Sesamestreet n-arylamide sulfonilmocevinnah acid, the retrieval method (variants), pharmaceutical composition and method of treatment

 

(57) Abstract:

The present invention relates to serotonim N-arylamides sulfonilmocevinnah acid of the formula I

where a1- phenylene, thiazoline and benzothiazolyl, and phenylene may be substituted; ring AND2that contains carbon atoms, a represents a benzene ring or aromatic monocyclic 5-6-membered heterocycle containing one or two ring heteroatoms selected from N, O and S. the Compounds are valuable pharmaceutically active compounds for the treatment and prevention of diseases, for example cardiovascular disease. In addition, the present invention relates to methods for producing compounds of formula (I), to their use for the treatment and prevention of these diseases and for the manufacture of a designated pharmaceuticals and to pharmaceutical preparations containing compounds of formula (I). 5 N. and 15 C.p. f-crystals.

The present invention relates to compounds of the formula I

where a1, A2, R1, R2, R3, X and n are defined as indicated below, which are useful pharmaceutically active soedineniya, angina, cardiac insufficiency, thromboses or atherosclerosis. The compounds of formula I capable of modulating the production of a body of cyclic guanosine monophosphate (cGMP, cGMP) and generally suitable for the treatment and prevention of diseases caused by imbalance of cGMP. In addition, the present invention relates to methods of preparing compounds of the formula I, to their use for the treatment and prevention of these diseases and for the manufacture of a designated pharmaceuticals and to pharmaceutical preparations containing compounds of formula I.

cGMP is an important intracellular messenger, which triggers a variety of effects through the modulation of cGMP-dependent protein kinases, phosphodiesterase and ion channels. Examples are the relaxation of smooth muscle, inhibition of platelet activation and inhibition of proliferation of smooth muscle cells and leukocyte adhesion. the cGMP is produced by particulate and soluble guanylate cyclase in response to several extracellular and intracellular stimulants. In the case of particulate guanilatcyclase stimulation cause basically peptide messengers, such as atrial natiure astavliaut a cytosolic heterodimeric hemoprotein, on the contrary, are governed mainly by the family nizkomolekulyarnykh factors, which are formed enzymatically. The most important stimulator is nitrogen monoxide (NO) or closely related to him the substance. Function of other factors, such as carbon monoxide or a hydroxyl radical, is still uncertain. As the mechanism of activation by NO is discussed linking with NO gem with the formation of heme-nitrosyl complex with coordination number 5. Associate release of histidine associated in the basal state with iron, converts the enzyme in an active conformation.

Active soluble guanylate cyclase are each of the - and-subunits. Already described some subtypes of subunits differing from each other in sequence, tissue-specific distribution and expression at different stages of development. Subtypes1and1mainly expressed in brain and lung, and2find, particularly in the liver and kidneys. Subtype2is, as shown, in the brain of a human embryo. Subunit 3and3were extracted from the human brain and are homologues 1and1. In later works described subunit2ithat contain the one domain. Enzymes presumably contain one heme on heterodimer, which is attached via1-Cys-78 and/or1-His-105 and is part of the control center.

Under pathological conditions the formation of factors, activating guanylate cyclase, can be reduced or increased presence of free radicals can promote their cleavage. Reduced as a result of this activation RHC results, because of the weakening of relevant cGMP-mediated cellular responses, such as increased blood pressure, platelet activation, or increased proliferation and adhesion of cells. And this, in turn, leads to endothelial dysfunction, atherosclerosis, hypertension, stable or unstable angina, thrombosis, myocardial infarction, shock, or erectile dysfunction. Pharmacological stimulation of RHC allows to normalize the production of cGMP, and therefore makes possible the treatment and/or prevention of such disorders.

For pharmacological stimulation RHC is still used almost exclusively of the compounds which are based on the interim release of NO, such as organic nitrates. The lack of such treatment for

In a number of publications authored by Wesely (Vesely) described various stimulants RHC acting not through the release of NO. However, these compounds, most of which are hormones, plant hormones, vitamins or natural compounds, such as, for example, poisons lizards, mostly have only weak effects on the formation of cGMP in the cell lysates (D. L. Vesely, Eur. J. Clin. Invest. 15 (1985) 258; D. L. Vesely, Biochem. Biophys. Res. Comm. 88 (1979) 1244). Stimulation of no with heme guanylate cyclase by protoporphyrin IX was shown by the authors Ignarro et al. (Adv. Pharmacol. 26 (1994) 35). Pettibone et al. (Eur. J. Pharmacol. 116 (1985) 307) described the antihypertensive diphenylethylenediamine and have attributed this to a stimulation of the RHC. According to Yu et al. (Brit. J. Pharmacol. 114 (1995) 1587) isoliquiritigenin, which has a relaxing effect on the selected aorta of rats, also activates the RHC. Ko et al. (Blood 84 (1994) 4226), Yu et al. (Biochem. J. 306 (1995) 787) and Wu et al. (Brit. J. Pharmacol. 116 (1995) 1973) demonstrated RHC-stimulating activity of 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole and showed antiproliferative and platelet-inhibitory effect. Pyrazoles and condensed pyrazoles, showing RHC-stimulating activity described in EP-A-908456 and DE-A-19744027.

Already was opiu as Deputy. These compounds, in which the N-aryl group usually has as additional substituents, which are easily oxidized, such as, for example, two of the hydroxy-group located in the para-position relative to each other, and which in this case can be considered as derivatives of hydroquinone are auxiliary substances for the manufacture of photographic materials (see, for example, Chemical Abstracts 119, 105757; 120, 41858; 123, 70224 or 126, 257007). If we consider the individual structural elements, the N-aryl group in these known compounds corresponds to the group R1-S(O)n-AND1in formula I when AND1represents 1,4-fenelonov group, which is in positions 2 and 5 has a hydroxy-group (or substituents in the form of actigraphy), and n is 0. In the publication the United Kingdom patent No. 876526 (Chemical Abstracts 56, e) disclosed N-(5-chloro-2-(4-chlorophenylurea)phenyl)amide 3,5-dichloro-2-methylsulfonylbenzoyl acid, which can be used to protect the wool from moths. Compounds covered by the patent GB-A-876526 correspond to compounds of the formula I, if both the ring AND1that contains the carbon atoms bearing the group C(=X)-NH - and NH-SO2R2together with grupamocarta of chlorine and bromine, R2is (C1-C4)-alkyl, X is oxygen and R1-S(OH)n-AND1is phenylmercapturic group (=phenylthiophene-), which is substituted by halogen and/or trifluoromethyl, and which may also be replaced by stands or (C1-C4)-alkoxy, and the total number of atoms of halogen and triptorelin groups greater than two. Pharmacological action of these known N-arylamido 2-sulfoaluminate acid is not disclosed.

Currently, it has been unexpectedly found that the compounds of the present invention provide a strong activation of guanylate cyclase and therefore suitable for the treatment and prevention of disorders associated with low levels of cGMP.

Thus, the present invention relates to compounds of the formula I

where a1represents a divalent group from the series consisting of phenylene, naphthylene and heteroaryl, which can all be substituted by one or more identical or different substituents from the series consisting of halogen, (C1-C5)-alkyl, phenyl, talila, CF3, NO2HE, -O-(C1-C5)-alkyl, -O-(C2-C4)-alkyl-O-(C1-C3)- The UB>2, -NH-CHO, -NH-CO-(C1-C5)-alkyl, -CN, -CO-NH2, -CO-NH-(C1-C3)-alkyl, -CO-N((C1-C3)-alkyl)2FROM-OH, -CO-O-(C1-C5)-alkyl, heterocyclyl, SNO, -CO-(C1-C5)-alkyl, -S(O)n-(C1-C4)-alkyl, -S(O)n-phenyl and-S(O)n-tolila;

ring AND2that contains the carbon atoms bearing the group C(=X)-NH - and NH-SO2R2represents a benzene ring, naphthalene ring, saturated or partially unsaturated 3-7-membered carbocycle, saturated or partially unsaturated or aromatic monocyclic 5-7-membered heterocycle containing one or more ring heteroatoms from the series consisting of N, O and S, or a saturated or partially unsaturated or aromatic bicyclic 8-10-membered heterocycle containing one or more ring heteroatoms from the series consisting of N, O and S;

R1represents aryl, heterocyclyl or (C1-C18)-alkyl which can be substituted by one or more identical or different residues R4or, if the number n in the group R1-S(O)n- is 2, R1can also be NR5R6or, if the number n in the group R1-S(O)nanyway or (C1-C10)-alkyl which can be substituted by one or more identical or different groups R4;

R3represents one or more identical or different groups from the series consisting of hydrogen, halogen, CF3HE, -O-(C1-C7)-alkyl, -O-(C2-C4)-alkyl-O-(C1-C7)-alkyl, -O-aryl, (C1-C2)-alkylenedioxy, NO2, -CN, NR7R8, -CO-NR7R8, -CO-OH, -CO-O-(C1-C5)-alkyl, heterocyclyl, -S(O)n-(C1-C5)-alkyl and (C1-C5)-alkyl which can be substituted by one or more identical or different groups R4;

R4represents fluorine, HE, -O-(C1-C10)-alkyl, -O-(C2-C4)-alkyl-O-(C1-C7)-alkyl, -O-aryl, -CN, NR7R8, -CO-NH2, -CO-NH-(C1-C3)-alkyl, -CO-N((C1-C3)-alkyl)2FROM-OH, -CO-O-(C1-C5)-alkyl, heterocyclyl or oxo;

R5represents hydrogen, (C1-C10)-alkyl which can be substituted by one or more identical or different substituents R4and/or aryl, or represents aryl, heterocyclyl, -CO-NR7R8, -CO-aryl or-CO-(C1-C10)-ALr>4;

R6regardless of R5has one of the meanings indicated for R5or R5and R6together with the nitrogen atom to which they are attached, form a 5-8-membered saturated or partially unsaturated ring which, in addition to the nitrogen atom carrying the groups R5and R6may contain one or more ring heteroatoms from the series consisting of N, O and S, and which may be substituted by one or more identical or different substituents from the series consisting of fluorine, (C1-C5)-alkyl, hydroxy-(C1-C3)-alkyl-, -(C1-C3)-alkyl-O-(C1-C4)-alkyl, aryl, CF3HE, -O-(C1-C7)-alkyl, -O-aryl, -O-(C2-C4)-alkyl-O-(C1-C7)-alkyl, (C2-C3)-alkylenedioxy, NR7R8, -CN, -CO-NH2, -CO-NH-(C1-C3)-alkyl, -CO-N((C1-C3)-alkyl)2FROM-OH, -CO-O-(C1-C5)-alkyl, Cho, -CO-(C1-C5)-alkyl, -S(O)n-(C1-C4)-alkyl, -S(O)n-NH2, -S(O)n-NH-(C1-C3)-alkyl, -S(O)n-N((C1-C3)-alkyl)2, oxo, -(CH2)m-NH2, -(CH2)m-NH-(C1-C4)-alkyl and -(CH2)m-N((C15;

R7represents hydrogen or (C1-C7)-alkyl which can be substituted by one or more identical or different substituents from the series consisting of HE, -O-(C1-C5)-alkyl, NH2, -NH-(C1-C4)-alkyl and-N((C1-C4)-alkyl)2where the Deputy-N((C1-C4)-alkyl)2two alkyl groups may be linked by a simple relationship, and then together with carrying their nitrogen atom, they form a 5-7-membered ring which in addition to the nitrogen atom and the carbon atoms may optionally contain as a ring member an oxygen atom, a sulfur atom or a group NR5;

R8regardless of R7has one of the values R7or represents-CO-(C1-C4)-alkyl;

aryl represents phenyl, naphthyl or heteroaryl, which can be substituted by one or more identical or different substituents from the series consisting of halogen, (C1-C5)-alkyl, FeNi is UB>-C3)-alkyl, (C1-C2)-alkylenedioxy, NH2, -NH-(C1-C3)-alkyl, -N((C1-C3)-alkyl)2, -NH-CHO, -NH-CO-(C1-C5)-alkyl, -CN, -CO-NH2, -CO-NH-(C1-C3)-alkyl, -CO-N((C1-C3)-alkyl)2FROM-OH, -CO-O-(C1-C5)-alkyl, heterocyclyl, SNO, -CO-(C1-C5)-alkyl, -S(O)n-(C1-C4)-alkyl, -S(O)n-phenyl and-S(O)n-tolila;

heteroaryl, heteroaryl represent the balance of monocyclic 5 - or 6-membered aromatic heterocycle or a bicyclic 8-10 membered aromatic heterocycle, each of which contains one or more ring heteroatoms from the series consisting of N, O and S;

heterocyclyl represents the balance monocyclic or polycyclic 5-11-membered saturated or partially unsaturated heterocycle which contains one or more ring heteroatoms from the series consisting of N, O and S, and which may be substituted by one or more identical or different substituents from the series consisting of fluorine, (C1-C5)-alkyl, HE, -O-(C1-C5)-alkyl, -O-(C2-C4)-alkyl-O-(C1-C3)-alkyl, NH2, -NH-(C1- 3
)-alkyl)2-WITH-HE-CO-O-(C1-C5)-alkyl;

n represents 0, 1 or 2;

m is 2, 3 or 4;

X represents O or NH or X represents a nitrogen atom, which, through a simple link attached to the ring carbon atom in the group AND1immediately adjacent to the carbon atom in the a1bearing a group-NH-C(=X)-, resulting in a group-NH-C(=X)- together with bearing its carbon atoms in A1forms annulirovano imidazole ring;

in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts;

moreover, however, excludes the compound of the formula I, in which both the ring AND2containing carbon atoms bearing the group C(=X)-NH - and NH-SO2R2represents benzene ring, substituted in positions 3 and 5 chlorine, R2represents methyl, X is oxygen, and R1-S(O)n-A1represents 5-chloro-2-(4-chlorophenylurea)phenyl group.

If in the compounds of formula I, groups or substituents, such as, for example, R3, R4, R5, aryl, heterocyclyl, alkyl, etc. or numbers n and m may appear neskaldowae or different.

