hypertension or hypertension.

The compounds of formula I

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their enantiomers and diastereoisomers and their pharmaceutically acceptable salts are antagonists endothelioma receptor, useful inter alia as anti-hypertensive funds. Throughout this description, the above symbols have the meanings defined as follows:

one of X and Y represents N and the other is O;

R1, R2, R3and R4each C of alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl, aryloxy, aralkyl or Alcoxy, any of which may be substituted by substituents Z1, Z2and Z3,

/c/ halogen,

/d/ hydroxy,

/e/ cyano,

/f/ nitro,

/g/ C/O/H or C/O/R5,

/h/ - CO2H or - CO2R5,

/i/ - Z4-NR6, R7,

/j/ - Z4-N/R10-Z5-NR8R9or

/k/ R3and R4together can also represent alkylene or albaniles, any of which may be substituted by substituents Z1, Z2and Z3final 4 - to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached.

R5represents alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of which may be substituted by substituents1, Z2and Z3;

R6, R7, R8, R9and R10each independently represents

/a/ hydrogen, or

/b/ alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl, any of which may be substituted by substituents, Z1, Z2which may be substituted by substituents Z1, Z2and Z3, completing a 3 - to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached, or any two of R8, R9and R10together represent alkylene or albaniles, any of which may be substituted by substituents Z1, Z2and Z3, completing a 3 - to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;

R11, R12, R13and R14each independently represents

/a/ hydrogen

/b/ alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl, aryloxy, aralkyl or Alcoxy, any of which may be substituted by substituents Z1, Z2and Z3,

/s/ heterocycle, substituted heterocycle or heterocyclic,

/d/ halogen,

/e/ hydroxyl,

/f/ cyano,

/g/ nitro,

/h/ - /O/H or C/O/R5,

/i/ - CO2H or - CO2R5,

/j/ - SH, -S/O/nR5- S/O/m-OH, -S/O/m- OR5, -O-S/O/m- OR5, -O-S/O/mOH or-O-S/O/m-OR5,

/k/ -Z4-NR6R7or

/I/ - Z4-N/R10/-Z5/NR8R9,

Z1, Z2and Z3each independent is aryl,

/g/ aralkyl,

/h/ alkoxy,

/i/ aryloxy,

/j/ arakaki,

/k/ a heterocycle, substituted heterocycle or heterocyclic,

/I/ -SH, -S/O/nZ6-S/O/m-OH, -S/O/m-OZ6, -O-S/O/m-Z6, -O-S/O/mOH or-O-S/O/m-O6,

/m/ oxo,

/n/ nitro,

/o/ cyano,

/p/ C/O/H or/O/Z6,

/q/ - CO2H or - CO2Z6;

/r/ -Z4-NZ7Z8;

/s/ -Z4-N/Z11/-Z5-H,

/t/ Z4-N/Z11/-Z5-Z6or

/u/ -Z4-N/Z11/-Z5-NZ7Z8,

Z4and Z5each independently represents

/a/ single bond,

/b/ -Z9-S/O/n-Z10-,

c /Z/9/C/O-Z10-,

/d/ -Z9-C/S/Z10-,

/e/ Z9-O-Z10-,

/f/ Z9-S-Z10-,

/c/ -Z9-O-C/O/-Z10- or

/h/ -Z9-C/O/-O-Z10-,

Z6is alkyl, alkyl substituted with one, two or three halogen, alkenyl, quinil, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl, aryl substituted with one, two or three halogen, aryl, substituted trihalomethyl, or aralkyl;

Z7and Z8each independently represents hydrogen, Alky who have alkylen or albaniles, the final 3 - to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached;

Z9and Z10each independently represents a single bond, alkylene, albaniles or akinyan;

Z11is:

/a/ hydrogen, or

/b/ alkyl, alkyl substituted with one, two or three halogen, cycloalkyl, cycloalkenyl, cycloalkenyl, aryl or aralkyl or any two of Z7, Z8and Z11together represent alkylene or albaniles, the final 3 - to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;

J is O, S, N or NR15;

K and L represent N or C, provided that at least one of K or L is C;

R15represents hydrogen, alkyl, hydroxyethoxymethyl or methoxyethoxymethyl;

each m independently is 1 or 2;

each n independently represents 0, 1 or 2; and p = 0, 1, or 2.

To compound I preferably:

R1and R2each was independently hydrogen, alkyl, alkoxy, aryl, hydroxyalkyl, - CO2R5or-Z4-NR6R7;

R3and R4each independently represented by hydrogen, guide lname compounds are compounds where:

R1and R2each independently is lower alkyl or hydrogen;

R3and R4each independently represents lower alkyl, especially methyl;

and R11and R12each independently represents hydrogen, hydroxy, heterocycle, alkenyl, carboxamide, or substituted lower alkyl.

The following are definitions of terms used in this description. These definitions apply to terms used throughout this description, individually or as part of another group, if they are not limited to, otherwise in specific cases.

The term "alkyl" or "ALK-" refers to hydrocarbon groups, straight or branched chain having 1-10 carbon atoms, preferably 1 to 7 carbon atoms. The expression "lower alkyl" refers to alkyl groups with 1-4 carbon atoms.

The term "alkoxy" refers to the group alkyl-O-.

The term "aryl" or "ar" refers to phenyl, naphthyl and biphenyl.

The term "alkenyl" refers to hydrocarbon groups with straight or branched chain with 2 to 10 carbon atoms, having at least one double bond. Preferred are groups with two to four atoms of carbon is ausim, at least one triple bond. Preferred groups with two to four carbon atoms.

The term "alkylene" refers to the bridge with a straight chain of 1 to 5 carbon atoms connected by single bonds /for example, /CH2/x- where x is 1-5/, which may be substituted by 1-3 lower alkyl groups.

The term "albaniles" refers to the bridge with a direct chain with 2-5 carbon atoms, having one or two double bonds, which is connected by single bonds and may be substituted by 1-3 lower alkyl groups. Examples alkenylamine groups are - CH=CH-CH=CH-, -CH2-CH=CH, -CH2- CH=CH-CH2-, -C/CH3/2CH=CH - and-CH/S2H5/-CH=CH-.

The term "akinyan" refers to the bridge with a direct chain of 2-5 carbon atoms, which has a triple bond and is attached by single bonds, and may be substituted by 1-3 lower alkyl groups. Examples alkenylamine groups are

The term "alkanoyl" refers to groups of the formula-C/O/alkyl.

The term "cycloalkyl" and "cycloalkenyl" refers to cyclic hydrocarbon groups with 3 to 8 carbon atoms.

The term "hydroxyalkyl" refers to an alkyl group that includes one or more ulichnye.

The terms "halo" and "halogen" refer to fluorine, chlorine, bromine and iodine.

The terms "heterocycle", "heterocyclic" and "heterocycle" refers to optionally substituted, fully saturated or unsaturated aromatic or nonaromatic cyclic group, for example, which represents a 4-7-membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in the ring, containing at least one carbon atom. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur, with the heteroatoms nitrogen and sulfur may be optionally oxidized and the nitrogen heteroatoms may be optionally quaternidinum. Heterocyclic group may join at any heteroatom or carbon atom.

Examples of monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolines, imidazoles, imidazolines, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, diazolidinyl, isothiazolin, isothiazolinones, furyl, tetrahed the sludge, 2 - oxoazetidin, azepine, 4 - piperidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiomorpholine, thiomorpholine, sulfoxide, themorphological, 1,3 - dioxolane and tetrahydro-1,1-DIOXOLANYL, and similar.

Examples of bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothiazyl, hinokitiol, chinoline, Tetra-hydroisoquinoline, ethenolysis, benzimidazolyl, benzopyranyl, indolizinyl, benzofuran, chromones, coumarinyl, benzopyranyl, cinnoline, honokalani, indazoles, pyrrolopyridine, properidine /such as furo/2,3-pyridinyl, furo /3,2-b/pyridinyl, furo/2,3-b/pyridinyl/, dihydroisoquinolyl, dihydroquinazolines /such as 3,4-dihydro - 4-oxo-hintline/ and similar.

Examples of tricyclic heterocyclic groups include carbazolyl, bunzendahl, phenanthrolines, acridines, phenanthridines, xantener and similar.

The terms "substituted heterocycle" refers to a heterocycle, substituted 1, 2 or 3 of the following substituents:

/a/ is alkyl, especially lower alkyl;

/b/ hydroxy or protected hydroxy/;

/c/ halogen;

/d/ oxo /ie = O/;

/e/ amino, alkylamino or dialkylamino;
alkoxycarbonyl: such as unsubstituted lower alkoxycarbonyl;

/k/ carbamyl, allylcarbamate or diallylbarbital;

/I/ mercapto,

/m/ nitro;

/n/ cyano;

/o/ carbalkoxy;

/p/ sulfonamide, sulfonamideubul or sulfonamideubul;

< / BR>
< / BR>
/s/ aryl,

/t/ alkylcarboxylic;

/u/ arylcarboxylic;

/v/ aaltio;

/w/ aryloxy;

/x/ alkylthio;

/y/ formyl;

/z/ arylalkyl; or

/a'/ aryl, substituted alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino, halogen or trihalomethyl.

The term "heterocyclic" denotes a heterocyclic group linked via an oxygen bridge.

Throughout the description of the group and their deputies selected to ensure stable fragments and joints.

The compounds of formula I form salts which are also covered by the scope of the invention. Preferred are pharmaceutically acceptable /ie, non-toxic, physiologically acceptable salts, although other useful salts, for example, when selecting or clearing the compounds of this invention.

The compounds of formula I may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as CA is-glycemic and hydrobasin, and with amino acids, such as arginyl, lysine and similar. Such salts can be obtained through reaction of compound I with the desired ion in a medium in which the salt precipitates or in an aqueous medium followed by lyophilization.

When the substituents R1-R4or R11-R14include the main fragment, such as amino or substituted amino, the compound I may form salts with various organic and inorganic acids. Such salts include salts formed with hydrochloric acid, hydrogen bromide, methanesulphonate, sulfuric acid, acetic acid, maleic acid, bansilalpet, toluensulfonate and various other sulfonates, nitrates, phosphates, borates, acetates, tartratami, maleate, citrates, succinate, benzoate, ascorbate, salicylates and similar. Such salts can be formed through reaction of compound I in the equivalent amount of acid in the medium in which the salt precipitates or in an aqueous medium followed by lyophilization.

In addition, when R1-R4or R11-R14the substituents include a core fragment, such as amino, can be formed zwitterionic /"internal salt"/.

The compounds of formula I are antagonists of ET-1, ET-2 and/or ET-3, and useful in the treatment of conditions associated with increased levels of ET /for example, dialysis, trauma and surgery/ and all the endothelin-dependent disorders. Thus, they are useful as antihypertensive agents. When assigning a composition having one or combination/ of the compounds of the present invention, decreases blood pressure in hypertensive mammals /for example,/. They are also useful when pregnancy-induced hypertension, and coma /pre-eclampsia and eclampsia/ acute portal hypertension and hypertension secondary to treatment with erythropoietin.

Compounds of the present invention are also useful in the treatment of disorders associated with renal function, glomer the Denia renal damage secondary to old age, or associated with dialysis, nephrosclerosis /especially hypertensive nephrosclerosis/, nephrotoxicity /including nephrotoxicity associated with visualisasi and contrast agents and cyclosporine/, renal ischemia, primary vesicoureteral reflux, glomerulosclerosis and similar. The compounds of this invention may also be useful in the treatment of disorders related to the function of paracrine and endocrine.

Compounds of the present invention are also useful in the treatment of endotoxemia or endotoxin shock and hemorrhagic shock.

Compounds of the present invention are also useful in the case of hypoxic or ischemic disease and as an anti-ischemic agents for the treatment of, for example, cardiac, renal and cerebral ischemia and reperfusion such as occurs after surgery using the heart-lung/, spasms of the coronary and cerebral vessels and similar.

In addition to the stated compounds of the present invention may also be useful as anti-arrhythmic agents, protivoallergennyh agentsletting agents; addition to cardioplegic solutions for cardiopulmonary bypass, auxiliary means for thrombolytic therapy, and as an anti - diarrhoeal agents. The compounds of this invention may be useful in the treatment of myocardial infarction; treatment of peripheral vascular disease /for example, disease Rened and disease, Takayasu's disease/, for the treatment of cardiac hypertrophy /for example, hypertrophic cardiomyopathy/; treatment of primary pulmonary hypertension /for example, plexogenic, embolic/ adults and neonates and pulmonary hypertension secondary to heart failure, radiation and chemotherapy damage, or other injuries; in the treatment of vascular disorders of the Central nervous system such as stroke, migraine and subarachnoid bleeding/; treatment of behavioural disorders, associated with the Central nervous system; in the treatment of gastrointestinal diseases such as ulcerative colitis, Crohn's disease, damage to the mucous membrane of the stomach, ulcerative and ischemic disease of the digestive tract; treatment of diseases of the gallbladder or bile ducts, such as cholangitis; in the treatment of pancreatitis; for the regulation of cell growth; in the treatment of EXT is transplantation; in the treatment of congestive heart failure, including inhibition of fibrosis; inhibition of dilatation of the left ventricle, reconstruction and dysfunction; and in the treatment of hepatitis and sudden death. The compounds of this invention can be useful in the treatment of sickle cell disease, including the initiation and/or evolution of painful crises for this disease; in the treatment of pernicious effects of ET-producing tumors, such as hypertension, resulting hemangiopericytoma; the treatment of early and advanced liver disease and damage, including the associated complications /for example, hepatotoxicity, fibrosis and cirrhosis/; in the treatment of spastic diseases of the urinary tract and/or bladder; treatment hepatorenal syndrome; in the treatment of immunological diseases, including vasculitis, such as lupus, General sclerosis, mixed cryoglobulinemia; in the treatment of fibrosis associated with renal dysfunction, and hepatotoxicity. The compounds of this invention may be useful in the treatment of metabolic and neurological disorders; cancer; insulin-dependent and non-insulin-dependent diabetes mellitus; neuropathy; retinopathy; pair; bone reconstruction; psoriasis; and chronic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, sarcoidosis and eczematous dermatitis /all types of dermatitis/.

The compounds of this invention can also be converted to finished forms of drugs in combination with inhibitors of endothelin-converting enzyme /ECE/ such as phosphoramidon; antagonists thromboxane receptors; the means for facilitating disclosure of potassium channels, inhibitors of thrombin /for example, hirudinea and similar/; inhibitors of growth factor, such as modulators of PDGF activity; antagonists of platelet activating factor /PAF/; receptor antagonists angiotensin II /AII/; renin inhibitors; inhibitors angiotenzinkonvertiruyuschego enzymes /ACE/, such as captopril, zofenopril, fosinopril, ceronapril, or - April, enalapril, delapril, pentopril, inapril, ramipril, lisinopril, and salts of such compounds, inhibitors of neutral endopeptidase /NEP/; Dual NEP-ACE inhibitors; inhibitors MWF COA reductase inhibitor such as pravastatin and mevacor, inhibitors of squalene synthetase; biliary acids; such as questran; calcium channel blockers; activitiesrelated, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichlormethiazide, polythiazide or benzothiazin, as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, muzolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds, and thrombolytic agents such as activator tissue plasminogen /tra/, recombinant TPA, streptokinase, urokinase, the PUK and the complex activator, streptokinase Antilibanus plasminogen /APASAC/. If the connections are formed as a fixed dose, such combination products contain compounds of this invention at doses described below and the other pharmaceutically active agents within the accepted range of doses. The compounds of this invention can also be formulated in the form of ready-made forms in combination with useful or useful in combination with them, antifungal and immunosuppressive agents such as amphotericin B, cyclosporine, and similar, to counter glomerular reduction and nephrotoxicity secondary to these compounds. The compounds of this invention can also be used in conjunction with hemodialysis.

Connection izopet is defined such diseases, for example, people in an effective amount in the range of doses from about 0.1 to 100 mg/kg, preferably from about 0.2 to 50 mg/kg, and more preferably from about 0.5 to 25 mg/kg or from about 1 to 2500 mg, preferably from about 5 to 2000 kg in a single dose or in doses, separated by 2-4 times.

The active substance may be used in compositions such as tablets, capsules, solutions or suspensions containing from about 5 to 500 mg of a compound or mixture of compounds of formula I in a single dose or in topical form for wound healing /0.01 to 5% by weight of compounds of formula I, 1 to 5 treatments per day. They can compoundrelated conventional manner with a physiologically acceptable carrier, excipient, binder, preservative agent, a stabilizer, a flavoring agent, etc. or with a topical carrier such as Plastibase /mineral oil, generowanie polyethylene/, as is customary in conventional pharmaceutical practice.

Compounds of the invention can also be assigned tapicerki for the treatment of peripheral vascular disease, and as such they are in the form of creams or ointments.

The compounds of formula I are prepared in the form of compositions such as stereometria with a physiologically acceptable diluent, the media, excipient, binder, preservative agent, stabilizer, etc. in the form of a unit dose in normal pharmaceutical practice. The amount of active substance in these compositions and preparations is to get the right dose at the specified interval.

Compounds of the present invention can be obtained as follows (see figure I in the end of the description).

As shown in scheme I, the target compound 4 can be obtained by using catalyzed by Pd /O/ combination of appropriately substituted phenylsulfonyl-2-bromovalerate intermediate compound 2 with 4 - heterocyclic helgaleena I in the presence of a suitable base, such as aqueous potassium carbonate and a solvent such as a mixture of toluene and ethanol.

Baronova acid (intermediate compound 2) can be obtained from 2-bromophenylacetate 5 /the receipt of which is described in EP publication N 0569193 /1993/ by litvinovna appropriate alkyllithium (such as n-utility), followed by treatment with trialkylborane (for example, triisopropylsilane/ and finally, add aqueous acid such as aqueous hydrochloric acid (see scheme II at the end of the national group, also described in EP publication N 0569193 /1993/.

The target compounds can also be synthesized using an alternative method, shown in scheme III in the end of the description.

