1-sulfonyl-1,3-dihydroindole-2-ones, pharmaceutical compositions (variants), method for their preparing and applying

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

 

This invention relates to new 1-sulfonyl-1,3-dihydro-1H-indole-2-Onam possessing physiological activity. More specifically, the present invention relates to specific physiological activity of these compounds that can be used as a "molecular tools", as well as active drug substances, selectively suppressing programmed cell death (apoptosis - Apoptosis: Pharmacological Implications and Therapeutic Opportunities. Kaufmann, S. H., Ed.; Academic Press: San Diego, 1997); and to pharmaceutical compositions containing these compounds as active substances; and also for obtaining these compositions and method of use of these compositions for the treatment and prevention of the development of various diseases associated with increased activation of apoptosis. This wide range of diseases includes, in particular, cardiovascular (e.g., acute ischemic lesion stroke, myocardial infarction), neurodegeneration, such as Parkinson's disease and Alzheimer's disease (Ryan C.; Salvesen G. Caspases and neuronal development. Biol. Chem. 2003, 384 (6), 855-861), viral diseases (such as hepatitis C and AIDS), etc. (Cryns, V. L.; Yuan, J. The cutting edge: Caspases in apoptosis and disease. In When Cells Die; Lockshin, R. A., Zakeri, Z., Tilly, J.L., Eds.; Wiley-Liss: New York, 1998, 177-210).

The basis of the pharmacological effect of 1-sulfonyl-1,3-dihydro-1H-indol-2-ones lies efficient suppression of apoptosis, real is used by inhibition of cysteine protease - caspase-3 plays a key role in the development of apoptosis.

Currently, it is quite clear that the life of multicellular organisms is based on the balance constantly processes the division and growth of cells, accompanied by an alternative process of removing old, damaged, mutated and other undesirable for the body cells. Managed form of programmed cell death with characteristic morphological and biochemical characteristics defined as apoptosis (Greek word corresponding to Russian "Listopad": Aro - branch, ptosis - falling) (Apoptosis: Pharmacological Implications and Therapeutic Opportunities. Kaufmann, S.H., Ed.; Academic Press: San Diego, 1997. When Cells Die; Lockshin, R.A.; Zakeri, Z.; Tilly, J.L.; Eds.; Wiley-Liss: New York, 1998). Today it is established that the violation of the control cell death leads to shifts of homeostasis and the development of various pathological conditions (Nicholson D.W. From bench to clinic with apoptosis-based therapeutic agents. Nature (London) 2000, 407, 810-816). In the case of increased activation of apoptosis occur most serious pathology related to cardiovascular, neurodegenerative, infectious, metabolic and other diseases (V.L. Cryns; Yuan J. The cutting edge: Caspases in apoptosis and disease. In When Cells Die; Lockshin, R.A.; Zakeri, Z.; Tilly, J.L.; Eds.; Wiley-Liss: New York, 1998, 177-210). It has been shown that the course of AIDS and the number of severe diseases of the nervous system (Parkinson's disease, Alzheimer's disease) is characterized by a surface is an increased activation of apoptosis (Hartmann, A.; Hunot S.; Michel, P.; Muriel M.-P.; Vyas, S.; Faucheux Century; Mouatt-Prigent, P.; Tunnel H.; Srinivasan, A.; Ruberg M.; Evan G.; Agid Y.; Hirsch E. Caspase-3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in PA's disease. PNAS 2000, 97 (6), 2875-2880). During cerebral ischemia and stroke, a significant portion of the cells in the affected area dies it is by the mechanism of apoptosis. In relation to the cells of humans and animals apoptosis in most cases is associated with proteolytic activation cascade of caspases - family evolutionary conservative cysteine proteases that specifically break down proteins after aspartic acid residues. On the basis of structural homology caspase divided into subfamilies (a) caspase-1 (caspase 1, 4, 5), 6) caspase-2 (caspase-2), and C) caspase-3 (caspase 3, 6-10). (Nicholson, D. W.; Thornberry, N. A. Caspases: killer proteases. Trends Biochem. Sci. 1997, 22, 299-306); (Nicholson D.W. Caspase structure, proteolytic substrates, and function during apoptotic cell death [Review]. Cell. Death. Diff. 1999, 6, 1028-1042).

A particularly important role, in fact, defines the life prospects of cells, plays the caspase-3 (Porter, A. G.; Janicke, R. U, Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 1999, 6, 99-104). Therefore, the search for highly effective inhibitors of caspase-3, is able to block apoptosis, is a very promising approach to the creation of fundamentally new cardioprotection (Chapman J.; Magee W.; Stukenbrok H.; Beckius G.; Milici, A.; Tracey W. A novel nonpeptidic caspase-3/7 inhibitor, (S)-(+)-5-[1-(2-methoxymethylpyrrolidinyl)-sulfonyl]isatin reduces myocardial ischemic injury. Eur. J. Pharmacol. 2002, 456(1-3), 59-6), neuroprotectors (Scott C.; Sobotka-Briner, S.; Wilkins, D.; Jacobs, R.; J. Folmer; W. Frazee; br R.; Ghanekar, S.; D. Aharony Novel Small Molecule Inhibitors of Caspase-3 Block Cellular and Biochemical Features of Apoptosis. Pharmacol. Exp. Therap. 2003, 304(1), 433-440), hepatic (Anselmo D.; Katori M.; M. Kaldas; Hoglen N.; Valentino, K.; Busuttil R.; Kupiec-Weglinski W.; Farmer, D. Apoptosis targeted therapy with the caspase inhibitor IDN-6556, ameliorates ex-vivo liver ischemia reperfusion injury. Am. J. Transplant. 2002, 2 (Suppl. 3), 920) for the treatment and protection against a wide range of diseases, a key element of which is apoptosis.

Numerous studies conducted in recent years, led to the discovery of highly effective inhibitors of caspase-3 in a row peptide (Garcia-Calvo, M.; Peterson, E.; Leiting Century; Ruel, R.; Nicholson, D.; Thornberry N. Inhibition of human caspases by peptide-based and macromolecular inhibitors. J. Biol. Chem. 1998, 273, 32608-32613) and coworkers peptide compounds (Karanewsky, D.; Bai, X.; Linton S.; Krebs, J.; Wu J.; Pham Century; Tomaselli K. Conformationally constrained inhibitors of caspase-1 and of the human CED-3 homologue caspase-3. Bioorg. Med. Chem. Lett. 1998, 8, 2757-2762). An example of this type of compounds can be, for example, the following coworkers peptide derivatives developed by firms Idun Pharmaceuticals, Inc. (K.J. Tomaselli; Gladstone P.L.; Ternansky R.J. Pat. PCT WO 0179162, 2001) and Vertex Pharmaceuticals Inc. (Golec, J.; Lang, P.; Diu-Hercend, A.; Knegtel, R.; Weber, P.; Miller, K.; Hercend, T.; Mortimore, M.; Miller, A. Pat. PCT WO 0285899, 2002).

However, such compounds have very limited clinical use because of their poor Farmak the kinetic and physicochemical properties (Scott C.; Sobotka-Briner, S.; Wilkins, D.; Jacobs, R.; J. Folmer; W. Frazee; br R.; Ghanekar, S.; D. Aharony Novel Small Molecule Inhibitors of Caspase-3 Block Cellular and Biochemical Features of Apoptosis. Pharmacol. Exp. Therap. 2003, 304(1), 433-440). In this regard, continue to look for ones low-molecular kaspasky inhibitors. So, have been found quite effective inhibitors (IC50=5-40 nM) caspase-3 in a series of satinov, for example (Chapman J.; Magee W.; Stukenbrok H.; Beckius G.; Milici, A.; Tracey W. A novel nonpeptidic caspase-3/7 inhibitor, (S)-(+)-5-[l-(2-methoxymethylpyrrolidinyl) sulfonyl]isatin reduces myocardial ischemic injury. Eur. J. Pharmacol. 2002, 456(1-3), 59-68) and (Lee, D.; Long, S.A.; Murray, J.H. et al. Potent and selective nonpeptide inhibitors of caspases 3 and 7. J. Med. Chem. 2001, 44(12), 2015-2026)

The discovery of compounds of this class stimulates further the search for inhibitors of caspase-3. So, recently discovered caspase inhibitors in a number of hintline, substances possess moderate activity and selectivity (Scott C.; Sobotka-Briner, S.; Wilkins, D.; Jacobs, R.; J. Folmer; W. Frazee; br R.; Ghanekar, S.; D. Aharony Novel Small Molecule Inhibitors of Caspase-3 Block Cellular and Biochemical Features of Apoptosis. Pharmacol. Exp. Therap. 2003, 304(1), 433-440).

Known substituted 1-sulfonyl-1,3-dihydroindol-2-ones (table 1), showing various types of biological activities, including selective modulators lysophospholipid GPCR receptors Edg-2, Edg-3, Edg-4 (b Edg-7, which "govern" the proliferation of cells and are used for the treatment of cancer and autoimmune diseases [WO 2003062392 A2, 2003], inhib the Torah telomerase representing anticancer drugs [WO 2001002394 A1, 2001] and others [WO 9725986 A1, 1997; Pat. JP 08092248, 1994].