Alkyl groups can be unbranched or branched. This also applies to cases when they are part of other groups, such as alkoxygroup, alkoxycarbonyl groups or amino groups, or when they are substituted by the groups. Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, axtel, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, n-isomers of these groups, isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, neopentyl, 3,3-dimethylbutyl. The term "alkyl" in the present description also includes unsaturated alkyl group, i.e. alkyl groups that contain one or more double bonds and/or one or more triple connections, such as, for example, alkeline and alkyline group. Of course, unsaturated alkyl group contains at least two carbon atoms. Therefore, specific alkyl groups, the number of carbon atoms of which can vary from 1 to a specified upper limit, also include unsaturated alkyl groups, the number of carbon atoms of which can vary from 2 to a specified upper limit. Examples of such groups include vinyl group, 1-PDEC is methyl-2-bucinellina group, etinilnoy group, 2-proponila group (propargyl group), 2-Butyrina group or 3-Butyrina group. In addition, the term "alkyl" in the present description also includes alkyl groups, in which by closing the inner ring in the alkyl group formed of a cyclic system, i.e., the term "alkyl" includes saturated and partially unsaturated cycloalkyl group and cycloalkenyl group (alkyl, substituted cycloalkyl). Of course, monocyclic cycloalkyl group contains at least three carbon atoms. Therefore, specific alkyl groups, the number of carbon atoms of which can vary from 1 to a specified upper limit, also include monocyclic cycloalkyl group, the number of carbon atoms of which can vary from 3 to a specified upper limit, and the corresponding cycloalkylation group. Examples of such cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, which can also be substituted by one or more identical or different (C1-C4)-alkyl groups, in particular the stands. Examples of such substituted cycloalkyl groups are 4-methylcyclohexyl, 4-E unsubstituted alkyl group, as well as alkyl groups, substituted by one or more (e.g. one, two, three or four identical or different aryl groups. The term "alkyl" in the present description also includes arylalkyl groups, such as, for example, aryl-(C1-C4)-alkyl, for example benzyl groups, phenylethylene group or indanamine group. In the substituted alkyl groups, for example, arylalkyl, hydroxyalkyl, such as -(C1-C3)-alkyl-HE, or alkoxyalkyl, such as -(C1-C3)-alkyl-O- (C1-C4)-alkyl, the substituents can be located in any required position.

Saturated or partially unsaturated 3-7-membered carbocycle representing the ring AND2can be made from the original monocyclic systems cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane or Cycloheptane. If carbocycle is unsaturated, it may contain, for example, a double bond or, in the case of 5-, 6 - or 7-membered ring, two double bonds, which can be isolated or conjugated. The double bond can be in any positions relative to the group C(=X)-NH - and NH-S2R2, i.e., for example, the double bond can exist between two annular angle the e group and heterocyclic group, for example, the heteroaryl groups may be unsubstituted or may have one or more (e.g. one, two, three or four identical or different substituents, which may be located in any desired positions. Unless otherwise noted, these groups may be present, for example, those substituents listed as substituents of aryl groups. The preferred number of substituents that may be present in the aryl group consisting of halogen, (C1-C5)-alkyl, phenyl, talila, CF3, NO2HE, -O-(C1-C5)-alkyl, -O-(C2-C4)-alkyl-O-(C1-C3)-alkyl, (C1-C2)-alkylenedioxy, NH2, -NH-(C1-C3)-alkyl, -N((C1-C3)-alkyl)2, -NH-CHO, -NH-CO-(C1-C5)-alkyl, -CN, -CO-NH2, -CO-NH-(C1-C3)-alkyl, -CO-N((C1-C3)-alkyl)2FROM-OH, -CO-O-(C1-C5)-alkyl, heterocyclyl, SNO, -CO-(C1-C5)-alkyl, -S(O)n-(C1-C4)-alkyl, -S(O)n-phenyl and-S(O)n-tolila. If in the compounds of formula I as substituents are nitro group in the molecule can be only up to two nitro groups. If as substituents, for example, aryl is gruppy, benzyl group or benzyloxy, these substituents of the benzene ring may be unsubstituted or substituted by one or more (e.g. one, two, three or four identical or different groups, for example groups from the series consisting of (C1-C4)-alkyl, halogen, hydroxy, (C1-C4)-alkoxy, trifloromethyl, cyano, hydroxycarbonyl, ((C1-C4)- alkoxy)carbonyl, aminocarbonyl, nitro, amino, (C1-C4)-alkylamino, di-((C1-C4)-alkyl) amino and ((C1-C4)-alkyl) carbylamine.

In monosubstituted phenyl groups Deputy may be in the 2-position, 3-position or 4-position, in disubstituted phenyl groups, the substituents can be in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In trisemester phenyl groups, the substituents can be in the 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position. Tolyl (=methyl-phenyl) can be 2-tolila, 3-tailam or 4-tailam. Naphthyl may be 1-naphthyl or 2-naphthyl. In monosubstituted 1-naftalina groups Deputy may be in the 2-position, 3-position, 4-position, 5-position is sterile in the 1-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8-position.

The above explanations and the following clarifications related to univalent groups, respectively, apply to the divalent groups: phenylene, naphthylene and heteroaryl. Free communication through which the divalent group attached to the adjacent groups, may be any of the carbon atoms in the ring. If phenylenebis group they may be in the 1,2-position (orthophenylene), 1,3-position (meta-phenylene or 1,4-position (para-phenylene). If Neftyanoi group free communication can be in the 1,2-position (=1,2-naftilan or 1,2-naphthalenediol) or 1,3-position, 1,4-position, 1,5-position, 1,6-position, 1,7-position, 1,8-position of 2,3-position, 2,6-position, or 2,7-position. In the case of 5-membered cyclic aromatic compounds containing one heteroatom, such as, for example, thiophene or furan, two free communication can be in the 2,3-position, 2,4-position, 2,5-position or the 3,4-position. Divalent group derived from pyridine, may be 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-pyridinediamine group. In the case of asymmetrical dwuhvalentnykh groups present invention covers all Gemina group is in the 2-position, and the other adjacent group in 3-position and a compound in which one of the adjacent group is in the 3-position and the other adjacent group in 2-position.

Heteroaryl group, heteroarenes group, heterocyclyl groups, heterocycles representing ring2and rings, which are formed by two groups attached to the nitrogen atom, together with the nitrogen atom are preferably derived from heterocycles containing one, two, three or four identical or different heteroatoms in the ring, more preferably from heterocycles containing one, two or three, in particular one or two, identical or different heteroatoms. Unless otherwise indicated, the compounds may be monocyclic or polycyclic, for example monocyclic, bicyclic or tricyclic. Preferably they are monocyclic or bicyclic. The rings are preferably 5-membered, 6-membered or 7-membered rings. Examples of monocyclic and bicyclic heterocyclic systems, which can be produced groups contained in the compounds of formula I, are pyrrole, furan, thiophene, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, 1,3-dioxole, 1,3-oxazole (=oxaz the Razin, Piran, thiopyran, 1,4-dioxin, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, 1,2-thiazin, 1,3-thiazin, 1,4-thiazin, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, azepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,3-oxazepine, 1,3-diazepine, indole, benzothiophene, benzofuran, benzothiazole, benzimidazole, quinoline, isoquinoline, cinnoline, hinzelin, cinoxacin, phthalazine, thienothiophene, 1,8-naphthiridine and other naphthirydines, pteridine or phenothiazines, each of them in a saturated form (perhydro), or a partially unsaturated form (for example, in the form of a dihydro or tetrahydro) or maximally unsaturated form, if the respective forms are known and stable. Thus, suitable heterocycles include, for example, saturated heterocycles pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine. The degree of saturation of the heterocyclic groups shown in their individual definitions. Unsaturated heterocycles may contain, for example, one, two or three double bonds in the ring system. 5 - and 6-membered rings, in particular, can also be aromatic.

The group produced from these heterocycles may be attached via any suitable carbon atom. Nitrogen heterocycles, which may have the hydrogen atom of HDE also be attached via a ring nitrogen atom, in particular, if the heterocyclic group in question attached to the carbon atom. For example, thienyl group may be present in the form of a 2-thienyl group or a 3-thienyl group, furilla group in 2-shriley group or 3-shriley group, Peregrina group in 2-peredelnoj group, 3-peredelnoj group or 4-peredelnoj group, piperidinyl group - 1-piperidinyloxy group (=piperidino), 2-piperidinyloxy group, 3-piperidinyloxy group or 4-piperidinyloxy group, (thio)morpholinyl group in 2-(thio)morpholinyl group, 3-(thio)morpholinyl group or 4-(thio)morpholinyl group (=thiomorpholine). The group is produced from 1,3-thiazole or imidazole, which is attached via a carbon atom, can be attached in 2-position, 4-position or 5-position.

If not stated otherwise, the heterocyclic group may be unsaturated or can have one or more, for example one, two, three or four identical or different substituent. The substituents in the heterocyclic compounds may be in any desired positions, for example 2-thienyl group or a 2-shriley group in 3-position and/or 4-position and/or 5-position, 3-thienyl the position, and/or 4-position and/or 5-position and/or 6-position, 3-peredelnoj group in 2-position and/or 4-position and/or 5-position and/or 6-position, 4-peredelnoj group in 2-position and/or 3-position and/or 5-position and/or 6-position. Unless otherwise specified, the substituents in the heterocyclic groups can be present, for example, in the form of the substituents listed in the definition of aryl groups, and in the case of saturated or partially unsaturated heterocycles as other substituents may also be present oxoprop and tocograph. The substituents in the heterocycle, and the substituents in carbocycle can also form a ring, i.e. a ring system may be condensed (or annulirovano) with other rings, so that the heterocycle may also be present, for example, cyclopentanecarbonyl, cyclohexanecarbonyl or benzododecinium rings. Suitable substituents at substitutable ring nitrogen atom in the heterocycle include, for example, unsubstituted (C1-C5)-alkyl groups and aryl-substituted alkyl groups, aryl groups, acyl groups such as-CO-(C1-C5)-alkyl, or sulfonylurea groups, such as-SO2-(C

Halogen represents fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

Examples of groups of compounds of the present invention, not limiting the invention, represented by formulas Ia, Ib, Ic, Id, Ie, If, Ig and Ih, where a2shown in the formula I, has a specific value. A1, R1, R2, R3, X and n in the formulas Ia, Ib, Ic, Id, Ie, If, Ig and Ih are defined as above for formula I, and the number k in the formula Ib is 1, 2, 3, 4 or 5, in particular 3 or 4.

In the benzene ring of the formula Ia, which contains the group-C(=X)-NH - and-NHSO2R2there are four positions that can carry the group R3. Thus, the compounds of formula Ia can have four groups of R3that in accordance with the definition of R3all can be independently from each other hydrogen or may be a value other than hydrogen, i.e. the compounds of formula Ia of the benzene ring shown in formula Ia, may be unsubstituted or may have one, two, three or four identical or different Zam is-O-(C1-C7)-alkyl, -O-aryl, (C1-C2)-alkylenedioxy, NO2, -CN, NR7R8, -CO-NR7R8FROM-OH, -CO-O-(C1-C5)-alkyl, heterocyclyl, -S(O)n-(C1-C5)-alkyl and (C1-C5)-alkyl which can be substituted by one or more identical or different groups R4. These clarifications respectively pertain to compounds of formula Ib-Ih.

The compounds of formula I, where X represents a nitrogen atom, which is a single bond attached to the ring carbon atom in the group AND1immediately adjacent to the carbon atom in the a1bearing a group-NH-C(=X)-, resulting in a group-NH-C(=X)- together with bearing the carbon atom in the a1forms annulirovano imidazole ring represented by formula Ii.

A2, R1, R2, R3and n in the formula Ii are defined as above for formula I. the Ring AND3that obtained from group a1by establishing communication with the nitrogen atom, X represents, and which contains, as shown in the formula Ii, two carbon atom bearing the nitrogen atoms annulirovano imidazole ring is a benzene ring, naphthalene ring or courtesans who am.

The present invention includes all stereoisomeric forms of the compounds of formula I. Centers of asymmetry present in the compounds of formula I can independently of each other to have the S - or R-configuration. The present invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and/or diastereomers, in all ratios. Thus, the enantiomers are the subject of the invention in enantiomerically pure form, both as levogyrate, and programada antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of CIS-TRANS isomerism present invention includes both CIS-form and TRANS-form, and mixtures of these forms in all ratios. Individual stereoisomers can be optionally obtained by separating a mixture of traditional methods, for example by chromatography or crystallization, using stereochemical homogeneous starting materials for synthesis or by stereoselective synthesis. Before separation of the stereoisomers can be carried out by an optional receipt derivatives. Separation of a mixture of stereoisomers can be made at the stage Sookie all tautomeric forms of compounds of formula I.

If the compounds of formula I contain one or more acidic or basic groups, the invention also covers the corresponding physiologically or toxicologically acceptable salts, in particular pharmaceutically acceptable salts. Thus, the compounds of formula I which contain acidic groups can be and can be used in accordance with the present invention, for example, in the form of salts of alkali metals, salts of alkaline-earth metal or ammonium salts. Examples of such salts are sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of formula I which contain one or more basic groups, i.e. groups which can be protonated, can be present and can be used in accordance with the present invention in the form of their acid additive salts with inorganic and organic acids, for example as salts with hydrogen chloride, bromoiodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluensulfonate acid, naphthalenedisulfonate acids, oxalic it is avinou acid, propionic acid, privalovoi acid, dietramszell acid, malonic acid, succinic acid, peelaway acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, etc. If the compounds of formula I simultaneously contain in the molecule of the acid and basic groups present invention, in addition to these salts, also includes internal salts or betaines (zwitterions). Salts can be obtained from compounds of the formula I by traditional methods known to the person skilled in the technical field, for example by mixing with organic(im) or inorganic(them) with an acid or a base in a solvent or dispersant, or by anion or cation exchange from other salts. The present invention also includes all salts of the compounds of the formula I which, because of their low physiological compatibility, are not suitable for direct use in pharmaceutical preparations, but can be used, for example, as intermediates for chemical reactions or to obtain physiologically priamerica or adducts with alcohols, and also derivatives of the compounds of formula I, such as, for example, esters, amides, prodrugs and active metabolites.

