1,3-dioxo-2,3-dihydro-1h-pyrrolo[3,4-c]quinolines (variants), pharmaceutical compositions (variants), method for their preparing (variants) and method for treatment (variants)

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines of the general formula (1)

that are effective inhibitors if caspase-3 that can be used for preparing medicinal agents and for experimental (in vitro, in vivo) investigation of apoptosis processes as "pharmacological tools". Also, invention proposes pharmaceutical composition and a method for their preparing and applying. In the general formula (1) radicals R1, R2, R3 and R8 represent independently of one another hydrogen atom, halogen atom, CF3, CN, inert substitute, optionally substituted hydroxyl group, optionally substituted carboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group; R4 represents hydrogen atom, halogen atom, inert substitute, optionally substituted amino-group, substituted hydroxyl group; R5 represents hydrogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; R6 and R7 represent independently of one another hydrogen atom, inert substitute, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; or R6 and R7 in common with nitrogen atom to which they are bound represent optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur, 3-10-membered cycle; or R6 and R7 in common with nitrogen atom to which they are bound represent condensed heterocycle being optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur.

EFFECT: improved preparing method and treatment.

9 cl, 19 sch, 7 tbl, 25 ex

 

This invention relates to novel 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline possessing physiological activity. More specifically, the present invention relates to specific physiological activity of 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline, allowing their use as molecular tools and medicinal substances that selectively inhibit 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 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline is vysokokapit who ate the suppression of apoptosis, implemented through inhibition of cysteine protease - caspase-3, which 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 - division and cell growth must be 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 (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). It has been shown that the course of AIDS and the number of severe diseases ner the Noah system (parkinsonism, Alzheimer's disease) is characterized by increased activation of apoptosis (Hartmann, A.; Hunot S.; Michel, P.; Muriel M.-P.; Vyas, S.; Faucheux Century; Mouatt-Prigent, P.; Turmel 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), (b) 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 of 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 new cardioprotection (Chapman J.; Magee W.; Stukenbrok H.; Beckius G.; Milici, A.; Tracey W.A novel nonpeptidic caspae-3/7 inhibitor, (S)-(+)-5-[1-(2-methoxymethylpyrrolidinyl)-sulfonyl]isatin reduces myocardial ischemic injury. Eur. J. Pharmacol. 2002, 456(1-3), 59-68), neuroprotection (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 (Anseimo D.; Katori M.; M. Kaldas; Hoglen N.; Valentine, 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. J), 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 applicability, th is is due to their poor pharmacokinetic 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 PM) 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-[1-(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)

However, the low selectivity of the 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).

It should be noted that some of 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline described in the scientific and patent literature (table 1) and only a couple of examples refers to the physiological activity of 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline, in particular, reported their cytotoxic activity (Ganjian, I.; Khorshidi, M.; Lalezari, I. Synthesis and cytotoxic activity of 2-dialkylaminoalyl-1,3-dihydropyrrolo[3,4-c]quinoline-1,3-diones and 6-(2-dimethylaminoethyl)-1H-dibenz[c,e]azepine-5,7-dione J.Heterocycl. Chem. 1991, 28 (5), 1173-1175) and antimalarial activity (Campaigne, E.; Hutchinson, J.H. Some N-Substituted 2-Amino-and 2-methylquinoline-3,4-dicarboximides. J. Heterocycl. Chem. 1970, 7, 655-659).

Information about by the activity of 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline in the scientific and patent literature to date has been lacking. As a result of research aimed at finding new biologically active compounds, including selectively suppressing programmed cell death (apoptosis), the inventors have discovered a new gametip ones inhibitors of caspases, namely 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline.