As shown above, the 4 - heterocyclic aryl halides 6 /see also connection 1/ can turn into baronova-acid intermediate compound 7 shows the sequence of reactions. This connection when catalyzed by Pd/O/ combined with compound 5 can give bearily analog 3, which upon removal of protection can lead to the ultimate compound 4. In some cases heteroatoms J and K or L may require protection to obtain Bronevoy acid 7, and/or to facilitate the reaction of combining /joining/ to obtain compound 3. For example, when J and K or L are N, one of the groups may be protected with suitable protective group, such as tertbutoxycarbonyl and others/. In some cases, also baronova acid may be replaced by a species of tin and/or halide group may be replaced by a fragment - OSO2CF3to conduct Pd catalyzed reaction combinations.

As for common approaches or guidelines for beryllina synthesis, see publication Bringmann and other Angew. Chem. Inst., eng. I they were compatible with the conditions of the reaction. Additionally, a particular group, R11- R14can become an alternative R11- R14group, or before, or after combination of compound 1 with compound 2, or compound 5 with compound 7, using methods known in the art.

The SYNTHESES of COMPOUNDS 1 and 6

Compounds 1 and 6 can be obtained according to the following schemes, 2-relaxatory obtained as shown in scheme IV, Methods A-H; 4 - relaxatory obtained as shown in scheme V, methods A-B; 5 - relaxatory obtained as depicted in scheme VI, methods A-B; thiazole obtained as shown in scheme VII, methods A-B; imidazoles are obtained as shown in scheme VIII; 2 - phenylalkylamines obtained as shown in scheme IX, methods A-B; pyrazoles are obtained, as shown in the diagram X; 3-increase of Ls concentration are obtained as shown in scheme XI; 5-increase of Ls concentration are obtained as shown in scheme XII; and N-arylamidase obtained according to scheme XIII. In these schemes, R11and R12are also selected to be compatible with shows the reaction conditions (scheme IV-XIII, see the end of the description).

A. 2-Relaxatory (see scheme IV, method A).

Acylamino compound 9 is obtained, as shown above, and may the CEC is their methods, see publication: Lakhan and others, Adv. Het Chem., 17 /1974/, 99.

Scheme IV. Method B (see the end of the description).

As shown, the heating together a mixture of benzamide II and - halogen-compounds 12 gives the corresponding oxazol 13. This method is widely used for the production of 2,4 - disubstituted oksazolov. For an overview, see: Lakhan and other, Ad.Het.Chem., 17, /1979/99-211.

Scheme IV. Method C (see the end of the description).

Ester 15 may be, or by reaction of haloalkene with benzoic acid 14 in the presence of a base, such as triethylamine, or complex esterification relevant - hydroxyketones. The connection 15 in the processing of ammonium acetate in acetic acid gives oxazol 16.

Scheme IV. Method D (see the end of the description).

Some acetylene carbinol, such as the connection 17 can react directly with arylnitrenes 18, giving 5 - methoxazole 19.

/see, for example, Y. Yura. Japanese patent 29849 /1964/.

Scheme IV. Method E (see the end of the description).

Acetylene amide 22 when heated cichlisuite the derived oxazole 23.

Scheme IV. Method F (see the end of the description).

4,5 - unsubstituted oxazole 26 can be obtained with the condensation of 4 - bromobenzene for example, publication Ferrini and others, Angew. Chem. Internat. Ed., volume 2, 1963, 99/.

Scheme IV. Method G (see the end of the description).

Cyclization of N-/2.2-dichlorethyl/ amide derivative 27, obtained using methods known in the art, in the presence of a suitable base, such as sodium ethylate, can also give oxazoline derivative 26. /Cm., for example, U.S. patent N 3953465/.

Scheme IV. Method H (see the end of the description).

Heating together a mixture of akriloilkhlorida 21 with oxime 29, where R1and R2represent alkyl, obtained by known in the art methods, can give a derivative oxazole 10 /Cm., for example, Bhatt, M. V. and Reddy, A. S., Tet. Lett., 21, 2359 /1980/.

Scheme IV. Method I (see the end of the description).

Heating together a mixture of acrilamide 21 with triazole 25, in which R is trimethylsilyl, obtained by methods known in the art, in a suitable solvent, such as toluene, can give a derivative oxazole 26 /see, for example, Williams, E. L., Tet. Lett., 33, 1033-1036 /1992//.

Derived oxazole 26 can also be obtained by using processing akriloilkhlorida 21 triazole /in which R represents a hydrogen/ in the presence of a suitable base such as potassium carbonate, followed by heating smeh">

Processing - bromoacetophenone derived 30 amidon at high temperatures /typically 130 - 150oC/ gives 4 - allocator 31.

Scheme V Method B (see the end of the description).

Some metilirovannye isonitrile 32 obtained by methods known in the art, interact with acylhomoserine, imidazoles or other activated acyl groups, giving 2-unsubstituted a oksazolov 33, in which R2is alkyl or aryl.

C. 5-Relaxatory

Scheme VI. Method A (see the end of the description).

Acylation - aminoacetophenone 34 acylchlorides network connection 35. The connection 35 after cyclization using a suitable dehydrating agent such as sulphuric acid, gives oxazol 36. /This method is similar to the method described in scheme IV, the method And/.

Scheme VI. Method B (see the end of the description).

4-Halogentated 37 is processed by toiletrieschoice 38 in the presence of a base such as potassium carbonate, in a suitable solvent, such as methanol, giving 5 - relaxazone derivative 39. /Cm. for example, A. M. Van Leusen and others, Tet. Lett., 2369 /1972//.

D. Thiazole

Scheme VII. Method A (see end of description)

4-Brompheniramine kitty and a suitable base (for example, aqueous potassium carbonate and the solvent, giving a thiazole 40.

Scheme VII. Method B (see the end of the description).

Condensation of p-bromobenzonitrile 18 thioketones gives directly to the thiazole derivative 44.

E. Imidazoles

Scheme VIII (see the end of the description).

The condensation of the benzaldehyde derivative 37 glyoxal and ammonia gives 2-arylamidine derivative 45. /Cm., for example, U.S. patent N 3682949/. This compound may be further substituted with reaction with alkylhalogenide in the presence of a suitable base, giving for example, N-alkyl-derivative 46.

Regarding the synthesis of imidazole see publication Adv. Het. Chem., 27 /1980/, 241-323.

F. 2-phenylalkylamines

Scheme IX. Method A (see end of description)

2-Phenylalkylamines 48, in which p represents 1 or 2, unsubstituted in the 4 and 5 positions can be obtained by heating together phenylalkylamine 47 together with vinylnorbornene 25 in the presence of the agent, such as polyphosphoric acid.

Scheme IX. Method B (see the end of the description).

2-Arylalkyl-4-substituted-oxazol 51, in which R1is alkyl, and n represents 1 or 2, can be obtained on the basis of nitrile 49, as shown above. /Cm., which of pyrazole 52 can be obtained by heating arylhydrazines 53 together with epichlorohydrin in the presence of a suitable base, such as triethylamine.

H. 3-the increase of Ls concentration

Scheme XI (Cm. at the end of the description).

Treatment of the oxime 54 obtained by methods known in the art, a mixture of HCl/Oxon, and subsequent treatment with base, such as triethylamine, gives areintroduced. Areintroduced usually not singled out and subjected to reaction with vinyl acetate, and the mixture is then heated in acid /for example, HCl/ in a suitable solvent, such as ethanol, giving the derived 3-arylisoxazoles 55.

1. 5-increase of Ls concentration

Scheme XII (see the end of the description).

,-Unsaturated ketone 56 obtained by methods known in the art, when processed by hydroxylamine gives the corresponding derived oxime. Cyclization of this material in the presence of iodine and potassium iodide gives the derived 5 - arylisoxazoles 57. R1this diagram represents alkyl or aryl. /Cm., for example, J. Het. Chem., 30, 467/1993/.

J. N-Arylamidase

Scheme XIII (see at the end in the end of the description).

N-Elliminating similar 59 can be obtained using the standard reaction of a combination of Ullman, known in the art, the compounds of 1,4-dibromobenzene with 58 with imidazole in the presence of copper salts, such as CuBr.

The invention d is subramania. These examples are intended to illustrate but not to limit.

Example 1

N-(3,4-Dimethyl-5-isoxazolyl)-4'- (2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide

< / BR>
A. 2 /4-Bromophenyl/oxazol

A mixture of 4-bromobenzophenone /4 g, 20 mmol/, vinylnorbornene /1,72 g, 20 mmol/ and 10 g of polyphosphoric acid was heated at 170oC for 3 hours. After cooling, the mixture was distributed between 200 ml of water and 200 ml of ethyl acetate. The aqueous layer was extracted with two portions of 150 ml of ethyl acetate. The combined organic liquid was washed with 100 ml water and 50 ml brine, dried and concentrated. The residue was chromatographically on silica gel using a 10:1 mixture of hexane/ethyl acetate, giving the connection A /2.49 g, 56%/ in the form of a white solid.

Century 2-Borono-N-/3,4-dimethyl-5-isoxazolyl/- N-/methoxyethoxymethyl/-benzosulfimide

To a solution of 2-bromo-N-/3,4-dimethyl-5-isoxazolyl/ N'/methoxyethoxymethyl/ benzosulfimide /5.67 g, 13.52 mmol obtained as described in EP 0563193 /1993// in 70 ml of tetrahydrofuran at -78oC, n-utility /2M solution in cyclohexane, 8.11 ml, 16.23 mmole/ was added over 10 minutes. The resulting solution is stirred at -78oC for 15 minutes, and added what was Savalas within 2 hours. The mixture was cooled to 0oC, was added 10% aqueous hydrochloric acid /120 ml, and the solution was mixed for 10 minutes. The mixture was concentrated to 120 ml and was extracted 4 x 60 ml ethyl acetate. The combined organic extracts were washed once with 100 ml brine, dried /magnesium sulfate/ and concentrated; giving connection /4.25 g 82%/ in the form of a light yellow resin.

C. N-(3,4-Dimethyl-5-isoxazolyl)-N-[(2 - methoxyethoxy)methyl]-4'-(2-oxazolyl) [1,1'-biphenyl]-2 - sulfonamide

To a solution of compound /315 mg of 0.82 mmole/ added connection And /456 mg, 2.05 mmole/ and 7.5 ml of toluene and 6 ml of 95% ethanol in an argon atmosphere were added tetrakis/triphenylphosphine/ palladium /O/ /95 mg, 0.082 mmole/ and then adding 4.5 ml of 2 M aqueous sodium carbonate. The reaction mixture was heated at 75oC for 4 hours, cooled and diluted with 50 ml ethyl acetate. The organic liquid was separated and was washed with 10 ml water and 10 ml brine, dried and concentrated. The residue was chromatographically on silica gel using a 2:1 mixture of hexane/ethyl acetate, giving the connection /279 mg, 70%/ in the form of a colourless resin.

D. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2 - oxazolyl) [1,1'-biphenyl]-2-sulfonamide

To rest is camping under reflux for 1 hour and 10 minutes. The reaction mixture was concentrated, and the pH of the solution was brought to 8 using sodium bicarbonate solution. The solution was then pagkilala to pH 5 with glacial acetic acid. The mixture was extracted 3 x 40 ml ethyl acetate. The organic liquid was washed with 10 ml water and 10 ml brine, dried and concentrated. The residue was chromatographically on silica gel using a mixture of 100:1 dichloromethane and methanol, yielding the target compound /117 mg, 52% of/ in the form of a white solid.

So pl. 90-98oC /amorphous substance/.

Analysis for C20H17N3O4S:

Calculated: 60,75, H 4,33, N 10,63, S 8,11.

Found: 60,80, H 4,15, N 10,38, S 8,12.

Example 2

N-(3,4-Dimethyl-5-isoxazolyl)-4'- (2-thiazolyl) [1,1'-biphenyl]-2-sulfonamide

< / BR>
A. 2-(4-Bromophenyl)thiazole

To a solution of 4-brompheniramine acid (3,01 g, 15 mmol), 2-bromothiazole (9,84 g, 60 mmol) in 120 ml of toluene and 96 ml of 95% ethanol in an argon atmosphere were added tetrakis (triphenylphosphine) palladium (0) (1.04 g, 0.9 mmole), followed by adding 72 ml of 2 M aqueous sodium carbonate. The reaction mixture was heated at 75oC for 1 hour and 15 minutes, cooled and diluted with 300 ml of ethyl acetate. Organic was chromatographically on silica gel using 30: 1 hexane/an ethyl acetate mixture, giving connection And /2.0 g, 56%/ in the form of a white solid.

C. N-(3,4-Dimethyl-5-isoxazolyl)-N-[(2 - methoxyethoxy)methyl]-4'-(2-thiazolyl)[1,1'-biphenyl]-2-sulfonamide

To a solution of the compound In example 1 (320 mg, or 0.83 mmole) and compound A (400 mg, 1,67 mmole) in 7.5 ml of toluene and 6 ml of 95% ethanol in an argon atmosphere were added tetrakis (triphenylphosphine) palladium (0) (96 mg, 0,083 mmole), and then 4.5 ml of 2 M aqueous sodium carbonate. The reaction mixture was heated at 75oC for 3 hours, cooled and diluted with 50 ml ethyl acetate. The organic liquid was separated and was washed with 10 ml water and 10 ml brine, dried and concentrated. The residue was chromatographically on silica gel using a 2.5:1 mixture of hexane and ethyl acetate, giving the connection /291 mg, 70%/ in the form of a colourless resin.

C. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-thiazolyl) [1,1' -biphenyl]-2-sulfonamide

To a solution of compound (290 mg, of 0.58 mmole) in 10 ml of 95% ethanol was added 10 ml of 6 N. aqueous hydrochloric acid and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated and the pH of the solution was brought to 8 using sodium bicarbonate solution. The mixture was then padillas to pH 5 using ice uksusnaya and 10 ml of saline solution, were dried and concentrated. The residue was chromatographically on silica gel using a 100: 1 mixture of dichloromethane and methanol, yielding the target compound (180 mg, 75%) as not quite white solid.

So pl. 87-97oC /amorphous/.

Analysis for C20H17N3O3S20,34 H2O:

Calculated: 57,52, H 4,27, N 10,06, S 15,35.

Found: 57,68, H 4,08, N 9,90, S 15,06.

Example 3

N-(3,4-Dimethyl-5-isoxazolyl)-4'-(4,5-dimethyl) 2 - oxazolyl) [1,1'-biphenyl]-2-sulfonamide

< / BR>
A. 4-Brabantia acid, 2-oxo-1-methylpropyloxy ether

To 3-hydroxy-2-butanone /1,32 g, 15 mmol/ and 4-bromobenzonitrile (3,29 g, 15 mmol) in 15 ml dichloromethane at 0oC was added dropwise 5 ml of pyridine. The reaction mixture was stirred at room temperature for 5 hours, was added 150 ml of ethyl acetate, and the mixture was filtered. The filtrate was washed 2 x 50 ml of 10% hydrochloric acid, 30 ml of water and 30 ml brine, dried and concentrated. The residue was chromatographically on silica gel using a 10:1 mixture of hexane and ethyl acetate, giving the compound (3.4 g, 84%) as a white solid.

Century 2-(4-Bromophenyl)-4,5-dimethoxy

A mixture of compound (3.4 g, 12,54 mmole), ACE is placed and the mixture was distributed between 150 ml of water and 200 ml of ethyl acetate. The organic liquid was washed with 50 ml water and 50 ml brine, dried and concentrated. The residue was chromatographically on silica gel using 25: 1 mixture of hexane and ethyl acetate, giving the compound (1.52 g, 48%) as a white solid.

C. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(4,5 - dimethyl-2-oxazolyl)-N-[(2-methoxyethoxy)methyl] [1,1'- biphenyl]-2-sulfonamide

To a solution of the compound In example 1 (320 mg, or 0.83 mmole) and the compound In the above stage (420 mg, 1,67 mmole) in 7.5 ml of toluene and 6 ml of 95% ethanol in an argon atmosphere were added tetrakis(triphenylphosphine) palladium (0) (96 mg, 0,083 mmole), and then 4.5 ml of 2 M aqueous sodium carbonate. The reaction mixture was heated at 75oC for 4 hours, cooled and diluted with 50 ml ethyl acetate. The organic liquid was separated and was washed with 10 ml water and 10 ml brine, dried and concentrated. The residue was chromatographically on silica gel using a 2:1 mixture of hexane/ethanol, yielding the compound (300 mg, 70%) as a colourless resin.

D. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(4,5 - dimethyl-2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide.

To a solution of compound C (300 mg, of 0.59 mmole) in 10 ml of 95% ethanol was added 10 ml of 6 N. aqueous hydrochloric acid,the pH of the solution was brought to 8 using sodium bicarbonate solution. The mixture was then padillas to pH 5 glacial acetic acid. The mixture was extracted 3x40 ml of ethyl acetate. The organic liquid was washed with 10 ml water and 10 ml brine, dried and concentrated. The residue was chromatographically on silica gel using 1:1 mixture of hexane/ethyl acetate, yielding the target compound (178 mg, 72%) as a white solid.

So pl. 96 - 102oC /amorphous/.

Analysis for C22H21N3O4S 0,24 H2O:

Calculated: 61,76, H Is 5.06, N 9,82, S 7,49.

Found: 61,67, H 4,76, To 9.91 N, S To 7.59.

Example 4

N-(3,4-Dimethyl-5-isoxazolyl)-4'- (5-oxazolyl) [1,1-biphenyl]-2-sulfonamide

< / BR>
A. 5-(4-Bromophenyl)oxazol

The mixture 4,74 g (of 25.6 mmole) p-bromobenzaldehyde, 5.0 g (of 25.6 mmole) of toiletrieschoice and 4.25 g (30,7 mole) of anhydrous potassium carbonate in 150 ml of methanol was heated under reflux for 3 hours. The solvent was then evaporated, and added to the residual solid matter 150 ml of water. Reddish-white solid was filtered off and were washed several times with water, and then dried, giving the compound a (3,65 g, 64%).

C. N-(3,4-Dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl] - 4'-(5-oxazolyl) [1,1'-biphenyl]-2-sulfonamide

C. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(5-oxazolyl) [1,1-biphenyl]-2-sulfonamide

To a solution of 0.49 g (a 1.01 mmole) of the compound In 10 ml of 95% ethanol was added 10 ml of 6 N. aqueous hydrochloric acid, and the mixture was heated under reflux for 1 hour. The mixture was then concentrated and diluted with 50 ml water. The solution was kind of balanced out to pH 7 using saturated aqueous sodium bicarbonate, and then pagkilala to pH 4 using glacial acetic acid. The obtained white solid was filtered and dried (0,37 g). Crystallization from a mixture of dichloromethane /ethyl acetate/ hexanol gave 0,23 g (58%) of target compound as a white solid.