AND1is preferably fenelonov group or 5 - or 6-membered heteroarenes group, and more preferably phenylene, all of these groups can be unsubstituted or substituted as indicated. If group a1substituted, i.e., if it has one or more substituents in addition to the group R1-S(O)n, preferably it is substituted by one or two identical or different substituents mentioned above. Preferably fenelonov group representing AND1is unsubstituted, i.e., except groups R1-S(O)n- C(=X)-NH, it has four atoms of hydrogen. The group R1-S(O)n- preferably attached to a carbon atom in the a1that does not directly adjacent to the carbon atom bearing the group C(=X)-NH. If a1is phenylene, the group R1-S(OH)nis preferably in meta - or para-position, more preferably in the para-position relative to the carbon atom carrying the group C(=X)-NH.

Ring AND2that contains two uglerodnaya preferably benzene or thiophene ring, particularly preferably a benzene ring, and these rings may be unsubstituted or substituted by one or more groups R3other than hydrogen.

R1is preferably (C1-C7)-alkyl, NR5R6or aryl, more preferably NR5R6, phenyl or 5 - or 6-membered heteroaryl, particularly preferably NR5R6and all of these groups can be unsubstituted or substituted as indicated, and, as indicated above, R1can represent NR5R6if the number n in the group R1-S(O)n- is 2.

R2is preferably aryl, more preferably phenyl or 5 - or 6-membered heteroaryl, particularly preferably phenyl, or a group of monocyclic 5 - or 6-membered aromatic heterocycle which contains one or two identical or different heteroatoms from the series consisting of N, O and S, such as, for example, phenyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridyl, and so on, in particular phenyl or 2-thienyl, all of these groups can be unsubstituted or substituted as indicated. Preferably the aryl group representing R2is substituted. the two or three, in particular one or two, identical or different substituents. Substituents in the aryl group representing R2, preferred are substituents from the series consisting of halogen, CF3, -O-CF3, NO2, -CN, (C1-C4)-alkyl and-O-(C1-C4)-alkyl, more preferably the substituents from the series consisting of F, Cl, Br, CF3, -O-CF3, NO2, -CN, CH3and-och3. Particularly preferred substituted aryl group representing R2is an aryl group substituted by chlorine, for example one or two (in particular one) chlorine atoms.

Rings representing AND2may be unsubstituted or substituted as indicated. When they loose, they are just groups of R3representing hydrogen. When they are substituted, they have one or more groups R3other than hydrogen. In those locations where there is no group, R3other than hydrogen, are hydrogen atoms. If the ring AND2has one or more groups R3other than hydrogen, it preferably has one or two such groups R3in particular, one such group, R3. Group R3other than hydrogen, predpochtitelno
-NH. If a2is saturated or partially unsaturated carbocycle, the group R3other than hydrogen, preferably represent a (C1-C4)-alkyl, in particular methyl. If a2represents an aromatic ring, in particular, if a2represents a benzene ring, the groups R3other than hydrogen, are preferably (C1-C3)-alkyl, halogen, (C1-C3)-alkoxy or CF3and more preferably methyl, chlorine or methoxy. If a2represents an aromatic ring, particularly a benzene ring, most preferred is the case where the ring has as substituents one chlorine atom or two metoxygroup, i.e. when there is one group R3being chlorine, or when there are groups of R3that represents methoxy, and in other positions of the benzene ring are hydrogen atoms. If a2represents a benzene ring, then the group R3other than hydrogen, preferably located in positions 4 and/or 5 (with respect to the group C(=X)-NH 1-position and the group R2-SO2-NH 2-position).

If the group is substituted by one or more groups R4. Preferably R4represents hydroxy, (C1-C4)-alkyloxy, di-((C1-C4)-alkyl)amino or heteroaryl.

R5and R6preferably represent independently of one another hydrogen, (C1-C9)-alkyl, (C1-C4)-alkyl-O-(C1-C3)-alkyl or 5 - or 6-membered aryl or together with the nitrogen atom bearing an R5and R6form a 5-7-membered heterocycle which, in addition to the nitrogen atom carrying the groups R5and R6may contain one additional ring heteroatom from the series consisting of N, O and S, and which may be substituted by one or more (e.g. one, two, three or four identical or different groups from the series consisting of (C1-C3)-alkyl, hydroxy-(C1-C3)-alkyl-, 5 - or 6-membered aryl, carbamoyl, hydroxy and oxo. It is especially preferred when R5and R6together with the nitrogen atom carrying these groups, form a 5-, 6 - or 7-membered heterocycle which, in addition to the nitrogen atom carrying the groups R5and R6may contain one additional ring heteroatom from the series consisting of N, O and S, and which may be substituted by one or more (e.g. one, two, Tr-(C1-C3)-alkyl-, 5 - or 6-membered aryl, carbamoyl, hydroxy and oxo, in particular (C1-C3)-alkyl, such as methyl. Preferably the heterocycle formed from groups of R5and R6together with the nitrogen atom carrying these groups is saturated.

Especially preferred heterocycle formed by the group3and R6together with the nitrogen atom carrying these groups is derived from the research, thiomorpholine, 1,1-dioxothiazolidine, 1-Osotimehin, dialkylanilines, such as dimethylmorpholine, 2,6-dimethylmorpholine, CIS-2,6-dimethylmorpholine, 3,5-dimethylmorpholine, CIS-3,5-dimethylmorpholine, 1-(pyrimidine-2-yl)piperazine, piperidine-4-carboxamide, 1-(2-hydroxyethyl)-piperazine, 1-methylpiperazine, 1-ethylpiperazine, 1-arylpiperazines, ethyl piperazine-1-carboxylate, piperidine, 2 methylpiperidine, 2,6-dimethylpiperidine, CIS-2,6-dimethylpiperidine, 3,5-dimethylpiperidine, CIS-3,5-dimethylpiperidine, 4-hydroxypiperidine, 4-oxopiperidine or Catala, such as 1,4-dioxa-8 azaspiro[4.5]decane, tetrahydropyridine, tetrahydropyrimidine, 1-methylhomopiperazine, thiazolidine, pyrroline, pyrrolidine, 3-hydroxypyrrolidine, 1,2,3,4-tetrahydroisoquinoline or 2,3-dihydro-1H-isoindoline ring nitrogen atom. More specifically, the preferred heterocycle formed by the group R5and R6together with the nitrogen atom carrying these groups is derived from the research, thiomorpholine, 1,1-dioxothiazolidine, 1-Osotimehin, 2,6-dimethylmorpholine, CIS-2,6-dimethylmorpholine, 3,5-dimethylmorpholine, CIS-3,5-dimethylmorpholine, 1-(pyrimidine-2-yl)piperazine, piperidine-4-carboxamide, 1,2,3,4-tetrahydroisoquinoline or 2,3-dihydro-1H-isoindole, more preferably of the research, 2,6-dimethylmorpholine or CIS-2,6-dimethylmorpholine, in particular the research or CIS-2,6-dimethylmorpholine, moreover, these rings are attached via a ring nitrogen atom or, in the case of a derivative of piperazine, through unsubstituted ring nitrogen atom.

R7preferably represents hydrogen, (C1-C3)-alkyl, (C1-C4)-alkyl)2N-(C1-C3)-alkyl or (C1-C4)-alkyl-O-(C1-C3)-alkyl-.

R8preferably represents hydrogen, (C1-C3)-alkyl or acetyl.

Aryl preferably represents phenyl or heteroaryl, in particular phenyl or 5 - or 6-membered heteroaryl. Unless otherwise stated, the preferred substituents in the aryl groups are halog the substituents are CF3, chlorine, methyl and methoxy.

Heteroaryl, heteroaryl preferably represent a group of monocyclic 5 - or 6-membered aromatic heterocycle, in particular a group derived from heteroaromatic compounds such as thiophene, pyrazole, thiazole, oxazole, isoxazol, pyridine, pyrimidine, pyridazine and tetrazole.

Heterocyclyl preferably represents a group derived from a saturated heterocycle, more preferably a group of monocyclic 5 - or 6-membered saturated heterocycle, in particular a group made from pyrrolidine, piperidine, N-alkylpiperazine, research, dialkylanilines, thiomorpholine or tetrahydrofuran. In addition, the above explanations concerning the preferred heterocycles formed by groups of R5and R6together with the nitrogen atom carrying these groups, respectively, apply to heterocyclyl groups attached through a ring nitrogen atom.

If a group S(O)nlinked to the nitrogen atom, the n for this group is 1 or 2, more preferably 2. The number n in the group R1-S(O)nis preferably from 0 to 2, particularly preferably 2.

X prefer group a1immediately adjacent to the carbon atom in the a1bearing a group-NH-C(=X)-, resulting in a group-NH-C(=X)- together with bearing its carbon atoms in A1forms annulirovano imidazole ring. It is especially preferred when X is O.

Preferred compounds of formula I are those compounds in which one or more groups have the preferred meanings, and all combinations of the preferred definitions of the substituents are the subject of the present invention. The present invention also covers all stereoisomeric forms, mixtures thereof in all ratios, and physiologically acceptable salts of all preferred compounds of the formula I. Compounds, for example, of the formulae Ia, Ib, Ic, Id, Ie, If, Ig and Ih, in which one or more groups have the preferred values are also preferred group of compounds in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts.

A group of especially preferred compounds comprise, for example, the compounds of formula I in which:

AND1represents phenylene or heteroaryl, and these groups can bytsevo from halogen, (C1-C4)-alkyl, CF3, -O-(C1-C4)-alkyl and -- CN;

ring AND2that contains two carbon atom carrying the group R2-SO2-NH and C(=X)-NH-, a is an aromatic ring;

R1is (C1-C7)-alkyl which can be substituted by one or more identical or different groups R4or aryl or, if the number n in the group R1-S(O)nis equal to 2, also represents a group NR5R6;

R2represents aryl;

R3represents one or more identical or different groups from the series consisting of hydrogen, halogen, CF3HE, -O-(C1-C4)-alkyl, -O-(C2-C4)-alkyl-O-(C1-C4)-alkyl, -O-aryl, NO2, -CN, NR7R8, -CO-NR7R8, -CO-OH, -CO-O-(C1-C4)-alkyl, heterocyclyl, -S(O)n-(C1-C4)-alkyl and (C1-C4)-alkyl which can be substituted by one or more identical or different groups R4;

R4represents fluorine, HE, -O-(C1-C10)-alkyl, -O-(C2-C4)-alkyl-O-(C1-C7)-alkyl, -O-aryl, -CN, NR7R8, -CO-NH2, -CO-NH-(C1-C3)-alkyl, -CO-N((C1< 6 represent independently from each other hydrogen, (C1-C9)-alkyl, (C1-C4)-alkyl-O-(C1-C3)-alkyl - or aryl or together with the nitrogen atom bearing an R5and R6form a 5-7-membered heterocycle which, in addition to the nitrogen atom carrying the groups R5and R6may contain one additional ring heteroatom from the series consisting of N, O and S, and which may be substituted by one or more identical or different groups from the series consisting of (C1-C3)-alkyl, hydroxy-(C1-C3)-alkyl-, aryl, carbamoyl, hydroxy and oxo;

R7represents hydrogen, (C1-C3)-alkyl, (C1-C4)-alkyl)2N-(C1-C3)-alkyl or (C1-C4)-alkyl-O-(C1-C3)-alkyl-;

R8represents hydrogen, (C1-C3)-alkyl or acetyl;

aryl represents phenyl or heteroaryl, which can be substituted by one or more identical or different substituents from the series consisting of halogen, (C1-C4)-alkyl, phenyl, CF3, NO2, -O-(C1-C4)-alkyl, -(C1-C2)-alkylenedioxy, NH2, -NH-CO-(C1-C4)-alkyl, -CN, -CO-NH2, -CO-HE-CO-PA 5 - or 6-membered aromatic heterocycle, which contains one or more identical or different ring heteroatoms from the series consisting of N, O and S;

heterocyclyl represents the balance monocyclic 5 - or 6-membered saturated heterocycle which contains one or more identical or different ring heteroatoms from the series consisting of N, O and S, and which may be substituted by one or more identical or different substituents from the series consisting of fluorine, (C1-C4)-alkyl, HE, -O-(C1-C4)-alkyl, NH2, -CN, -CO-NH2, -CO-OH and-CO-O-(C1-C4)-alkyl;

n represents 0, 1 or 2;

X represents oxygen;

in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts.

The group is still more preferred compounds comprise, for example, the compounds of formula I in which:

AND1represents phenylene, unsubstituted or substituted by one or more identical or different substituents from the series consisting of halogen, (C1-C4)-alkyl, CF3, -O-(C1-C4)-alkyl and -- CN;

ring AND2that contains two carbon atom carrying the group R2;

R2represents aryl;

R3represents one or more identical or different groups from the series consisting of hydrogen, halogen, CF3, -O-(C1-C4)-alkyl, -CN, and (C1-C4)-alkyl;

R5and R6together with the nitrogen atom bearing an R5and R6form a 5-7-membered saturated, a heterocycle which, in addition to the nitrogen atom carrying the groups R5and R6may contain one additional ring heteroatom from the series consisting of N, O and S, and which may be substituted by one or more identical or different groups from the series consisting of (C1-C3)-alkyl, hydroxy-(C1-C3)-alkyl-, aryl, carbamoyl, hydroxy and oxo;

aryl represents phenyl or 5 - or 6-membered heteroaryl containing one or more identical or different ring heteroatoms from the series consisting of N, O and S, which (these groups may be substituted by one or more identical or different substituents from the series consisting of halogen, (C1-C4)-alkyl, CF3, NO2, -O-(C1-C4)-alkyl, -NH-CO-(C1-C4)-alkyl and -- CN;

n represents 2;

X is sour acceptable salt.