More specifically this invention relates to new and known 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline possessing physiological activity, including specific physiological activity, allowing their use as molecular tools and 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, for example acute ischemic lesions (eg, stroke, myocardial Mika is Yes), neurodegenerative (e.g., Parkinson's disease and Alzheimer's disease), viral diseases (such as hepatitis C and AIDS), as well as cardiac or cerebral ischemia, diabetes, immunodeficiency syndromes, cerebral trauma or stroke, spinal cord injury, organ damage during transplantation, alopecia, aging, sepsis, meningitis, neurodegenerative diseases, down syndrome, muscle atrophy, multiple sclerosis, toxic or infectious lesions of the liver and other

Below are definitions of terms used in the description of the invention: “Combinatorial library” means a collection of compounds 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, agony the tov, antagonists and the like) specific 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, for example, some form of physiological activity. We can say, for example, "new gametip activators of 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 or group that is attached to another moiety or group to scaffold, including, but not limited to the halogen atom, the “inert Deputy”, the nitrogroup, alphagraph, a sulfa group, hydroxyl group, amino group, carboxialkilnuyu group, alkoxycarbonyl group, carnemolla group and others

“Inert Deputy” ("Non-interfering substituent"means low or directionspanel RA is hiccuping, inert to further transformations and the environment, including, but not limited to C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-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 has a value from 1 to 7, n=1, 2. Preferred inert 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 carold” means, accordingly, the group, the radical or scaffold, have a Deputy, including, but not limited to inert Deputy, a halogen atom, a nitro-group, cyano, alphagraph, hydroxyl group, amino group, carboxialkilnuyu group, carboxyl group, carnemolla group. For example: substituted alkyl means alkyl with one or more substituents, such as hydroxyalkyl or methoxycarbonylethyl, amino-methoxycarbonyl-methyl, 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, acetyl-methoxycarbonylmethylene group and others; substituted phenyl means phenyl, which has one or more substituents, such as 2-ethoxycarbonylphenyl, 4-amino-3-ethoxycarbonylphenyl, 3,4-diaminophenyl and other

“Optionally substituted group optionally substituted radical or scaffold” means a group, the radical or scaffold, including groups, radicals or scaffold with deputies and without deputies. For example, the concept of optional substituted amino group includes an unsubstituted amino group and amino group containing any, not inconsistent with chemistry substituents, including, but not limiting what I acylamino group, N,N-dialkylamino, N-acyl-N-aryl-amino, acyl-methoxycarbonylmethyl-amino group and others

“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 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 or 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 are new 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]Hino is ins.

This goal is achieved by the new substituted 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline of General formula 1

or their pharmaceutically acceptable salts, N-oxides or hydrates, in which:

R1, R2and R3is independently selected from: hydrogen atom, halogen atom, CF3, CN, NO2inert substituent selected from the group comprising low - or directionspanel radical C1-C7alkyl, C2-C7alkenyl,2-C7quinil,1-C7alkoxy, C7-C12aralkyl, substituted aralkyl, C7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C2-C12alkoxyalkyl,3-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 has a value from 1 to 7; n=1, 2; optionally substituted hydroxyl group, optionally substituted carboxy-C2-C6alkyl group, optionally zameshano the karbamoilnuyu group, provided that two of R1, R2and R3mean hydrogen;

R4represents: a hydrogen atom, a halogen atom, an inert Deputy, substituted C1-C7alkyl, substituted C2-C7alkenyl, optionally substituted by an amino group or optionally substituted hydroxyl group;

R5represents: a hydrogen atom, an inert Deputy selected from the group comprising low - or directionspanel radical C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl, substituted aralkyl, C7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh, C7-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 has a value from 1 to 7; n=1, 2; optionally substituted hydraxis1-5alkyl, optionally substituted by an amino group, optionally substituted hydroxyl group, Zam is on C 1-C7alkyl, substituted C2-C7alkenyl, substituted C2-C7quinil substituted in the alkyl or aryl fragment With7-C12aralkyl substituted in the alkyl or heterocyclic fragment With7-C12geterotsiklicheskikh substituted in the alkyl or aryl fragment With7-C12alkaryl, substituted C3-C10cycloalkyl, substituted C3-C10cycloalkenyl, substituted phenyl, substituted aryl, substituted heterocyclyl;