Table 1.
Known substituted 1-sulfonyl-1H-indol-2-ones.
No.FormulaNameLiterature
11-methylsulphonyl-1H-indole-2,3-dioneAngell, B.C.; Black, D.S.C.; Kumar, N. Magn. Reson. Chem. 1992, 30(1), 1-5
21-benzazolyl-1H-indole-2,3-dioneAngell, E.C.; Black, D.S.C.; Kumar, N. Magn. Reson. Chem. 1992, 30(1), 1-5
35-bromo-1-benzazolyl-1H-indole-2,3-dionePat. Germany, 2431842, 1976
41-(2-nitro-benzazolyl)-1H-indole-2,3-dioneAngell, E.G.; Black, D.S.C.; Kumar, N. Magn. Reson. Chem. 1992, 30(1), 1-5
51-(toluene-4-sulfonyl)-1H-indole-2,3-dioneThe Tomchin, A.V.; Krylova, I.M.; Zhur.org.chem., 1986, 22(11), 2420-2434
6 5-methyl-1-(toluene-4-sulfonyl)-1H-indole-2,3-dionePat. Germany, 489645
75-chloro-1-(toluene-4-sulfonyl)-1H-indole-2,3-dioneWO 2001002394 A1, 2001
85-methoxy-1-(toluene-4-sulfonyl)-1H-indole-2,3-dioneBD CHEMCATS of STN, 2003, RN381170-51-0.
95-ethoxy-1-(toluene-4-sulfonyl)-1H-indole-2,3-dioneBD CHEMCATS of STN, 2003, RN442524-95-0.
101-(4-methoxybenzenesulfonyl)-1H-indole-2,3-dioneBD CHEMCATS of STN, 2003, RN442524-94-9.
11Indian Drugs, 1985, 22 (12), 633-639
121-(2,4-dimethoxyphenylacetone)-1H-indole-2,3-dioneWO 2003008407 A2, 2003
131-(3,4-dimethoxyphenylacetone)-1H-indole-2,3-dioneWO 9636611 A1,1996
14 Methyl ester of 4-[(2,3-dihydro-2,3-dioxo-1H-indol-1-yl]-sulfonyl-3-thiophencarboxylic acidWO 2001002394 A1, 2001
15[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-acetonitrileKurichara, T.; Hanakawa, M.; Harusawa, S.; Yontda, R. Chem. Pharm. Bull. 1986, 34(11), 4545-4553
163-bis-[(4-methoxyphenyl)methylene]-1,3-dihydro-1-[(4-were]-2H-indol-2-heWO 9725986 A1, 1997
171-(phenylsulfonyl)-1,3-dihydro-3-(4-oxo-2-thioxo-5-thiazolidinone)-2H-indol-2-hePat. JP 08092248, 1994
181-[(2,5-dichlorophenyl)sulfonyl]-1,3-dihydro-3-(4-oxo-2-thioxo-5-thiazolidinone)-2H-indol-2-hePat. JP 08092248, 1994
191-[(2,4,5-trichlorophenyl)sulfonyl]-1,3-dihydro-3-(4-oxo-2-thioxo-5-thiazolidinone)-2H-indol-2-hePat. JP 08092248, 1994
201-(phenylsulfonyl)-1,3-dihydro-3-(2,4-dioxo-5-thiazolidinone)-2H-indol-2-hePat. JP 0092248, 1994
211-[(2,5-dichlorophenyl)sulfonyl]-1,3-dihydro-3-(2,4-dioxo-5-thiazolidinone-2H-indol-2-hePat. JP 08092248, 1994
224(2,4,5-trichlorophenyl)sulfonyl]-1,3-dihydro-3-(2,4-dioxo-5-thiazolidinone-2H-indol-2-hePat. JP 08092248, 1994
233-(2-amino-4-oxo-5(4H)-thiazolidin)-1,3-dihydro-1-[(4-were)sulfonyl]-2H-indol-2-heWO 2003062392 A2, 2003
245-chloro-3-(2,4-dioxo-5-thiazolidinone)-1,3-dihydro-1-[(4-were)sulfonyl]-2H-indol-2-heWO 2001002394 A1, 2001. Pat. US 6372742 B1, 2002
255-chloro-3-(2,4-dioxo-5-thiazolidinone)-1,3-dihydro-1-[(4-nitrophenyl)sulfonyl]-2H-indol-2-heWO 2001002394 A1, 2001
26Methyl ester of 4-[[3-(2,4-dioxo-5-thiazolidinone)-2,3-dihydro-2-oxo-1H-indol-1-yl]-sulfonyl]-3-thiophencarboxylic acidWO 2001002394 A1, 2001

Information about antiproteases actively the ti substituted 1-sulfonyl-1,3-dihydro-1H-indol-2-ones in the scientific and patent literature to date was missing.

As a result of research aimed at finding new biologically active compounds selectively inhibit programmed cell death (apoptosis), the inventors have discovered a new gametip ones inhibitors of caspase-3, namely 1-sulfonyl-1,3-dihydro-1H-indol-2-ones.

More specifically this invention relates to substituted 1-sulfonyl-1,3-dihydro-1H-indole-2-Onam with specific physiological activity that can be used as a "molecular tools", as well as active drug substances, selectively suppressing programmed cell death (apoptosis); and to pharmaceutical compositions containing these compounds as active substances; as well as to its preparation and method of its use for the treatment and prevention of the development of various diseases associated with increased activation of apoptosis, such as acute ischemic lesions (eg, stroke, myocardial infarction), neurodegenerative (e.g., Parkinson's disease and Alzheimer's disease), viral diseases (such as hepatitis C and AIDS), etc. This invention relates to new substituted 1-sulfonyl-1,3-dihydro-1H-indole-2-Onam.

Below are definitions of terms used in the description:

"Combinatorial library" means the number is under connections, obtained by parallel synthesis, and orientated leader or optimize the biological activity of lead compounds, with each compound of the library meets the General scaffold and the library is a collection of related homologues or analogues.

"Focused library" means a combinatorial library, or a combination of several combinatorial library, or a set of libraries and substances, specially organized for the purpose of increasing the probability of finding hits and leaders, or to improve the efficiency of their optimization. The design of focused libraries, typically associated with directional search effectors (inhibitors, activators, agonists, antagonists, etc.) certain biological targets (enzymes, receptors, ion channels, and so on).

"Lead compound" means a compound with outstanding activity related to a particular disease.

"Scaffold" means the General structural formula, or molecular skeleton, or invariant connections area common to all compounds included in the combinatorial library.

"Gametip" means a series of compounds having a common structural formula and with a certain common property, such as some form of physiological activity. We can say, for example, "new gametip AK is autorow potassium channels" or "known gametip kinase inhibitors", etc. As a rule, the presence of common structural fragment of compounds within one chemotype is a necessary and sufficient condition for the existence of common properties.

"Deputy" means a chemical moiety that is attached to scaffold or semi-synthesis in the process of their synthesis. As the Deputy may serve as a halogen atom, a hydroxyl group, carboxialkilnuyu group, carboxyl group, carnemolla group or inert Deputy.

"Inert Deputy" ("Non-interfering substituent"means low or directionspanel radical including, but not limited to C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh. With7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C2-C12alkoxyalkyl,2-C10alkylsulfonyl,2-C10alkylsulfonyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted aryl, substituted alkoxy, foralkyl, aryloxyalkyl, heterocyclyl, substituted heterocyclyl and nitroalkyl; where m and n have a value from to 7. Preferred "inertie substituents are C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted aryl, heterocyclyl and substituted heterocyclyl.

"Substituted group, substituted radical or scaffold" means respectively the group: radical or scaffold, have a Deputy, including but not limited to inert Deputy, a halogen atom, a nitro-group, a cyano, alphagroup, hydroxyl group, amino group, carboxialkilnuyu group, carboxyl group, karbamoilnuyu group. For example, substituted alkyl means alkyl with one or more substituents, such as hydroxyalkyl or methoxycarbonylethyl, aminoethoxyethanol, dimethylaminoethyl, 2-hydroxy-2-methoxycarbonyl-ethyl and others; substituted amino group means an amino group which has one or two substituent, such as alluminare, N,N-dialkylamino, N-acyl-N-aryl-amino group, acetyldeoxynivalenol and others; substituted phenyl means phenyl, which has the Dean or more substituents, for example, 2-ethoxycarbonylphenyl, 4-amino-3-ethoxycarbonylphenyl, 3,4-diaminophenyl and other

"Optionally substituted group optionally substituted radical or scaffold" means respectively the group, the radical or scaffold, including groups, radicals or scaffold with deputies and without deputies. For example, the concept of optional substituted amino group include an unsubstituted amino group and amino group containing any, not inconsistent with chemistry substituents, including, but not limited to alluminare, N,N-dialkylamino, N-acyl-N-killingray, allocarbitraryblob and other

"Aryl" means one or more aromatic cycles, each of which includes 5 or 6 carbon atoms. "Aryl" may be condensed political, such as naphthalene, or unfused, such as biphenyl. "Substituted aryl" has one or more "not interfering" deputies.

"Halogen" means fluorine atom, chlorine, bromine or iodine.

"Heterocycle" means one or more saturated or aromatic cycles with 5, 6 or 7 atoms, at least one of which is a heteroatom.

Preferred heteroatoms are sulfur, oxygen and nitrogen.

"Heterocycle" may be condensed political, such as benzimidazole, benzoxazole, benzthiazole, quinoline, Il is unfused, for example, as bipyridyl.

"Azaheterocycle" means a heterocycle comprising at least one nitrogen atom, such as benzimidazole, benzoxazole. benzthiazole, quinoline.

"Substituted heterocycle" means a heterocycle having one or more "not interfering" deputies.

"Parallel synthesis" means a method for chemical synthesis of combinatorial libraries of individual connections.

The aim of the present invention is the creation of new inhibitors of caspase-3, intended for experimental (in vitro, in vivo) studies of apoptosis as pharmacological tools.