A group of especially preferred compounds comprise, for example, the compounds of formula I in which:

AND1is unsubstituted divalent fenelonov group;

ring AND2that contains two carbon atom carrying the group R2-SO2-NH and C(=X)-NH-, a represents a benzene ring;

R1represents a group NR5R6;

R2represents aryl;

R3represents one or more identical or different groups from the series consisting of hydrogen, halogen, -O-(C1-C4)-alkyl and (C1-C4)-alkyl;

R5and R6together with the nitrogen atom bearing an R5and R6form a saturated 6-membered heterocycle which, in addition to the nitrogen atom carrying the groups R5and R6may contain one additional ring heteroatom from the series consisting of N, O and S, and which may be substituted by one or more identical or different groups from the series consisting of (C1-C3)-alkyl, aryl, oxo and carbamoyl;

aryl represents phenyl or 5 - or 6-membered heteroaryl containing one or more identical or different ring heteroatoms from the series, sostoiatelni of the series, consisting of halogen, (C1-C4)-alkyl, CF3and-O-(C1-C4)-alkyl;

n represents 2;

X represents oxygen;

in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts.

The group of most preferred compounds comprise, for example, the compounds of formula I in which:

AND1is unsaturated divalent 1,4-fenelonov group;

ring AND2that contains two carbon atom carrying the group R2-SO2-NH and C(=X)-NH-, together with groups of R3represents a benzene ring having one or two substituent from the series consisting of chlorine and methoxy;

R1represents a group NR5R6;

R2represents phenyl or thienyl substituted by one or two chlorine atoms;

R5and R6together with the nitrogen atom bearing an R5and R6form a saturated 6-membered heterocycle which, in addition to the nitrogen atom carrying the groups R5and R6may contain one additional ring heteroatom from the series consisting of O and S and which is unsubstituted or substituted by one or two who ireasoning forms and mixtures thereof in all ratios, and their physiologically acceptable salts.

The present invention relates also to methods of preparing compounds of the formula I, which are described below and which can be obtained the compounds of the present invention. According to the Scheme 1 compounds of the present invention can be obtained, for example, by first communicating aminocarbonyl acid of formula II with sulphonylchloride formula R2-SO2-Cl or sulfonic acid anhydride in the presence of a base in a solvent such as water, pyridine or ether. Suitable bases are inorganic bases such as sodium carbonate, or organic bases, such as, for example, pyridine or triethylamine. Received sulphonilecarbomide acid of formula III can then be activated, for example by interaction with gloriouse agent such as pentachloride phosphorus, phosphorus oxychloride or thionyl chloride, in an inert solvent to obtain the carboxylic acid of formula IV, which is then subjected to interaction with arylamines. But the activation of the carboxylic acid group in the compounds of formula III can also be implemented differently, for example one of the numerous well-known specialist in educational methods, amide St. and through the use of carbodiimide, like dicyclohexylcarbodiimide.

The interaction of activated sulfonilmocevinnah acid with arylamino it is advisable to carry out in an inert solvent, such as, for example, pyridine, tetrahydrofuran or toluene, in the absence or in the presence of an inert auxiliary base, such as, for example, tertiary amine or pyridine. If arylamine, which is used in the reaction with an activated carboxylic acid, already contains the desired substituent R1-S(O)nreaction immediately gives the target compound of formula I. the compounds of formula I, in which the number n in the group R1-S(O)2is 1 or 2, can also be obtained by interaction of the activated carboxylic acid with mercaptoamines arylamino formula R1-S-A1-NH2and then oxidation of mercaptopropyl in the compound of formula V under standard conditions, for example, a peroxide such as hydrogen peroxide, or percolate, such as 3-chloroperbenzoic acid or monoperoxyphthalic acid, in a solvent such as, for example, dichloromethane or acetone. Activated carboxylic acids can also first be subjected to interaction with arylamine formula A1-NH2
1-SO2for example , by interaction with appropriate amines in the substance or in a solvent such as N-organic, dimethylformamide, toluene or ether, optionally in the presence of an auxiliary base. Similarly, activated carboxylic acid can be subjected to interaction with foralternative formula F-SO2-AND1-NH2and received forcalifornia intermediate compounds of formula VII can be converted under standard conditions in the compounds of formula I of the present invention.

The compounds of formula I of the present invention can also be obtained by interaction of activated sulfonilmocevinnah acids, for example anhydrides of acids of the formula IV, shown in Scheme 1, with mercaptoethylamine formula H2N-A1-SH, unsubstituted on the sulfur atom. The resulting reactions of nucleophilic substitution product of formula VIII can then be alkilirovanii or areleaving the sulfur atom by alkylhalogenide or arylhalides or other reactive compound under standard pleaidians formula V (see Scheme 2).

The compounds of formula I can be obtained, for example, by first activating the appropriate way substituted nitrocarbonyl acid of the formula IX, for example by conversion to the corresponding acid chloride of the formula X or any other way, and then communicating it with substituted arylamino formula R1-S(OH)n-A1-NH2as described above (see Scheme 3).

In this case, can also be used as arylamino foralternative formula F-SO2-AND1-NH2and in the resulting N-(persulphuric)carboxamido formula XI forcalifornia group can be converted under standard conditions to the group R1-SO2according to the present invention, for example, with an amine of the formula HNR5R6.

Before any subsequent recovery in the received intermediate nitro compound of formula XII of nitro group to amino group can be used to trigger an action of the nitro group on the ring AND2and a suitable group R3for example, the halogen atom can be replaced by another group, R3by interaction with a nucleophile such as an amine. The restoration of the nitro group with obtaining aminor the underwater metal or preferably, in the presence of Raney Nickel in a solvent such as ethanol, glacial acetic acid or ethanolic solution of hydrogen chloride, or it can be done by restoring the base metal, such as zinc, tin or iron, in the presence of acid. Recovery can also be implemented, for example, tin chloride (II) or by interaction with dithionite sodium, preferably in a mixture of methanol, tetrahydrofuran and water as solvent. Sulfonylamine amino group in the reaction product recovery, having the formula XIII, with the activated derivative of sulfonic acid, which may be implemented as described above reaction, for example, a sulfonic acid chloride in pyridine gives the target compound of formula I.

The compounds of formula I in which X represents a nitrogen atom attached via a simple connection to the ring carbon atom in the group AND1adjacent to the carbon atom in the a1bearing a group-NH-C(=X)-, i.e., benzimidazole derivatives having the formula II can, for example, be obtained by interaction of activated derivative sulfonylamino formula IV (or, by analogy with Scheme 3, derived nitrocarbonyl acid) with 1,2-diaminopurine in the presence of a dehydrating agent such as, for example, thionyl chloride or pentachloride phosphorus (see chart 4).

The reaction is usually carried out in an inert solvent, for example in a hydrocarbon, such as toluene or xylene. 1,2-damenuhren may already contain a finite group, R1-S(O)nor previous group, for example R1-S. can Then be carried out as described above, the subsequent stage, for example, the reaction of the sulfur atom. So, can be used unsubstituted 1,2-diaminoethane and the resulting products of formula XIV can be chlorsulfuron, for example, chlorinol acid, and the resulting sulphonylchloride can be converted to the target compounds, containing the group R1-SO2for example , by communicating with the appropriate amine.

All reactions for the synthesis of compounds of formula I themselves well known to the expert and can be carried out under standard conditions according to or analogously to the methods described in the literature, for example, in Houben-Weyl, Methods der Organischen Chemie (Methods of organic chemistry), Thieme-Verlag, Stuttgart, or Organic Reactions, John Wiley & Sons, New York. According to the necessary or useful to temporarily block functional groups by introducing protective groups and unlock them at a later stage or to introduce functional groups in the form of the preceding groups, which at a later stage of the reaction is converted into the desired functional groups. This method of synthesis and protective previous group suitable for each case, well-known specialist. If necessary, the compounds of formula I can be purified by conventional purification methods, for example by recrystallization or chromatography. Starting compound to produce compounds of formula I are commercially available or can be obtained by the methods described in the literature.

The compounds of formula I of the present invention increase the concentration of cGMP through activation of soluble guanylate cyclase (RGC) and therefore they are a useful means for the treatment and prevention of disorders that are associated with low or reduced levels of cGMP or caused such level of cGMP or for the treatment or prevention of which requires increasing the existing level of cGMP. Activation RHC compounds of formula I can be checked, for example, by analyzing the activity described below.

Disorders and pathological conditions that are associated with a low cGMP level or require increased levels of cGMP and for the treatment and prevention which can be applied sidestories dysfunction, atherosclerosis, hypertension, stable and unstable angina pectoris, thromboses, restenoses, myocardial infarction, strokes, heart failure or pulmonary hypertension, or, for example, erectile dysfunction, asthma, chronic renal failure and diabetes. The compounds of formula I can also be used to treat cirrhosis of the liver and to increase the limited memory or ability to learn.

The compounds of formula I and their physiologically acceptable salts can be introduced to animals, preferably mammals, in particular humans, in the form of medicines per se, in mixtures with something else or in the form of pharmaceutical preparations. Thus, the object of the present invention are also the compounds of formula I and their physiologically acceptable salts for use as pharmaceuticals, their use to activate soluble guanylate cyclase, to normalize the disturbed balance of cGMP and, in particular, for the treatment and prophylaxis of the abovementioned syndromes, as well as their use for the manufacture of drugs for these purposes. In addition, the subject of the present invention are pharmaceutical preparring least one of the compounds of formula I and/or physiologically acceptable salts and conventional pharmaceutically acceptable carrier, i.e., one(I) or more pharmaceutically acceptable carrier substances and/or additives. The object of the present invention are those compounds of formula I, which were already known in themselves and which the introduction of appropriate conditions excluded from the above defined compounds of formula I, which are themselves the subject of the present invention, and their physiologically acceptable salts as activators of soluble guanylate cyclase. All of the above and the below claims regarding the pharmacological effects and uses of the compounds of formula I are, therefore, to the compound of formula I, in which both the ring AND2that contains the carbon atoms bearing the group C(=X)-NH - and NH-SO2R2represents benzene ring, substituted in positions 3 and 5 chlorine, R2represents methyl, X is oxygen and R1-S(O)n-A1is 5-chloro-2-(4-chlorophenylurea)phenyl group, and its physiologically acceptable salts. Thus, the object of the present invention are, for example, the specified connection and its physiologically acceptable salts for use as pharmaceutical preparations containing an effective dose of rmaceuticals acceptable carrier, and use the specified connection and/or its physiologically acceptable salts for the treatment or prophylaxis of the abovementioned syndromes, as well as their use for the manufacture of drugs for these purposes.

Medicines according to the present invention can be administered orally, for example in the form of pills, tablets, pills, coated with glaze, tablets coated with sugar, granules, hard and soft gelatin capsules, aqueous, alcoholic and oily solutions, syrups, emulsions or suspensions, or rectally, for example in the form of suppositories. The introduction can be also carried out parenterally, for example subcutaneously, intramuscularly or intravenously, in the form of solutions for injection or infusion. Other suitable routes of administration are, for example, percutaneous or local injection, for example, in the form of ointments, tinctures, aerosols or dermal therapeutic systems, or inhalation introduction in the form of an aerosol for nasal or aerosol mixtures, or, for example, the introduction in the form of microcapsules, implants or rods. The preferred route of administration depends, for example, from a disease that should be treated, and its severity.

The number of active compound of the formula I and/ultimele from 1 to 200 mg per dose, but depending on the type of pharmaceutical drug it can be higher. The pharmaceutical preparations normally contain 0.5 to 90% by weight of compounds of the formula I and/or their physiologically acceptable salts. The pharmaceutical preparations may be manufactured in known per se manner. For this purpose, one or more compounds of the formula I and/or their physiologically acceptable salts together with one or more solid or liquid pharmaceutical agents, carriers and/or additives (or auxiliary substances) and, if required, in combination with other pharmaceutically active compounds having therapeutic or prophylactic action, is subjected to processing for obtaining a suitable for administration form or dosage form which can then be used as a pharmaceutical in human or veterinary medicine.

For the manufacture of pills, tablets, tablets, sugar coated and hard gelatin capsules can be used, for example, lactose, starch, such as maize starch or starch derivatives, talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, p. the solutions, for example, solutions for injection, or of emulsions or syrups are, for example, water, physiological solution of sodium chloride, alcohols such as ethanol, glycerol, polyols, sucrose, invert sugar, glucose, mannitol, vegetable oil, etc. Can also be liofilizirovanny the compounds of formula I and their physiologically acceptable salts and use the resulting lyophilizate, for example, for the manufacture of preparations for injection or infusion. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic and lactic acid.

In addition to the active compounds and carriers, the pharmaceutical preparations can also contain conventional additives, for example fillers, disintegrating agents, binders, lubricants, moisturizing agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, dyes, corrigentov, aromatizers, thickeners, diluents, buffer substances, solvents, soljubilizatory, means for ensuring a depot effect, salts for modifying the osmotic pressure, substances for coating or antioxidants.

The dosage of the active compounds of formula I and/or physiologically acceptable salts depends on concr is to function effectively. So, it depends on the nature and severity of the violation, which should be treated, but also gender, age, weight and individual responsiveness of the human or animal being treated, the effectiveness and duration of action of the compounds used, on whether therapy emergency, long-term or prophylactic, or on whether other active compounds other than compounds of formula I. generally, a daily dose of about 0.01 to 100 mg/kg, preferably 0.1 to 10 mg/kg, in particular 0.3 to 5 mg/kg (in each case mg per kg of body weight), is appropriate for an adult weighing about 75 kg, to obtain the desired results. The daily dose can be entered at one time or, in particular, when you enter a greater number of medicines can be divided into several, for example two, three or four separate doses. In some cases, depending on individual reactions, it may be necessary to increase or decrease the daily dose indicated.

The compounds of formula I activate soluble guanilatziklazu, mainly by linking in gamesweasel pocket of the enzyme. Taking into account this property, except for use as pharmaceutically active soy is an aid in biochemical research in which it is assumed such an impact on guanilatziklazu, as well as for diagnostic purposes, for example in vitro diagnostic sample of cells or tissue samples. The compounds of formula I and their salts can also be used, as mentioned above, as intermediates for other pharmaceutically active compounds.

The following examples of compounds of formula I and intermediates for their production illustrate the present invention without limiting it.