R8represents: the group

or

R8means a hydrogen atom, halogen atom, CF3, CN, NO2inert Deputy selected from the group comprising low - or directionspanel radical C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-C12alkoxyalkyl,2-C10alkylsulfonyl,2-C10alkylsulfonyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, who alseny aryl, substituted alkoxy, foralkyl, aryloxyalkyl, heterocyclyl, substituted heterocyclyl and nitroalkyl; where m has a value from 1 to 7, n=1, 2; optionally substituted hydroxyl group, optionally substituted carboxy1-6alkyl group, optionally substituted karbamoilnuyu group;

R6and R7independently from each other represent: a hydrogen atom, an inert Deputy, optionally substituted amino1-7alkyl, optionally substituted by an amino group, optionally substituted hydroxyl group;

or

R6and R7together with the nitrogen atom to which they are attached, represent a 3-10-membered cycle, optionally including additional heteroatom, selected from the group oxygen, nitrogen or sulfur, optionally condensed and optionally substituted;

ex: N-oxide 2-methyl or 2-phenyl)-3,4-chinainternational; 2-(2-dimethyl (or diethyl)aminoethyl)or 2-(3-dimethylaminopropyl)-4-methyl-1H-pyrrolo[3,4-C]quinoline-1,3(2H)-dione and 8-bromo-2-(2-dimethyl (or diethyl)aminoethyl)or 8-bromo-2-(3-dimethylaminopropyl)-4-methyl-1H-pyrrolo[3,4-C]quinoline-1,3(2H)-diones and connection 1, in which both R1=R2=R3=R8=R5=H, a R4=N or CH3; connection 1, in which both R1=R2=R3=R8=N, and R4=CH3, 2-(3,4-dichlorophenyl)-vinyl, N 2, N(O)CH3and R5=2-(dibutylamino)ethyl, 2-pyrrolidin-1-yl-ethyl, 2-piperidine-1-yl-ethyl; compound 1, in which one of R1-R3=H, CL, Br, and the other two are H, R8=Cl, Br, NO2, R4=CH3, ADHD2, phenyl, R5=N, CH3; connection 1, in which at the same time two of R1-R3mean hydrogen and one of R1-R3and R8are the same or different hydrogen atom, halogen atom, CF3, CN, IT, alkyl, cycloalkyl, alkoxy, alkylthio, R4=H, alkyl, phenyl; R5=H, alkyl, cycloalkyl, alkoxy, cycloalkane, benzyl, phenyl, 2-(1-methylpyrrole-2-yl)ethyl, 2-morpholine-4-yl-ethyl, 2-(4-perbenzoate)-ethyl; compound 1, in which both R1=N, R8=substituted Altamarena group, R4=CH3, R5=inert Deputy; R1-R3is hydrogen, R4still, R5- p-tolyl, p-methoxyphenyl, phenyl, R8is hydrogen, chlorine, bromine, methyl, nitro; R1=R2=R3=R5=H, a R4- aminocarbonyl group.

The aim of the present invention is to provide a new farmatsevticheskii composition having biological activity, intended for the treatment and prevention of the development of various human and animal diseases.

This goal is achieved by a pharmaceutical composition in the form of the e pills, capsules, or injections, placed in pharmaceutically acceptable packing with by (caspase) activity intended for the treatment and prevention of the development of various human and animal diseases, which contains as active substance pharmaceutically effective amount of 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline of General formula 1 or their pharmaceutically acceptable salts, N-oxides or hydrates.

The aim of the present invention is to provide a method of obtaining a new pharmaceutical composition having biological activity, including by having (caspase) activity intended for the treatment and prevention of the development of various human and animal diseases associated with increased activation of apoptosis.

This goal is achieved by a method of obtaining a pharmaceutical composition by mixing an inert diluent and/or excipient and active substance as an active substance used 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline of General formula 1 or its pharmaceutically acceptable salt, N-oxide or hydrate.