So pl. 189-191oC.

Analysis for C20H17N3O4S 0,28 H2O:

isoxazolyl)-4'- (4-oxazolyl) [1,1'-biphenyl]-2-sulfonamide

< / BR>
A. 4-(4-Bromophenyl)oxazol

A mixture of 5.0 g (18 mmol) ,p-dibromoacetone and of 4.05 g (83,9 mmole) of formamide was mixed with an oil bath at 130oC for 3 hours. The mixture was then poured into 150 ml of a mixture of ice and water, and the solution was extracted 3 × 100 ml ether. The combined ether extracts were washed once with water, dried and evaporated. The residue was chromatographically on 200 ml of silica gel using a mixture of hexane/ethyl acetate 3:1, yielding 1.3 g (32%) of compound A as a light brown solid.

C. N-(3,4-Dimethyl-5-isoxazolyl)-N-(2 - methoxyethoxy)methyl-4'-(4-oxazolyl) [1,1'-biphenyl]-2 - sulfonamide

To a solution of 0,668 g (1,74 mmole) of the compound from example 1 and 0.104 g g (0,09 mmole) tetrakis (tri-phenylphosphine) palladium (0) in 25 ml of toluene in an argon atmosphere was added 15 ml of 2 M aqueous sodium carbonate, and then 0.52 g (2,32 mmole) of the compound in 15 ml of 95% ethanol. The mixture was heated under reflux for 3 hours, it was diluted with 100 ml water and extracted 3 x 75 ml ethyl acetate. The combined organic extracts were washed once with 100 ml brine, dried and evaporated. The residue was chromatographically on 50 g of silica gel using a mixture of hexanol and ethyl acetate 2:1, giving 0,43 g (51%) fonemed

To a solution of 0.75 ml of 1.55 mmole) of the compound In 8 ml of acetonitrile at 0oC in argon atmosphere was added a 2.01 g trimethylsilylpropyne and 2,73 g of sodium iodide, and the mixture is stirred at room temperature for 1 hour. The mixture was then diluted with 10 ml water and was extracted with 100 ml of ethyl acetate. The organic layer was washed with 10 ml of saturated aqueous sodium thiosulfate, dried and evaporated. This material was purified using preparative PHLC with reversed phase 30 × 500 mm ODS S10 column using 68% solvent A (90% methanol, 10% water, 0.1% of triperoxonane acid) and 32% solvent B (10% methanol, 90% water, 0.1% of triperoxonane acid). The appropriate fractions were collected and were kind of balanced out the water with sodium bicarbonate to pH 7 and concentrated to 10 ml of the Solution was pagkilala to pH 4 using glacial acetic acid and the white solid was filtered off and dried, yielding 0.33 g (54%) of target compound.

So pl. 85-93oC (amorphous)

Analysis for C20H17N3O4S0,21 H2O:

Calculated: 60,18, H 4,40, N 10,53, S 8,03.

Found: 60,27, H Of 4.05, N 10,44, S 7,88.

Example 6

N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-methyl-4 - oxazolyl) [1,1-biphenyl]-2-sulfonamide

th) was heated at 130oC for 3 hours. This mixture was poured onto 30 g of ice was added 150 ml of ethyl acetate. The organic layer was separated and was washed with 30 ml of 1 N. sodium hydroxide, 30 ml of 1 N. hydrochloric acid and 30 ml of brine, dried and concentrated. The residue was chromatographically on silica gel using a mixture of 15:1 hexane/ethyl acetate, giving the compound (1.29 g, 54%) as a white solid.

B. N-(3,4-Dimethyl-5-isoxazolyl)-N- [(2-methoxyethoxy)methyl] - 4'-(2-methyl-4-oxazolyl) [1,1'-biphenyl] -2-sulfonamide

To a solution of compound (402 mg, 1.7 mmole) and the compound In example 1 (259 mg, 0.68 mmole) in 6.5 ml of toluene and 5.2 ml of 95% ethanol in an argon atmosphere were added tetrakis (triphenylphosphine) palladium (0) (0,78 mg, 0,068 mmole), and then to 3.9 ml of 2 M aqueous sodium carbonate. The reaction mixture was heated at 75oC for 3.5 hours, cooled and diluted with 40 ml ethyl acetate. The organic liquid was separated and was washed with 10 ml water and 10 ml brine, dried and concentrated. The residue was chromatographically on silica gel using 2:1 hexane/ethyl acetate, giving the compound (183 mg, 54%) as a colourless resin.

C. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-methyl-4 - oxazolyl) [1,1'-biphenyl]-2-sulfonamide

To rasasi under conditions of reflux distilled for 55 minutes. The reaction mixture was concentrated, and the pH of the solution was brought to 8 using sodium bicarbonate solution. The solution was then pagkilala to pH 5 glacial acetic acid. The mixture was extracted 3 x 30 ml ethyl acetate. The organic liquid was washed with 10 ml of saline solution, dried and concentrated. The residue was chromatographically on silica gel using 100:1 dichloromethane/methanol, yielding the target compound (56 mg, 38%) as a pale yellow solid.

So pl. 90 - 100oC /amorphous/.

Analysis for C21H19N3O4S:

Calculated: 61,60, H 4,68, N 10,26, S 7,83.

Found: 61,56, H 4,33, N 9,85, S 7,94.

Example 7

N-(3,4-Dimethyl-5-isoxazolyl)-4'- (4-methyl-2-oxazolyl) [1,1' - biphenyl] -2-sulfonamide

< / BR>
A. 2-(4-Bromophenyl)-4-methoxazole

4-Bromobenzonitrile (9.1 g, 50 mmol) and propargilovyh alcohol (2.8 g, 50 mmol) was added dropwise 12.5 ml of concentrated sulfuric acid at -15oC. the Reaction mixture was stirred at 0oC for 3 hours, heated to room temperature slowly and stirred overnight. The mixture was poured into 200 ml of ice water was kind of balanced out by the sodium bicarbonate and was extracted 3 x 200 were formed. The residue was chromatographically on silica gel using 30: 1 mixture of hexane/ethyl acetate, giving the compound (1.44 g, 12%) as a white solid.

C. N-(3,4-Dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl] - 4'-[(4-methyl-2-oxazolyl)] [1,1'-biphenyl]-2-sulfonamide

To a solution of the compound In example 1 (320 mg, or 0.83 mmole) and compound (397 mg, 1,67 mmole) in 7.5 ml of toluene and 6 ml of 95% ethanol in an argon atmosphere were added tetrakis (triphenylphosphine) palladium (0) (96 mg, 0,083 mmole), and then 4.5 ml of 2 M aqueous sodium carbonate. The reaction mixture was heated at 75oC for 4 hours, cooled and diluted with 50 ml ethyl acetate. The organic liquid was separated, was washed with 10 ml water and 10 ml brine, dried and concentrated. The residue was chromatographically on silica gel using a mixture of 2:1 hexane and ethyl acetate, giving the compound (300 mg, 72%) as a colourless resin.

C. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(4 - methyl-2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide

To a solution of compound (300 mg, 0.60 mmole) in 10 ml of 95% ethanol was added 10 ml of 6 N. aqueous hydrochloric acid, and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated and the pH of the solution was brought, and the Mixture was extracted 3 x 40 ml ethyl acetate.

The organic liquid was washed with 10 ml water and 10 ml brine, dried and concentrated. The residue was chromatographically on silica gel using a mixture of 100:1 dichloromethane and methanol, yielding the target compound (200 mg 81%) as a white solid.

So pl. 85 - 95oC /amorphous/.

Analysis for C21H19N3O4S 0,25 H2O:

Calculated: 60,92, H 4,75, N 10,15 S 7,74.

Found: 61,15, H 4,60, N 9,89, S A 7.62.

Example 8

N-(3,4-Dimethyl-5-isoxazolyl)-4'- (5-methyl-2 - oxazolyl) [1,1'-biphenyl] -2-sulfonamide

< / BR>
A. 2-(4-Bromophenyl)-5-methoxazole

To 4-bromobenzonitrile (4,39 g, 20 mmol) in 40 ml dichloromethane at 0oC was added propargylamine (1.10 g, 20 mmol) and then triethylamine (of 4.05 g, 40 mmol). The mixture is stirred at room temperature for 40 minutes. Was added 150 ml of ethyl acetate and the mixture was filtered, the filtrate was washed with 2 x 40 ml water and 40 ml of brine, dried and concentrated yielding 4-bromo-N-(2-PROPYNYL)benzamide. 4-Bromo - N-(2-PROPYNYL) benzamide was added to the chilled 47 ml of concentrated sulfuric acid. The reaction mixture is stirred at 5-10oC for 3 hours and at room temperature over night. Smartime ethyl acetate. The combined organic extracts were washed with 200 ml of water and 100 ml brine, dried and concentrated, giving the compound (4.5 g, 95%) as a pale yellow solid.

So pl. 61-63oC.

C. N-(3,4-Dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]- 4'-(5-methyl-2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide

To a solution of the compound In example 1 (320 mg, or 0.83 mmole) and compound (397 mg, 1,67 mmole) in 7.5 ml of toluene and 6 ml of 95% ethanol in an argon atmosphere were added tetrakis (triphenylphosphine) palladium (0) (96 mg, 0,083 mmole) followed by the addition of 4.5 ml of 2 M aqueous sodium carbonate. The reaction mixture was heated at 75oC for 3 hours, cooled and diluted with 50 ml ethyl acetate. The organic liquid was separated and was washed with 10 ml water and 10 ml brine, dried and concentrated. The residue was chromatographically on silica gel using a 2:1 mixture of hexane/ethyl acetate, giving the compound (298 mg, 72%) as a colourless resin.

C. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(5-methyl-2 - oxazolyl) [1,1-biphenyl] -2-sulfonamide

To a solution of compound (298 mg, 0.60 mmole) in 10 ml of 95% ethanol was added 10 ml of 6 N. aqueous hydrochloric acid, and the mixture was heated under reflux for 1 is sodium carbonate. The solution was then pagkilala to pH 5 glacial acetic acid. The mixture was extracted 3 times with 40 ml portions of ethyl acetate. The organic liquid was washed with 10 ml water and 10 ml brine, dried and concentrated. The residue was chromatographically on silica gel using a 100:1 mixture of dichloromethane and methanol, yielding the target compound (147 mg, 60%) as not quite white solid.

So pl. 90 - 100oC (amorphous).

Analysis for C21H19N3O4S:

Calculated: 61,60, H 4,68, N 10,26, S 7,83.

Found 61,39, H 4,11, N There Is A 10.03, S To 7.61.

Example 9

N-(3,4-Dimethyl-5-isoxazolyl)-4'- (1H-pyrazole-1-yl) [1,1'-biphenyl]-2-sulfonamide

< / BR>
A. 1-(4-Bromophenyl)-IH-pyrazole

To ethylchloride (4 g, 43,23 mmole) and 4-bromophenylacetate (19.32 g, 86,46 mmole) in 20 ml of 60% ethanol was added dropwise a triethylamine (8,75 g, 12,05 mmole). The mixture was slowly heated, and then was heated with reverse

refrigerator for 1 hour. The solvent was evaporated, and the residue was heated at 170oC for 30 minutes and at 200oC for 10 minutes. Was added 150 ml of water, and the mixture was extracted three times with 200 ml portions of ethyl acetate. The combined organic liquid was washed 5 is of 40:1 mixture of hexane and ethyl acetate, giving the connection A (2,92 g, 30%), which crystallized from hexane, yielding yellow needles.

So pl. 72-74oC.

C. N-(3,4-Dimethyl-5-isoxazolyl)-N-[(2 - methoxyethoxy)methyl] -4'-(1H-pyrazole-1-yl) [1,1'- biphenyl]-2-sulfonamide

To a solution of the compound In example 1 (320 mg, or 0.83 mmole) and compound (372 mg, 1,67 mmole) in 7.5 ml of toluene and 6 ml of 95% ethanol in an argon atmosphere were added tetrakis (triphenylphosphine) palladium (0) (96 mg, 0,083 mmole) followed by the addition of 4.5 ml of 2 M aqueous sodium carbonate. The reaction mixture was heated at 75oC for 2.5 hours, cooled and diluted with 50 ml ethyl acetate. The organic liquid was separated, was washed with 10 ml water and 10 ml brine, dried and concentrated. The residue was chromatographically on silica gel using a mixture of 3.5:1 hexane/ethyl acetate, giving the compound (280 mg, 70%) as a colourless resin.

C. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(1H - pyrazole-1-yl) [1,1'-biphenyl]-2-sulfonamide

To a solution of compound (260 mg, of 0.58 mmole) in 10 ml of 95% ethanol was added 10 ml of 6 N. aqueous hydrochloric acid, and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated, and the pH was brought to 8 by using a solution bicarbonate ethyl acetate. The organic liquid was washed with 10 ml water and 10 ml brine, dried and concentrated. The residue was chromatographically on silica gel using a mixture of 100:0,8 dichloromethane/methanol, yielding the target compound (161 mg, 70%) as not quite white solid.

So pl. 88-98oC (amorphous).

Analysis for C20H18N4O3S 0,12 H2O:

Calculated: 60,56, With 4.64 H, N 14,12, S 8,08.

Found: C 61,26, H To 4.52, N 13,96, S 8,06.

Example 10

N-(3,4-Dimethyl-5-isoxazolyl)-4'-[1-[(2-methoxyethoxy)methyl] - 1H-imidazol-2-yl] [1,1'-biphenyl]-2-sulfonamide

< / BR>
A. 2-(4-Bromophenyl)-1H-imidazol

To 4-Bromobenzaldehyde (9,25 g, 50 mmol) and glyoxal (40 wt.%, an aqueous solution of 11.6 ml, 80 mmol) in 20 ml of methanol was added dropwise 60 ml of 30% aqueous ammonium hydroxide. The mixture is stirred at room temperature over night. The solvent was evaporated under vacuum. The rest were slightly podslushivaet the addition of aqueous sodium hydroxide and was extracted with three portions of 300 ml of ethyl acetate. The combined organic extracts CoDeSys and concentrated. The residue was dissolved in 100 ml of methanol and filtered. The filtrate was concentrated, and the residue was pulverized with 20 ml of ethyl metoxi)methyl]-1H - imidazol

To the compound (400 mg, to 1.79 mmole) in 18 ml of tetrahydrofuran was added sodium hydride 60% in mineral oil (86 mg, 2.15 mmol). The mixture is stirred at room temperature for 10 minutes, was added dropwise methoxyethoxymethyl (335 mg, at 2.59 mmole). The reaction mixture was stirred at room temperature for 2 hours and concentrated. Was added 100 ml of ethyl acetate, and the organic liquid was washed with 20 ml water and 10 ml brine, dried and concentrated. The residue was chromatographically on silica gel using 100:400:1 mixture of hexane, ethyl acetate and triethylamine, giving compound (390 mg, 70%).

C. N-(3,4-Dimethyl-5-isoxazol)-N- [(2-methoxyethoxy)methyl]- 4'-[1-[(2-methoxyethoxy) methyl]-1H-imidazol-2-yl] [1,1'- biphenyl]-2-sulfonamide

To a solution of the compound In example 1 (722 mg, of 1.88 mmole) and the compound, obtained above (390 mg, 1.25 mmole), 11,25 ml of toluene and 9 ml of 95% ethanol in an argon atmosphere were added tetrakis (triphenylphosphine) palladium (0) (145 mg, 0.125 mmole) followed by the addition of 6.75 ml of 2 M aqueous sodium carbonate. The reaction mixture was heated at 75oC for 3 hours, cooled and diluted with 75 ml ethyl acetate. The organic liquid was separated, was washed 15 ml vozovna 100:0.2 to a mixture of ethyl acetate and triethylamine, giving the compound (400 mg, 56%) as a colourless resin.

D. N-(3,4-dimethyl-5-isoxazolyl)-4'-[1-[(2-methoxy)methyl] -1H - imidazol-2-yl] [1,1'-biphenyl]-2-sulfonamide

To a solution of compound (400 mg, 0.70 to mmole) in 12 ml of 95% ethanol was added 12 ml of 6 N. aqueous hydrochloric acid, and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated and the pH of the solution was brought to 8 using sodium bicarbonate solution. The solution was then pagkilala to pH 5 glacial acetic acid. Then added 200 ml of ethyl acetate, and the organic liquid was washed with 20 ml water and 20 ml brine, dried and concentrated. The residue was chromatographically on silica gel using a mixture of 100:4:0,2 dichloromethane/methanol/ammonium hydroxide, giving the target compound (210 mg, 62%), which crystallized from a mixture of ethyl acetate and hexane, giving white crystals. So pl. 81-84oC.

Analysis for C24H26N4O5S 0,24 H2ABOUT:

Calculated: 59,20, H 5,48, N 11,51, S 6,58.

Found: 59,25, H 5,42, N 11,46, S 6,39.

Example 11

N-(3,4-Dimethyl-5-isoxazolyl)-4'-[1-[(2- hydroxyethoxy)methyl]-1H-imidazol-2-yl] [1,1'-biphenyl]-2-sulfonamide

< / BR>
A. N-(3,4-Dimethyl-5-isoxazolyl)-40 mg, 0.25 mmole) in 2.5 ml dichloromethane at 0oC was added dropwise trichromacy Bor (1 M solution in dichloromethane, and 0.37 ml, 0.37 mmole). The reaction mixture was stirred at 0-3oC for 45 minutes. Was added 5 ml of saturated aqueous sodium bicarbonate, and the mixture was mixed for 10 minutes. The mixture was then padillas to pH 5 glacial acetic acid and was extracted with three portions of 40 ml of a mixture of 100: 5 dichloromethane and methanol. The combined organic extracts were dried and concentrated. The residue was purified using preparative HPLC on a column of 30 x 500 mm S S10 using 62% solvent A (10% methanol, 90% water, 0.1% of triperoxonane acid) and 38% solvent B (90% methanol, 10% water, 0.1% tetrahydrofuran), Deva target compound (80 mg, 69%) as a white solid. So pl. 93 - 103oC.