EXAMPLES

1) 2-(4-chlorophenylsulfonyl)-4,5-dimethoxybenzoic acid

In 250 ml of water was dissolved 33,71 g (0.32 mol) of sodium carbonate and the solution was heated to 60C. Was introduced into a solution of 25.00 g (0.13 mol) of 2-amino-4,5-dimethoxybenzoic acid and to this solution was added in portions over 15 minutes 29,55 g (0.14 mol) of 4-chlorobenzenesulfonamide. After cooling, the mixture was filtered with suction, the residue was dissolved in 1% sodium hydrogen carbonate solution, the solution was filtered and the product precipitated with addition of 1 N. chloroethanol acid. Got 25,90 g (55%) of 2-(4-chlorophenylsulfonyl)-4,5-dimethoxybenzoic acid with a melting point (so square) 212-S.

In a similar way were is chlorpheniramine)benzoic acid;

5) 2-(4-chlorophenylsulfonyl)cyclopentanecarbonyl acid, so pl. S;

6) 2-(4-chlorophenylsulfonyl)-5-methylbenzoic acid, so pl. S;

7) 3-(4-chlorophenylsulfonyl)thiophene-2-carboxylic acid, so pl. 180C;

8) 3-(4-chlorophenylsulfonyl)pyrazole-4-carboxylic acid, oil;

9) 2-(4-chlorophenylsulfonyl)pyridine-3-carboxylic acid, so pl. >360S with decomposition (decomp.);

10) 2-(4-chlorophenylsulfonyl)-4,5-dimethoxybenzoate.

With 75 ml of toluene were mixed 25,90 g (0.07 mol) of 2-(4-chlorophenylsulfonyl)-4,5-dimethoxybenzoic acid was added 17,30 g (0.08 mol) of pentachloride phosphorus and the mixture was stirred at 40-45C for 2.5 hours. Then the mixture was concentrated in vacuo to half its volume and precipitated precipitated product was filtered with suction and washed with a small amount of toluene. Received 25,30 g (93%) of 2-(4-chlorophenylsulfonyl)-4,5-dimethoxybenzonitrile, having a melting point 175-S.

Similarly were obtained:

11) 5-chloro-2-(4-chlorophenylsulfonyl)benzoyl chloride, so pl. 127S;

12) 5-chloro-2-(3,4-dichlorophenylamino)benzoyl chloride, so pl. 117S;

13) 2-(4-chlorophenylsulfonyl)C is illorin, so pl. S;

15) 3-(4-chlorophenylsulfonyl)thiophene-2-carboxylic acid, acid chloride, so pl. S;

16) 3-(4-chlorophenylsulfonyl)pyrazole-4-carboxylic acid, acid chloride, so pl. C (decomp.);

17) 2-(4-chlorophenylsulfonyl)pyridine-3-carboxylic acid to the acid chloride.

18) 4-((2-(4-chlorophenylsulfonyl)-4,5-dimethoxybenzoyl)amino)benzolsulfonate

With 300 ml of toluene were mixed 10,00 g (25.6 mmol) of 2-(4-chlorophenylsulfonyl)-4,5-dimethoxybenzonitrile added of 4.49 g (25.6 mmol) of 4-aminobenzenesulfonamide and the mixture was heated under reflux for 4 hours. After cooling, the precipitated precipitated solid was filtered with suction and washed with toluene. Received 11,71 g (87%) indicated in the title compound, having a melting point 216-S.

Similarly were obtained:

19) 4-((5-chloro-2-(4-chlorophenylsulfonyl)benzoyl)amino) benzolsulfonate, so pl. S;

20) N-(4-aminosulphonylphenyl)-5-chloro-2-(4-chlorophenylsulfonyl)benzamid, so pl. S;

21) 5-chloro-2-(4-chlorophenylsulfonyl)-N-((4-(4-nitrophenyl)mercapto)phenyl)benzamide, so pl. S;

22) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(finished, so pl. 220C;

24) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(2-methylbenzothiazol-5-yl)benzamid, so pl. S;

25) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(3-diethylamino-2-hydroxypropylamino)phenyl)benzamide, so pl. 1 0 2;

26) 4-((5-chloro-2-(3,4-dichlorophenylamino)benzoyl)amino) benzolsulfonate, so pl. 232C;

27) 4-(2-(4-chlorophenylsulfonyl)cyclopentanecarboxylate) benzolsulfonate, so pl. S;

28) 4-((2-(4-chlorophenylsulfonyl)-5-methylbenzoyl)amino)benzolsulfonate, so pl. S;

29) 4-((3-(4-chlorophenylsulfonyl)thiophene-2-carbonyl)amino)benzolsulfonate, so pl. S;

30) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-mercaptophenyl)benzamid, so pl. S;

31) 4-((3-(4-chlorophenylsulfonyl)pyrazole-4-carbonyl) amino)benzolsulfonate, so pl. S;

32) 3-((5-chloro-2-(4-chlorophenylsulfonyl) benzoyl)amino)benzolsulfonate, so pl. S;

33) 4-(2-(4-chlorophenylsulfonyl)pyridine-3-carbonyl)amino)benzolsulfonate, so pl. 263-S;

34) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-methyl-5-(thiomorpholine-4-sulfonyl)thiazol-2-yl)benzamid, so pl. 265-S;

35) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(2-methylmercaptopurine)b-2-(4-chlorophenylsulfonyl)-N-(4-(5-methylisoxazol-3-ylsulphonyl)phenyl)benzamide;

38) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(4-nitrophenyloctyl)phenyl)benzamide;

39) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(5-ethylsulfonyl-2-hydroxyphenyl)benzamide;

40) N-(3-butylsulfonyl)-5-chloro-2-(4-chlorophenylsulfonyl)benzamide;

41) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(2-nitro-5-propylmercaptan)benzamide;

42) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-thiocyanatopropyl)benzamide;

43) N-(4-acetylaminophenol)-5-chloro-2-(4-chlorophenylsulfonyl)benzamide;

44) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(2-phenylmercapturic)benzamide;

45) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(2-chloro-5-(2-lunatically)phenyl)benzamide;

46) N-(5-butylsulfonyl-2-methoxyphenyl)-5-chloro-2-(4-chlorophenylsulfonyl)benzamide;

47) N-(4-benzoylmethylene)-5-chloro-2-(4-chlorophenylsulfonyl)benzamide;

48) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(2-chloro-4-methylsulfinylphenyl)benzamide;

49) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(hexadecacarbonyl)phenyl)benzamide;

50) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(butylaminomethylphosphonate)phenyl)benzamide;

51) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(2-sulf same;

53) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(3-methylsulfinylphenyl)benzamide;

54) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(3-(2-hydroxyarylalkyl)phenyl)benzamide;

55) (4-(5-chloro-2-(4-chlorophenylsulfonyl)benzoylamine)phenylmercaptan)acetic acid;

56) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(3,4-dimethylisoxazol-5-ylsulphonyl)phenyl)benzamide;

57) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(thiazol-2-ylsulphonyl)phenyl)benzamide;

58) 5-chloro-2-(3,4-dichlorophenylamino)-N-(4-ethylmercaptan)benzamid, so pl. S;

59) 2-(4-chlorophenylsulfonyl)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)phenyl)benzamide.

In 1 ml thiomorpholine was dissolved 500 mg (0.95 mmol) 4-((2-(4-chlorophenylsulfonyl)-4,5-dimethoxybenzoyl)amino)benzosulfimide and the solution was heated up to 90 ° C for 30 minutes. For processing the mixture was poured into 50 ml of a mixture of ice and 1 N. chloroethanol acid, the precipitate was filtered with suction, dried in a vacuum drying chamber above pjatiokisi phosphorus and recrystallized from a mixture of hexane-ethyl acetate. Received 378 mg (65%) indicated in the title compound, having a melting point S.

Similarly were obtained:

61) N-(4-(4-carbamoylbiphenyl-1-sulfonyl)phenyl)-2-(4-chlorophenylsulfonyl)pyridine-3-carboxamide, so pl. 273-S;

62) 2-(4-chlorophenylsulfonyl)-N-(4-(piperidine-1 - sulfonyl)phenyl)pyridine-3-carboxamide, so pl. 180-S;

63) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(thiomorpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

64) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(4-methylpiperazin-1-sulfonyl)phenyl)benzamide, so pl. S;

65) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(2,6-dimethylmorpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

66) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(CIS-2,6-dimethylmorpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

67) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(4-hydroxypiperidine-1-sulfonyl)phenyl)benzamide, so pl. S;

68) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(1,4-dioxa-8 azaspiro[4.5]decane-8-sulfonyl)phenyl)benzamide, so pl. S;

69) 5-chloro-2-(3,4-dichlorophenylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

70) 5-chloro-2-(3,4-dichlorophenylamino)-N-(4-(thiomorpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

71) 5-chloro-2-(3,4-dichlorophenylamino)-N-(4-(4-methylpiperazin-1-sulfonyl)phenyl)benzamide, so pl. S;

73) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(4-(2-hydroxyethyl)piperazine-1-sulfonyl)phenyl)benzamide, so pl. S;

74) 2-(4-chlorophenylsulfonyl)-N-(4-(morpholine-4-sulfonyl)phenyl)cyclopentanecarboxylic, so pl. 180C;

75) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(diethylcarbamoyl)phenyl)benzamide, so pl. S;

76) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(piperidine-1-sulfonyl)phenyl)benzamide, so pl. S;

77) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(2-methoxyethanol)phenyl)benzamide, so pl. S;

78) 2-(4-chlorophenylsulfonyl)-5-methyl-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

79) 3-(4-chlorophenylsulfonyl)-N-(4-(morpholine-4-sulfonyl)phenyl)thiophene-2-carboxamid, so pl. 220C;

80) 3-(4-chlorophenylsulfonyl)-N-(4-(morpholine-4-sulfonyl)phenyl)-1H-pyrazole-4-carboxamide, oil;

81) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(3-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

82) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(3-(thiomorpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

83) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(3-(4-methylpiperazin-1-sulfonyl)phenyl)benzamide hydrochloride, T. pl. S;

84) 3-(4-chlorophenylsulfonyl)-N-(4-(thiomorpholine-4-sulfonyl)Fe the Nile)benzamid, so pl. S;

86) 2-(4-chlorophenylsulfonyl)-5-methyl-N-(4-(thiomorpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

87) 2-(4-chlorophenylsulfonyl)-4,5-dimethoxy-N-(4-(4-methylpiperazin-1-sulfonyl)phenyl)benzamide, so pl. S;

88) 2-(4-chlorophenylsulfonyl)-N-(4-(CIS-2,6-dimethylmorpholine-4-sulfonyl)phenyl)-4,5-dimethoxybenzamide, so pl. S;

89) 2-(4-chlorophenylsulfonyl)-N-(4-(4-hydroxypiperidine-1-sulfonyl)phenyl)-4,5-dimethoxybenzamide, so pl. S;

90) 2-(4-chlorophenylsulfonyl)-4,5-dimethoxy-N-(4-piperidine-3-sulfonyl)phenyl)benzamide, so pl. S;

91) 2-(4-chlorophenylsulfonyl)-4,5-dimethoxy-N-(4-(thiazolidin-3-sulfonyl)phenyl)benzamide, so pl. S;

92) 2-(4-chlorophenylsulfonyl)-N-(4-(2,5-dihydro-1H-pyrrol-1-sulfonyl)phenyl)-4,5-dimethoxybenzamide, so pl. S;

93) 2-(4-chlorophenylsulfonyl)-N-(4-(1,2,3,6-tetrahydropyridine-1-sulfonyl)phenyl)-4,5-dimethoxybenzamide, so pl. S;

94) 2-(4-chlorophenylsulfonyl)-4,5-dimethoxy-N-(4-(2-methylpiperidin-1-sulfonyl)phenyl)benzamide, so pl. S;

95) 2-(4-chlorophenylsulfonyl)-4,5-dimethoxy-N-(4-(piperazine-1-sulfonyl)phenyl)benzamide, so pl. S;

96) 4-(4-(2-(4-chlorophenylsulfonyl)-4,5-dimethoxyphenethylamine)vinylsulfonic-N-(4-(4-methylpiperidin-1-sulfonyl)phenyl)benzamide, so pl. S;

98) 2-(4-chlorophenylsulfonyl)-4,5-dimethoxy-N-(4-(4-methylpregna[1,4]diazepin-1-sulfonyl)phenyl)benzamide, so pl. S;

99) 2-(4-chlorophenylsulfonyl)-N-(4-(4-ethylpiperazin-1-sulfonyl)phenyl)-4,5-dimethoxybenzamide, so pl. S;

100) 2-(4-chlorophenylsulfonyl)-N-(4-((2-dimethylaminoethyl)ethylsulfonyl)phenyl)-4,5-dimethoxybenzamide, so pl. >C (decomp.);

101) 2-(4-chlorophenylsulfonyl)-N-(4-(1,4,5,6-tetrahydropyrimidin-1-sulfonyl)phenyl)-4,5-dimethoxybenzamide, so pl. >C (decomp.);

102) 2-(4-chlorophenylsulfonyl)-4,5-dimethoxy-N-(4-(4-(pyrimidine-2-yl)piperazine-1-sulfonyl)phenyl)benzamide, so pl. >C (decomp.);

103) 2-(4-chlorophenylsulfonyl)-N-(4-(4-(4-chlorophenyl)-piperazine-1-sulfonyl)phenyl)-4,5-dimethoxybenzamide, so pl. >C (decomp.);

104) 2-(4-chlorophenylsulfonyl)-N-(4-(indan-1-ylsulphonyl)phenyl)-4,5-dimethoxybenzamide, so pl. S;

105) 2-(4-chlorophenylsulfonyl)-N-(4-((2-(1H-indol-3-yl)ethyl)methylcarbamoyl)phenyl)-4,5-dimethoxybenzamide, so pl. S;

106) 1-(4-((2-(4-chlorophenylsulfonyl)-4,5-dimethoxybenzoyl)amino)phenylsulfonyl)piperidine-4-carboxamide, so pl. S;

107) 2-(4-chlorophenylsulfonyl)-N-(4-cyclopropanesulfonyl)-4,5-dimethoxybenzamide, so pl. S;

109) N-(4-(arylcyclohexylamines)phenyl-2-(4-chlorophenylsulfonyl)-4,5-dimethoxybenzamide, so pl. S;

110) 1-(4-((2-(4-chlorophenylsulfonyl)-4,5-dimethoxybenzoyl)amino)phenylsulfonyl)pyrrolidin-2-carboxylic acid, so pl. S (sintering);

111) 5-chloro-2-nitrobenzoate.