The aim of the present invention is to provide a new pharmaceutical composition having by (caspase) activity intended for the treatment and prevention of the development of various diseases alive is the shaft and the people, associated with increased activation of apoptosis.

This goal is achieved by a pharmaceutical composition in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing with by (caspase) activity intended for the treatment and prevention of the development of various human and animal diseases associated with increased activation of apoptosis, containing as active substance pharmaceutically effective amount of 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline of General formula 1

or its pharmaceutically acceptable salt, N-oxide or hydrate, in which:

R1, R2and R3is independently selected from: hydrogen atom, halogen atom, CF3, CN, NO2inert substituent selected from the group comprising low - or directionspanel radical C1-C7alkyl, C2-C7alkenyl, C2-C7quinil, C1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-C12alkoxyalkyl,2-C10alkylsulfonyl,2-C10Ala is sulfonyl, (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 has a value from 1 to 7; n=1, 2; optionally substituted hydroxyl group, optionally substituted carboxy-C2-C6alkyl group, optionally substituted karbamoilnuyu group, provided that two of R1, R2and R3mean hydrogen;

R4represents: a hydrogen atom, a halogen atom, an inert Deputy, substituted C1-C7alkyl, substituted C2-C7alkenyl, optionally substituted by an amino group or optionally substituted hydroxyl group;

R5represents: a hydrogen atom, an inert Deputy selected from the group comprising low - or directionspanel radical C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl, substituted aralkyl, C7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh, C7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-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 has a value from 1 to 7; n=1, 2; optionally substituted hydraxis1-5alkyl, optionally substituted by an amino group, optionally substituted hydroxyl group, substituted C1-C7alkyl, substituted C2-C7alkenyl, substituted C2-C7quinil substituted in the alkyl or aryl fragment With7-C12aralkyl substituted in the alkyl or heterocyclic fragment With7-C12geterotsiklicheskikh substituted in the alkyl or aryl fragment With7-C12alkaryl, substituted C3-C10cycloalkyl, substituted C3-C10cycloalkenyl, substituted phenyl, substituted aryl, substituted heterocyclyl;

R8represents: the group

or

R8means a hydrogen atom, halogen atom, CF3, CN, NO2inert Deputy selected from the group comprising low - or directionspanel radical C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl, semese the hydrated aralkyl, With7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh, C7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C2-C12alkoxyalkyl, C2-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 has a value from 1 to 7; n=1, 2; optionally substituted hydroxyl group, optionally substituted carboxy1-6alkyl group, optionally substituted karbamoilnuyu group;

R6and R7independently from each other represent: a hydrogen atom, an inert Deputy, optionally substituted amino1-7alkyl, optionally substituted by an amino group, optionally substituted hydroxyl group;

or

R6and R7together with the nitrogen atom to which they are attached, represent a 3-10-membered cycle, optionally including additional heteroatom, selected from the group oxygen, nitrogen or sulfur, optionally condensed and optionally substituted.

The aim of the present invention is to provide a method of obtaining new is farmacevticheskoi composition, possessing biological activity, including by having (caspase) activity intended for the treatment and prevention of the development of various human and animal diseases associated with increased activation of apoptosis.

This goal is achieved by a method of obtaining a pharmaceutical composition by using as the active substance 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline of General formula 1 or its pharmaceutically acceptable salt, N-oxide or hydrate.

The aim of the present invention is to provide a method of treatment or prevention of diseases or conditions in animals and humans associated with increased activation of apoptosis.

This goal is achieved by a method for the treatment or prevention of diseases or conditions in animals and humans associated with increased activation of apoptosis, which is the appointment of patients in need of treatment, an effective amount of pharmaceutical composition containing as active substance 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline of General formula 1 or its pharmaceutically acceptable salt, N-oxide or hydrate.