Analysis for C23H24N4O5S 0,75 H2O

Calculated: 57,31, H 5,33, Are 11.62 N, S Of 6.65.

Found: 57,61, H 5,04, N 11,33, S 6,55.

Example 12

N-(3,4-Dimethyl-5-isoxazolyl)-4'- (1-methyl-1H - imidazol-2-yl) [1,1'-biphenyl]-2-sulfonamide, lithium salt,

< / BR>
A. 2-(4-Bromophenyl)-1-methyl-1H-imidazol

To the compound of example 10 (700 mg, 3,14 mmole) in 7.8 ml of tetrahydrofuran and 7.8 ml of dimethylformamide to which the temperature for 10 minutes. Dropwise added logmean (891 mg, 6,28 mmole). The reaction mixture was stirred at room temperature for 1 hour and concentrated. Was added 100 ml of ethyl acetate, and the organic liquid was washed with 20 ml water and 20 ml brine, dried and concentrated. The residue was chromatographically on silica gel using a mixture of 100: 1:0.1 to dichloromethane/methanol/ammonium hydroxide, giving the compound a (500 mg, 67%).

C. N-(3,4-Dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]- 4'-(1-methyl-1H-imidazol-2-yl) [1,1'-biphenyl]-2-sulfonamide

To a solution of the compound from example I (320 mg, or 0.83 mmole) and compound (395 mg, 1,67 mmole) in 7.5 ml of toluene and 6 ml of 95% ethanol in an argon atmosphere were added tetrakis (triphenylphosphine) palladium (0) (96 mg, 0,083 mmole), and then 4.5 ml of 2M aqueous sodium carbonate. The reaction mixture was heated at 75oC for 3 hours, cooled and diluted with 50 ml ethyl acetate. The organic liquid was separated and was washed with 10 ml water and 10 ml brine, dried and concentrated. The residue was chromatographically on silica gel using a mixture of 100:1,5:a 0.1 dichloromethane/methanol/ammonium bicarbonate, giving compound (204 mg, 61%) as a colourless resin.

C. Lithium salt of N-(3,4-Di,50 mmole) in 9 ml of 95% ethanol was added to 9 ml of 6 N. aqueous hydrochloric acid, and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated, and the pH of the solution was brought to 8 using sodium bicarbonate solution. The solution was then pagkilala to pH 5 glacial acetic acid. The mixture was extracted with 200 ml of ethyl acetate, and the organic layer was washed with 20 ml water and 20 ml brine, dried and concentrated. The residue was chromatographically on silica gel using a mixture of 100:0,6 be:0.3 dichloromethane/methanol/ammonium bicarbonate, giving N-(3,4-dimethyl-5-isoxazolyl)-4'-(1-methyl-1H - imidazol-2-yl) [1,1'-biphenyl]-2-sulfonamide (189 mg, 92%) which was dissolved in 1 BC, lithium hydroxide, were added to HP-20 column and elyuirovaniya water and then a mixture of 10:3 water and methanol, giving the target compound as a white solid. So pl. more than 200oC decomp.

Analysis for C21H19N4O3SLi2,75 H2ABOUT:

Calculated: 54,37, H 5,32, N 12,08, S 6,91.

Found: 54,58, H Of 5.05, N 11.87 Per, S 6,80.

Example 13

Lithium salt of N-(3,4-dimethyl-5-isoxazolyl)-4'-(1H - imidazol-2-yl) [1,1'-biphenyl]-2-sulfonamida

< / BR>
A. 1,1-dimethylethylene ester 2-(4-bromophenyl)-1H - imidazole-1-carboxylic acid

To the compound of example 10 (446 m is g, 0.2 mmole). The reaction mixture was stirred at room temperature overnight and concentrated. The residue was chromatographically on silica gel using a 6:1 mixture of hexane and ethyl acetate, giving the compound a (500 mg, 77%) as a pale yellow oil.

Century 4'-[1-[(1,1-Dimethylmethoxy)carbonyl]-1H - imidazol-2-yl]-N-(3,4-dimethyl-5-isoxazolyl)-N- [(2-methoxyethoxy)methyl] [1,1'-biphenyl]-2-sulfonamide.

To a solution of the compound In example 1 (496 mg, of 1.29 mmole) and compound A (500 mg, of 1.55 mmole) of 11.25 ml of toluene and 9 ml of 95% ethanol in an argon atmosphere were added tetrakis (triphenylphosphine) palladium (0) (149 mg, 0,129 mmole), and then to 6.75 ml of 2 M aqueous sodium carbonate. The reaction mixture was heated at 75oC for 3 hours, cooled and diluted with 75 ml ethyl acetate. The organic liquid was separated and was washed 15 ml water and 15 ml of brine, dried and concentrated. The residue was chromatographically on silica gel using a mixture of 40:60:0.2 hexane, ethyl acetate and triethylamine, giving compound (380 mg, 51%) as a colourless resin.

C. Lithium salt of N-(3,4-dimethyl-5-isoxazolyl)-4'- (1H-imidazol-2-yl)-[1,1'-biphenyl]-2-sulfonamida

To a solution of compound (380 mg, 0.65 mmole) in 12 ml of 95% ethanol we use the Naya and the mixture was concentrated, and the pH of the solution was brought to 8 using sodium bicarbonate solution. The solution was then pagkilala to pH 5 glacial acetic acid, was extracted with three portions of 80 ml of a mixture of 100:5 dichloromethane and methanol. The organic extracts were dried and concentrated. The residue was dissolved in 1 BC, lithium hydroxide and chromatographically on HP-20 column, eluruumi water and then a mixture of 10: 2 water and methanol, yielding the target compound as a white solid (180 mg, 69%) So pl. above 220oC decomp.

Analysis for C20H17N4O3SLi 2.06 H2O:

Calculated: C 54,91, H 4,87, N 12,81, S 7,33.

Found: C 54,99, H 4,78, Of 12.73 N, S 6,95.

Example 14

N-(3,4-Dimethyl-5-isoxazolyl)-4'-(5-methyl-4 - oxazolyl)[1,1'-biphenyl]-2-sulfonamide

< / BR>
A. 4-(4-Bromophenyl)-5-methoxazole

To 4'-bromopropiophenone (3,52 g, 16.5 mmol) and formamide (10,81 g, 240 mmol) at 50oC was added dropwise bromine for 10 minutes. The reaction mixture was heated from 50oC to 130oC for 20 minutes and then was heated at 130oC for 4 hours. After cooling, was added 150 ml of ethyl acetate and the liquid was washed with 2 x 20 ml water and 20 ml brine, dried and concentrated. The remainder of the HRO is setacci)methyl] - 4'-(5-methyl-4-oxazolyl) [1,1'-biphenyl]-2-sulfonamide

To a solution of the compound In example 1 (384 mg, 1.0 mmole) and the compound (408 mg, 1.7 mmole) in 9 ml of toluene and 7.2 ml of 95% ethanol in an argon atmosphere were added tetrakis (triphenylphosphine) palladium (0) (116 mg, 0,l0 mmole), and then to 5.4 ml of 2 M aqueous sodium carbonate. The reaction mixture was heated at 75oC for 3 hours, cooled and diluted with 60 ml of ethyl acetate. The organic liquid was separated and was washed 15 ml water and 15 ml of brine, dried and concentrated. The residue was chromatographically on silica gel using a mixture of 2.5:1 hexane and ethyl acetate, giving the compound (317 mg, 64%) as a colourless resin.

C. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(5-methyl-4 - oxazolyl) [1,1'-biphenyl]-2-sulfonamide

To a solution of compound (300 mg, 0.60 mmole) in 10 ml of 95% ethanol was added 10 ml of 6 N. aqueous hydrochloric acid and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated, and the pH was brought to 8 using sodium bicarbonate solution. The mixture was then padillas to pH 5 glacial acetic acid. The mixture was extracted three times with 40 ml Vym portions of ethyl acetate, and the organic extracts were washed with 10 ml water and 10 ml S10 column using 30% solvent A (10% methanol, 90% water, 0.1% of triperoxonane acid) and 70% solvent B (90% methanol, 10% water, 0.1% tetrahydrofuran) to give the target compound (150 mg, 61%) as a white solid.

So pl. 86-96oC /atmospheric substance/.

Analysis for C21H19N3O4S0.16 H2ABOUT:

Calculated: 61,17, H 4,72, N 10,19, S To 7.77.

Found: 61,20, H 4,35, N 10,16, S 7,58.

Example 15

N-(3,4-Dimethyl-5-isoxazolyl)-4'- (1H-imidazol-1-ylmethyl) [1,1'-biphenyl] -2-sulfonamide

< / BR>
A. N-(3,4-Dimethyl-5-isoxazolyl)-2-bromo-benzosulfimide

To a solution of 3.0 g (11,74 mmole) of 2 - bromobenzaldehyde in 10 ml of pyridine was added to 1.32 g (11,74 mmole) of 3,4 - dimethyl-5-isoxazolidine. The mixture was mixed at room temperature in an argon atmosphere during the night, were added to 150 ml of ice water and filtered. The filtrate was pagkilala to pH 2 6 N. aqueous hydrochloric acid, and the grey solid was filtered off and dried. The solid was precrystallization from a mixture of methanol and water, giving 4.0 g (100%) compounds And in the form of a reddish-brown crystalline needles /so pl. 125-126oC, Rfor = 0.51 (10% methanol/dichloromethane)/.

C. 2-bromo-N-(3,4-dimethyl-5-isoxazolyl)-N'- (methoxyethoxymethyl)-benzolsulfonat the elk 0,19 g (4.8 mmole) of sodium hydride (60% suspension in mineral oil) in portions and the solution is stirred at room temperature for 10 minutes. Then added methoxyethoxymethyl (0.55 g, 4.4 mmole) and the solution stirred over night. The mixture was concentrated and diluted with 30 ml water and was extracted with 40 ml ethyl acetate. The combined organic extracts were washed with 50 ml brine, dried and evaporated, giving 1.2 g (87%) of compound B as a brown resin.

C. N-(3,4-Dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl] - 4'-methyl[1,1'-biphenyl]-2-sulfonamide

To a solution of compound V, 4 methylbenzeneboronic acid (4,76 g, 35 mmol) in 250 ml of toluene and 200 ml of 95% ethanol in an argon atmosphere were added tetrakis (triphenylphosphine) palladium (0) (2,43 g, 2.1 mmole), and then 150 ml of 2 M aqueous sodium carbonate. The reaction mixture was heated at 80oC for 2.5 hours, cooled and diluted with 300 ml of ethyl acetate. The organic liquid was separated and was washed with 200 ml of water and 200 ml of brine, dried and concentrated. The residue was chromatographically on silica gel using a mixture of 5: 1 hexane and ethyl acetate, giving the compound (9.0 g, 60%) as a colourless resin Rf= 0,74, silica gel 1:1 hexane/ethyl acetate.

D. 4'-(methyl bromide)-N-(3,4-dimethyl-5-isoxa aristovo carbon was added n-bromosuccinimide (4,14 g, 23,25 mmol) and benzoyl peroxide (385 mg, 1.59 mmole). The reaction mixture was heated under reflux for 1.5 hours. After cooling, the reaction mixture was diluted with 200 ml dichloromethane, was washed with 2 x 100 ml of water and 100 ml brine, dried and concentrated. The residue was chromatographically on silica gel with elution with a mixture of 4: 1 hexane and ethyl acetate, giving the compound D (of 3.64 g, 40%) as a colourless resin.

Rf= 0.38 (silica gel: 2:1 hexane/ethyl acetate.

E. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(1H-imidazol-1 - ylmethyl)-N-[(2-methoxyethoxy)-methyl] [1,1'-biphenyl] -2-sulfonamide

To the compound (400 mg, 0.79, which mmole) and imidazole (133 mg, 1,95 mmole) was added potassium carbonate /K2CO3/ (326 mg, a 2.36 mmole). The reaction mixture was stirred at room temperature for 10 hours and then at 50oC for 1 hour. The mixture was diluted with 50 ml of ethyl acetate, was washed with 10 ml water and 10 ml brine, dried and concentrated. The residue was chromatographically on silica gel using a mixture of 100:1,5 dichloromethane and methanol, giving the compound E (320 mg, 56%) as a colourless resin.

Rf= 0,52, silica gel, 10:1 trichloromethane/methanol

F. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(1H-imides the 6 ml 6 N. aqueous hydrochloric acid. The reaction mixture was heated under reflux for 2 hours, cooled and concentrated. The reaction mixture was kind of balanced out with saturated aqueous sodium bicarbonate /NaHCO3/ and then padillas to pH below 5 with acetic acid. Filtration of the mixture gave a white solid (91 mg, 50%), which was dissolved in 1 N. HCl and concentrated under vacuum, giving chlorhydrate salt of the target compound as a white solid (so pl. 150oC decomp.)

Rf= 0,27, silica gel, 10:1 dichloromethane/methanol.

Analysis for C21H20N4O3S1.1 H2O0,8 HCl:

Calculated: 55,02, H 5,28, N 12,22, S 6,99, Cl Is 6.19.

Found: 54,67, H 4,88, N Of $ 11.97, S 6,93, Cl 6,30.

Example 16

N-(3,4-Dimethyl-5-isoxazolyl)-4- (3-isoxazolyl) [1,1'-biphenyl]-2-sulfonamide

< / BR>
A. 4-Bromo-N-hydroxybenzotriazole

To a 0.5 M solution of hydrochloric acid in dimethylformamide was added 8.5 g (42.5 mmol/4-bromobenzaldehyde, and the mixture was cooled to 5oC. Then portions were added 13 g oxone. The mixture was slowly heated to room temperature and stirred for 8 hours. The reaction mixture was poured into 300 ml of cold water and was extracted and brine (150 ml), were dried and evaporated, yielding 7.9 g (79%) of compound A.

Century 5-(atomic charges)-3-(4-bromophenyl)-4,5-dihydroisoxazole

A mixture of 4.0 g (17,06 mmole) of compound A, 7,34 g (85.3 mmol) of vinyl acetate and 1.9 g (18,76 mmole) of triethylamine in 50 ml of toluene was mixed with 75oC for 2 hours. The mixture was cooled and was added to 150 ml of water. The organic layer was separated, and the aqueous layer was extracted with two portions of 50 ml. ethyl acetate the combined organic extracts were washed once with 100 ml brine, dried and evaporated. The residue is crystallized from a mixture of hexanol and ethyl acetate, yielding 3.6 g (74%) of compound B as a white solid.

C. 3-(4-Bromophenyl)-isoxazol

To a solution of 3.0 g (10,56 mmole) of the compound In 100 ml of absolute ethanol was added 5 ml of 6 N. aqueous hydrochloric acid, and the solution was heated under reflux for 3 hours. The mixture was concentrated to approximately 10 ml, and the solution was kind of balanced out using aqueous sodium bicarbonate. The resulting mixture was extracted with two portions of 50 ml of ether. The combined organic extracts were washed once with 100 ml brine, dried and evaporated. The residue was chromatographically per 100 g of the silica compound is TBA.

D. N-(3,4-Dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl] - 4'-(3-isoxazolyl) [1,1'- biphenyl]-2-sulfonamide

To a solution of 0.45 g (1,17 mmole) of the compound from example 1 and 0,058 g (0.05 mmole) tetrakis (triphenylphosphine) palladium (0) in 20 ml of toluene in an argon atmosphere was added 12 ml of 2 M aqueous sodium carbonate, and then 0,315 g (1.4 mmole) of the compound in 12 ml of 95% ethanol. The mixture was heated under reflux for 2 hours, it was diluted with 100 ml water and extracted 3 x 50 ml of ethyl acetate. The combined organic extracts were washed once with 100 ml brine, dried and evaporated. The residue was chromatographically on 50 g of silica gel using a mixture of hexanol and ethyl acetate 2:1, giving 0.27 g (56%) of compound D in the form of a colourless resin.

E. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(3-isoxazolyl) [1,1'- biphenyl]-2-sulfonamide

To a solution of 0.26 g (0.54 mmole) of compound D in 10 ml of 95% ethanol was added 10 ml of 6 N. aqueous hydrochloric acid, and the mixture was heated under reflux for 1 hour. The mixture was then concentrated, diluted with 50 ml water and was extracted three times with 25 ml Vym portions of ethyl acetate. The combined organic extracts were washed once with water, dried and evaporated (0.21 g). This substance is the sight of the El In (90% methanol, 10% water, 0.1% of triperoxonane acid) and 33% solvent A (10% methanol, 90% water, 0.1% of triperoxonane acid). The appropriate fractions were collected, were kind of balanced out the water with sodium bicarbonate to pH 7 and concentrated to 10 ml of the Solution was then pagkilala to pH 4 using glacial acetic acid and the white solid was filtered off and dried, yielding of 0.13 g (61%) of target compound. So pl. 85 - 90oC.

Analysis for C20H17N3O4S0,26 H2O:

Calculated: 60,04, H To 4.41, N 10,50, S 8,01.

Found: 60,04, 4,30 H, N 10,50, S 8,15.

Example 17

N-(3,4-Dimethyl-5-isoxazolyl)-4'- (2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide

< / BR>
A. 4-Bromobenzoate

To a solution of 6 g (of 27.9 mmole) 4-bromoferrocene acid in 200 ml of dichloromethane in an atmosphere of argon was added 14 ml of 2 M oxalicacid in dichloromethane. Then were added 4 drops of dimethylformamide, and the mixture is stirred at room temperature for 1 hour. The solution was evaporated and dried in vacuum. The residue was dissolved in 150 ml of methanol, and to the mixture was added 30 ml of 28% aqueous ammonium hydroxide. The solution is stirred at room temperature overnight and then diluted with 150 ml of water. The resulting white verapamil)methyl]oxazol

A mixture of compound A (2 g, 9,34 mmole) and vinylnorbornene (0.9 g, 10,45 mmole) in 6 g of polyphosphoric acid was heated at 170oC for 3 hours. The residue was added to 100 ml of water and extracted twice with 100 ml of Vym portions of ethyl acetate. The combined organic extracts were washed once with water, dried and evaporated. The residue was chromatographically on 200 ml of silica gel using a mixture of hexane/ethyl acetate 2:1, yielding 1.12 g (50%) of compound C as a white solid.