With 72,20 g (0.61 mol) of thionyl chloride were mixed 100,00 g (0.50 mol) of 5-chloro-2-nitrobutane acid and the mixture was heated under reflux for 2 hours. Excess thionyl chloride was removed under vacuum. Received 106,50 g (about 98%) of crude 5-chloro-2-nitrobenzotrifluoride in the form of butter.

Similarly received:

112) 5-methyl-2-nitrobenzoate, oil;

113) 4-(5-chloro-2-nitrobenzylamine)benzolsulfonate.

In 300 ml of toluene was dissolved of 86.00 g (to 0.39 mol) of 5-chloro-2-nitrobenzotrifluoride, was added dropwise a solution of 62,00 g (0.35 mol) of 4-aminobenzenesulfonamide and the mixture was heated under reflux for 4 hours. Then it was cooled, concentrated in vacuo to half volume, cooled and precipitated precipitated solid was filtered with suction. Received 121,60 g (86%) indicated in the title compound, having a melting point 182-S.

115) 5-chloro-N-(4-ethylmercaptan)-2-nitrobenzamide.

116) 5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)-2-nitrobenzamide

In 1200 ml of toluene was stirred at 60C for 2 days 120,00 g (0.33 mol) of 4-(5-chloro-2-nitrobenzylamine)benzosulfimide, 29,10 g (0.33 mol) of the research and 33,85 g (0.33 mol) of triethylamine. Precipitated precipitated solid was filtered with suction and recrystallized from a mixture of acetone-n-hexane. Received 102,10 g (71%) indicated in the title compound, having a melting point 243-S.

Similarly were obtained:

117) 5-chloro-2-nitro-N-(4-(thiomorpholine-4-sulfonyl)phenyl)benzamide, so pl. 120C;

118) 5-methyl-N-(4-(morpholine-4-sulfonyl)phenyl-2-nitrobenzamide, so pl. S.

119) N-(4-(morpholine-4-sulfonyl)phenyl)-5-(morpholine-4-yl)-2-nitrobenzamide.

20,00 g (of 0.56 mol) of 4-(5-chloro-2-nitrobenzylamine)benzosulfimide in to 48.5 g (0,557 mol) of the research was heated under reflux for 1 hour. Then the mixture was cooled, then poured into a mixture of ice and chloroethanol acid and filtered with suction. Received 26,0 g (98%) indicated in the title compound, having a melting point S.

120) 2-amino-5-chloro-N-(4-(morpholine-4-colfontaine-4-sulfonyl)phenyl)-2-nitrobenzamide and to the resulting solution was added dropwise a solution of 27,23 (156,4 mmol) dithionite sodium in 330 ml of water. After stirring for 1 hour at room temperature the organic solvents were removed in a rotary evaporator and precipitated precipitated product was filtered with suction and purified by chromatography on silica using a mixture of methylene chloride-methanol (9:1). Received of 5.68 g (55%) indicated in the title compound, having a melting point 229-S.

Similarly were obtained:

121) 2-amino-5-chloro-N-(4-(thiomorpholine-4-sulfonyl)phenyl) benzamide, so pl. S;

122) 2-amino-N-(4-(morpholine-4-sulfonyl)phenyl)-(5-morpholine-4-yl)benzamid, so pl. S;

123) 2-amino-5-chloro-N-(4-ethylsulfonyl)benzamide, so pl. 159-S.

124) 5-chloro-2-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-N-(4-(thiomorpholine-4-sulfonyl)phenyl)benzamide.

In 10 ml of anhydrous pyridine was dissolved 250 mg (of 0.60 mmol) 2-amino-5-chloro-N-(4-(thiomorpholine-4-sulfonyl)phenyl)benzamide and to the resulting solution was added dropwise at 0 solution of 195 mg (0.85 mmol) of 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulphonylchloride in 5 ml of pyridine. After 2 hours the mixture was poured on ice, precipitated precipitated solid was filtered with suction and purified by chromatography on silica using a mixture of m the I 215-S.

Similarly were obtained:

125) 5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)-2-(4-methylphenylsulfonyl)benzamide, so pl. S;

126) 5-chloro-2-(3,4-dimethoxyphenylethylamine)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

127) 5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)-2-(4-triftormetilfullerenov)benzamid, so pl. S;

128) 2-((4-acetylaminophenol)sulfonylamino)-5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

129) 5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

130) 5-chloro-2-(5-chloro-1,3-dimethylpyrazol-4-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

131) 5-chloro-2-((1-Mei-4-sulfonyl)amino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

132) 5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)-2-(pyridine-3-sulfonylamino)benzamid, so pl. S;

133) 2-(4-benzyloxycarbonylamino)-5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

134) 5-chloro-2-(ethylsulfonyl)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. 274-S;

135) 2-((2-acetamido-4-methylthiazole-5-sulfonyl)amino)-5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

13 the folin-4-sulfonyl)phenyl)-2-(4-triftormetilfullerenov)benzamid, so pl. S;

138) 2-(4-bromophenylacetonitrile)-5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. 232C;

139) 2-(3,5-bis-triftormetilfullerenov)-5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

140) 5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)-2-(4-nitrophenylacetylene)benzamid, so pl. S;

141) 5-chloro-2-(4-sanofisynthelabo)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

142) 5-chloro-2-(4-methylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

143) 5-chloro-2-(4-isopropylbenzenesulfonyl)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. 105C;

144) 5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)-2-((2-phenylethenyl)sulfonylamino)benzamid, so pl. S;

145) 5-chloro-2-(4,5-dibromothiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. 232C;

146) 5-chloro-2-(4-fortunaltely)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

147) 5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)-2-(5-phenylsulfonylacetate-2-sulfonylamino)benzamid, so pl. S;

148) 5-chloro-2-(3-chloro-4-methoxyphenylacetylene)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

149) 5-chloro-N-(4-(morpholine-4-sulfonyl)phenethyltrimethoxysilane)benzamid, so pl. S;

151) 5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)-2-(3-nitrophenylacetylene)benzamid, so pl. 220C;

152) 5-chloro-2-(4-methoxyphenylacetylene)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. -269°;

153) 5-chloro-2-methylsulfonylamino-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

154) 5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)-2-phenylmethylsulfonyl, so pl. S;

155) 5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)-2-(2,2,2-cryptgethashparam)benzamid, so pl. S;

156) 2-(butylsulfonyl)-5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. 1 0 2;

157) 5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)-2-(3-triftormetilfullerenov)benzamid, so pl. S;

158) 2-(4-bromo-2,5-dichlorothiophene-3-sulfonylamino)-5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

159) 5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)-2-(2-triftormetilfullerenov)benzamid, so pl. S;

160) 5-chloro-2-(3-chlorophenylsulfonyl)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

161) 2-(4-bromo-2-methoxyphenylacetylene)-5-chloro-N-(4- (morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

162) 5-chloro-2-(2,6-dichlorophenylamino)-N-(4-(morpholine-4-sulfanilamide, so pl. 200C;

164) 2-(4-butoxybenzaldehyde)-5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

165) 5-chloro-2-(7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. 120C;

166) 5-chloro-2-(3-fortunaltely)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

167) 2-(4-chlorophenylsulfonyl)-N-(4-(morpholine-4-sulfonyl)phenyl)-5-(morpholine-4-yl)benzamid, so pl. S;

168) 5-chloro-N-(4-ethylsulfonyl)-2-(4-methylphenylsulfonyl)benzamide, so pl. 188-S;

169) 5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-ethylsulfonyl)benzamide, so pl. 195-S;

170) 5-chloro-2-(4-chloro-3-nitrophenylacetylene)-N-(4-ethylsulfonyl)benzamide, so pl. 196-S;

171) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-ethylsulfonyl)benzamide, so pl. 180-S;

172) 5-chloro-2-(3,5-dimethylisoxazol-4-sulfonylamino)-N-(4-ethylsulfonyl)benzamide, so pl. >C (decomp.);

173) 5-chloro-2-ethylsulfanyl-N-(4-ethylsulfonyl)- benzamid, so pl. S.

174) 4-chloro-N-(2-(1H-benzimidazole-2-yl)-4-chlorophenyl)benzosulfimide

to 1.00 g (2.7 mmol) of 5-chloro-2-(4-chlorophenylsulfonyl)of benzoyl chloride and 296 mg (2.7 mmol) of o-phenylenedimethylene with suction and the filtrate evaporated. The residue was dissolved in 50 ml of toluene, was added 600 mg of thionyl chloride and the mixture was again heated under reflux for 10 hours. It was then cooled and precipitated precipitated solid was filtered with suction. Received 280 mg (25%) indicated in the title compound, having a melting point of 225-S.

175) 2-(4-chlorophenylsulfonyl)-4,5-dimethoxy-N-(4-(1,1-diocletianopolis-4-sulfonyl)phenyl)benzamide and

176) 2-(4-chlorophenylsulfonyl)-4,5-dimethoxy-N-(4-(1-Osotimehin-4-sulfonyl)phenyl)benzamide

500 mg (0.82 mmol) of 2-(4-chlorophenylsulfonyl)-4,5-dimethoxy-N-(4-thiomorpholine-4-sulfonyl)phenyl)benzamide in 50 ml of acetone was cooled to 0C. Was added a solution of 371 mg (1,23 mmol) 57% m-chloroperbenzoic acid in 20 ml of acetone and the mixture was stirred at room temperature overnight. For handling poured it into ice water and the precipitate was filtered with suction. Two products are obtained in the form of a mixture separated by chromatography on silica, using a mixture of dichloromethane-methanol (97:3).

In a similar way have been obtained;

177) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(1,1-diocletianopolis-4-sulfonyl)phenyl)benzamide, so pl. S;

178) 5-CHL is 2-(3,4-dichlorophenylamino)-N-(4-ethylsulfonyl)benzamide, so pl. S;

180) 5-chloro-N-(4-ethylsulfonyl)-2-nitrobenzamide.

181) 4-chloro-N-(4-chloro-2-(6-(morpholine-4-sulfonyl)-1H-benzimidazole-2-yl)phenyl)benzosulfimide

To 1 ml chlorinol acid was added at 0C 200 mg (0.5 mmol) 4-chloro-N-(2-(1H-benzimidazole-2-yl)-4-chlorophenyl)benzosulfimide and the mixture was heated to 60C for 30 minutes. Then the mixture was poured into ice water and the solid was filtered with suction, dried and added at 0C to 1 ml of the research. After stirring at room temperature for 1 hour the mixture was poured into chloroethanol acid with ice and was extracted with ethyl acetate. The extracts are evaporated and the residue was purified by chromatography on silica, using a mixture of hexane-ethyl acetate (1:1). Received 20 mg (7%) indicated in the title compound, having a melting point of 225-S.

1H-NMR (D6-DMSO): (M. D.)=2,9 (m, 4H, morpholine-H), and 3.6 (m, 4H, morpholine-H), and 7.5 (DD, 4H, phenylene-N), of 7.4 to 8.2 (m, 6N, benzo-H, phenyl-H).

182) 5-chloro-N-(4-(morpholine-4-sulfonyl)phenyl)-2-(2-(pyrrolidin-1-yl)ethylsulfonyl)benzamide

The compound was obtained using 2-chloro-ethylsulfonyl. Selected as an intermediate compound 1-(2-(4-chloro-2-(4-(morpholine-4-is Oluchi the result is specified in the header of the connection.

1H-NMR (D6-DMSO): (M. D.)=1,8 (m, 4H, pyrrolidin-N) to 2.65 (m, 4H, pyrrolidin-N), and 3.0 (m, 4H, morpholine-H), 3,1 (t, 2H, ethylene-N) to 3.35 (t, 2H, ethylene-N in), 3.75 (m, 4H, morpholine-H), to 7.50 (DD, 1H, H-4), 7.7 (d, 1H, H-3), of 7.75 (DD, 1H, H-6), 7,85 ("DD", 4H, phenylene-N).

183) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-isopropylaminomethyl)benzamid

In 25 ml of dimethylformamide was dissolved in 1.00 g (2.21 mmol) of 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-mercaptophenyl)benzamide was added 0.25 g (2.21 mmol) of potassium tert-butylate. The mixture was stirred at room temperature for 15 minutes, then added dropwise 0.27 g (2.21 mmol) of Isopropylamine and the mixture was heated to 60C for 8 hours. For processing, it was poured into water and was extracted with ethyl acetate. The combined extracts are evaporated and the residue was purified by chromatography on silica, using a mixture of hexane-ethyl acetate (3:1). Received 420 mg (39%) indicated in the title compound, having a melting point of 168 -169 PAGES.

Similarly were obtained:

184) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-cyanomethylation)benzamid, so pl. S;

185) 4-((5-chloro-2-(4-chlorophenylsulfonyl)benzoyl)amino)phenylmercaptan)acetic acid ethyl ester, so pl. S;

188) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(prop-2-inyl)mercapto)phenyl)benzamide, so pl. S;

189) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-isopropylmalate)phenyl)benzamide, so pl. -169 PAGES.

190) 5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide sodium salt

A mixture of 0.48 g of crushed into fine powder of sodium hydroxide and 7 g of 5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide in 250 ml of ethanol were transferred to the solution by briefly heating. The mixture is then evaporated under vacuum, was added 50 ml of water and again evaporated in vacuum to dryness. This procedure was repeated twice. The obtained product was dried in vacuum at 50C, So pl. C (decomp.).