The aim of the present invention is to provide a method of treatment or prevention of diseases or conditions in animals and humans, the pathogenesis of which involves caspase.

Set goals the ü is achieved by a method for the treatment or prevention of diseases or conditions in animals and humans, in the pathogenesis involving caspase, which is the appointment of patients in need of treatment, an effective amount of pharmaceutical composition containing as active substance 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline of General formula 1 or its pharmaceutically acceptable salt, N-oxide or hydrate.

According to the invention is a method of treatment or prevention of diseases or conditions in animals and humans, the pathogenesis of which involves caspase preferably used for the treatment or prophylaxis of the following diseases or conditions: cardiac or cerebral ischemia; diabetes; immunodeficiency syndromes, including AIDS, cerebral trauma or stroke; spinal cord injury; damage to organs in transplantation; alopecia; aging; sepsis; meningitis; neurodegenerative disease; down syndrome; muscle atrophy; multiple sclerosis; toxic or infectious liver disease; Alzheimer's disease; Parkinson's disease.

The aim of the present invention is the use of “pharmacological tools of caspase inhibitors intended for experimental (in vitro, in vivo) studies of the processes of apoptosis.

This goal is achieved by the use as pharmacological tools of caspase inhibitors, which are intended for experimental in vitro, in vivo studies of apoptosis 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline General formula 1:

or its pharmaceutically acceptable salt, N-oxide or hydrate, in which:

R1, R2and R3is independently selected from: hydrogen atom, halogen atom, CF3, CN, NO2inert substituent selected from the group comprising low - or directionspanel radical C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh,7-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 has a value from 1 to 7; n=1, 2; optionally substituted hydroxyl group, optionally substituted carboxy-C2-C6alkyl group, optionally substituted karbamoilnuyu group, the ri condition, that two of R1, R2and R3mean hydrogen;

R4represents: a hydrogen atom, a halogen atom, an inert Deputy, substituted C1-C7alkyl, substituted C2-C7alkenyl, optionally substituted by an amino group or optionally substituted hydroxyl group;

R5represents: a hydrogen atom, an inert Deputy selected from the group comprising low - or directionspanel radical C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh, C7-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 has a value from 1 to 7; n=1, 2; optionally substituted hydraxis1-5alkyl, optionally substituted by an amino group, optionally substituted hydroxyl group, substituted C -C7alkyl, substituted C2-C7alkenyl, substituted C2-C7quinil substituted in the alkyl or aryl fragment With7-C12aralkyl substituted in the alkyl or heterocyclic fragment With7-C12geterotsiklicheskikh substituted in the alkyl or aryl fragment With7-C12alkaryl, substituted C3-C10cycloalkyl, substituted C3-C10cycloalkenyl, substituted phenyl, substituted aryl, substituted heterocyclyl;

R8represents: the group

or

R8means a hydrogen atom, halogen atom, CF3, CN, NO2inert Deputy selected from the group comprising low - or directionspanel radical C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh, C7-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, semese the hydrated aryl, substituted alkoxy, foralkyl, aryloxyalkyl, heterocyclyl, substituted heterocyclyl and nitroalkyl; where m has a value from 1 to 7, n=1, 2; optionally substituted hydroxyl group, optionally substituted carboxy1-6alkyl group, optionally substituted karbamoilnuyu group;

R6and R7independently from each other represent: a hydrogen atom, an inert Deputy, optionally substituted amino1-7alkyl, optionally substituted by an amino group, optionally substituted hydroxyl group;

or

R6and R7together with the nitrogen atom to which they are attached, represent a 3-10-membered cycle, optionally including additional heteroatom, selected from the group oxygen, nitrogen or sulfur, optionally condensed and optionally substituted;

or R8represents: a hydrogen atom, halogen atom, CF3, CN, NO2inert Deputy, optionally substituted hydroxyl group, optionally substituted carboxy1-6alkyl group, optionally substituted karbamoilnuyu group.