C. N-(3,4-Dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]- 4-(2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide

To a solution of 0.6 g (of 1.56 mmole) of compound B from example 1 and 0,092 g (0.08 mmole) tetrakis (triphenylphosphine) palladium (0) in 30 ml of toluene in an argon atmosphere was added 15 ml of 2M aqueous sodium carbonate, and then 0.45 g (of 1.87 mmole) of the compound, obtained above, 15 ml of 95% ethanol. The mixture was heated under reflux for 2 hours, it was diluted with 100 ml water and was extracted with three 50-ml portions of ethyl acetate. The combined organic extracts were washed once with 100 ml brine, dried and evaporated. The residue was chromatographically on 200 ml of silica gel using a mixture of hexanol and ethyl acetate 2:1, yielding 0.7 g (yl] -2-sulfonamide

To a solution of 0.7 g (1,41 mmole) of compound C in 15 ml of 95% ethanol was added 15 ml of 6 N. aqueous hydrochloric acid, and the solution was heated under reflux for 1 hour. The mixture was then concentrated, diluted with 250 ml of water and was extracted with three 50-ml portions of ethyl acetate. The combined organic extracts were washed once with water, dried and evaporated, giving 0,41 g of a colorless resin. The residue was purified using preparative HPLC in the reversed-phase 30 x 500 mm S S10 column using 67% of solvent B (30% methanol, 10% water, 0.1% of triperoxonane acid) and 23% solvent A (10% methanol, 90% water, 0.1% of triperoxonane acid). The appropriate fractions were collected and were kind of balanced out the water with sodium bicarbonate to pH 7 and was controlled to 10 ml of the Solution was then pagkilala to pH 4 using dilute hydrochloric acid and the resulting white solid was filtered off and dried, giving 0,098 g (17%) of target compound.

So pl. 65-70oC.

1H NMR (CDCl3): 1,80 (C., 3H), 2,11 (C., 3H), 4,16 (S., 2H),? 7.04 baby mortality (S., 1H), 7,27 - 8,02 (m, 10H).

13C NMR (CDCl3): 6,99, 11,20, 34,67, 108,10, 127,54, 128,32, 128,92, 129,47, 130,82, 133,15, 133,44, 135,95, 137,91, 138,51, 139,37, 141,25, 154,69, 162,27, 183,42.

Example 18

N-(3,4-Dimethy the-1-he

A solution of 7.0 g (35,2 mmole) of 4-bromoacetophenone in 7 ml of N,N - dimethylformamidine was heated under reflux for 20 hours. The solution was then diluted with 100 ml of ether and cooled to 0oC. Yellow crystalline solid was filtered off and dried, yielding compound (6.85 g, 77%).

Century 5-(4-Bromophenyl)isoxazol

To a solution of 6.2 g (24,4 mmole) of compound a in 70 ml of methanol at 0oC was added a solution of 3.31 g (to 29.27 mmole) of hydroxylamine-0-sulfonic acid in 20 ml of methanol over a period of 3 minutes. After stirring at room temperature for 1 hour, the reaction mixture was poured into a mixture of cold saturated sodium bicarbonate solution (200 ml) and ice water (200 ml). The resulting mixture was given in the sediment of 5.1 g of light yellow solid. Recrystallization of the substance in mixture of hexane and ethyl acetate then gave 3.12 g (57%) of compound B in the form of not-quite-white solid.

C. N-(3,4-Dimethyl-5-isoxazolyl)-N-[(2 - methoxyethoxy)methyl]-4'-(5-isoxazolyl) [1,1'-biphenyl]- 2-sulfonamide

To a solution of 0.56 g (of 1.46 mmole) of compound 1 from example 1 and of 0.081 g (0.07 mmole) tetrakis (triphenylphosphine) palladium (0) in 25 ml of toluene in an argon atmosphere dobavlyalost refrigerator for 2 hours, it was diluted with 100 ml water and was extracted with three 50-ml portions of ethyl acetate. The combined organic extracts were washed once with 100 ml brine, dried and evaporated. The residue was chromatographically on 50 g of silica gel using a mixture of hexane/ethyl acetate 2:1, yielding 0.26 g /37%/ connection in the form of a colourless resin.

D. N-(3,4-dimethyl-5-isoxazolyl)-4'-(5 - isoxazolyl) [1,1'-biphenyl]-2-sulfonamide

To a solution of 0.25 g /0,52 mmole/ join With in 10 ml of 95% ethanol was added 10 ml of 6 N. hydrochloric acid, and the mixture was heated under reflux for 1 hour. The mixture was then concentrated, diluted with 100 ml water and was extracted with three portions of 50 ml of ethyl acetate. The combined organic extracts were washed once with water, dried and evaporated /0.21 g/. This substance was purified using preparative HPLC in the reversed phase column (30 x 500 mm S S10 using 63% solvent B (90% methanol, 10% water, 0.1% of triperoxonane acid) and 31% solvent A (10% methanol, 90% water, 0.1% of triperoxonane acid). The appropriate fractions were collected and were kind of balanced out the water with sodium bicarbonate to pH 7 and concentrated to 10 ml of the Solution was pagkilala to pH 4 using ice UKS the tx2">

So pl. 85-90oC.

Analysis for C20H17N3O4S 0,27 H2O:

Calculated: 60,02, H 4,42, N 10,50, S 8,01.

Found: 60,16, H 4,24, N 10,36, S 8,17.

Example 19

< / BR>
N-(3,4-Dimethyl-5-isoxazolyl)-2'-hydroxy - 4'-(2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide

A. 4-Bromo-3-hydroxybenzoic acid

Bromine /58 g, 19 ml of 0.36 mol/ acetic acid /50 ml/ slowly over 2 hours was added to a solution of 3 - hydroxybenzoic acid /50 g of 0.36 mol/ acetic acid /145 ml/ under stirring at 15oC. After stirring for 15oC for an additional hour and then at ambient temperature for 17 hours, the resulting solid substance was filtered off and propulsives acetic acid /20 ml/. Drying by passing air through the filter cake for 4 hours gave 23,5 g /30%/ connections A.

Century Methyl ester 4-bromo-3-hydroxybenzoic acid

Sulfuric acid /concentrated, and 9.4 ml was added to a solution of compounds And /23,5 g of 0.11 mol/ methanol /350 ml/. After heating under reflux for 19 hours, the reaction mixture was left to cool to room temperature, and the pH was brought to about 4 feast upon the Extraction with ether /2 x 200 ml/, wash combined organic layers with brine /50 ml) and drying over magnesium sulfate gave 25 g of raw or crude product after evaporation of the solvent. Recrystallization from a mixture of ether and hexane gave 13.3 g /53%/ connections Century.

C. Methyl ester 4-bromo-3-methoxybenzoic acid

Dimethylsulfate /6,4 ml, 67 mmol) and potassium carbonate /10 g/ was added to a solution of compound B (13,3 r, 57 mmol) in acetone /86 ml/.

After heating under reflux for 13 hours, the reaction mixture was cooled, the precipitate was filtered, and the filtrate was evaporated in vacuo, giving of 14.7 g of crude product. Flash-chromatography /silica, 50 mm diameter, 10% ethyl acetate /hexane/ gave a 13.9 g of compound C /100%/.

D. 4-Bromo-3-methoxybenzoic acid

Potassium hydroxide /2 N., 120 ml, 240 mmol/ was added to a solution of compound C /19 g, 79 mmol/ methanol /670 ml/. After stirring at ambient temperature for 5.5 hours, water was added (100 ml) and the methanol was removed in vacuum. The remaining solution was extracted with methylene chloride, and then pagkilala 6 N. hydrochloric acid to pH of 1.5. Extraction with methylene chloride /1 x 500 ml 2 x 200 ml/ gave 17 g /93%/ connections D. after wilforlide /0.3 ml/ thionyl chloride /18 ml, a 3.5 mol/ was heated at 60oC for 2 h After evaporation of the reaction mixture in vacuo and azeotropic distillation with toluene /twice/ the residue was dissolved in tetrahydrofuran /30 ml and was slowly added to vigorously stirred concentrated solution of ammonium hydroxide /95 ml/. Precipitated precipitated substance was filtered off, rinsed with water and dried in a vacuum desicator during the night, yielding 17 g /100%/ connections E.

G. 2-(4-Bromo-3-methoxyphenyl)oxazol

Polyphosphoric acid /18 g/ were added to the compound E /8.5 g, 37 mmol) and the mixture was heated and stirred until then, until it became homogeneous. Added vinylenecarbonate /3.2 g, 2.4 ml, 37 mmol) and the reaction mixture was stirred at 160oC turning 2 hours, during which time the reaction mixture was allocated gas and became black and resinous. After cooling, water was added and the ether, all mixed decentralise /three times/. Desantirovanie layers were filtered through Celite, and the filtrate was transferred to a separating funnel. The organic layer was washed with water /10 ml/ 1 N. sodium hydroxide /30 ml and dried over magnesium sulfate, giving the crude product after evaporation of the solvent. Any remaining reacts who was ivalsa 1 N. sodium hydroxide /30 ml and dried over magnesium sulfate. Two batches of crude product amounted to only 3.6, Flash-chromatography /silica, 50 mm diameter, 30% ethyl acetate /hexane/ gave 2.3 g (24%) of compound F.

So pl. 68,5-70,5oC.

G. of N-(3,4-Dimethyl-5-isoxazolyl)-2'-methoxy-N- (2-methoxyethoxymethyl)-4'-(2-oxazolyl) [1,1-biphenyl]-2-sulfonamide

A solution of the compound In example 1 /2.3 g, 2.9 mmole/ ethanol /purged with argon for 20 minutes, 16 ml was added to a solution of compound F /1.1 g, 4.4 mmole/ toluene /purged with argon for 20 minutes, 32 ml/.

To this solution was added a solution of sodium carbonate /1.0 g/ water /purged with argon for 20 minutes, 16 ml/, and then tetrakis/triphenylphosphine/palladium/0/ /0.28 g, 0.24 mmole/.

After heating under reflux in an argon atmosphere for 2 hours the solution was cooled and poured into brine /40 ml/. Extraction with ethyl acetate /2 x 150 ml) and drying of the combined organic layers over magnesium sulfate gave 4.1 g of crude product after evaporation of the solvent. Flash-chromatography /silica, 50 mm diameter, 40% ethyl acetate/ hexane/ gave 0.50 g /34%/ connections G.

H. N-(3,4-Dimethyl-5-isoxazolyl)-2'-methoxy-4'- (2-oxazolyl) [1,1-biphenyl]-was little more than when 90oC. After 3.5 hours, the ethanol was evaporated in vacuo, and the residue was transferred into a separating funnel with a mixture of dichloromethane and water. Extraction with dichloromethane /2 x 50 ml) and drying over magnesium sulfate gave 0,37 g (100%) of compound H after evaporation of the solvent.

1. N-(3,4-Dimethyl-5-isoxazolyl)-2'-hydroxy - 4'-(2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide

Trichromacy Bor /1 M in dichloromethane, 6.2 ml, 6.2 mmole/ was added to a solution of compound H /0.33 g, 0.77 mmole/ and in methylene chloride /27 ml/ under stirring at -78oC. After stirring at -78oC for 30 minutes, the cold bath was removed. After stirring just over 2.5 hours, the reaction mixture was transferred into a separating funnel with dichloromethane and water. The pH was brought to 3.5 with saturated sodium bicarbonate.

Extraction with dichloromethane /2 x 70 ml) and drying over magnesium sulfate gave 0.68 g of crude product after evaporation of the solvent. Two procedures flash-chromatography /silica, 25 mm diameter, 6% methanol: dichloromethane, and silica, 15 mm diameter, 50% ethyl acetate /dichloromethane/ gave 60 mg /19%/ target connection. So pl. 111.0-115.0oC.

Analysis for C20H17N3O5S0,15S4H8ABOUT220

< / BR>
2-[2'-[[(3,4-Dimethyl-5-isoxazolyl) amino]-sulfonyl] [1,1'-biphenyl]-4 - yl]-4 - oxazolidone

A. 2-(4-Bromophenyl)-4-oxazolidinyl

The mixture of compounds from example 7 /810 mg, 3,40 mmole/, selenium dioxide /1,89 g, 17 mmol/ and 6.8 ml of dioxane was heated under reflux for 24 hours. After cooling, the mixture was filtered, and the filtrate was concentrated. The residue was chromatographically on silica gel using 60: 1 mixture of dichloromethane and ethyl acetate, giving the connection A /406 mg, 47% of/ in the form of a light yellow solid.

C. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(4-formyl-2 - oxazolyl)-N-[(2-methoxyethoxy)methyl][1,1'-biphenyl]- 2-sulfonamide

To a solution of the compound In example 1 /772 mg, 2.0 mmole/, connection /390 mg. of 1.55 mmole/ in 15 ml of toluene and 12 ml of 95% ethanol in an argon atmosphere were added tetrakis/triphenylphosphine/palladium /0/ /116 mg, 0.1 mmole/ then add 9 ml of 2 M aqueous sodium bicarbonate. The reaction mixture was heated at 75oC for 1 hour, cooled and diluted with 80 ml of ethyl acetate. The organic liquid was separated, was washed 15 ml water and 15 ml of brine, dried and concentrated. The residue was chromatographically on silica gel using a 3:2 mixture of hexa[(2 - methoxyethoxy)methyl]amino-sulfonyl] [1,1'-biphenyl]-4 - yl]-4-oxazolidone

Connection B /285 mg of 0.56 mmole/, obtained above, and sulfamic acid /108 mg, 1,11 mmole/ 5.6 ml of tetrahydrofuran at 0oC was added to ice a solution of sodium chloride /101 mg, 1,11 mmole/ 5.6 ml of water. The mixture is stirred at 0oC for 3 minutes. Was added 50 ml of dichloromethane, and the organic liquid was washed with 10 ml of saline solution, dried and concentrated, giving 2-[2'-[[(3,4-dimethyl-5 - isoxazolyl) [(2-methoxyethoxy)methyl] - amino]sulfonyl] [1,1'-biphenyl]-4-yl]-4 - oxazolidinone acid.

To 2-[2'-[[(3,4-dimethyl-5-isoxazolyl) [(2-methoxyethoxy)methyl] -amino] sulfonyl] [1,1'-biphenyl]-4 - yl-4-oxazolidinone acid and of 0.014 ml of dimethylformamide in 5.6 ml of dichloromethane was added oxalicacid /2 M in dichloromethane, of 0.56 ml, 1.11 mmole), and the mixture stirred for 0.5 hour and concentrated. To this mixture was added 10 ml of tetrahydrofuran and 2 ml of concentrated ammonium hydroxide. The reaction mixture was stirred at room temperature for 50 minutes and concentrated. The organic liquid was washed 15 ml water and 15 ml of saline solution, dried and evaporated. The residue was chromatographically on silica gel using 1:4 mixture of hexane and ethyl acetate, giving connected the[1,1'-biphenyl]-4-yl]-4-oxazolidone

To a solution of compound C /240 mg, and 0.46 mmole/ 4.6 ml of acetonitrile at 0oC was added trimethylacetylchloride /297 mg, is 2.74 mmole/ and then sodium iodide /410 mg, is 2.74 mmole/. The mixture is stirred at room temperature for 1 hour. Was added 6 ml of water, and the mixture was extracted with 50 ml ethyl acetate. The organic liquid was washed with 5 ml saturated aqueous sodium thiosulfate and 5 ml of brine, dried and concentrated. The residue was purified using preparative HPLC on a 30 x 500 mm S S10 column using 37% solvent A /10% methanol, 90% water, 0.1% of triperoxonane acid and 63% solvent /90% methanol, 10% water, 0.1% tetrahydrofuran/, giving the target compound /122 mg, 61%/ in the form of a white solid.

So pl. 195oC decomp.

Analysis for C21H18N4O5S 0,23 H2O:

Calculated: 57,00; H 4,20; N 12,66; S 7,24.

Found: 57,01; H 4,10; N Is 12.85; S 7,18.

Example 21

N-(3,4-Dimethyl-5-isoxazolyl)-2'- [(formylamino) methyl] -4'-(2-oxazolyl)-[1,1'-biphenyl]-2 - sulfonamide

< / BR>
A. 4-Bromo-3-methylbenzamide

To a solution of 10 g /46.5 mmol of 4-bromo-3-methylbenzoic acid in 200 ml of dichloromethane in an atmosphere of argon was added 30 ml of a 2 M solution of oxalicacid in dichloromethane is CA. The solution was evaporated and dried in vacuum. The residue was dissolved in 10 ml of methanol, and to the mixture was added 25 ml of 28% aqueous ammonium hydroxide. The solution was mixed at room temperature for 3 hours and then was diluted with 500 ml of water. The resulting white solid was filtered, rinsed with water and dried, giving 8,9 g /89%/ connections A.

Century 2-(4-Bromo-3-were)oxazol

The mixture of compounds And /12 g, 56 mmol/ vinylnorbornene /6.5 g, 75.5 mmol/ 25 g of polyphosphoric acid was heated at 170oC for 3 hours. The residue was then added to 700 ml of water and extracted 3 x 250 ml ethyl acetate. The combined organic extracts were washed once with water, dried and evaporated. The residue was chromatographically on 200 g of silica gel using dichloromethane, giving 6.7 g /50%/ connections in the form of a white solid.

C. 2-[4-Bromo-3-(methyl bromide)phenyl]oxazol

The mixture of compounds In /6.5 g, 27.3 mmole/, N-bromosuccinimide /9,72 g, 54.6 mmol) and benzoyl peroxide/ 250 mg/ 250 ml of carbon tetrachloride was heated under reflux for 8 hours when the lighting solution lamp sunlight. The mixture was then cooled and filtered. The filtrate was concentrated, giving 10 ptx2">

D. 2-Bromo-5-(2 oxazolyl)benzaldehyde

To a solution of 7 g of crude compound in 15 ml of anhydrous dimethyl sulfoxide in an atmosphere of argon was added 5.5 g of anhydrous trimethylamine-N-oxide (obtained as described in the work Soderquist and other Tet. Letters., 27, 3961, /1986/), and the mixture is stirred at 55oC for 6 hours. The mixture then was cooled, was added to 150 ml of a mixture of ice and water and extracted with three portions of 100 ml of ethyl acetate. The combined organic extracts were washed once with 100 ml brine, dried and evaporated. The residue was chromatographically on 300 ml of silica gel using a mixture of hexane/ethyl acetate 8: 1, giving 2.2 g /46% in two phases/ connection in the form of a white solid.