Similarly, the above compounds were obtained compounds of the following examples:

191) 4,5-dimethoxy-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(N-methyl-N-(pyridine-3-ylmethyl)aminosulfonyl)phenyl)-benzenedithiol, so pl. S;

192) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(morpholine-4-sulfonyl)-3-were)benzamid, so pl. S;

193) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(3,5-dimethylpiperidin-1-sulfonyl)-3-were)benzamid, so pl. S;

195) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(piperidine-1-sulfonyl)-3-were)benzamid, so pl. S;

196) 4,5-dimethoxy-2-(3,5-dimethylisoxazol-4-sulfonylamino)-N-(4-(N-methyl-N-(pyridine-3-ylmethyl)aminosulfonyl)phenyl)benzamide, so pl. S;

197) 4,5-dimethoxy-2-(3,5-dimethylisoxazol-4-sulfonylamino)-N-(4-(N-(pyridine-3-ylmethyl)aminosulfonyl)phenyl)-benzamid, so pl. S;

198) 5-chloro-2-(2,4-dimethylthiazol-5-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. 190S;

199) 4,5-dimethoxy-2-(4-chlorophenylsulfonyl)-N-(4-(3,5-dimethylpiperidin-1-sulfonyl)phenyl)benzamide, so pl. C (decomp.);

200) 2-(4-chlorophenylsulfonyl)-N-(4-(N-methyl-N-(pyridine-3-ylmethyl)aminosulfonyl)phenyl)benzamide, resin;

201) 3,4-dimethoxy-2-(4-chlorophenylsulfonyl)-N-(4-(N-methyl-N-(pyridine-3-ylmethyl)aminosulfonyl)phenyl)benzamide, so pl. S;

202) 5-bromo-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)-3-were)benzamid, so pl. S;

203) 5-bromo-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(CIS-2,6-dimethylmorpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

204) 5-bromo-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(thiomorpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

205) 4,5-dimethoxy-2206) 4,5-dimethoxy-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(thiomorpholine-4-sulfonyl)phenyl)benzamide, so pl. 232C;

207) 4,5-dimethoxy-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(CIS-2,6-dimethylpiperidin-1-sulfonyl)phenyl)benzamide, so pl. S;

208) 5-chloro-2-(3,5-dimethylisoxazol-4-sulfonylamino)-N-(4-(1,2,3,4-tetrahydroisoquinoline-2-sulfonyl)phenyl)benzamide, so pl. S;

209) 5-chloro-2-(3,5-dimethylisoxazol-4-sulfonylamino)-N-(4-(N-methyl-N-(pyridine-3-ylmethyl)aminosulfonyl)phenyl)benzamide, so pl. 65S (sintering);

210) 6-methyl-2-(4-chlorophenylsulfonyl)-N-(4-(peligrosas-1-sulfonyl)phenyl)benzamide, so pl. S;

211) 6-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(pyrrolidin-1-sulfonyl)phenyl)benzamide, so pl. S;

212) 6-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(4-hydroxyethylamino)sulfonyl)phenyl)benzamide, resin;

213) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(N-ethyl-N-(pyridine-4-ylmethyl)aminosulfonyl)phenyl)benzamide, resin;

214) 2-(4-chlorophenylsulfonyl)-N-(4-(thiomorpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

215) 3-methyl-2-(4-chlorophenylsulfonyl)-N-(4-(N-methyl-N-(2-(pyridin-2-yl)ethyl)aminosulfonyl)phenyl)benzamide, so pl. S;

216) 4,5-debtor-2-(4-chlorophenylsulfonyl)-N-(4-(4-aminocarbonylmethyl-1-sulfonyl)phenyl)benzamide, so pl. S;

217) 4,5-debtor-2-(4-chlorophenylsulfonyl-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, oil;

219) 5-chloro-4-methoxy-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(CIS-2,6-dimethylmorpholine-1-sulfonyl)phenyl)benzamide, so pl. 89S;

220) 5-chloro-4-methoxy-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(N-(pyridin-3-yl)-N-methylaminomethyl)phenyl)benzamide, so pl. S;

221) 4,5-dimethoxy-2-(4-chlorophenylsulfonyl)-N-(4-(CIS-2,6-dimethylmorpholine-4-sulfonyl)phenyl)benzamide sodium salt, so pl. 330C (decomp.);

222) 5-chloro-2-(3,5-dimethylisoxazol-4-sulfonylamino)-N-(4-(CIS-2,6-dimethylmorpholine-4-sulfonyl)phenyl)benzamide, so pl. 230S;

223) 5-chloro-2-(3,5-dimethylisoxazol-4-sulfonylamino)-N-(4-(3,5-dimethylpiperidin-1-sulfonyl)phenyl)benzamide, so pl. 61C;

224) 5-chloro-2-(3,5-dimethylisoxazol-4-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, so pl. S;

225) 5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-phenylsulfonyl)phenyl)benzamide, so pl. S;

226) 4-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(CIS-2,6-dimethylmorpholine-4-sulfonyl)phenyl)benzamide, so pl. S.

Additional examples of compounds

By methods similar to those described above in the examples of this application were obtained the following compounds.

227) 2-(4-chlorophenylsulfonyl)-6-methyl-N-(4-(diamino-4-sulfonyl)phenyl)benzamide;

229) 6-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(thiomorpholine-4-sulfonyl)phenyl)benzamide;

230) 6-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(2,6-dimethylmorpholine-4-sulfonyl)phenyl)benzamide;

231) 2-(4-chlorophenylsulfonyl)-5-methoxy-N-(4-(thiomorpholine-4-sulfonyl)phenyl)benzamide;

232) 2-(4-chlorophenylsulfonyl)-5-methoxy-N-(4-(piperidine-1-sulfonyl)phenyl)benzamide;

233) 2-(4-chlorophenylsulfonyl)-4,5-methylendioxy-N-(4-(thiomorpholine-4-sulfonyl)phenyl)benzamide;

234) 5-chloro-2-(3,5-dimethylisoxazol-4-sulfonylamino)-N-(4-(CIS-2,6-dimethylmorpholine-4-sulfonyl)phenyl)benzamide, sodium salt;

235) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(3-methyl-4-(1,2,3,4-tetrahydroisoquinoline-2-sulfonyl)phenyl)benzamide;

236) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(3-methyl-4-(2,3-dihydro-1H-isoindole-2-sulfonyl)phenyl)benzamide;

237) 2-(4-chlorophenylsulfonyl)-N-(4-(cyclopentylmethyl)phenyl)benzamide;

238) 2-(4-chlorophenylsulfonyl)-N-(4-(benzylcarbamoyl)phenyl)benzamide;

239) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(N-methyl-N-(2-phenylethyl)aminosulfonyl)phenyl)benzamide;

240) 2-(4-chlorophenylsulfonyl)-4,5-debtor-N-(4-(pyridine-3-iletilmesini)phenyl)benzenesulfonamide)-4,6-dimethoxy-N-(4-(peligrosas-1-ylsulphonyl)phenyl)benzamide;

243) 5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(4-(pyrimidine-2-yl)piperazine-1-sulfonyl)phenyl)benzamide;

244) 5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(4-aminocarbonylmethyl-1-sulfonyl)phenyl)benzamide;

245) 2-(4-chlorophenylsulfonyl)-N-(4-(3-diethylaminocarbonylmethyl-1-sulfonyl)phenyl)-5-methylbenzamide;

246) 5-chloro-2-(4-chlorophenylsulfonyl)-N-(4-(4-oxopiperidin-1-sulfonyl)phenyl)benzamide.

For these compounds tested on the activation of soluble guanylate cyclase (see below).

PHARMACOLOGICAL STUDIES

1) Activation of soluble guanylate cyclase

Activation of soluble guanylate cyclase (RGC), which catalyzes the conversion of GTP-independent (GTP, GTP) into cyclic guanosine monophosphate (cGMP) and pyrophosphate, using the compounds of the present invention was determined quantitatively by immunofermentative analysis (EIA, ELISA) Amersham (Amersham). For this purpose, subjects substances are first incubated with RHC in the title microplate and then determine the amount of the formed cGMP.

Used RHC was isolated from bovine lung (see Methods in Enzymology, volume 195, page 377). Solutions for testing (100 is utation (GSH), 0.1 mm GTP, 1 mm 3-isobutyl-1-methylxanthines (IBMX), properly diluted enzyme solution and the test substance or, in control experiments, the solvent. The subjects of the substance was dissolved in dimethyl sulfoxide (DMSO) and the solution was diluted with a mixture of DMSO-water so that the final concentration of test substance in the solution for testing had the value specified in the table. The concentration of DMSO in the solution for tests was 5% (V/V). The reaction was initiated by addition of RHC. The reaction mixture was incubated at C for 15-20 minutes, after which the reaction was stopped by cooling with ice and add inhibitor to the reaction (50 mm EDTA, pH 8.0). Take an aliquot of 50 μl and used for determination of cGMP using techniques acetylation of a set of Amersham for immunofermentative analysis cGMP. Using reader titration microplate was determined by the absorbance of the samples at 450 nm (reference wavelength 620 nm). Determined cGMP concentration from the standard curve, which was obtained under the same test conditions. Activation RHC test substance is given in the form of n-fold stimulation of basal activity of the enzyme determined in control experiments (using solvent pax is F.]counter.).

The results were as follows:

2) Relaxation of rat aorta

For tests were euthanized by a blow on the neck of the rat, male Wistar-Kyoto with normal blood pressure. By median sternotomy were dissected abdomen and thorax. Then deleted the descending aorta, freed her from the connective tissue and divided into 8 rings length of approximately 4 mm Into the lumen 4 of 8 rings have introduced the tips of a pair of tweezers. Carefully turning the rings on the tips of the tweezers, remove the endothelium. All 8 rings of aorta (4 endothelium and 4 without endothelium) was suspended in an organic bath (Schuler-Organbad; Hugo Sachs Elektronik) at a constant temperature S for isometric determine the contractile tone. Within 30 minutes of the rings grooved at voltage alone 1 g carbonized (95% O2; 5% CO2) the solution of Krebs-Henseleit (Krebs-Henseleit) (composition: Na+144, 0mm mm; K+5,9 mm; CL-126,9 mm; CA2+1.6 mm; Mg2+1.2 mm; H2PO-41.2 mm; SO2-41.2 mm; HCO-325,0 mm; D-glucose of 11.1 mm) with pH 7.4. In addition, in the solution of Krebs-Henseleit was added 1 mmol/l indomethacin add phenylephrine (concentration in solution: 1 μm) and tested endothelium-dependent relaxation or functional loss of endothelium by adding acetylcholine concentration in the solution: 1 μm). After a 30-minute flushing ring again subjected to preliminary reduction by the addition of phenylephrine (1 μm) and determined the relaxing effect of the tested compounds of the formula I by introducing the cumulative doses of the latter. Data were evaluated by standard methods. Data represent the concentration of the IC50where the reduction is inhibited by 50% (50% relaxation).

The results were as follows:

3) Hemodynamic effects in pigs

Three pigs (German Landrace) were anestesiologi (Ketamine 20 mg/kg C. M., Metomidate 8 mg/kg century B., The xylazine 2.5 mg/kg C. M. and Pentobarbital 25 mg/kg centuries plus bolus 0.16 mg/kg per minute). The trachea was intubated and provided animal artificial respiration air. Added oxygen to maintain normal parameters of the gas content in the blood. To register blood pressure [KD (BP); KD(C)(BP(s))=systolic blood pressure, KD(l)(VR(d))=diastolic blood pressure] by means of the pressure sensor Statham 23Db inserted a catheter in the right femoral artery. Left ventricular pressure (LVD, LVD), left ventricular end-diastolic pressure (LCD, LVEDP), contractility (dP/dt) and the frequency serdechnyiy ventricle. After a 30-min period of stabilization of hemodynamic parameters were administered the test substance with the specified dose in Nude duodenum through the catheter. The obtained data were evaluated by standard methods. Data represent mean values and standard deviations (M±SEM) of the original values and the maximum changes of individual parameters (=maximum effects).

The results were as follows:

1. Sesamestreet N-arylamide sulfonilmocevinnah acid of General formula I

where a1represents a divalent radical selected from phenylene, which is not substituted or substituted by one or more identical or different substituents from the series consisting of halogen, (C1-C4)-alkyl, CF3, -O-(C1-C4)-alkyl and -- CN; thiazolidine; and benzothiazolinone;

ring AND2that contains the carbon atoms bearing the group C(=X)-NH - and-NH-SO2-R2represents a benzene ring or aromatic monocyclic 5-6-membered heterocycle containing one or two ring heteroatoms selected from N, O and S;

R1o n in the group R1-S(O)n- is 2, may also be NR5R6;

R2represents phenyl or a monocyclic 5-6-membered heteroaryl containing one or two ring heteroatoms selected from N, O and S, which may be substituted by one or more identical or different substituents from the series consisting of halogen, CF3, -O-CF3, -O-(C1-C4)-alkyl, NO2, -CN, -NH-CO-(C1-C4)-alkyl and -(C1-C4)-alkyl; or represents (C1-C4)-alkyl which can be substituted one to three fluorine atoms, or represents benzyl;

R3represents one or more identical or different groups from the series consisting of hydrogen, halogen, CF3, -O-(C1-C4)-alkyl, (C1-C2)-alkylenedioxy, -CN, and -(C1-C4)-alkyl;

R5and R6independently from each other, represent hydrogen; -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -(C3-C7-cycloalkyl or containing a total of up to 10 carbon atoms,- (C3-C7-cycloalkyl-(C1-C4)-alkyl which can be substituted by phenyl, chlorophenyl, indolium, pyridium or-O-(C1-C4)-alkyl; or

R5and R6may contain one additional ring heteroatom from the series consisting of N, O and S, and which may be substituted by one or more identical or different substituents from the series consisting of -(C1-C4)-alkyl, hydroxy-(C1-C3)-alkyl, phenyl, chlorphenyl, pyrimidyl, carbamoyl, hydroxy and oxo, and which may be condensed with a benzene ring;

n represents 0, 1 or 2;

X represents O or X represents a nitrogen atom, which, through a simple link attached to the ring carbon atom in the group AND1immediately adjacent to the carbon atom in the a1bearing a group-NH-C(=X)-, resulting in a group-NH-C(=X)- together with bearing its carbon atoms in A1forms annulirovano imidazole ring;

in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically acceptable salts; and, however, no compound of the formula I, in which both the ring AND2containing carbon atoms bearing the group C(=X)-NH - and NH-SO2R2represents benzene ring, substituted in positions 3 is Oh 5-chloro-2-(4-chlorophenylurea)phenyl group.

2. The compound of formula I under item 1, in which AND1represents phenylene, unsubstituted or substituted by one or more identical or different substituents from the series consisting of halogen, (C1-C4)-alkyl, CF3, -O-(C1-C4)-alkyl and -- CN, in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically acceptable salt.