1,3-dioxo-2,3-Dihydro-1H-pyrrolo[3,4-C]quinoline of General formula 1 are as in schemes 1 and 2:

Methods of obtaining a quinoline-3,4-dicarboxylic acid 4, their anhydrides, 5 and imides 2,3-dihydro-1,3-dioxo-1H-pyrrolo[3,4-C]khinolinov described in patents (Shapiro, H.S. Pyrrolo[3,4-c]quinoline compounds and pharmaceutical compositions, metods for their use and preparation. Pat. USA 4268513, 1981. Ivashchenko, A.V.; Kobak, V.V.; grip, A.V.; Il'in, A.P.; Kravchenko, V.V.; Cherkasenko. 6-Sulfamoylbenzoic-4-carboxylic acids and their derivatives, method for their production and combinatorial library. Application for patent of Russia 2003106182, 2003) and article (Ried, W.; Weidemann, P. Chem. Ber. 1971, 104, 3341-3349. Ganjian, I.; Khorshidi, M.; Lalezari, I.).

Methods of obtaining a quinoline-3,4-dicarboxylic acid 7, their anhydrides, 8 and 1,3-dioxo -2,3-dihydro-1H-pyrrolo[3,4-C]quinoline 1 described in clauses (Rooy et al. J. Chem. Soc. (C) 1969, 1886-1891. Brown, R.F.C.; Coulston, K.J.; Eastwood, F.W.; Moffat, M.R. Synthesis of indeno[1,2-b]indole by flash vacuum pyrolysis of 2-phenylquinoline-3,4-dicarboxylic anhydride. Tetrahedron Lett. 1991, 32(6), 801-802; Brown, R.F.C.; Coulston, K.J.; Eastwood, F.W.; Moffat, M.R. Pyrolysis of quinoline-3,4-dicarboxylic anhydrides bearing 2-phenyl, 2-benzyl, and 2-o-tolyl substituents: formation of products of carbine insertion and addition. Tetrahedron 1992, 48(36), 7763-7774) and patents (Shaw, K.; Yuan, J. Preparation of pyrroloquinolinones as GABA brain receptor ligands. Pat. USA 5243049,1993; Shaw, K.; Yuan, J. Certain pyrroloquinolinones; a new class of GABA brain receptor ligands. 5604235, 1997), and 2-amino-3,4-dicarboxylic acid 9 and 2,3-dihydro-1,3-dioxo-1H-pyrrolo[3,4-C]quinoline 1 described in clauses (Compaigne, E.; Hutchinson, J.H. N-substituted 2-amino - and 2-methylquinoline-3,4-dicarboximides. J. Heterocycl. Chem. 1970, 7 (3), 655-659. Ganjian, I.; Khorshidi, M.; Lalezari, I. Synthesis and cytotoxic activity of 2-dialkylaminoalkyl-1,3-dihydropyrrolo[3,4-c]quinoline-1,3-diones and 6-(2-dimethylaminoethyl)-1H-dibenz[c,e]azepine-5,7-dione. J. Heterocycl. Chem. 1991, 28(5), 1173-1175).

Methods of obtaining pharmaceutical compositions is besvesti and depending on the finished forms (tablets, capsules or injection) include a mixture of diluents and/or excipients with the active substance.

Antiproteaznaya activity of the compounds of formula 1 were determined by 9 the serine proteases (Caspase 1-9), which are involved in the regulation of programmed cell death (apoptosis) and inflammatory processes. The Caspase activity was determined by the rate of cleavage of the corresponding substrate, representing a peptide specific for each used caspase sequence of amino acids attached fluorescent group (methylcoumarin). The method described in [H.R. Stennicke and Salvesen G.S. Biochemical Characteristics of Caspase-3, -6, -7 and-8. The Journal of Biological Chemistry, 1997, 272(41) 25719-25723].