This goal is achieved physiologically active 1-sulfonyl-1,3-dihydro-1H-indole-2-areas of General formula 1

in which

R1is inert Deputy, which means low or directionspanel optionally substituted radical, such as C1-C7alkyl, C2-C7alkenyl,2-C7quinil,2-C7alkoxy, C7-C12aralkyl, C7-C12geterotsiklicheskikh, C7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, aryl, heterocyclyl;

R2and R4independently from each other represent a hydrogen atom, a halogen atom, a C 3inert Deputy, which means low or directionspanel optionally substituted radical, such as C1-C7alkyl, C2-C7alkenyl,2-C7quinil,2-C7alkoxy, C7-C12aralkyl, C7-C12geterotsiklicheskikh, C7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, aryl, heterocyclyl; NO2, CN, COOH, optionally substituted Altamarena group, optionally substituted carbamide group, optionally substituted carboxy1-6alkyl group;

R5represents an oxygen atom or a carbon atom included in optional condensed, optionally substituted and optionally containing one or more heteroatoms selected from the group of nitrogen, oxygen, sulfur, 4-7-membered cycle; the term includes substituted substituents, selected from the group of halogen atom, hydroxyl group, substituted hydroxyl group, substituted amino group, carboxialkilnuyu group, substituted carboxialkilnuyu group, carnemolla group, substituted carbonilla group or inert Deputy, which means low or directionspanel optionally substituted radical, such as C1-C7alkyl, C2-C7alkenyl,2-the 7quinil,2-C7alkoxy, C7-C12aralkyl, C7-C12geterotsiklicheskikh, C7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, aryl, heterocyclyl possessing properties of inhibitors of caspase-3, intended for experimental (in vitro, in vivo) studies of apoptosis as pharmacological tools.

The aim of the present invention is to provide new pharmaceutical compositions having the properties of inhibition of caspase-3.

This goal is achieved by a pharmaceutical composition having the property of inhibiting caspase-3, in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, containing as active substance pharmaceutically effective amount of 1-sulfonyl-1,3-dihydro-1H-indole-2-it General formula 1.

This goal is achieved is also a pharmaceutical composition intended for treating and preventing various diseases of warm-blooded animals and humans associated with increased activation of apoptosis, in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, containing as active substance pharmaceutically effective amount of 1-sulfonyl-1,3-dihydro-1H-indole-2-nobsa formula 1.

The aim of the present invention is to provide a method of producing pharmaceutical compositions having the properties of inhibition of caspase-3.

This goal is achieved by mixing the active substance and an excipient, diluent or solvent, the distinctive feature of which is that as the active substance used pharmacologically effective amount of 1-sulfonyl-1,3-dihydro-1H-indole-2-it General formula 1.

The aim of the present invention is a method of treating and preventing various diseases of warm-blooded animals and humans associated with increased activation of apoptosis.

This goal is achieved by the introduction of a warm-blooded animal or human pharmaceutical compositions containing as active substance pharmaceutically effective amount of 1-sulfonyl-1,3-dihydro-1H-indole-2-it General formula 1.

The aim of the present invention is a new substituted 1-sulfonyl-1,3-dihydro-1H-indol-2-ones.

This goal is achieved substituted 1-sulfonyl-1,3-dihydro-1H-indole-2-it General formula 1 in which R1, R2, R3, R4and R5have the above value, ex: 1-methylsulphonyl-1H-indole-2,3-dione, 1-benzazolyl-1H-indole-2,3-dione, 5-bromo-1-benzazolyl-1H-indole-2,3-dione, 1-(2-nitro-baselslt who yl)-1H-indole-2,3-dione, 1-(toluene-4-sulfonyl)-1H-indole-2,3-dione, 5-methyl-1-(toluene-4-sulfonyl)-1H-indole-2,3-dione, 5-chloro-1-(toluene-4-sulfonyl)-1H-indole-2,3-dione, 5-methoxy-1-(toluene-4-sulfonyl)-1-indole-2,3-dione, 5-ethoxy-1-(toluene-4-sulfonyl)-1-indole-2,3-dione, 1-(4-methoxybenzenesulfonyl)-1H-indole-2,3-dione, 1-(2,4-dimethoxyphenylacetone)-1H-indole-2,3-dione, 1-(3,4-dimethoxyphenylacetone)-1H-indole-2,3-dione, methyl ester 4-[(2,3-dihydro-2,3-dioxo-1H-indol-1-yl]-sulfonyl-3-thiophencarboxylic acid, [2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-acetonitrile, 3-bis-[(4-methoxyphenyl)methylene]-1,3-dihydro-1-[(4-were]-2H-indol-2-it, 1-(phenylsulfonyl)-1,3-dihydro-3-(4-oxo-2-thioxo-5-thiazolidinone-2H-indol-2-it, 1-[(2,5-dichlorophenyl)sulfonyl]-1,3-dihydro-3-(4-oxo-2-thioxo-5-thiazolidinone-2H-indol-2-it, 1-[(2,4,5-trichlorophenyl)sulfonyl]-1,3-dihydro-3-(4-oxo-2-thioxo-5-thiazolidinone-2H-indol-2-it, 1-(phenylsulfonyl)-1,3-dihydro-3-(2,4-dioxo-5-thiazolidinone-2H-indol-2-it, 1-[(2,5-dichlorophenyl)sulfonyl]-1,3-dihydro-3-(2,4-dioxo-5-thiazolidinone-2H-indol-2-it, 1-[(2,4,5-trichlorophenyl)sulfonyl]-1,3-dihydro-3-(2,4-dioxo-5-thiazolidinone-2H-indol-2-it, 3-(2-amino-4-oxo-5(4H)-thiazolidin)-1,3-dihydro-1-[(4-were)sulfonyl]-2H-indol-2-it, 5-chloro-3-(2,4-dioxo-5-thiazolidinone)-1,3-dihydro-1-[(4-were)sulfonyl]-2H-indol-2-it, 5-chloro-3-(2,4-dioxo-5-thiazolidinone)-1,3-dihydro-1-[(4-nitrophenyl)sulfonyl]-2H-indol-2-he and methyl ester of 4[[3-(2,4-dioxo-5-thiazolidinone)-2,3-dihydro-2-oxo-1H-indol-1-yl]-sulfonyl]-3-thiophenecarbonitrile the acid.

Preferred substituted 1-sulfonyl-1,3-dihydro-1H-indole-2-areas are substituted 1-sulfonyl-1H-indole-2,3-diones of General formula 1.1

in which

R1, R2, R3and R4have the above value, excluding 1-methylsulphonyl-1H-indole-2,3-dione, 1-benzazolyl-1H-indole-2,3-dione, 5-bromo-1-benzazolyl-1H-indole-2,3-dione, 1-(2-nitro-benzazolyl)-1H-indole-2,3-dione, 1-(toluene-4-sulfonyl)-1H-indole-2,3-daone, 5-methyl-1-(toluene-4-sulfonyl)-1H-indole-2,3-dione, 5-chloro-1-(toluene-4-sulfonyl)-1H-indole-2,3-dione, 5-methoxy-1-(toluene-4-sulfonyl)-1H-indole-2,3-dione, 5-ethoxy-1-(toluene-4-sulfonyl)-1H-indole-2,3-dione, 1-(4-methoxybenzenesulfonyl)-1H-indole-2,3-dione, 1-(2,4-dimethoxyphenylacetone)-1H-indole-2,3-dione, 1-(3,4-dimethoxyphenylacetone)-1H-indole-2,3-dione, methyl ester 4-[(2,3-dihydro-2,3-dioxo-1H-indol-1-yl]-sulfonyl-3-thiophencarboxylic acid.

Preferred substituted 1-sulfonyl-1,3-dihydro-1H-indole-2-areas are also substituted 1-sulfonyl-3-(4-oxothiazolidine-5-ilidene)-1,3-dihydroindol-2-ones of General formula 1.2

in which

R1, R2, R3and R4have the above meaning;

R6represents a hydrogen atom or an inert Deputy;

X represents a sulfur atom or an oxygen atom, excluding 1-(phenylsulfonyl)-1,3-dihydro-3-(4-ACS is-2-thioxo-5-thiazolidinone-2H-indol-2-it, 1-[(2,5-dichlorophenyl)sulfonyl]-1,3-dihydro-3-(4-oxo-2-thioxo-5-thiazolidinone-2H-indol-2-it, 1-[(2,4,5-trichlorophenyl)sulfonyl]-1,3-dihydro-3-(4-oxo-2-thioxo-5-thiazolidinone-2H-indol-2-it, 1-(phenylsulfonyl)-1,3-dihydro-3-(2,4-dioxo-5-thiazolidinone-2H-indol-2-he, 1-[(2,5-dichlorophenyl)sulfonyl]-1,3-dihydro-3-(2,4-dioxo-5-thiazolidinone-2H-indol-2-it, 1-[(2,4,5-trichlorophenyl)sulfonyl]-1,3-dihydro-3-(2,4-dioxo-5-thiazolidinone-2H-indol-2-it, 3-(2-amino-4-oxo-5(4H)-thiazolidin)-1,3-dihydro-1-[(4-were)sulfonyl]-2H-indol-2-it, 5-chloro-3-(2,4-dioxo-5-thiazolidinone)-1,3-dihydro-1-[(4-were)sulfonyl]-2H-indol-2-it, 5-chloro-3-(2,4-dioxo-5-thiazolidinone)-1,3-dihydro-1-[(4-nitrophenyl)sulfonyl]-2H-indol-2-he and methyl ester 4-[[3-(2,4-dioxo-5-thiazolidinone)-2,3-dihydro-2-oxo-1H-indol-1-yl]-sulfonyl]-3-thiophencarboxylic acid.