E. N-(3,4-Dimethyl-5-isoxazolyl)-2'- formyl-N - [(2-methoxyethoxy)methyl] -4'-(2-oxazolyl)[1,1'- biphenyl]-2-sulfonamide

To a solution of 2.3 g /6 mmol/ connections In example 1 and 0.3 g /0,2/ 0,26 mmole/ tetrakis/triphenylphosphine/palladium /0/ in 40 ml of toluene in an atmosphere of argon was added 20 ml of 2 M aqueous sodium carbonate, and then 1.0 g /6,28 mmole/ connection D in 20 ml of 95% ethanol. The mixture was heated under reflux for 2 hours, it was diluted with 100 ml water and extracted 3 x 50 ml of ethyl acetate. The combined organic Aisne 200 ml of silica gel using a mixture of hexane /ethyl acetate 1:1, giving 1,69 g /55%/ join E in the form of a colourless resin.

F. N-(3,4-Dimethyl-5-isoxazolyl)-2'-formyl-4'- (2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide

To a solution of 1.68 g /3,28 mmole/ join E in 30 ml of 95% ethanol was added 30 ml of 6 N. aqueous hydrochloric acid and the mixture was heated under reflux for 1 hour. The mixture was then concentrated and diluted with 250 ml of water and was extracted with three portions of ethyl acetate in 150 ml the combined organic extracts were then washed once with water, dried and evaporated, giving 1,46 g /90%/ connection F in the form of a colourless resin.

G. 2'-(Aminomethyl)-N-(3,4-dimethyl-5-isoxazolyl) -4'-(2-oxazolyl)-[1,1'-biphenyl]-2-sulfonamide

To a solution of 0.28 g /0,66 mmole/ join F in 25 ml of methanol was added 5 g of ammonium acetate and 1 g of 3A molecular sieves, and the mixture is stirred at room temperature for 1 hour. Added triacetoxyborohydride sodium /0,42 g, 1.98 mmole) and the mixture stirred for an additional 45 minutes. The solution was filtered, concentrated to 10 ml, diluted with 25 ml water and was extracted with three portions of 25 ml of ethyl acetate. The combined organic extracts were then washed once with water, dried and evaporated. The remainder chromatographia the Dogo substances

H. N-(3,4-Dimethyl-5-isoxazolyl)-2'-[(formylamino) methyl]-4'-(2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide

To a solution of 0.06 g /0,14 mmole/ join G in 10 ml of dichloromethane at 0oC was added 0.02 g explorerview anhydride and 0.02 g of triethylamine. The mixture was slowly heated to room temperature and stirred for 1 hour. The mixture was diluted with 10 ml dichloromethane, was washed with 20 ml of 0.1 N. aqueous hydrochloric acid and then with 20 ml of water. The organic layer was dried and evaporated. The residue was purified using preparative HPLC with reversed phase 30 x 500 mm S S10 column using 56% solvent /90% methanol, 10% water, 0.1% of trioxane acid and 44% solvent A /10% methanol, 90% water, 0.1% of triperoxonane acid/.

The appropriate fractions were collected, were kind of balanced out the water with sodium bicarbonate to pH 7 and concentrated to 10 ml of the Solution was then pagkilala to pH 4 using dilute hydrochloric acid and the white solid was filtered off and dried, giving 0,013 g /21%/ target connection.

So pl. 105-109oC.

1H NMR /CDCl3/: 1,87 /c.3H/, 2,12 /s,3H/, 3,89 /AB sq, J = 4,1, to 15.8 Hz, 1H/, 4,50 /AB sq, J = 7,6, to 15.8 Hz, 1H/, 6,63 / Shir., C., 1H/, 7,03-7,93 /m, 10H/, 8,14 /s, 1H/.

13C NMR: /CDCl3

Example 22

N-(3,4-dimethyl-5-isoxazolyl)-2'- [[(methoxycarbonyl) amino]methyl]-4'-(2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide

< / BR>
A. N-(3,4-Dimethyl-5-isoxazolyl)-2'-[[(methoxycarbonyl) amino]methyl]-4-(2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide

To compound G from example 21 /75 mg of 0.18 mmole/ 3.5 ml of tetrahydrofuran was added triethylamine /35 mg, 0.35 mmole/ followed by the addition of methylchloroform /17 mg of 0.18 mmole/. The reaction mixture was stirred at room temperature for 1 hour. Added additional triethylamine /18 mg of 0.18 mmole/ and methylchloroform /17 mg of 0.18 mmole) and the reaction mixture stirred at 40oC for 1.5 hours. The reaction mixture was concentrated and the residue was purified using preparative HPLC on a 30 x 500 mm S S10 column using 42% solvent A /10% methanol, 90% water, 0.1% of triperoxonane acid and 58% solvent /90% methanol, 10% water, 0.1% of triperoxonane acid, giving the target connection /30 mg, 35%/ in the form of a white solid. So pl. 110-120oC /amorphous/.

Analysis for C23H22N4O6S 0,41 H2O:

Calculated: 56,39, H 4,69, N 11,44, S 6,54.

Found: 56,11, H 4,48, N 11,19, S Of 6.49.

Example 23

N-[[2'-[(3,4-Dimethyl-5-isoxazolyl) ail) amino] sulfonyl]-4-(2-oxazolyl)-[1,1'-biphenyl]-2 - yl]methyl]-metalmachine

To compound G from example 21 /75 mg of 0.18 mmole/ 7.1 ml of tetrahydrofuran was added methyl isocyanate /71 mg, 1,24 mmole/. The reaction mixture was stirred at room temperature overnight and concentrated. The residue was purified using preparative HPLC on a 30 x 500 mm OS S10 column using 46% solvent A/ 10% methanol, 90% water, 0.1% of triperoxonane acid and 54% solvent B (90% methanol, 10% water, 0.1% of triperoxonane acid), giving the target connection /36 mg, 45%/ in the form of a white solid. So pl. above 150oC, Razlog.

Analysis for C23H23N5O5S 0,45 H2O0,2 CH2Cl2:

Calculated: 55,00, H A 4.83, N 13,82, S 6,33.

Found: 54,57, H 4,58, N 13,61, S 5,95.

Example 24

N-(3,4-Dimethyl-5-isoxazolyl)-2'- [[(methylsulphonyl)amino] methyl]-4'-(2-oxazolyl)-[1,1'-biphenyl]-2-sulfonamide

< / BR>
A. N-(3,4-Dimethyl-5-isoxazolyl)-2'-[[(methylsulphonyl)amino] methyl]-4'-(2-oxazolyl)-[1,1'-biphenyl]-2-sulfonamide

To compound G from example 21 /75 mg of 0.18 mmole/ and triethylamine /54 mg, of 0.53 mmole/ 7.1 ml of tetrahydrofuran was added methanesulfonamide /57 mg, 0.5 mmole/. The reaction mixture was stirred at 45oC for 2 hours. The reaction mixture was concentrated, and the pH value is glacial acetic acid. The mixture was extracted with dichloromethane. The organic liquid was concentrated, and the residue was purified using preparative HPLC on a 30 x 500 mm S S10 column using 47% solvent A /10% methanol, 90% water, 0.1% of triperoxonane acid/ and 53% solvent /90% methanol, 10% water, 0.1% of triperoxonane acid, giving the target compound /27 mg, 30%/ in the form of a white solid.

So pl. 110-120oC /amorphous/.

Analysis for C22H22N4O6S0,1% CH3COOH:

Calculated: 52,37, H Of 4.45, N 10,96, S 12,56.

Found: 52,43, H 4,37, N 10,76, S 12,11.

Example 25

N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino] sulfonyl]-4-(2 - oxazolyl)-[1,1'-biphenyl]-2-yl]-methyl]-ndimethylacetamide

< / BR>
A. N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino] sulfonyl] -4- (2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]ndimethylacetamide

To a solution of 0.075 g /0,177 mmole/ compound G from example 21 in 10 ml of dichloromethane at 0oC was added 0,019 g /0,19 mmole/ acetic anhydride and 0,019 g of triethylamine. The mixture was then slowly heated to room temperature and stirred for 1 hour. The mixture was diluted with 10 ml dichloromethane and was washed with 20 ml water. The organic layer was dried and evaporated. The residue was purified using preparative HPLC with a treatment acid/ and 42% solvent A /10% methanol, 90% water, 0.1% of triperoxonane acid/. The appropriate fractions were collected and were kind of balanced out the water with sodium bicarbonate to pH 7 and concentrated to 10 ml of the Solution was pagkilala to pH 4 using dilute hydrochloric acid and the white solid was filtered off and dried, giving 0,041 g /50%/ target connection. So pl. 105-107oC.

Analysis for C23H22N4O5S 0.42 H2O:

Calculated: 58,27, H A 4.86, N 11,82, S 6,76.

Found: 58,38, H 4,71, N 11,71, S 6,93.

Example 26

N-[[2-[[3,4-Dimethyl-5-isoxazolyl] amino] sulfonyl]-4-[2-oxazolyl[-[1,1-biphenyl]-2 - yl]methyl]-N-prilocaine

< / BR>
A. N-[[2'-[(3,4-Dimethyl-5-isoxazolyl)amino] sulfonyl]-4-(2-oxazolyl) [1,1'-biphenyl]-2-yl] methyl] - N'-prilocaine

To compound G from example 21 /25 mg, 0,059 mmole/ in 3 ml of tetrahydrofuran was added phenylisocyanate /56 mg, of 0.47 mmole/. The reaction mixture was stirred at room temperature overnight and concentrated. The residue was purified using preparative HPLC chromatography on a 30 x 500 mm S S10 column using a solvent And /10% methanol, 90% water, 0.1% of triperoxonane acid and 67% solvent /90% methanol, 10% water, 0.1% of triperoxonane acid, giving the target connection /18 cm., 1H/, 6,91 - 8,03 /m,15H/.

13C NMR /CDCl3/: 7,60, 11,81, 42,65, 109,39, 119,92, 123,29, 124,13, 127,10, 128,26, 129,61, 130,68, 130,79, 132,96, 134,80, 157,72, 139,56, 140,00, 140,25, 140,43, 155,63, 156,58.

Example 27

N-[[2'-[(3,4-Dimethyl-5-isoxazolyl) amino]sulfonyl]-4- (2-oxazolyl)-[1,1'-biphenyl]-2-yl]methyl]-N'- proprotein

< / BR>
A. N-[[2'-[(3,4-Dimethyl-5-isoxazolyl)amino] sulfonyl]-4-(2-oxazolyl) [1,1'-biphenyl]-2-yl] methyl]-N'-proprotein

To the compound from example 21 /20 mg 0,047 mmole/ in 3 ml of tetrahydrofuran was added propositional /36 mg, 0,424 mmole/. The reaction mixture was stirred at room temperature overnight and concentrated. The residue was chromatographically on silica gel using a mixture of 100:4.5 dichloromethane and methanol, yielding the target compound /16 mg, 67% of/ in the form of a light yellow solid.

1H NMR /CD3OD/: 0,89 /so, J= 7 Hz, 3H/, 1.46 /m, 2H/, 1,70 /s, 3H/, 2,10 /s, 3H/, 3.06 /so, J= 7 Hz, 2H/; 4,08 /s, 2H/, 7,10 - 8,12 /m, 9H/.

13WITH NMR /CD3OD/: 6,57, 10,58, 11,62, 24,37, 42,91, 124,83, 125,06, 127,97, 129,10, 129,62, 130,34, 131,67, 133,11, 133,74, 139,83, 140,44, 140,87, 141,24, 141,96, 160,91, 162,99, 163,42.

Example 28

N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino] - sulfonyl] -4-(2-oxazolyl)-[1,1'-biphenyl]-2-yl] methyl]-N-methylacetamide

< / BR>
A. N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino] sulfon in 15 ml dichloromethane was added methylamine /33% solution in absolute ethanol, of 0.13 ml, 1.06 mmole/ glacial acetic acid /0.12 g, 2 mmole/ 1 g of 3A molecular sieves. The mixture is stirred at room temperature for 1 hour. Added triacetoxyborohydride sodium /0,22 g, of 1.06 mmole) and the mixture stirred over night. The solution is then filtered, washed once with water, dried and evaporated. The residue thus obtained was dissolved in 10 ml of dichloromethane, and added 0,072 g /0,70 mmole/ acetic anhydride and 0,071 g /0,70 mmole/ triethylamine. The mixture is stirred at room temperature for 16 hours and evaporated. The residue was purified using preparative HPLC with reversed phase 30 x 500 mm OS S10 column using 58% solvent /90% methanol, 10% water and 0.1% triperoxonane acid/ and 42% solvent A (10% methanol, 90% water, 0.1% of triperoxonane acid). The appropriate fractions were collected, were kind of balanced out water bicarbonate sodium to pH 7 and concentrated to 10 ml of the Solution was pagkilala to pH 4 using glacial acetic acid and the white solid was filtered off and dried, giving 0,069 g /41%/ target compound as a pale yellow solid. So pl. 105-115oC.

Example 29

N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl) amino] sulfone is(2-oxazolyl) [1,1'-biphenyl]-2-yl - methyl]benzamide

To compound G from example 21 /70 mg, 0.17-mmole/ and benzoyl chloride /23 mg, 0.17-mmole/ 3.3 ml of dichloromethane was added triethylamine /37 mg, of 0.36 mmole/. The reaction mixture was stirred at room temperature for 1.5 hours and concentrated. The residue was purified using preparative HPLC on a 30 x 500 mm S S10 column using 33% solvent A /10% methanol, 90% water, 0.1% of triperoxonane acid and 67% solvent /90% methanol, 10% water, 0.1% of triperoxonane acid, giving the target connection /30 mg, 34% of/ in the form of a white solid.

So pl. 128-135oC /amorphous/.

1H NMR /CDCl3/: 1,91 /s, 3H/, 2,18 /s, 3H/, 4,16 was 4.76 /m, 2H/, 7,13-8,13 /m, 14H/.

Example 30

N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl) amino] sulfonyl]-4-(2-oxazolyl)- [1,1'-biphenyl]-2 - yl]methyl]-2,2-dimethylpropanamide

< / BR>
A. N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino] sulfonyl]-4-(2-oxazolyl) [1,1'-biphenyl]-2-yl] methyl]-2,2-dimethylpropanamide

To compound G from example 21 /105 mg, 0.25 mmole/ and trimethylacetylchloride /30 mg, 0.25 mmole/ 4.9 ml of dichloromethane was added triethylamine /55 mg, 0.54 mmole/. The reaction mixture was stirred at room temperature overnight and concentrated. The residue was purified using preparative HPLC on a 30 x 500 male /90% methanol, 10% water, 0.1% of triperoxonane acid, giving the target connection /52 mg, 34% of/ in the form of a white solid.

So pl. 122-128oC.

1H NMR /CDCl3/: 1,18 /s, 9H/, 1,93 /s, 3H/, 2,18 /s,3H/, 3,96-4,46 /m, 2H/, 7,24-8,05 /m, 9H/.

Example 31

Methyl ester of 2'-[[(3,4-dimethyl-5 - isoxazolyl)amino] sulfonyl]-4-(2-oxazolyl) [1,1'- biphenyl]-2-carboxylic acid

< / BR>
A. 2'-[[(3,4-Dimethyl-5-isoxazolyl)amino] sulfonyl]-4-(2-oxazolyl)-[1,1'-biphenyl]-2 - carboxylic acid.

To compound F of example 21 /2.20 g, 5,20 mmole/ and sulfamic acid /1.01 g, 10.39 mmol/ 52 ml of THF at 0oC was added to ice a solution of sodium chloride /940 mg, 10.39 mmol/ 52 ml of water. The mixture is stirred at 0oC for 2 minutes, and then it was diluted with 150 ml dichloromethane. The organic liquid was separated and was washed with saline, dried and concentrated. The residue was purified using preparative HPLC on S S10 column using 43% solvent A /10% methanol, 90% water, 0.1% of triperoxonane acid and 57% solvent /90% methanol, 10% water, 0.1% of triperoxonane acid/ giving connection And /503 mg, 22% of/ in the form of a white solid.

C. Methyl ether 2'-[[(3,4-dimethyl-5-isoxazolyl) amino]sulfonyl]-4-(2-aalsa 1,1'-carbonyldiimidazole /209 mg, of 1.29 mmole/. After stirring at room temperature for 1 hour was added 1 ml of methanol, and the reaction mixture stirred at room temperature over night. Added additional 3 ml of methanol, and the mixture was heated at 50oC for an additional hour. After cooling to room temperature was added 10 ml of 0.5 N. aqueous HCl, and the mixture was mixed for 10 minutes. Was added 60 ml of ethyl acetate, and the organic liquid was separated and was washed with saline, dried and concentrated. The residue was purified using preparative HPLC on S S10 column using 34% solvent A /10% methanol, 90% water, 0.1% of triperoxonane acid and 66% solvent /90% methanol, 10% water, 0.1% of triperoxonane acid, giving the target compound /98 mg, 37% of/ in the form of a white solid.

So pl. 106-112oC /amorphous/. Rf= 0,54, silica gel, 20:1 dichloromethane/methanol.

1H NMR /CDCl3/: 1,84 /s, 3H/, 2,17 /s, 3H/, to 3.73 /s, 3H/, 7,27-8,62 /m, 10H/.