Anti-apoptotic activity of the compounds of formula 1 were determined in cell line T obtained from ATS (American Type Culture Collection) no method described in [Burchiel SW, Edwards BS, Kuckuck FW, Lauer FT, Prossnitz ER, Ransom JT, Sklar LA. Analysis of free intracellular calcium by flow cytometry: multiparameter and pharmacologic applications. Methods, 2000, 21(3), 221-230].

Prophylactic treatment of apoptosis of brain and yolk SAC Zebra-fish (zebrafish) were carried out according to the method described in [Kimmel, C.B. Patterning the brain of the zebrafish embryo. Annu Rev Neurosci. 1993, 16, 707-732].

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

Examples 1-10 (Table 2-6) describe the acquisition of the initial reagents;

examples 11-19 (table 7) describe the receipt ,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline of General formula 1;

examples 20-22 describe how to obtain pharmaceutical compositions;

examples 23 and 24 describe the biological activity of 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline of General formula 1;

example 25 describes the prophylactic treatment of apoptosis of brain and yolk SAC Zebra-fish (zebrafish) a pharmaceutical composition comprising 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline of formula 1.

The structure of the obtained compounds was confirmed by the data of chemical, chromatographic and spectral analysis. Liquid-phase parallel sites new compounds and combinatorial libraries was carried out using a special synths "CombiSyn-012-3000" [M Bar, A. Ivashchenko, Patent of Russia 2180609, 2002; PCT WO 02/087740 Al, 2002] and equipment [Technology Platform., In Custom Chemistry; Chemical Diversity Labs, Inc.; San Diego, CA, 2002; p. 5, http://www.chemdiv.com.].

All solvents and reagents were obtained from commercial sources, such as ACROS (Acros) (Belgium), Sigma-Aldrich (Sigma-Aldrich) (United States), Lancaster (Lancaster) (UK) and Chemdiv (ChemDiv) (USA). The melting point (TPL) were obtained on the instrument company Buchi (Buchi) (Switzerland) model-520.1H and13The NMR spectra were obtained on a spectrometer Gemini-300 (300 and 75 MHz, respectively) firm Varian (Varian) (USA) in CDCl3or dimethyl sulfoxide-d6. Chemical shifts are given in the scale δ (ppm). Internal standard tetrameth the silane.

The content of the basic substance was controlled by HPLC on the device Shimadzu (Shimadzu) 10-AV (column Luna C18, Phenomenex, 25 cm × 4.6 mm, UV detection at 215 and 254 nm) and LC-MS (VGH-MS) instrument Applied Biosystems (Shimadzu 10-AV LC, automatic sample Gilson-215, mass spectrometer API 150EX, UV (215 and 254 nm) and ELS detectors, column Luna C18, Phenomenex, 5 cm × 2 mm).

Analytical TLC was performed on silica gel on aluminium plates Silufol UV254(5 cm × 15 cm) (Kavalier, Czech Republic) or on glass slides with a 0.25-mm layer of silica gel 60 F254(Merck, Germany). Visualization was accomplished with UV light at a wavelength of 254 nm. For chromatographic purification of used silica gel 5-40 μm (Chemapol, Czech Republic) and 63 ám (EM Science, USA). In accordance with these LC/MS all the synthesized compounds had a basic substance content above 95% (unless otherwise specified).

Example 1. A common way to obtain 3,3-dichloro-2-oxo-2,3-dihydro-1H-indol-5-sulfonyl chloride 11 (scheme 3).

Gradually add the isatin 2: R2=N (0.1 mole) chlorosulfonic acid (50 ml), maintaining the temperature of 55-60°C. the Reaction mass was kept at 60° 2-3 hours, cooled to room temperature and poured with stirring on ice. The precipitate was filtered, washed with water, dried in vacuum and recrystallized from dichloromethane, and then from a mixture of tol is ol-petroleum ether (8: 2). Received 3,3-dichloro-2-oxo-2,3-dihydro-1H-indol-5-sulfonyl chlorides 11, with the release of 40-75%, containing according to LC MS more than 95% of the basic substance (table 2).