1-Sulfonyl-1,3-dihydro-1H-indol-2-ones of General formula 1 can be obtained, for example, according to the following scheme:

To obtain 1-sulfonyl-1,3-dihydro-1H-indol-2-ones of General formulas 1, 1.1 and 1.2 can be used are well known in the chemistry of isatin techniques. For example, 1-sulfonyl-1H-indole-2,3-diones 1.1 can be obtained by methods known 1-sulfonyl-1H-indole-2,3-diones; obtaining 1-sulfonyl-3-(4-oxo-thiazolidin-5-ilidene)-1,3-dihydro-1H-indol-2-ones 1.2, you can use the techniques described in [Pat. JP 08092248, 1994], on the basis of Saedinenie 1.1 and 4.

Biological (antiproteaznaya) activity of the compounds was determined on the serine protease (Caspase 3), which are involved in the regulation of programmed cell death (apoptosis). The activity of Caspase 3 was determined by the rate of cleavage of the peptide substrate containing fluorescent molecule (methylcoumarin) in accordance with the Protocol described in Technical Bulletin company Sigma-Aldrich [www.sigmaaldrich.com/sigma/bulletin/casp3fbul.pdf].

Used in the synthesis of 1-sulfonyl-1,3-dihydro-1H-indol-2-ones of General formula 1,1 .1 and 1.2 source reagents are commercially available.

Below the invention is described using specific examples of the preparation of specific compounds and combinatorial libraries. The structure of the obtained compounds was confirmed by the data of chemical, chromatographic and spectral analysis. Liquid-phase parallel synthesis of new compounds and combinatorial libraries was carried out using a special synths "CombiSyn-012-3000" [Mbaru, Aevidence, Patent of Russia 2180609, 2002; PCT WO 02/087740 A1, 2002] and equipment [Technology Platform. In Custom Chemistry; Chemical Diversity Labs, Inc.; San Diego, CA, 2002; p].

The invention is illustrated by, but is not limited to the following examples.

Examples 1. A common way to obtain 1-sulfonyl-1H-indol-2-ones 1,1 .1 (a Combinatorial library 1-sulfonyl-1H-indol-2-ones 1,1 .1). To a suspension of 1 mmol of isatin 2 (R4/sup> =H) in 2 ml of acetonitrile was added 1.2 mmol of triethylamine and 1 mmol of sulphonylchloride 3. The resulting mixture was stirred for 10 h at room temperature. The reaction mass was diluted with 2 ml water, the precipitate was filtered, dried under vacuum, washed affirm or ethyl acetate. Was obtained after drying combinatorial library of known and new 1-sulfonyl-1H-indol-2-ones 1,1 .1: 1-Methanesulfonyl-1H-indole-2.3-dione 1.1(1); Mol. weight 225,22. LS MS m/z 326 (M+1); N1NMR (DMSO-d6) δ 3.49 (s, 3H), 7.34 (m, 1H), 7.74 (m, 3H);

1-(Toluene-4-sulfonyl)-1H-indole-2,3-dione 1.1(2); Mol. weight 301,32. LS MS m/z 302 (M+1); H1NMR (DMSO-d6) δ 2.40 (s, 3H), 7.31 (t, J=7.5 Hz, 1H), 7.47 (d, J=8.1 Hz, 2H), 7.67 (d, J=7.5 Hz, 1H), 7.75 (t, J=7.5 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.97 (d, J=8.1 Hz, 2H);

1-Methanesulfonyl-5-methoxy-1H-indole-2,3-dione 1.1(3);

5-Methoxy-1-(toluene-5-sulfonyl)-1H-indole-2,3-dione 1.1(4); Mol. weight 331,35. LS MS m/z 332 (M+1); H1NMR (DMSO-d6) δ 2.39 (s, 3H), 3.77 (s, 3H), 7.22 (d, J=2.8 Hz, 1H), 7.34 (dd, J1=2.8 Hz, J2=9.1 Hz, 1H), 7.46 (d, J=9.0 Hz, 1H), 7.77 (d, J=9.1 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H);

1-Methanesulfonyl-5-methyl-1H-indole-2,3-dione 1.1(5);

5-Methyl-1-(toluene-5-sulfonyl)-1H-indole-2,3-dione 1.1(6); Mol. weight 315,35. LS MS m/z 316 (M+1); H1NMR (DMSO-d6) δ 2.30 (s, 3H), 2.40 (s, 3H), 7.47 (d, J=8.0 Hz, 2H), 7.50 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.94 (d, J=8.0 Hz, 2H);

1-Methanesulfonyl-2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonic acids of diethylamid 1.1(7);

2,3-Dioxo-1-(toluene-5-sulfonyl)-2,3-dihydro-1H-indole-5-sulfonic di is telemed 1.1(8);

5-fluoro-1-(toluene-5-sulfonyl)-1H-indole-2,3-dione 1.1(9): Mol. weight 319,31. LS MS m/z 320 (M+1); H1NMR (DMSO-d6) δ 2.41 (s, 3H), 7.47 (d, J=8.1 Hz, 2H), 7.62 (m, 2H), 7.88 (m, 1H), 7.97 (d, J=8.1 Hz, 2H);

5-fluoro-1-methanesulfonyl-1H-indole-2,3-dione 1.1(10);

1-Methanesulfonyl-5-(morpholine-4-sulfonyl)-1H-indole-2,3-dione 1.1(11);

5-(Morpholine-4-sulfonyl)-1-(toluene-5-sulfonyl)-1H-indole-2,3-dione 1.1(12);

1-Methanesulfonyl-5-(4-methyl-piperidine-1-sulfonyl)-1H-indole-2,3-dione 1.1(13);

5-(4-Methyl-piperidine-1-sulfonyl)-1-(toluene-5-sulfonyl)-1H-indole-2,3-dione 1.1(14);

1-Methanesulfonyl-2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonic[1,3]dioxolane-2-ylmethyl-methyl-amide 1.1(15);

2,3-Dioxo-1-(toluene-5-sulfonyl)-2,3-dihydro-1H-indole-5-sulfonic[1,3]dioxolane-2-ylmethyl-methyl-amide 1.1(16);

1-Methanesulfonyl-5-(1,4,7-trioxa-10-azacyclopentadecan-10-sulfonyl)-1H-indole-2,3-dione 1.1(17);

1-(Toluene-5-sulfonyl)-5-(1,4,7-trioxa-10-azacyclopentadecan-10-sulfonyl)-1H-indole-2,3-dione 1.1(18);

1-Methanesulfonyl-5-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-1H-indole-2,3-dione 1.1(19);

5-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-1-(toluene-5-sulfonyl)-1H-indole-2,3-dione 1.1(20);

5-(2-Hydroxymethyl-pyrrolidin-1-sulfonyl)-1-methanesulfonyl-1H-indole-2,3-dione 1.1(21);

5-(2-Hydroxymethyl-pyrrolidin-1-sulfonyl)-1-(toluene-5-sulfonyl)-1H-indole-2,3-dione 1.1(22);

1-Methanesulfonyl-5-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-sulfonyl)-1H-indole-2,3-dione 1.1(23);

5-(2-P is Raiden-1-ylmethyl-pyrrolidin-1-sulfonyl)-1-(toluene-5-sulfonyl)-1H-indole-2,3-dione 1.1(24);

1-(3,5-dimethyl-isooctanol-4-sulfonyl)-1H-indole-2,3-dione 1.1(25);

1-Phenylmethanesulfonyl-1H-indole-2,3-dione 1.1(26); Mol. weight 301,32. LS MS m/z 302 (M+1); N1NMR (DMSO-d6) δ 4.96 (s, 2H), 7.26-7.74 (overlapping m, 7H), 7.63 (t, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H);

1-(Naphthalene-2-sulfonyl)-1H-indole-2,3-dione 1.1(27);

1-(2,3-Dihydrobenzo[1,4]dioxin-6-sulfonyl)-1H-indole-2,3-dione 1.1(28);

1-(4-Fluoro-benzazolyl)-1H-indole-2,3-dione 1.1(29); Mol. weight 305,29. LS MS m/z 306 (M+1); N1NMR (DMSO-d6) δ 7.33 (t, J=7.5 Hz, 1H), 7.53 (t, J=8.8 Hz, 2H), 7.69 (d, J=7.5 Hz, 1H), 7.77 (t, J=7.5 Hz, 1H), 7.84 (d, J=7.5 Hz, 1H), 8.26 (dd, J1=4.8 Hz, J2=8.8 Hz, 2H);

1-(Thiophene-2-sulfonyl)-1H-indole-2,3-dione 1.1(30);

1-(2-Oxo-2,3-dihydroisoxazole-6-sulfonyl)-1H-indole-2,3-dione 1.1(31);

1-(2,3-Dioxo-1H-indol-5-sulfonyl)-1H-indole-2,3-dione 1.1(32);

5-Ethoxy-1-(toluene-4-sulfonyl)-1H-indole-2,3-dione 1.1(33).