Example 32

N-(3,4-dimethyl-5-isoxazolyl)-2'- (1-hydroxy-1-methylethyl)-4'- (2-oxazolyl) [1,1-biphenyl]-2-sulfonamide

< / BR>
A. N-(3,4-Dimethyl-5-isoxazolyl)-2'-(1 - hydroxy-1-methylethyl)-4'-(2-oxazolyl) [1,1'- biphenyl]-2-sulfonamid M in a mixture of toluene /THF 75:25, of 0.43 ml, 0.60 mmole/. The reaction mixture was stirred at 0oC for 10 minutes and at room temperature for 3 hours. Added additional methylmagnesium /1.4 M in a mixture of toluene /THF 75:25, 0,069 ml, 0,096 mmole) and the mixture was mixed for an additional 10 minutes. The reaction was extinguished with a mixture of ice and water and acetic acid /45 mg, 0.77 mmole/ and stirred for 10 minutes. The mixture was extracted with ethyl acetate, and the organic extract was washed with saline, dried and concentrated. The residue was purified using preparative HPLC on S S10 column using 37% solvent A /10% methanol, 90% water, 0.1% of triperoxonane acid and 63% solvent /90% methanol, 10% water, 0.1% of triperoxonane acid, giving the target compound /40 mg, 46% of/ in the form of a white solid.

So pl. 112-118oC /amorphous/. Rf= 0,27, silica gel, 20:1 dichloromethane/methanol.

1H NMR /CDCl3/: 1,46 /s, 3H/, 1,76 /s, 3H/, 1,91 /s, 3H/, 2,19 /s, 3H/, 7,11-8,08 /m, 10H/.

Example 33

N-[[2-[[(3,4-Dimethyl-5-isoxazolyl) amino] sulfonyl] -4-(2-oxazolyl)-[1,1'-biphenyl]-2-yl]-methyl]-2-methylpropanamide

< / BR>
A. N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl) amino]-sulfonyl]-4-(2-oxazolyl) [1,1'-biphenyl]-2 - yl]methyl]-2-methylpropanamide

So pl. 112-120oC /amorphous/. Rf= 0.31, silica gel, 20:1 dichloromethane/methanol.

1H NMR /CDCl3/: 1,13 /m, 6H/, 1,93 /s, 3H/, 2,19 /s, 3H/; 2,42 / m , 1H/; 4,04-4,43 / m, 2H/; 6,56-8,40 /m, 11H/.

Example 34

N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl) amino] sulfonyl] -4-(2 - oxazolyl)-[1,1'-biphenyl]-2-yl]methyl]-2,2,2-triptorelin

< / BR>
A. N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino] sulfonyl]-4-(2-oxazolyl) [1,1'-biphenyl]-2-yl]- methyl]-2,2,2-triptorelin

To compound G from example 21 /40 mg, 0,094 mmole/ 1.9 ml of dichloromethane was added triethylamine /19 mg, 0,19 mmole/ and then triperoxonane anhydride /20 mg, 0,094 mmole/. The reaction mixture was stirred at room temperature for 2 hours and concentrated. The residue was purified using preparative HPLC on a 30 x 500 mm S S10 column using 37% solvent A /10% IU giving the target connection /20 mg, 41%/ in the form of a white solid. So pl. 112-120oC /amorphous/. Rf= 0.31, silica gel, 20:1 dichloromethane/methanol.

1H NMR /CDCl3/: 1,94 /s, 3H/, 2,19 /s, 3H/, a 4.03-4,56 /m, 2H/, 7,06-8,06 /m,10H/.

Example 35

N-(3,4-Dimethyl-5-isoxazolyl)-2'- [(methylamino) carbonyl] -4'-(2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide

< / BR>
A. N-(3,4-Dimethyl-5-isoxazolyl)-2'-[(methylamino) carbonyl] -4'-(2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide.

To the compound of example 31 /124 mg, of 0.28 mmole/ 2.8 ml of THF at 0oC was added 1,1'-carbonyldiimidazole /101 mg, of 0.62 mmole/. After stirring at room temperature for 2 hours was added 1 ml of methylamine /40% water/ and the reaction mixture stirred at room temperature for 3 hours. Was added 10 ml of 1 N. HCl and the mixture was mixed for 3 minutes. The mixture was extracted with 50 ml of ethyl acetate, and the organic extract was washed with water and brine, dried and concentrated. The residue was dissolved in 3 ml of saturated aqueous sodium bicarbonate solution and filtered. The filtrate was pagkilala to pH less than 5 sodium bisulfate, and the mixture was then filtered, yielding the target compound as white solids /80 mg, 63%/.

So pl. 122-131oC.

C., 3H/, was 2.76 /e, f = 3.5 Hz, 3H/, 6,53-8,16 /m, 11H/.

Example 36

N-(3,4-Dimethyl-5-isoxazolyl)-2', 4'-bis(2 - oxazolyl)[1,1'-biphenyl]-2-sulfonamide

< / BR>
A. 2'-[[(3,4-Dimethyl-5-isoxazolyl) [(2 - methylethoxy)methyl] amino] -sulfonyl]-4-(2 - oxazolyl) [1,1'-biphenyl]-2 carboxylic acid.

To compound E from example 21 /525 mg of 1.03 mmole/ and sulfamic acid /199 mg, 2.05 is mmole/ 14.7 ml of THF at 0oC was added to ice a solution of sodium chloride /186 mg of 2.05 mmole/ 14.7 ml of water. The mixture is stirred at 0oC for 2 minutes and then was diluted with 100 ml dichloromethane. The organic liquid was separated and was washed with saline, dried and concentrated, giving the compound a in the form of a resin, which was used without further purification.

C. 2'-[[(3,4-Dimethyl-5-isoxazolyl) [(2-methylethoxy) methyl]amino]-sulfonyl]-4-(2-oxazolyl) [1,1'-biphenyl] -2-carbonylchloride

Connection And and was 0.026 ml of DMF in dichloromethane was added oxalicacid /2 M in dichloromethane, 1.3 ml, 2.6 mmole/. The reaction mixture was stirred at room temperature for 1 hour and concentrated, giving the connection Century.

C. N-(3,4-Dimethyl-5-isoxazolyl)-N-[(2 - methylethoxy)methyl] -2', 4'-bis(2-oxazolyl) [1,1'- biphenyl]-2-sulfonamide

The mixture is 140oC for 3 hours. The mixture was diluted with 100 ml of ethyl acetate, was washed with water and brine, dried and concentrated. The residue was chromatographically on silica gel using 50:70:0,1 mixture of hexane, ethyl acetate and triethylamine, giving connection With.

D. N-(3,4-Dimethyl-5-isoxazolyl)-2', 4'-bis(2 - oxazolyl) [1,1'-biphenyl] -2-sulfonamide

To connect With in 10 ml of 95% ethanol was added 10 ml of 6 N. HCl. The mixture was heated under reflux for 1 hour and concentrated. The residue was kind of balanced out to pH 5 with sodium bicarbonate and was extracted with ethyl acetate. The organic extracts were washed with saline, dried and concentrated. The residue was purified using preparative HPLC on S S10 column using 35% solvent A /10%methanol, 90% water, 0.1% of triperoxonane acid and 65% solvent B /90% methanol, 10% water, 0.1% of triperoxonane acid, giving the target compound /56 mg, 12% in four stages/ in the form of a white solid. So pl. 108-113oC /amorphous/. Rf= 0,30, silica gel, 20:1 dichloromethane/methanol.

1H NMR /CDCl3/ 1,90 /s, 3H/, 2,19 /s, 3H/, 7,02-being 9.61 /m, 12H/.

Examples 37 and 38

(Z)-N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-(2 - phenylethenyl)-[1,1'-biphenyl]- 2-is

< / BR>
A. (Z)-N-(3,4-Dimethyl-5-isoxazolyl)-N-[(2 - methylethoxy)methyl]-4'-(2-oxazolyl)-2'-(2-phenylethenyl) [1,1'- biphenyl]-2-sulfonamide

and

C. (E)-N-(3,4-Dimethyl-5-isoxazolyl)-N-[(2 - methylethoxy)methyl]-4'-(2-oxazolyl)-2'-(2-phenylethenyl) [1,1'- biphenyl]-2-sulfonamide

To benzyltriphenylphosphonium /300 mg, 0.77 mmole/ 7.7 ml of THF at -78oC was added n-utility /2 M in pentane, to 0.39 ml to 0.78 mmole/. The cold bath was removed and the mixture stirred at room temperature for 45 minutes before cooling again to -78oC. Compound E from example 21 /304 mg, of 0.59 mmole/ was added at -78oC, and the reaction mixture was then stirred at room temperature for 2.5 hours. Was added 10 ml of water and 40 ml of ethyl acetate. The organic liquid was separated and was washed with saturated aqueous ammonium chloride and brine, dried and concentrated. The residue was chromatographically on silica gel using a 2:1 mixture of hexane/ethyl acetate, yielding a mixture of compounds a and B.

C. (Z)-N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2 - oxazolyl)-2'-(2-phenylethenyl) [1,1'-biphenyl]-2 - sulfonamide

and

D. (E)-N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2 - oxazolyl)-2'-(2-phenylethenyl)-[1,1'-biphenyl]-2 - sulfonamide

To a solution of compounds a and b in 6 ml of 95 hours. The reaction mixture was concentrated, and added 80 ml of ethyl acetate. The organic liquid was separated and was filtered salt brine, dried and concentrated. The residue was purified using preparative HPLC on S S10 column using 22% of solvent

A /10% methanol, 90% water, 0.1% of triperoxonane acid and 78% solvent /90% methanol, 10% water, 0.1% of triperoxonane acid, giving a connection To the target compound of example 37 /73 mg, 19% for two steps/ in the form of a white solid.

So pl. 102-109oC /amorphous/, Rf= 0,32 /silica gel, 20:1 dichloromethane/methanol/.

HPLC column was lirowaus same solvents additionally, giving the mixture, which was chloromethylketones on silica gel using a mixture of 100:2 dichloromethane/methanol, giving a connection D, the target compound of example 38 /27 mg, 7% for two steps/ in the form of a light yellow solid.

So pl. 109 -116oC /amorphous/, Rf= 0,32 /silica gel, 20:1 dichloromethane /methanol/.

1H NMR /CDCl3/ target compound of example 37:

1,86 /s, 3H/, 2,16 /s, 3H/, 6,38-6,51 /m, J= 12.3 Hz, 2H/, 6,60-7,98 /m, 15H/.

1H NMR /CDCl3/ target compound of example 38: 1,74 /s, 3H/, 2,01 /s , 3H/, 6,72-7,10 /m, J= 16.4 Hz, 2H,/, 7,17-7,�]-2- yl]methyl] phenylacetamide

< / BR>
A. 4-Chloro-N-[[2-[[(3,4-dimethyl-5-isoxazolyl) amino] sulfonyl]-4-(2-oxazolyl)-[1,1'-biphenyl]- 2-yl]methyl]phenylacetamide

To a solution of 0.20 g /0,47 mmole/ connection from example 21 in 15 ml dichloromethane was added 0,082 g /0,47 mmole/ 4 - chlorobenzylchloride and 0.104 g g /1,03 mmole / triethylamine. The mixture was then stirred at room temperature for 16 hours and evaporated. The residue was purified using preparative HPLC with reversed phase 30 x 500 mm S S10 column using 79% solvent /90% methanol, 10% water, 0.1% of triperoxonane acid and 21% solvent A /10% methanol, 90% water, 0.1% of triperoxonane acid/. The appropriate fractions were collected and were kind of balanced out the water with sodium bicarbonate to pH 7 and concentrated to 10 ml of the Solution was then pagkilala to pH 4 using glacial acetic acid and the white solid was filtered off and dried, giving 0,033 g /12,5%/ target compound as a white solid. So pl. 130-134oC.

Example 40

N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl) amino] sulfonyl] -4-(2-oxazolyl)-[1,1'-biphenyl]-2-yl] methyl]-N, 2,2-trimethylpropane

< / BR>
A. N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl) amino]sulfonyl]-4-(2-oxazolyl) [1,1'-biphenyl]-2 - yl]methyl] -N,2,2-trimethylpropane

KV 10 ml dichloromethane was added 0,078 g /0.65 mmole/ pivaloyloxy and 0,131 g /1,30 mmole/ triethylamine. The mixture was then stirred at room temperature for 16 hours and evaporated. The residue was purified using preparative HPLC with reversed phase 30 x 500 mm S S10 column using 75% solvent /90% methanol, 10% water, 0.1% of triperoxonane acid and 25% solvent A /10% methanol, 90% water, 0.1% of triperoxonane acid/. The appropriate fractions were collected and were kind of balanced out the water with sodium bicarbonate to pH 7 and concentrated to 10 ml of the Solution was then pagkilala to pH 4 using aqueous sodium bisulfate, and the white solid was filtered off and dried, giving 0,033 g /12%/ target compound as a white solid.

So pl. 125-130oC.

Example 41

N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl) amino] sulfonyl] -4-(2 - oxazolyl)-[1,1'-biphenyl]-2-yl]methyl]-N-methylbenzamide

< / BR>
A. N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino] sulfonyl]-4-(2-oxazolyl) [1,1'-biphenyl]-2-yl]methyl]-N - methylbenzamide

To a solution of 0.25 g /0,59 g, mmole/ intermediate compounds formed when the connection is obtained from example 28, in 10 ml dichloromethane was added 0.10 g /0,71 mmole/ benzoyl chloride and 0.13 g /1.3 mmole/ triethylamine. The mixture was then stirred at room temperature for 16 hours and what use 68% solvent /90% methanol, 10% water, 0.1% of triperoxonane acid/ and 32% solvent A /10% methanol, 90% water, 0.1% of triperoxonane acid/. The appropriate fractions were collected and were kind of balanced out the water with sodium bicarbonate to pH 7 and concentrated to 10 ml of the Solution was then pagkilala to pH 4 using aqueous sodium bisulfate, and the white solid was filtered off and dried, giving 0.075 g /23%/ target compound as a white solid.

So pl. 132-140oC.

Example 42

N-(3,4-Dimethyl-5-isoxazolyl)-2'- oxazolin-5 - yl-4'-oxazol-2-yl-[1,1'-biphenyl]-2 - sulfonamide

< / BR>
A. N-(3,4-Dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl] - 2'-oxazolin-5-yl-4'-oxazol-2-yl-[1,1'-biphenyl]-2-sulfonamide

A solution of compound F of example 21 /300 mg, 0.57 mmole/, toiletrieschoice /112 mg, 0.57 mmole) and potassium carbonate /95 mg, 0,69 mmole/ in 4 ml of methanol was heated under reflux for two hours, after cooling to room temperature the reaction mixture was pre-absorbed on celite, and the resulting powder was placed in a 2.5 x 20 cm silicagel column. Elution was carried out stepwise gradient of 200 ml of a mixture of ethyl acetate: hexane, 50:5, to ethyl acetate with 10% intervals. Pure fractions con is l)-2'-oxazolin-5-yl-4'-oxazol-2-yl [1,1'-biphenyl]-2-sulfonamide

The mixture of compounds And /90 mg, 0.16 mmole/, 6 N. HCl /1.6 ml/ ethanol /1.6 ml/ was heated under reflux for 2.5 hours. After cooling to room temperature the solvent was removed in vacuo, and the residue was distributed between ethyl acetate /75 ml/ and a saturated solution of ammonium chloride /50 ml/. The organic layers were washed with water /50 ml and saline /50 ml/. Drying (magnesium sulfate) and concentration gave a pink solid, attempts to dissolve this solid in a saturated sodium bicarbonate were unsuccessful and the resulting suspension was filtered and washed thoroughly with water. Drying under deep vacuum gave 30 mg /41%/ target compound as a pale pink solid.

So pl. 212-218oC /colour / div./.

1H NMR /DMCO-d6/: 1,56 /s, 3H/, to 2.06 /s, 3H/, of 5.82 /s, 1H/, 7,21 /d, J= 8 Hz, 1H/, of 7.36 /feet, 1H/, 7,47 /s, 1H/, 7,79 /m, 2H/, 7,92 /d, J= 8 Hz, 1H/, 8,13 /m, 1H/, 8,32 /s, 2H/, 8.34 per /sec, 1H/.

Other compounds covered by this invention include the following compounds:

1. N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino] sulfonyl]-4-(2-oxazolyl) [1,1'-biphenyl]-2-yl] methyl]-N-methylcyclopropane,

2. N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino] sulfonyl]-4-(2-oxazolyl) [1,1'-b is about]sulfonyl] -4- (2-oxazolyl), [1,1'- biphenyl]-2-yl]methyl]-2,2 - dimethylpropanamide,

4. N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino] sulfonyl]-4-(2-oxazolyl) [1,1'-biphenyl]-2-yl] methyl]-2,2-dimethyl-N-(2,2,2-triptorelin)-propanamide,

5. N-(3,4-Dimethyl-5-isoxazolyl)-2'-[2-(1 -methylethyl)-5-oxazolyl]-4'-(2-oxazolyl) [1,1'-biphenyl] -2-sulfonamide,

6. N-(3,4-Dimethyl-5-isoxazolyl)-2'-(4-oxazolyl)-4'-(2 - oxazolyl)-[1,1'-biphenyl]-2-sulfonamide,

7. N-(3,4-Dimethyl-5-isoxazolyl)-2'-[2-(1-methylethyl)-4 - oxazolyl]-4'-(2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide,

8. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-(2 - oxazolyl - methyl)-[1,1'-biphenyl]-2-sulfonamide,

9. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'- [[5-(1-methylethyl)-2-oxazolyl]methyl] [1,1'- biphenyl]-2-sulfonamide,

10. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'- [[4-(1-methylethyl)-2-oxazolyl]methyl] [1,1'-biphenyl]-2-sulfonamide,

11. (E)-N-(3,4-Dimethyl-5-isoxazolyl)-2'-(4-methyl-2-pentenyl)-4'-(2 - oxazolyl) [1,1'-biphenyl]-2-sulfonamide,

12. (Z)-N-(3,4-Dimethyl-5-isoxazolyl)-2'-(4-methyl-2 - pentenyl)-4'-(2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide,

13. N-(3,4-Dimethyl-5-isoxazolyl)-2'-(4 - methylpentyl)-4'-(2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide,

14. TRANS-N-(3,4-Dimethyl-5-isoxazolyl)-2'-[[2-(1-methylethyl) cyclopropyl]methyl]-4'-(2-oxazolyl) [1,1'- biphenyl]-2-sulfonamide,

15. C is R> 16. N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl) [1,1':2',1"-terphenyl]-2 - sulfonamide,

17. N-(3,4-Dimethyl-5-isoxazolyl)-3"-(1-methylethyl)-4'- (2-oxazolyl) [1,1':2',1"-terphenyl]-2-sulfonamide,

18. N-(3,4-Dimethyl-5-isoxazolyl)-4"-(1-methylethyl)-4'-(2 - oxazolyl)-[1,1':2',1"]-terphenyl]-2 - sulfonamide,

19. N-(3,4-Dimethyl-5-isoxazolyl)-2'-[(2-methylpropoxy) methyl]-4'-(2-oxazolyl) [1,1'-biphenyl]-2 - sulfonamide,

20. N-(3,4-Dimethyl-5-isoxazolyl)-2'-[2-(1-methylethoxy)ethyl] - 4'-(2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide and

21. N-(3,4-Dimethyl-5-isoxazolyl)-2'-[2-[(1-methylethyl)sulfonyl]- ethyl] -4-(2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide.