3. The compound of formula I according to any one of p. 1 or 2, in which X represents oxygen, in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically acceptable salt.

4. The compound of formula I according to any one of paragraphs.1-3, in which R2represents phenyl which is not substituted or substituted by one or more identical or different substituents from the series consisting of halogen, CF3, -O-CF3, -O-(C1-C4)-alkyl, NO2, -CN, -NH-CO-(C1-C4)-alkyl and -(C1-C4)-alkyl, in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically acceptable salt.

5. The compound of formula I according to any one of paragraphs.1-4, in which R1is NR5R6and R5and R6independently from each other, represent water up to 9 carbon atoms,- (C3-C7-cycloalkyl-(C1-C4)-alkyl or -(C1-C4)-alkyl-O-(C1-C3)-alkyl; or R5and R6together with the nitrogen atom to which they are attached, form a 5-7-membered saturated or partially unsaturated ring which, in addition to the nitrogen atom carrying the groups R5and R6may contain one additional ring heteroatom from the series consisting of N, O and S, and which may be substituted by one or more identical or different substituents from the series consisting of -(C1-C3)-alkyl, hydroxy-(C1-C3)-alkyl, phenyl, chlorphenyl, pyrimidyl, carbamoyl, hydroxy and oxo; in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically acceptable salt.

6. The compound of formula I according to any one of paragraphs.1-5, in which AND1represents phenylene, unsubstituted or substituted by one or more identical or different substituents from the series consisting of halogen, (C1-C4)-alkyl, CF3, -O-(C1-C4)-alkyl and -- CN; ring AND2that contains the carbon atoms bearing the group C(=X)-NH - and-NH-SO2-R2represents a benzene ring or aromatic monocyclic 5-6-h is C1-C4)-alkyl, or phenyl, or, if the number n in the group R1-S(O)nis equal to 2, also represents a group NR5R6; R2represents phenyl which is not substituted or substituted by one or more identical or different substituents from the series consisting of halogen, CF3, -O-CF3, -O-(C1-C4)-alkyl, NO2, -CN, -NH-CO-(C1-C4)-alkyl and -(C1-C4)-alkyl; R3represents one or more identical or different groups from the series consisting of hydrogen, halogen, CF3, -O-(C1-C4)-alkyl, -CN, and -(C1-C4)-alkyl; R5and R6independently from each other, represent hydrogen, -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -(C3-C7-cycloalkyl, containing a total of up to 9 carbon atoms,- (C3-C7-cycloalkyl-(C1-C4)-alkyl or -(C1-C4)-alkyl-O-(C1-C3)-alkyl; or R5and R6together with the nitrogen atom to which they are attached, form a 5-7-membered saturated, a heterocycle which, in addition to the nitrogen atom carrying the groups R5and R6may contain one additional ring heteroatom from the series consisting of N, O and S, and which may be substituted by one ilxi-(C1-C3)-alkyl, phenyl, chlorphenyl, pyrimidyl, carbamoyl, hydroxy and oxo; n is 0, 1 or 2; X is oxygen; in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically acceptable salt.

7. The compound of formula I according to any one of paragraphs.1-6, in which AND1represents phenylene, unsubstituted or substituted by one or more identical or different substituents from the series consisting of halogen, (C1-C4)-alkyl, CF3, -O-(C1-C4)-alkyl and -- CN; ring AND2that contains the carbon atoms bearing the group C(=X)-NH - and-NH-SO2-R2represents a benzene ring; R1represents a group NR5R6; R2represents phenyl which is not substituted or substituted by one or more identical or different substituents from the series consisting of halogen, -(C1-C4)-alkyl, -O-(C1-C4)-alkyl, CF3, -O-CF3, NO2, -NH-CO-(C1-C4)-alkyl and -- CN; R3represents one or more identical or different groups from the series consisting of hydrogen, halogen, CF3, -O-(C1-C4)-alkyl, -CN, and -(C1-C4)-alkyl; R5and R6together with the atom asego group, R5and R6may contain one additional ring heteroatom from the series consisting of N, O and S, and which may be substituted by one or more identical or different substituents from the series consisting of -(C1-C3)-alkyl, hydroxy-(C1-C3)-alkyl, phenyl, chlorphenyl, pyrimidyl, carbamoyl, hydroxy and oxo; n is 2; X is oxygen; in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically acceptable salt.

8. The compound of formula I according to any one of paragraphs.1-7, in which AND1is unsaturated divalent fenelonov group; ring AND2that contains the carbon atoms bearing the group C(=X)-NH - and-NH-SO2-R2represents a benzene ring; R1represents a group NR5R6; R2represents phenyl which is not substituted or substituted by one or more identical or different substituents from the series consisting of halogen, CF3, -O-(C1-C4)-alkyl and -(C1-C4)-alkyl; R3represents one or more identical or different groups from the series consisting of hydrogen, halogen, -O-(C1-C4)-alkyl and -(C1-C4)-alkyl; R55and R6may contain one additional ring heteroatom from the series consisting of N, O and S, and which may be substituted by one or more identical or different substituents from the series consisting of -(C1-C3)-alkyl, phenyl, chlorphenyl, pyrimidyl, carbamoyl and oxo; n is 2; X is oxygen; in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically acceptable salt.

9. The compound of formula I according to any one of paragraphs.1-8, in which AND1is unsaturated divalent 1,4-fenelonov group; ring AND2that contains the carbon atoms bearing the group C(=X)-NH - and-NH-SO2-R2together with groups of R3represents a benzene ring having one or two substituent from the series consisting of chlorine and methoxy; R1represents a group NR5R6; R2represents phenyl or thienyl substituted by one or two chlorine atoms; R5and R6together with the nitrogen atom to which they are attached, form a 6-membered saturated a heterocycle which, in addition to the nitrogen atom carrying the groups R5and R6may contain one additional Kohl is a methyl group; n is equal to 2; X is oxygen; in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically acceptable salt.

10. Connection on p. 9, which is 2-(4-chlorophenylsulfonyl)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)phenyl)benzamide, and its physiologically acceptable salt.

11. Connection on p. 9, which is 2-(4-chlorophenylsulfonyl)-N-(4-(CIS-2,6-dimethylmorpholine-4-sulfonyl)phenyl)-4,5-dimethoxybenzamide, and its physiologically acceptable salt.

12. Connection on p. 9, which represents 5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide, and its physiologically acceptable salt.

13. Connection on p. 9, which represents 5-chloro-2-(3,5-dimethylisoxazol-4-sulfonylamino)-N-(4-(CIS-2,6-dimethylmorpholine-4-sulfonyl)phenyl)benzamide, and its physiologically acceptable salt.

14. The salt of the compound according to any one of paragraphs.1-13, which is a sodium salt.

15. The compound of formula I according to any one of paragraphs.1-13 and/or its physiologically acceptable salts for use as an activator of soluble guanylate cyclase.

16. The compound of formula I according to any one of paragraphs.1-13 the diseases, endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, angina pectoris, thromboses, restenoses, myocardial infarction, shock, heart failure, pulmonary hypertension or erectile dysfunction.

17. The method of obtaining the compounds of formula I according to any one of paragraphs.1-13, including the conversion of cyclic aminocarbonyl acid of the formula II in sulphonilecarbomide acid of the formula III and the transformation of compounds of formula III to the compound of the formula I

moreover, in formulas I, II and III group A1, A2, R1, R2, R3and X and n have the values specified in paras.1-13, or a functional group may also be present in protected form or in the form of the preceding groups.

18. The method of obtaining the compounds of formula I according to any one of paragraphs.1-13, including the conversion of cyclic nitrocarbonyl acid of the formula IX in nitrocarburised formula XII and the conversion of compounds of formula XII to a compound of formula I by restoring the nitro group to the amino group and sulfonylurea amino

moreover, in the formulae I, IX, and XII, A1, A2, R1, R2, R3and X and n have the values specified in paras.1-13, or functional is whitesky drug able to activate guanilatziklazu containing one or more compounds of the formula I according to any one of paragraphs.1-13 and/or their physiologically acceptable salt in an effective amount and a pharmaceutically acceptable carrier.

20. Method for the treatment or prevention of cardiovascular diseases, endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, angina pectoris, thromboses, restenoses, myocardial infarction, shock, heart failure, pulmonary hypertension or erectile dysfunction, characterized in that the patient is in need of a specific treatment or prophylaxis administered one or more compounds of the formula I according to any one of paragraphs.1-13 and/or their physiologically acceptable salt in an effective amount.

 

Same patents:

The invention relates to N-substituted aminotetralin formula 1

< / BR>
where R1independently selected from the group consisting of hydrogen; hydroxy; halogen; C1-8-alkoxy; substituted C1-8-alkoxy, where the Deputy is a halogen; n is 0-2; Y is methylene; m is 0-3;1means hydrogen;2means hydrogen; R2selected from the group consisting of hydrogen; hydroxy; C1-6-alkyl, C1-6-alkenyl; phenyl; substituted phenyl where the Deputy is chosen from halogen, C1-6-alkyl, C1-6-alkoxy, trifter-C1-6-alkyl, nitro; naphthyl and pyridyl; L is chosen from the group consisting of C1-8-alkylene; C1-4-alkylen-C3-7-cycloalkyl-C1-4-alkylene; C1-4-alkylen-aryl-C1-4-alkylene; R3selected from phenyl; substituted phenyl where the Deputy is chosen from halogen, nitro, C1-8-alkoxy, trifloromethyl and amino-C1-8-alkyl; naphthyl; and tanila and their enantiomers, diastereoisomers and pharmaceutically acceptable salts

The invention relates to new derivatives of nitromethylene General formula 1 in which R represents the radical (I), (II) or (III)

The invention relates to a new group of antibiotics, the carbapenems and their non-toxic pharmaceutically acceptable salts, having antimicrobial activity, which can be used both separately and in combination with other antibiotics to treat bacterial infections in humans and animals

The invention relates to new heterocycles compounds, more particularly to a new heterocycles compounds which are inhibitors of the enzyme 5-lipoxygenase (5-LO)

The invention relates to arylpiperazines General formula I

< / BR>
where is phenyl, pyridyl or pyrimidyl; each R3- H, halogen, NO2, СООR, where R is H, C1-6alkyl, CN, CF3WITH1-6alkyl, -S - C1-6alkyl, -SO-Cl - C1-6alkyl, -SO2-Cl-C1-6alkyl, C1-6alkoxy and up to10aryloxy, n= 1, 2, or 3; R is a direct bond; And - piperazinil, X1and X2IS N; Y IS-SO2-; Z IS - N(OH)-CHO; Q - CH2-; R1- H, C1-6alkyl, C5-7cycloalkyl until10aryl, until10heteroaryl until1-2aralkyl or until12heteroallyl, R4- H, C1-6alkyl, and others; R2- H, C1-6alkyl, or together with R1- carbocyclic or heterocyclic Spiro 5-, 6 - or 7-membered ring containing at least one heteroatom selected from N, O or S, and the group Q can be associated either with R1or R2with the formation of 5,- 6 - or 7-membered alkyl or heteroalkyl ring that includes one or more O, S or N

The invention relates to compounds of the formula I

< / BR>
in which R1denotes-C(=NH)-NH2which may be substituted once by a group-COA, -CO-[C(R6)2]n-Ar, -COOA, -HE or normal aminosidine group

< / BR>
R2denotes H, A, OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSО2Ar, COOR6, SOPS(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,

R3means And, cycloalkyl, - [C(R6)2]nAr, - [C(R6)2]n-O-Ar, -[C(R6)2]nHet or-C(R6)2=C(R6)2-Ar,

R6denotes H, a or benzyl,

X is absent or represents-CO-, -C(R6)2-, -C(R6)2-C(R6)2-, -C(R6)2-CO-, -C(R6)2-C(R6)2-CO-, -C(R6)= C(R6)-CO-, NR6CO-, -N{[CR6)2]n-COOR6} -CO - or-C(COOR6R6-C(R6)2-CO-,

Y represents-C(R6)2-, -SO2-, -CO-, -COO - or-CONR6-,

And denotes alkyl with 1-20 C-atoms, where one or two CH2-groups can be replaced by O - or S-atom or single, two - or three-fold substituted by the group And, Ah', OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr', NHSO2A, NHSО2Ar', COOR6, CON(R6)2, CONHAr', COR6, COAr', S(O)nA or S(O)nAr is phenyl or naphthyl,

AG' refers to unsubstituted or one-, two - or three-fold substituted by a group A, OR6N(R6)2, NO2CN, Hal, NHCOA, COOR6, SOPS(R6)2, COR6or S(0)nA phenyl or naphthyl,

Het denotes a single or dual core unsubstituted or one - or multi-substituted by a group of Hal, A, Ar', COOR6, CN, N(R6)2, NO2, Ar-CONH-CH2and/or carbonyl oxygen saturated or unsaturated heterocyclic ring system containing one, two, three or four identical or different heteroatoms, such as nitrogen, oxygen or sulphur,

Hal denotes F, C1, Br or J,

n denotes 0, 1 or 2,

and their salts

The invention relates to new derivatives of formula (I), where R1- R4- hydrogen atoms; X - alkylene with 1 to 6 carbon atoms; Y is lower alkyl; B is - NR5R11where R5is a hydrogen atom, R11selected from 5 - to 6-membered heterocyclic radical, in which one ring member is a carbon and 1 to 4 members of the heteroatoms nitrogen, or sulfur, or their pharmaceutically acceptable salts, are useful as inhibitors of the synthesis of nitric oxide

The invention relates to therapeutically active hydroxamic acids and derivatives of carboxylic acids, processes for their preparation, to pharmaceutical compositions containing these compounds and to the use of such compounds in medicine

The invention relates to the basic organic synthesis and concerns a method for obtaining asymmetrically disubstituted ureas of General formula I

R-NH--Nwhere R is phenyl, unsubstituted or mono - or multiply substituted by halogen atom, lower alkyl, lower alkoxygroup, arroceros, trifluoromethyl, and unsubstituted or once substituted lower alkoxygroup benzothiazolyl, or benzoxazolyl, R1and R2means a hydrogen atom or lower alkyl, and R1and R2cannot simultaneously denote a hydrogen atom

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
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