Examples 2. 1-Sulfonyl-3-(4-oxo-thiazolidin-5-ilidene)-1,3-dihydroindol-2-ones of General formula 1.2 is obtained by the method described in example 1. Parallel synthesis of combinatorial libraries 1-sulfonyl-3-(4-oxo-thiazolidin-5-ilidene)-1,3-dihydro-indol-2-ones were carried out in 1.2 synthesizer "CombiSyn-012-3000". Below is a combinatorial library 64 synthesized 1-sulfonyl-3-(4-oxo-thiazolidin-5-ilidene)-1,3-dihydro-indol-2-ones 1.2, including:

3-(3-Benzyl-4-oxo-2-thioxo-thiazolidin-5-ilidene)-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2{1} Mol. weight 506,63. LS MS m/z 507 (M+1);

3-(3-Allyl-4-oxo-thioxo-thiazolidin-5-ilidene)-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {2};

3-(3-Furan-2-ylmethyl-4-oxo-2-thioxo-thiazolidin-5-ilidene)-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {3} Mol. weight 496,59. LS MS m/z 497 (M+1);

3-[3-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-yl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {4} Mol. weight 526,62. LS MS m/z 527 (M+1);

1-Methanesulfonyl-3-(3-methyl-4-oxo-2-thioxo-thiazolidin-5-ilidene)-1,3-dihydro-indol-2 he 1.2 {5} Mol. weight 354,43. LS MS m/z 355 (M+1);

3-[3-(4-Ethoxy-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2 he 1.2 {6};

3-[3-(1,5-dimethyl-3-oxo-2-phenyl-pyrazolidine-4-yl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2 he 1.2 {7};

3-[5-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionic acid 1.2 {8};

4-[5-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-butyric acid 1.2 {9};

3-[3-(3-Chloro-phenyl)-4-oxo-1,2-dihydro-indol-3-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2 he 1.2 {10};

3-(4-Hydroxy-phenyl)-2-[5-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionic acid 1.2 {11};

3-[3-(4-Bromo-phenyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-1-methanesulfonyl-1,3-dihydro-indol-2 he 1.2{12};

3-[3-(2,4-Dimethyl-phenyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-1-methanesulfonyl-1,3-dihydro-indol-2 he 1.2 {13}, Mol. weight 444,55. LS MS m/z 445 (M+1);

3-(3-Cyclohexyl-4-oxo-2-thioxo-thiazol the DIN-3-yl)-1-methanesulfonyl-1,3-dihydro-indol-2 he 1.2 {14};

1-Methanesulfonyl-3-[4-oxo-2-thioxo-3-(3-trifluoromethyl-phenyl)-thiazolidin-5-ilidene]-1,3-dihydro-indol-2 he 1.2 {15};

2-[5-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-3-phenyl-propionic acid 1.2 {16};

3-[3-(4-Hydroxy-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2 he 1.2 {17};

3-[3-(4-Chloro-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2 he 1.2 {18};

1-Methanesulfonyl-3-[3-(4-nitro-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1,3-dihydro-indol-2 he 1.2 {19};

3-[3-(4-Fluoro-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2 he 1.2 {20};

3-[3-(2,3-Dimethyl-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2 he 1.2 {21};

1-Methanesulfonyl-3-[4-oxo-2-thioxo-3-(2-trifluoromethyl-phenyl)-thiazolidin-5-ilidene]-1,3-dihydro-indol-2 he 1.2 {22};

3-[3-(2-Fluoro-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2 he 1.2 {23};

[5-(1-Methanesulfonyl-2-oxo-1,2-digiteo-indol-3-ilidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid methyl ester 1.2 {24};

3-[5-(1-Methanesulfonyl-2-oxo-1,2-digiteo-indol-3-ilidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-benzoic acid 1.2 {25};

3-[3-(3-Fluoro-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2 he 1.2 {26};

3-[3-(4-Dimethylamino-phenyl)-4-oxo-2-thioxo-thiazolidin-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2 he 1.2 {27};

2-[5-(1-Methanesulfonyl-2-oxo-1,2-digiteo-indol-3-ilidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-benzoic acid methyl ester 1.2 {28};

3-[3-(1,1-Dioxo-tetrahydro-thiophene-3-yl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2 he 1.2 {29};

3-[3-(3-Hydroxy-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2 he 1.2 {30};

1-Methanesulfonyl-3-(4-oxo-2-thioxo-3-m-tolyl-thiazolidin-5-ilidene)-1,3-dihydro-indol-2 he 1.2 {31};

3-(3-Benzol[1,3]dioxol-5-yl-4-oxo-2-thioxo-thiazolidin-5-ilidene)-1-methanesulfonyl-1,3-dihydro-indol-2 he 1.2 {32};

[5-(1-Methanesulfonyl-2-oxo-1,2-digiteo-indol-3-ilidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid 1.2 {33};

3-[4-Oxo-2-thioxo-3-(1,2,5-trimethyl-oxo-2,3-dihydro-1H-pyrazole-4-yl)-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {34};

3-[3-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-yl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2 he 1.2 {35};

1-Methanesulfonyl-3-[4-oxo-2-thioxo-3-(1,2,5-trimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-yl)-thiazolidin-5-ilidene]-1,3-dihydro-indol-2 he 1.2 {36};

3-(3-Methyl-4-oxo-2-thioxo-thiazolidin-5-ilidene)-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {37};

3-[3-(4-Ethoxy-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {38};

3-{4-Oxo-5-[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-2-Digue is draw-indol-3-yl}-propionic acid 1.2 {39};

4-{4-Oxo-5-[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-2-thioxo-thiazolidin-3-yl}-butane acid 1.2 {40};

3-[3-(3-Chloro-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {41};

3-(4-Hydroxy-phenyl)-2-{4-oxo-5-[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-2-thioxo-thiazolidin-3-yl}-propionic acid 1.2 {42};

3-[3-(4-Bromo-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {43};

3-[3-(2,4-Dimethyl-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {44};

3-(3-Cyclohexyl-4-oxo-2-thioxo-thiazolidin-5-ilidene)-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {45};

3-[4-Oxo-2-thioxo-3-(3-trifluoromethyl-phenyl)-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {46};

2-{4-Oxo-5-[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-2-thioxo-thiazolidin-3-yl}-3-phenyl-propionic acid 1.2 {47};

3-[3-(4-Hydroxy-phenyl)-4-oxo-2-thioxo-thiazolidin-iligan]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {48};

3-[3-(4-Chloro-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {49};

3-[3-(4-Nitro-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {50};

3-[3-(4-Fluoro-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {51};

3-[3-(2,3-Di is ethyl-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {52};

3-[4-Oxo-2-thioxo-3-(2-trifluoromethyl-phenyl)-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {53};

3-[3-(2-Fluoro-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {54};

{4-Oxo-5-[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-2-thioxo-thiazolidin-3-yl}-acetic acid methyl ester 1.2 {55};

3-{4-Oxo-5-[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-2-thioxo-thiazolidin-3-yl}-benzoic acid 1.2 {56};

3-[3-(3-Fluoro-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {57};

3-[3-(4-dimethylamino-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {58};

2-{4-Oxo-5-[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-2-thioxo-thiazolidin-3-yl}-benzoic acid ethyl ester 1.2 {59};

3-[3-(1,1-Dioxo-tetrahydro-thiophene-3-yl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {60};

3-[3-(3-Hydroxy-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {61};

3-(4-Oxo-2-thioxo-3-m-tolyl-thiazolidin-5-ilidene)-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {62};

3-(3-Benzo[1,3]dioxol-5-yl-4-oxo-2-thioxo-thiazolidin-5-ilidene)-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2 he 1.2 {63} Mol. weight 536,61. LS MS m/z 537 (M+1);

{4-Oxo-5-[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-2-t the oxo-thiazolidin-3-yl}-acetic acid 1.2 {64}, Mol. weight 474,54. LS MS m/z 475 (M+1);

Examples 3. 1-Sulfonyl-3-(5-oxo-pyrazole-4-ilidene)-1,3-dihydro-indol-2-ones of General formula 1 are obtained by analogy with the method described in Pat. US 6372742 B1, 2002. Below is a combinatorial library 30 synthesized 1-sulfonyl-3-(5-oxo-pyrazole-4-ilidene)-1,3-dihydro-indol-2-ones 1, including

4-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester 1 {65}, Mol. weight 439,45. LS MS m/z 440 (M+1);

4-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid 1 {66};

3-(1-Benzothiazol-2-yl-5-oxo-3-phenyl-1,5-dihydro-pyrazole-4-ilidene)-1-methanesulfonyl-1,3-dihydro-indol-2-it 1 {67}, Mol. weight 500,56. LS MS m/z 501 (M+1);

3-(1-Benzothiazol-2-yl-5-oxo-3-propyl-1,5-dihydro-pyrazole-4-ilidene)-1-methanesulfonyl-1,3-dihydro-indol-2-it 1 {68}

3-[1-(5-Hydroxy-6-methyl-[1,2,4]triazine-3-yl)-3-methyl-5-oxo-1,5-dihydro-pyrazole-4-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2-it 1 {69}

4-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester 1 {70}

3-[4-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-5-oxo-3-phenyl-4,5-dihydro-1H-pyrazole-1-yl]-benzoic acid 1 {71}

[4-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-1-(4-methoxy-phenyl)-5-oxo-4,5-dihydro-1H-pyrazole-1-yl]-acetic acid methyl ester 1 {72}

[4-(1-who econsultancy-2-oxo-1,2-dihydro-indol-3-ilidene)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-1-yl]-acetic acid methyl ester 1 {73}

1-Methanesulfonyl-3-[3-(3-methoxy-phenyl)-1-methyl-5-oxo-1,5-dihydro-pyrazole-4-ilidene]-1,3-dihydro-indol-2-it 1 {74}

3-[1-(3-Chloro-phenyl)-5-oxo-3-phenyl-1,5-dihydro-pyrazole-4-ilidene]-1-methanesulfonyl-1,3 - dihydro-indol-2-it 1 {75}

3-(3-tert-Butyl-5-oxo-1-phenyl-1,5-dihydro-pyrazole-4-ilidene)-1-methanesulfonyl-1,3-dihydro-indol-2-it 1 {76}

4-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-5-oxo-1-phenyl-4,5-dihydro-pyrazole-3-carboxamide 1{77}

4-[4-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3-methyl-5-oxo-4,5-dihydro-pyrazole-1-yl]-3-methyl-benzosulfimide 1 {78}

4-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-5-oxo-1-(4-sulfo-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester 1 {79}

5-Oxo-4-[2-oxo-1-toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-1-phenyl-4,5-dihydro-pyrazole-3-carboxylic acid ethyl ester 1 {80}