The above compounds correspond (by numbers) structures 1-21 (see the end of the description).

Example 43. The test compounds for biological activity.

The methodology used to obtain these data are described in the article by Stein et al. Discovery and Structure - Activity Relationships of Sulfonamide ETA- Selective Antagonists (J. Med. Chem. vol 38, No. 8, 1995, 1344-1354). Test results:

Example N - ETAKi(nm)

1 - 1,4

5 - 0,5

19 - 1,1

22 - 0,2

23 - 0,15

25 - 0,2

26 - 0,2

27 - 0,1

28 - 0,2

29 - 0,4

31 - 3,3

32 - 1,2

35 - 3,7

36 - 22

38 - 2,5

42 - 32-

1. Biphenylenediisocyanate f N, N-R15,

K and L - or N, provided that one of them C;

p = 0, 1;

R1is hydrogen, lower alkyl, the group Z4- NR6R7where Z4represents a group Z9COZ10and Z4, Z9, Z10every means single bond, R6is hydrogen, alkyl, R7is hydrogen;

R2is hydrogen or lower alkyl;

R3and R4each is lower alkyl;

R12, R13, R14each hydrogen;

R15is hydrogen, alkyl, hydroxyethoxymethyl, methoxyethoxymethyl;

R11represents 1) hydrogen, 2) hydroxyl, 3) CO2R5where R5- alkyl, oxazolyl, alkenyl, substituted phenyl, 4) Z4- NR6R7where Z4- Z9COZ10where Z9and Z10each represents a single bond, R6and R7defined above, 5) alkyl substituted by a group Z2where Z2the hydroxyl group

< / BR>
where Z4- connection;

Z5represents a group Z9COZ10, Z9C(O)OZ10, Z9S(O)nZ10, Z9, Z10each is a single bond;

Z11is hydrogen, alkyl;

Z6is hydrogen, alkyl, phenyl, phenyl substituted by one halogen atom, alkyl, substituted with three atoms GA represents a group Z9COZ10where Z9and Z10represent a single bond;

Z7is hydrogen;

Z8- alkyl, phenyl;

Z11is hydrogen or alkyl.

2. Connection on p. 1, where R3and R4each is alkyl with 1-4 carbon atoms.

3. Connection on p. 1, where R3and R4each is methyl.

4. Connection on p. 1, where R11and R12each hydrogen.

5. Connection on p. 1, in which R1and R2each independently is hydrogen or lower alkyl; R3and R4each independently is alkyl with 1-4 carbon atoms and R11and R12each independently is hydrogen, hydroxyl.

6. Connection, under item 1, in which R1and R2each is hydrogen or lower alkyl, R3and R4each independently is alkyl with 1-4 carbon atoms, R11is hydrogen, hydroxy, oxazolyl, carboxamide, alkenyl, substituted phenyl, lower alkyl, substituted Z1, R12- hydrogen.

7. Connection on p. 6, where R3and R4each is methyl.

8. Connection on p. 1, where p = 0.

9. Connection on p. 1, where R = 1.

10. Connection on p. 1, where p = 0, R1and R2each independently is hydrogen or lower alkyl, R3the Ohm, carboxamide, lower alkyl, substituted Z1.

11. Connection on p. 1, where p = 1, R1and R2each is hydrogen or lower alkyl, R3and R4each is methyl.

12. Connection on p. 1, selected from the group consisting of the following compounds:

methyl ester of 2'-[[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-carboxylic acid;

N-(3,4-dimethyl-5-isoxazolyl)-2'-(1-hydroxy-1-methylethyl)-4'-(2-oxazolyl)[1,1-biphenyl]-2-sulfonamide;

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]-methyl]-2-methylpropanamide;

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-2,2,2-triptorelin;

N-(3,4-dimethyl-5-isoxazolyl)-2'-[(methylamino)carbonyl] -4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-2', 4'-bis(2-oxazolyl)[1,1'-biphenyl] -2-sulfonamide;

(Z)-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-(2-phenylethenyl)[1,1'-biphenyl]-2-sulfonamide;

(E)-N-(3,4-dimethyl-5-isooxazolyl)-4'-(2-oxazolyl)-2'-(2-phenylethenyl)[1,1'-biphenyl]-2-sulfonamide;

4-chloro-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl]-4-2-oxazolyl)-[1,1'-biphenyl]-2-yl]methyl]phenylacetamide;

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N-methylbenzamide;

N-(3,4-dimethyl-5-isoxazolyl)-2'-oxazolin-5-yl-4'-oxazol-2-yl-[1,1'-biphenyl]-2-sulfonamide.

13. Connection on p. 1, selected from the group consisting of the following compounds:

N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-thiazolyl)[1,1'-biphenyl] -2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-4'-(4,5-dimethyl-2-oxazolyl)[1,1'-biphenyl] -2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-4'-2-(5-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-4'-(4-oxazolyl)[1,1-biphenyl] -2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-methyl-4-oxazolyl)[1,1'-biphenyl] -2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-4'-(4-methyl-2-oxazolyl)[1,1'-biphenyl] -2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-4'-(5-methyl-2-oxazolyl)[1,1'-biphenyl] -2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-4'-(1H-pyrazole-1-yl)[1,1'-biphenyl]-2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-4'-[1-[(2-methoxyethoxy)methyl]-1H-imidazol-2-yl][1,1'-biphenyl]-2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-4'-[1-[(2-hydroxyethoxy)methyl] -1H-imidazol-2-yl][1,1'-biphenyl]-2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-4'-(1-methyl-1H-imidazol-2-yl)[1,1'-biphenyl]-2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-4'-(1H-imidazol-2-yl)[1,1'-bifen is methyl-5-isoxazolyl)-4'-(1H-imidazol-1-yl-methyl)[1,1'-biphenyl] -2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-4'-(3-isoxazolyl)[1,1'-biphenyl] -2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl] -2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-4'-(5-isoxazolyl)[1,1'-biphenyl] -2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-2'-hydroxy-4'-(2-oxazolyl)[1,1'-biphenyl] -2-sulfonamide;

2-[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl][1,1'-biphenyl]-4-yl] -4-oxazol-carboxamide;

N-(3,4-dimethyl-5-isoxazolyl)-2'-[(formylamino)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl-2'-[[(methoxycarbonyl)amino] methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)-[1,1'-biphenyl]-2-yl]methyl]-N-metalmachine;

N-(3,4-dimethyl-5-isoxazolyl)-2'-[[(methylsulphonyl)amino]methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]ndimethylacetamide;

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)-[1,1'-biphenyl]-2-yl]-methyl-N'-prilocaine

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)-amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N'-proprotein

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]meth is same and

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl)-2-yl]methyl]-2,2-dimethylpropanamide.

14. Connection on p. 1, selected from the group consisting of the following compounds:

N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl] -2-sulfonamide,

N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-thiazolyl)[1,1'-biphenyl]-2-sulfonamide,

N-(3,4-dimethyl-5-isoxazolyl)-4'-(1H-pyrazole-1-yl)[1,1'-biphenyl]-2-sulfonamide,

N-(3,4-dimethyl-5-isoxazolyl)-4'-(1-methyl-1H-imidazol-2-yl)[1,1'-biphenyl]-2-sulfonamide,

N-(3,4-dimethyl-5-isoxazolyl)-2'-hydroxy-4-(2-oxazolyl)[1,1'-biphenyl] -2-sulfonamide,

2-[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl][1,1'-biphenyl]-4-yl] -4-oxazolidone,

N-(3,4-dimethyl-5-isoxazolyl)-2'-[(formylamino)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide,

N-(3,4-dimethyl-5-isoxazolyl)-2'-[[(methoxycarbonyl)amino] methyl] -4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide,

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)-[1,1'-biphenyl]-2-yl]methyl] - N'-metalmachine,

N-(3,4-dimethyl-5-isoxazolyl)-2'-[[(methylsulphonyl)amino]methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide,

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)-[1,1'-biphenyl]-2-yl]methyl]acetamide", she

N-[[2'-[[(3,4-dimethy sexaaay)amino] sulfonyl] -4-(2-oxazolyl)-[1,1'-biphenyl]-2-yl]methyl]-N'-propylbetaine,

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N-methylacetamide,

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]benzamide, and

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-2, 2-dimethylpropanamide.

15. Connection on p. 1, selected from the group consisting of the following compounds:

methyl ester of 2'-[[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-carboxylic acid;

N-(3,4-dimethyl-5-isoxazolyl)-2'-(1-hydroxy-1-methylethyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-2-methylpropanamide

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-2,2,2-triptorelin;

N-(3,4-dimethyl-5-isoxazolyl)-2'-[(methylamino)-carbonyl] -4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide;

N-(3,4-dimethyl-5-isoxazolyl)-2', 4'-bis(2-oxazolyl)[1,1'-biphenyl] -2-sulfonamide;

(Z)-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-(2-phenylethenyl)[1,1'-biphenyl]-2-sulfonamide;

(E)-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-(2-phenylethenyl)[1,1'-biphenyl - [2-sulfonamide;

4-chloro-N-[[2'-[[(�Tyl-5-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N,2,2-trimethylpropane;

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N-methylbenzamide

N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)-2'-oxazolin-5-yl-4'-oxazol-2-yl[1,1'-biphenyl]-2-sulfonamide.

Priority points and features:

26.08.1994 under item 1 (except for compounds in which R" is oxazolyl, alkenyl, substituted phenyl, Z6is phenyl substituted with one halogen, alkyl, substituted with three Halogens), PP.2 to 5 and 6 (except R - oxazolyl, alkenyl, substituted phenyl), PP.7 - 11, 13, and 14;

04.01.1995 on PP.13 and 14;

25.08.1995 on PP.12, 15.

 

Same patents:

The invention relates to derivatives of N-sulfanilimide formula I, where R1and R2denote hydrogen, halogen, C1-4alkyl, C1-4alkoxycarbonyl or phenyl which can be substituted one to three times, equal or different residues from the group comprising halogen, C1-4alkyl, trifluoromethyl; R3- halogen, cyano, trifluoromethyl; R4- 4-isoxazolyl, pyrazolyl, which may be substituted with halogen, C1-4the alkyl, amino group, cycloalkyl, as well as their acid-salt additive

The invention relates to new derivatives of 4.1-benzoxazepin-2-she is of the formula (I), where R1lower alkyl, substituted by at least one optionally substituted hydroxyl group, R2and R3independently of one another is hydrogen or phenyl, which is substituted by 1-3 substituents selected from the group consisting of lower C1-C4alkoxygroup; X is a bond, methylene group or a linking group with a chain length of 1-7 atoms, selected from the group consisting of -(CH2)m-E-(CHR6)n-, where m and n = 1 or 2 independently from each other: E-bond or an oxygen atom, -NR5-, -CONR7-, where R5-methylsulphonyl, R6and R7independently of one another(i) hydrogen, (ii) lower alkyl, which is not substituted or substituted by substituents selected from the group consisting of piperidine, indolyl, possibly esterified carboxypropyl, (iii) benzyl, Y is optionally substituted carbarnoyl and/or the substituents on the N atom of carbamoyl, taken together, form a ring which may be substituted, or tetrazolyl, or piperidine, and the ring And is substituted by 1-3 substituents selected from the group consisting of atoms of Halogens or their salts

The invention relates to arylalkylamines formula I, where In - unsubstituted pyridyl, pyrazinyl, isoxazolyl or thienyl; Q - CH2; X - CH2or S; R1and R2each - H; and R3- OR5; R4OA; R5- Or cycloalkyl with 4-6 C atoms; And the alkyl with 1-6 C-atoms, and their physiologically acceptable salts

- aminohydroxylation and carboxylic acid" target="_blank">

The invention relates to new compounds of General formula I, where Q, A, R1n, m are listed in the value formula

The invention relates to a derivative of 7- (alkoxycarbonyl-substituted) -10-hydroxy-taxan following formula 3b:

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in which R1, R2, R4, R5, R6and R14defined above

The invention relates to new phenylsulfonyl derivative of General formula I, where the values of R1, R2, R3, R4, R5described in paragraph 1 of the claims

The invention relates to new derivatives of salicylic acid f-ly Gets-NR-SO2-Ph1A Ph2(COOH)(OH), (I), where Het represents (R1, R2, R3-Het1That gets1represents a cyclic systemin which the free valence is associated with a group NR; X is a group: a) -O-CH=CH-, -CH=CH-O-, -CH= CH-S - or b) -CH=CH-CH=CH-, -CH=CH-CH=N-, -CH=N-CH=CH-, -CH=CH-N=CH-, -N= CH-CH= CH-; R1, R2and R3are substituents at the carbon atom in Het and represent hydrogen, C1-C6- alkyl, halogen, hydroxy - or benzyloxy; R is hydrogen or C1-C6- alkyl; Ph1- phenylene, Ph2is phenyl which may be substituted with halogen, lower alkyl or benzyloxypropionic, provided that the carboxy - and hydroxy-group are in the ortho-position to each other; And a represents - CC-, -CH=CH-, -CH2-CH2-, -CO-CH=CH-, -CH=CH-CO-

The invention relates to pharmaceutical compositions containing as active ingredient at least one substance inhibiting NO-synthetase, and at least one substance that traps the reactive forms of oxygen, and, optionally, a pharmaceutically acceptable carrier

The invention relates to pharmaceutical compositions containing as active ingredient at least one substance inhibiting NO-synthetase, and at least one substance that traps the reactive forms of oxygen, and, optionally, a pharmaceutically acceptable carrier

The invention relates to a method for producing compounds of formula (I) consists in the fact that the compound of formula (IX):

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in which R1' has the abovementioned meaning and M represents a hydrogen atom or the radical R2' which has the values specified above for R2in which the possible reactive functions can be protected by a protective group, is subjected to reaction with the compound of the formula (VIII) defined above, to obtain a product of formula (X):

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in which R1' M and R4' have the above values, the obtained compound of formula (X), if M implies R2' defined above, is subjected to a halogenation reaction, to obtain the product of formula (XI):

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in which R1', R2', R4' and Hal have the above values, which is subjected to the reaction of the exchange of the halogen-metal, then the reaction with the compound of the formula (XII):

< / BR>
in which R9' matter referred to in paragraph 1 for R9where possible reaction ф�g/rupat4/200110/01/2174513-36t.gif" ALIGN="ABSMIDDLE">< / BR>
in which R1', R2', R4' and R9' have the above meanings and, if necessary, or interact product of formula (I2) with the compound of the formula (XV):

O=C=N-R6' (XV)

in which R6' matter referred to in paragraph 1 for R6in which the possible reactive functions can be protected by a protective group, to obtain a product of formula (I3):

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in which R1', R2', R4', R6' and R9' have the above meanings, or the product of formula (I2) is subjected to a saponification reaction with the product of formula (I4):

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in which R1', R2', R4' and R9' have the above meanings, is subjected to reaction with COCl2to obtain a product of formula (I5):

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in which R1', R2', R4' and R9' have the above meanings, or the product of formula (X), provided that M denotes a hydrogen atom, is subjected to a halogenation reaction to obtain a product of formula (XIV):

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in which R1', R4'Hal and R3" have the above values, the compound obtained is subjected to the reaction of the exchange of the halogen-metal, then the processing of the compound of formula (IVa') (IVb'), (IVc'), (IVd') or (IVe') defined above, to obtain a product of formula (I7):

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in which R1', R4', R2and R3" have the above meanings; then the above products of formula I2, I3, I4, I5, I6, I7that are a product of the formula I, allocate or subjected, if necessary, one or more reactions of transformation to other products of the formula I, in any order:

a) esterification of the acid function,

(b) saponification functions of ester to acid functions,

C) transforming functions of ester function acyl,

d) transforming Sinopoli in an acid function,

e) conversion of the acid function to an alcohol function,

g) transforming functions alkoxy function hydroxyl or hydroxyl function in the function alkoxy,

h) oxidation of the alcohol function to the aldehyde, acid or keto-function

i) the conversion of the formyl radical in the radical carbarnoyl,

j) turning radical carbarnoyl in the nitrile radical,

k) converting the nitrile radical in tetrazolyl,

l) oxidation of ancilliary or aristocraty to the corresponding sulfoxide or sulfone,

m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,

n) the transformation function oxo function of thioxo,

a) transforming radical

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in radical

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p) conversion of the acid function in function

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q) is the transformation function of beta-keto-sulfoxide in the function of alpha-ketotioefir,

r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

s) removal of protective groups, which can protect the reaction functions,

t) salt formation using mineral or organic cisisomer, enantiomers and diastereoisomers

The invention relates to compositions intended for parenteral or oral administration

The invention relates to compounds of the formula I, in all stereoisomeric forms and mixtures in any ratio, where NV denotes maleic acid, to a method for producing compounds of formula I, which lies in the fact that compounds of the formula II exercise anionic exchange with maleic acid and/or maleate

The invention relates to compounds of the formula I, in all stereoisomeric forms and mixtures in any ratio, where NV denotes maleic acid, to a method for producing compounds of formula I, which lies in the fact that compounds of the formula II exercise anionic exchange with maleic acid and/or maleate

The invention relates to medicine, namely to anesthesiology

The invention relates to new sulfonamidnuyu derivatives or their pharmaceutically acceptable salts, which have the properties of inhibitor action of endothelin receptors and can find application in the treatment of diseases associated with disorders in the circulatory system, such as hypertension, ischemia, angina, spasms of the blood vessels as well as to pharmaceutical drugs based on them
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