5-Oxo-4-[2-oxo-1-toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-1-phenyl-4,5-dihydro-pyrazole-3-carboxylic acid 1 {81}

3-(1-Benzothiazol-2-yl-5-oxo-3-phenyl-1,5-dihydro-pyrazole-4-ilidene)-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2-it 1 {82}

3-(1-Benzothiazol-2-yl-5-oxo-propyl-1,5-dihydro-pyrazole-4-ilidene)-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2-it 1 {83}

3-[1-(5-Hydroxy-6-methyl-[1,2,4]triazine-3-yl)-3-methyl-5-oxo-1,5-dihydro-pyrazole-4-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2-it 1 {84}

5-Oxo-4-[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-and the Eden]-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester 1 {85}

3-{5-Oxo-4-[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-3-phenyl-4,5-dihydro-pyrazole-1-yl}-benzoic acid 1 {86}

{1-(4-Methoxy-phenyl)-5-oxo-4-[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-4,5-dihydro-1H-pyrazole-yl}-acetic acid methyl ester 1 {87}

{5-Oxo-4-[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-1-phenyl-4,5-dihydro-pyrazole-1-yl}-acetic acid methyl ester 1 {88}

3-[3-(3-Methoxy-phenyl)-1-methyl-5-oxo-1,5-dihydro-pyrazole-4-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2-it 1 {89}

3-[1-(3-Chloro-phenyl)-5-oxo-3-phenyl-1,5-dihydro-pyrazole-4-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2-it 1 {90}

3-(3-tert-Butyl-5-oxo-1-phenyl-1,5-dihydro-pyrazole-4-ilidene)-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2-it 1 {91}

5-Oxo-4-[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxamide 1 {92}

3-Methyl-4-{3-methyl-5-oxo-4-[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-4,5-dihydro-pyrazole-1-yl}-benzene-acid 1 {93}

5-Oxo-4-[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester 1 {94}, Mol. Weight 595,61. LS MS m/z 596 (M+1).

Examples 4. 1-Sulfonyl-3-heterocyclisation-1,3-dihydro-indol-2-ones of General formula 1 are obtained by analogy with the method described in Pat. US 6372742 B1, 2002. Below is a combinatorial library 72 sinisiraan the x 1-sulfonyl-3-(3,5-dioxo-pyrazolidine-4-ilidene)-1,3-dihydro-indol-2-ones 1, including

4-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-1-m-tolyl-pyrazolidine-3,5-dione 1{95}, Mol. weight 397,41. LS MS m/z 398 (M+1);

1-(4-Chloro-phenyl)-4-[2-oxo-1-(toluene-4-sulfonyl)for 3,5-dioxo-pyrazolidine]-pyrazolidine-3,5-dione 1{96}

4-[4-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)for 3,5-3,5-dioxo-pyrazolidine-1-yl]-benzoic acid ethyl ester 1 {97}

1-(3,4-Dimethyl-phenyl)-4-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-pyrazolidine-3,5-dione 1{98}

4-[2-Oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-1-m-tolyl-pyrazolidine-3,5-dione 1 {99}

1-(4-Chloro-phenyl)-4-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-pyrazolidine-3,5-dione 1 {100}

4-{3,5-Dioxo-4-[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-pyrazolidine-1-yl}-benzoic acid ethyl ester 1 {101}

1-(3,4-Dimethyl-phenyl)-4-[2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydro-indol-3-ilidene]-pyrazolidine-3,5-dione 1 {102}

2-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-benzo[4,imidazo[2,1-b]thiazole-3-one 1 {103}

5-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3-phenyl-thiazolidin-2,4-dione 1{104}

3-(3-Chloro-phenyl)-7-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3,4-dihydro-2H-thiazolo[3,2-a][1,3,5]triazine-6-he 1 {105}

2-(1-Methanesulfonyl-2-oxo-},2-dihydro-indol-3-ilidene)-5-(4-methoxy-phenyl)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 1 {106}

5-(4-Dimethylamino-phenyl)-2-(1-who econsultancy-2-oxo-1,2-dihydro-indol-3-ilidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 1 {107}

5-Benzo[1,3]dioxol-5-yl-2-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 1 {108}

3-(4-Ethoxy-phenyl)-5-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-thiazolidin-2,4-dione 1 {109}

3-(3-Hydroxy-phenyl)-5-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-thiazolidin-2,4-dione 1 {110}

5-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3-m-tolyl thiazolidin-2,4-dione 1 {111}

1-Methanesulfonyl-3-(5-oxo-1-phenyl-2-thioxo-imidazolidin-4-ilidene)-1,3-dihydro-2-it 1 {112}

5-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3-(4-methoxy-phenyl)-thiazolidin-2,4-dione 1{113}

3-[3-(3,4-Dimethyl-phenyl)-2-(3-nitro-phenyl)-1,1,4-trioxo-5-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2-it 1 {114}

5-(4-Chloro-phenyl)-2-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3-oxo-7-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 1 {115}

5-(2,4-Dimethoxy-phenyl)-2-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 1 {116}

2-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-7-methyl-3-oxo-5-n-tolyl-2,3-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 1 {117}

5-(4-Chloro-phenyl)-2-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carbon is howling acid phenylamide 1 {118}

2-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-7-methyl-3-oxo-5-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid methyl ester 1 {119}

5-(2,5-Dimethoxy-phenyl)-2-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 1 {120}

5-(3-Bromo-4-methoxy-phenyl)-2-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 1 {121}

2-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-5-(4-methoxy-phenyl)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid isopropyl ester 1 {122}

5-(4-Chloro-phenyl)-2-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid isopropyl ester 1 {123}

2-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-5-(3-methoxy-phenyl)-3-oxo-7-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 1 {124}

5-(4-Fluoro-phenyl)-2-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3-oxo-7-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 1 {125}

2-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-5-(4-methylsulphonyl-phenyl)-3-oxo-7-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 1 {126}

2-(1-Methanesulfonyl-2-oxo-12-dihydro-indol-3-ilidene)-7-methyl-3-oxo-5-thiophene-2-yl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid phenylamide 1 {127}

2-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3-oxo-7-phenyl-5-thiophene-2-yl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 1 {128}, Mol. weight 591,69. LS MS m/z 592 (M+1)

7-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-1,3-dimethyl-1H-thiazolo[2,3-f]purine-2,4,6-Trion 1 {129}

7-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3-n-tolyl-3,4-dihydro-2H-thiazolo[3,2-a][1,3,5]triazine-6-he 1 {130}

7-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3-(3-nitro-phenyl)-3,4-dihydro-2H-thiazolo[3,2-a][1,3,5]triazine-6-he 1 {131}

1-Methanesulfonyl-3-(5-oxo-1,3-diphenyl-2-thioxo-imidazolidin-4-ilidene)-1,3-dihydro-indol-2-it 1{132}

2-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3-oxo-7-phenyl-5n-tolyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 1 {133}

3-(3-Benzoyl-5-oxo-2-thioxo-imidazolidin-4-ilidene)-1-methanesulfonyl-1,3-dihydro-indol-2-it 1 {134}

5-(4-Chloro-phenyl)-2-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid allyl ester 1 {135}

1-Methanesulfonyl-3-[1-(4-methoxy-phenyl)-5-oxo-2-thioxo-imidazolidin-4-ilidene)-1,3-dihydro-indol-2-it 1 {136}

3-(4-Ethyl-phenyl)-7-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3,4-dihydro-2H-thiazolo[3,2-a][1,3,5]triazine-6-he 1 {137}

3-(4-Fluoro-phenyl)-7-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3,4-dihydro-2H-thiazolo[3,2-a][1,3,5]triazine-6-on {138}

7-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3-m-tolyl-3,4-dihydro-2H-thiazolo[3,2-a][1,3,5]triazine-6-he 1 {139}

3-(4-Chloro-phenyl)-7-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3,4-dihydro-2H-thiazolo[3,2-a][1,3,5]triazine-6-he 1 {140}

4-{2-[5-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-2,4-dioxo-thiazolidin-3-yl]-acetylamino}-benzoic acid ethyl ester 1 {141}

3-[2,3-Bis-(4-fluoro-phenyl)-1,1,4-trioxo-thiazolidin-5-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2-it 1 {142}

[5-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-4-oxo-3-phenyl-2-thioxo-imidazolidin-1-yl]-acetic acid methyl ester 1 {143}

5-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3-phenethyl-thiazolidin-2,4-dione 1 {144}

3-[1-(4-Ethoxy-phenyl)-3-methyl-5-oxo-2-thioxo-imidazolidin-4-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2-it 1 {145}

3-[1-(3,4-Dimethyl-phenyl)-3-methyl-5-oxo-2-thioxo-imidazolidin-4-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2-it 1 {146}

3-(2-Chloro-phenyl)-5-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-thiazolidin-2,4-dione 1 {147}

5-(4-Isopropyl-phenyl)-2-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-7-methyl-3-ox-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 1 {148}

7-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3-phenyl-3,4-dihydro-2H-thiazolo[3,2-a][1,3,5]triazine-6-he 1 {149}

5-(4-Dimethylamino-phenyl)-2-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-and the Eden)-3-oxo-7-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 1 {150}

4-[7-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-6-oxo-6,7-dihydro-2H-thiazolo[3,2-a][1,3,5]triazine-3-yl]-benzoic acid ethyl ester 1 {151}

1-Methanesulfonyl-3-[1-(4-methoxy-phenyl)-5-oxo-3-thiophene-2-ylmethyl-2-thioxo-imidazolidin-4-ilidene]-1,3-dihydro-indol-2-it 1 {152}

1-Methanesulfonyl-3-[1-(3-methoxy-phenyl)-5-oxo-3-thiophene-2-ilidene-2-thioxo-imidazolidin-4-ilidene]-1,3-dihydro-indol-2-it 1 {153}

1-Methanesulfonyl-3-[1-(2-methoxy-phenyl)-5 oxo-3-thiophene-2-ilidene-2-thioxo-imidazolidin-4-ilidene]-1,3-dihydro-indol-2-it 1 {154}

3-[1-(3-Chloro-4-methyl-phenyl)-3-(3-methyl-thiophene-2-ylmethyl)-5-oxo-2-thioxo-imidazolidin-4-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2-it 1 {155}

3-[3-Benzyl-1-(2-methoxy-phenyl)-5 oxo-3-thiophene-2-ilidene-2-thioxo-imidazolidin-4-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2-it 1 {156}

3-(3-Benzyl-5-oxo-2-thioxo-1-o-tolyl-imidazolidin-4-ilidene)-1-methanesulfonyl-1,3-dihydro-indol-2-it 1 {157}

3-[3-Benzyl-1-(2-chloro-phenyl)-5-oxo-3-thiophene-2-ilidene-2-thioxo-imidazolidin-4-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2-it 1 {158}

3-[3-Benzyl-1-(3-methylsulphonyl-phenyl)-5-oxo-3-thiophene-2-ilidene-2-thioxo-imidazolidin-4-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2-it 1 {159}

3-[3-Benzyl-1-(3-chloro-4-methoxy-phenyl)-5 oxo-3-thiophene-2-ilidene-2-thioxo-imidazolidin-4-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2-it 1 {160}

4-[3-Benzyl-4-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-5-oxo-thioxo-imidazolidin-1-yl]-benzoic acid ethyl ester 1 {161}

4-[3-Benzyl-4-(1-methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-5-oxo-2-thioxo-imidazolidin-1-yl]-benzoic acid ethyl ester 1 {162}

3-[1-(2-Fluoro-phenyl)-3-(3-methyl-thiophene-2-ylmethyl)-5-oxo-3-thiophene-2-ilidene-2-thioxo-imidazolidin-4-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2-it 1 {163}

1-Methanesulfonyl-3-[1-(3-methanesulfonyl-phenyl)-3-(3-methyl-thiophene-2-ylmethyl)-5-oxo-3-thiophene-2-ilidene-2-thioxo-imidazolidin-4-ilidene]-1,3-dihydro-indol-2-it 1 {164}

4-[4-(1-Methanesulfonyl-2-oxo-1,2-dihydro-indol-3-ilidene)-3-(3-methyl-thiophene-2-ylmethyl)-5-oxo-2-thioxo-imidazolidin-1-yl]-benzoic acid ethyl ester 1 {165}

3-[1-(2-Chloro-phenyl)-3-(3,4-dimethoxy-benzyl)-5-oxo-3-thiophene-2-ilidene-2-thioxo-imidazolidin-4-ilidene]-1-methanesulfonyl-1,3-dihydro-indol-2-it 1 {166}.

Example 5. Was focused library, including 538 known and new compounds, including 209 known and new 1-sulfonyl-1,3-dihydro-indol-2-ones of General formula 1, and tested it on antiprotease activity. Antiproteaznaya activity was determined by the serine protease (Caspase 3), which are involved in the regulation of programmed cell death (apoptosis). The activity of Caspase 3 was determined by the rate of cleavage of the peptide substrate containing fluorescent molecule (methylcoumarin). Removal methylcoumarin from the peptide molecules in the proteolytic reaction fer the enta accompanied by increased fluorescence intensity, measurements which were performed with fluorescent parallel reader VICTOR2V (PerkinElmer, USA) at a wavelength of excitation of 355 nm and the wavelength of emission of 460 nm. For carrying out reactions used an optical 96-hole of the blade. In our experiments we used the caspase 3 and the fluorescent substrate of the company Sigma (USA). The reaction conditions and the composition of the medium used in accordance with the recommendation of the manufacturer. The starting solutions of test compounds were prepared by dissolution in DMSO (dimethyl sulfoxide) to a concentration of 10 mm. The original solutions of compounds were added to the enzyme solution in such an amount to obtain a final concentration of 10 μm. After 10-minute incubation of the enzyme with the test compound to the solution was added an enzyme substrate and measurement of fluorescence was performed after 1 hour after addition of the substrate (Fie). For the correction on its own fluorescence of the tested compounds fluorescence measurement (Fi0) was performed in a separate circuit boards that do not contain enzyme reagents (enzyme plus substrate). Full enzyme activity was measured by fluorescence in reaction wells containing all reaction components except the test compounds (F100), and zero activity was determined by fluorescence is UNOC, containing the appropriate test connection and all the reaction reagents except the enzyme (F0).

Calculation of inhibition was produced by the following formula:

where Fi=Fei-Fi0, subscript corresponds to the test compound, in the presence of which is measured fluorescence, and the superscripts (e) and (0) means the presence or absence of enzymatic reagents, respectively.

Some examples of the tested compounds showed when scringe library high activity, are shown in the following table 2, and the concentration dependence of inhibition shown in the drawing.

Table 2
Proteasa activity of some 1-sulfonyl-1,3-dihydro-indol-2-ones
IDThe structure of connectionsIC50nmActivity
1.2 {3}1790Inhibition
1.2 {4}52Inhibition

The concentration dependence of inhibition of caspase 3

3-(3-furan-2-ylmethyl-4-oxo-2-t the oxo-thiazolidin-5-ilidene)-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2-one 1.2{3} and 3-[3-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-yl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-2-indol-2-one 1.2 {4}.

Example 6. An example illustrating the preparation of tablets containing 50 mg of active ingredient. Mix 800 mg of starch, 800 mg of powdered lactose, 200 mg of talc and 500 mg of 3-[3-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-yl)-4-oxo-2-thioxo-thiazolidin-5-ilidene]-1-(toluene-4-sulfonyl)-1,3-dihydro-indol-2-it 1.2 {4} with spracovavat in the bar. The resulting block is crushed into granules and sieved through a sieve, collecting the granules with a size 14-16 mesh. The obtained granules tabletirujut in a suitable form tablets weighing 280 mg each. According to the invention likewise receive pharmaceutical composition in the form of tablets containing as active ingredient other compounds of General formula 1.2.

Example 7. Capsules containing 200 mg of compound 1.2{3}, according to the invention can be obtained by thorough mixing of the compounds 1.2 {4} with lactose powder in a 2:1 ratio. Received poroshkoobraznuju mix pack 300 mg in gelatin capsules of suitable size.

Example 8. Injectable compositions for intramuscular, intraperitoneal or subcutaneous injection can be prepared by mixing 500 mg of active ingredient with suitable solubility, such as connections 1.2 {4}, 300 mg chlorbutanol, 2 ml of propylene glycol and 100 ml of injectable water. The resulting solution is filtered and placed in 1 ml ampoule, which sepai is up and sterilized in the autoclave.

Frienemies physiologically active 1-sulfonyl-1,3-dihydro-1H-indol-2-ones of General formula (1)

in which R1is inert Deputy, which means low or directionspanel optionally substituted radical selected from C1-C7of alkyl, C2-C7alkenyl,2-C7the quinil,1-C7alkoxyl,7-C12aralkyl,7-C12geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,2-C12cycloalkenyl, phenyl, aryl, heterocyclyl;

R2, R3and R4independently from each other represent a hydrogen atom, halogen atom, CF3inert Deputy, which means low or directionspanel optionally substituted radical, such as1-C7alkyl, C2-C7alkenyl,2-C7quinil,2-C7alkoxy, C7-C12aralkyl, C7-C12geterotsiklicheskikh,7-C12aralkyl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, aryl, heterocyclyl; NO2, CN, COOH, optionally substituted Altamarena group, optionally substituted carbamide group, optionally substituted carboxy1-6alkyl group;

R5represents an oxygen atom or a carbon atom included in optional condensed, optionally substituted and optionally containing one or more heteroatoms selected from the group nitrogen, oxygen, sulfur, 4-7-membered cycle; the term includes substituted substituents selected from the group of halogen atom, hydroxyl group, substituted hydroxyl group, substituted amino group, carboxialkilnuyu group, substituted carboxialkilnuyu group, carnemolla group, substituted carnemolla group or inert Deputy, which means low or directionspanel optionally substituted radical, such as1-C7alkyl, C2-C7alkenyl,2-C7quinil,2-C7alkoxy, C7-C12aralkyl, C7-C12geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, aryl, heterocyclyl,

as inhibitors of caspase-3, which can be used to obtain drugs and experimental (in vitro, in vivo) studies of apoptosis as pharmacological tools.

2. Pharmaceutical composition having the property of inhibiting caspase-3, in the form of tablets, capsules, or injections, placed in FA is matemticas acceptable packaging containing as active substance pharmaceutically effective amount of 1-sulfonyl-1,3-dihydro-1H-indole-2-it General formula (1)according to claim 1.

3. Pharmaceutical composition for treating and preventing various diseases of warm-blooded animals and humans associated with increased activation of apoptosis, in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, containing as active substance pharmaceutically effective amount of 1-sulfonyl-1,3-dihydro-1H-indole-2-it General formula 1 according to claim 1.

4. A method of obtaining a pharmaceutical composition according to claim 2 or 3, which consists in mixing the active substance with an inert filler, diluent and/or solvent, characterized in that the active substance used pharmacologically effective amount of 1-sulfonyl-1,3-dihydro-1H-indole-2-it General formula 1 according to claim 1.

5. A method of treating and preventing various diseases of warm-blooded animals and humans associated with increased activation of apoptosis, by introducing a warm-blooded animal or human pharmaceutical composition according to claim 2 or 3.

6. Substituted 1-sulfonyl-1H-indol-2-ones of General formula 1

in which R1, R2, R3, R4and R5have the above meant what I excluding 1-methylsulphonyl-1H-indole-2,3-dione, 1-benzazolyl-1H-indole-2,3-dione, 5-bromo-1-benzazolyl-1H-indole-2,3-dione, 1-(2-nitrobenzenesulfonyl)-1H-indole-2,3-dione, 1-(toluene-4-sulfonyl)-1H-indole-2,3-dione, 5-methyl-1-(toluene-4-sulfonyl)-1H-indole-2,3-dione, 5-chloro-1-(toluene-4-sulfonyl)-1H-indole-2,3-DIONE, 5-methoxy-1-(toluene-4-sulfonyl)-1-indole-2,3-dione, 5-ethoxy-1-(toluene-4-sulfonyl)-1H-indole-2,3-dione, 1-(4-methoxybenzenesulfonyl)-1H-indole-2,3-dione, 1-(2,4-dimethoxyphenylacetone)-1H-indole-2,3-dione, 1-(3,4-dimethoxyphenylacetone)-1H-indole-2,3-dione, methyl ester 4-[(2,3-dihydro-2,3-dioxo-1H-indol-1-yl]-sulfonyl-3-thiophencarboxylic acid, [2-oxo-1-(toluene-4-sulfonyl)-1,2-dihydroindol-3-ilidene]-acetonitrile, 3-bis-[(4-methoxyphenyl)methylene]-1,3-dihydro-1-[(4-were]-2H-indol-2-it, 1-(phenylsulfonyl)-1,3-dihydro-3-(4-oxo-2-thioxo-5-thiazolidinone)-2H-indol-2-it, 1-[(2,5-dichlorophenyl)sulfonyl]-1,3-dihydro-3-(4-oxo-2-thioxo-5-thiazolidinone)-2H-indol-2-it, 1-[(2,4,5-trichlorophenyl)sulfonyl]-1,3-dihydro-3-(4-oxo-2-thioxo-5-thiazolidinone)-2H-indol-2-it, 1-(phenylsulfonyl)-1,3-dihydro-3-(2,4-dioxo-5-thiazolidinone)-2H-indol-2-it, 1-[(2,5-dichlorophenyl)sulfonyl]-1,3-dihydro-3-(2,4-dioxo-5-thiazolidinone)-2H-indol-2-it, 1-[(2,4,5-trichlorophenyl)sulfonyl]-1,3-dihydro-3-(2,4-dioxo-5-thiazolidinone)-2H-indole-2-it, 3-(2-amino-4-oxo-5(4H)-thiazolidin)-1,3-dihydro-1-[(4-were)sulfonyl]-2H-indol-2-it, 5-chloro-3-(2,4-dioxo-5-t is Solidaridad)-1,3-dihydro-1-[(4-were)sulfonyl]-2H-indol-2-it, 5-chloro-3-(2,4-dioxo-5-thiazolidinone)-1,3-dihydro-1-[(4-nitrophenyl)sulfonyl]-2H-indol-2-he and methyl ester 4-[[3-(2,4-dioxo-5-thiazolidinone)-2,3-dihydro-2-oxo-1H-indol-1-yl]-sulfonyl]-3-thiophencarboxylic acid.

7. Compounds according to claim 6, representing 1-sulfonyl-1H-indole-2,3-diones of General formula 1.1

in which R1, R2, R3and R4have the above values, excluding 1-methylsulphonyl-1H-indole-2,3-dione, 1-benzazolyl-1H-indole-2,3-dione, 5-bromo-1-benzazolyl-1H-indole-2,3-dione, 1-(2-nitro-benzazolyl)-1H-indole-2,3-dione, 1-(toluene-4-sulfonyl)-1H-indole-2,3-dione, 5-methyl-1-(toluene-4-sulfonyl)-1H-indole-2,3-dione, 5-chloro-1-(toluene-4-sulfonyl)-1H-indole-2,3-dione, 5-methoxy-1-(toluene-4-sulfonyl)-1H-indole-2,3-dione, 5-ethoxy-1-(toluene-4-sulfonyl)-1H-indole-2,3-dione, 1-(4-methoxybenzenesulfonyl)-1H-indole-2,3-dione, 1-(2,4-dimethoxyphenylacetone)-1H-indole-2,3-dione, 1-(3,4-dimethoxyphenylacetone)-1H-indole-2,3-dione, methyl ester 4-[(2,3-dihydro-2,3-dioxo-1H-indol-1-yl]-sulfonyl-3-thiophencarboxylic acid.

8. Compounds according to claim 6, representing 1-sulfonyl-3-(4-oxo-thiazolidin-5-ilidene)-1,3-dihydro-1H-indol-2-ones of General formula 1.2

in which R1, R2, R3and R4have the above meaning;

R6represents a hydrogen atom or inert the first Deputy;

X represents a sulfur atom or an oxygen atom, excluding 1-(phenylsulfonyl)-1,3-dihydro-3-(4-oxo-2-thioxo-5-thiazolidinone)-2H-indol-2-it, 1-[(2,5-dichlorophenyl)sulfonyl]-1,3-dihydro-3-(4-oxo-2-thioxo-5-thiazolidinone)-2H-indol-2-it, 1-[(2,4,5-trichlorophenyl)sulfonyl]-1,3-dihydro-3-(4-oxo-2-thioxo-5-thiazolidinone)-2H-indol-2-it, 1-(phenylsulfonyl)-1,3-dihydro-3-(2,4-dioxo-5-thiazolidinone)-2H-indol-2-it, 1-[(2,5-dichlorophenyl)sulfonyl]-1,3-dihydro-3-(2,4-dioxo-5-thiazolidinone)-2H-indol-2-it, 1-[(2,4,5-trichlorophenyl)sulfonyl]-1,3-dihydro-3-(2,4-dioxo-5-thiazolidinone)-2H-indol-2-it, 3-(2-amino-4-oxo-5(4H)-thiazolidin)-1,3-dihydro-1-[(4-were)sulfonyl]-2H-indol-2-it, 5-chloro-3-(2,4-dioxo-5-thiazolidinone)-1,3-dihydro-1-[(4-were)sulfonyl]-2H-indol-2-it, 5-chloro-3-(2,4-dioxo-5-thiazolidinone)-1,3-dihydro-1-[(4-nitrophenyl)sulfonyl]-2H-indol-2-he and methyl ester 4-[[3-(2,4-dioxo-5-thiazolidinone)-2,3-dihydro-2-oxo-1H-indol-1-yl]-sulfonyl]-3-thiophencarboxylic acid.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to methods for treatment of diseases or syndromes associated with metabolism of fatty acids and glucose and to new compounds and their pharmaceutically acceptable salts. Invention relates to applying new compounds and pharmaceutical compositions for treatment of cardiovascular diseases, diabetes mellitus, cancer diseases, acidosis and obesity by inhibition of activity of enzyme malonyl-CoA-decarboxylase. Indicated compounds correspond to formulae (I) and (II) wherein Y, C, R1, R2, R6 and R7 have values given in the invention claim.

EFFECT: valuable medicinal and biochemical properties of azoles.

27 cl, 8 tbl

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to the field of production of new heterocyclic o-dicarbonitriles

The invention relates to a new method for the preparation of 3-substituted cephalosporins of the formula (I):

where R1is a para-nitrobenzyl or allyl, X is a halogen; comprising the stage of: a) cyclization trimethylphosphine the compounds of formula (IIIA):

where R1is a para-nitrobenzyl or allyl, R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl; in a solvent to form compounds of the formula (II):

where R1is a para-nitrobenzyl or allyl; R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl; and (b) interaction of the compounds of the formula (II) with acid

The invention relates to polycyclic, thiazolidin-2 - ildenafil amines and their physiologically acceptable salts and physiologically functional derivatives

The invention relates to a method for producing [1,2,4]triazolo[3,4-b][1,3]benzothiazol-3(2H)-thione of the formula

including fusion [1,2,4]triazolo[3,4-b][1,3]benzothiazole with excess sulfur in for 5-20 minutes at a temperature of 180-200With subsequent isolation of the target product

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to biologically active compounds, in particular, to substituted 5R1,6R2-thiadiazine-2-amines and pharmaceutical compositions comprising thereof that can be used in medicine as potential pharmacologically active substances eliciting the unique combination of properties: expressed anticoagulant activity in combination with capacity to inhibit aggregation of platelets. Effect of these substances differ from preparations used in medicinal practice and they can be used therefore in treatment of such diseases as myocardium infarction, disturbance in cerebral circulation, rejection of transplanted organs and tissues and so on. Indicated compounds correspond to the formula (I):

wherein values of radicals R1, R2 and R3 are given in the invention claim.

EFFECT: valuable medicinal properties of compounds.

4 cl, 2 tbl, 7 dwg, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

The invention relates to organic chemistry, in particular, optionally N-oxidized compounds represented by the formula:

in which R1represents a hydrogen atom, a C1-6alkyl group, phenyl group, optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, or amino group, optionally substituted (i) C1-6alkyl group, or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl; R2is6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy, or 5 - or 6-membered aromatic heterocyclic group containing one sulfur atom or one nitrogen atom; R3represents a phenyl group, optionally substituted by one or two C1-6alkyl groups or C1-6alkoxy; X represents a sulfur atom; Y represents O, S, SO2or NR4where R4represents a hydrogen atom or a C1-6alkyl group; and Z represents a bond, C1-6alkylenes group, optional zameshannuu oxo or C1-6alkyl group

The invention relates to polycyclic, thiazolidin-2 - ildenafil amines and their physiologically acceptable salts and physiologically functional derivatives

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

Up!