Example 2. A common way to obtain amides 3,3-dichloro-2-oxo-2,3-dihydro-1H-indole-5-sulphonic acids 12: (scheme 4).

in which R1has the above value, a R6R7N represents optionally substituted by an amino group.

To a solution of 3,3-dichloro-2-oxo-2,3-dihydro-1H-indol-5-sulfonyl chloride 11 (10 mmol) in 15 ml of anhydrous tetrahydrofuran (THF) was added under stirring consistently amine 10 (10.5 mmol)and then triethylamine (1.0 ml, 10.5 mmol). The reaction mass was stirred at room temperature for 8-12 h, the precipitate was filtered, and the filtrate was evaporated in vacuum. The product was chromatographically on silica gel with a mixture of dichloromethane with THF. Received amides 3,3-dichloro-2-oxo-2,3-dihydro-1H-indole-5-sulphonic acids with 12 output 54-87%, containing according to LC MS more than 95% of the basic substance (table 3).

Example 3. A common way to obtain amides of 2,3-dioxo-2,3-dihydro-1H-indole-5-sulphonic acids 2.1 (scheme 5).

in which R1has the above value, a R6R7N represents optionally substituted by an amino group.

Mixed 8-12 hours at 50-70°With the sulphonamide 12 (5 mmol) and Na2CO3 (1.26 g, 12 mmol) in 20 ml of water. The reaction mass was evaporated in vacuum to dryness. The residue was dissolved in 30 ml of Asón, added a few drops of concentrated hydrochloric acid and boiled water for 1-3 hours, then evaporated in vacuum to dryness. From the solids were extracted the product with ethyl acetate, the extract was filtered and evaporated in vacuum. The residue was chromatographically on silica gel with a mixture of dichloromethane-THF. Received amides of 2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonic 2.1, with access 46-82%, containing according to LC MS more than 95% of the basic substance (table 4).

Example 4. A common way to obtain 6-sulfamoylbenzoic-3,4-dicarboxylic acids of the formula 4 (scheme 6).

in which R1, R3and R6R7N have the above meaning.

Dissolve 3,3-dichloro-2-oxo-2,3-dihydro-1H-indol-5-sulfonyl chloride 12 (0.02 mol) in dioxane (60 ml). The resulting solution was cooled to 5°and with stirring was added the amine 10 (0.02 mol), N-methylmorpholine (2.2 ml). The reaction mixture is stirred for 1 hour, after which the reaction mixture is added in small portions of ice water, trying to keep the product was allocated in the form of solids, and did not give an emulsion. Precipitate the zatin 2.1 is filtered off, washed on the filter with water, dissolved in dioxane (60 ml) and added dropwise with vigorous stirring 5N NaOH solution (120 ml). The reaction is th mixture becomes intense red-brown staining, but after 10-15 min of mixing becomes brownish-yellow. To the reaction mixture are added methylene-active compound 3 (0.3 mol) and stirred for 10-12 hours. The reaction mixture under cooling and vigorous stirring acidified with 2N hydrochloric acid to pH=2-3, stirred for 2 hours, then incubated for 10-12 hours at 5°C. the Precipitate is filtered off, washed on the filter repeatedly with water, then washed with isopropanol (3 times) and dried in vacuum. Receive, with the release of 45-85%, 6-sulfamoyl-quinoline-3,4-dicarboxylic acid of formula 4, containing according to LC MS more than 95% of the basic substance (table 5).

Example 5. A common way of obtaining 6-sulfo-quinoline-3,4-dicarboxylic acids of the formula 4 (scheme 7).

in which R1, R3and R6R7N have the above meaning.

To a solution of NaOH (12 g, 0.3 mol) in water (80 ml) is gradually added at room temperature and stirring 3,3-dichloro-2-oxo-2,3-dihydro-1H-indol-5-sulfonyl chloride 12 (0.03 mol), continue to stir for 1.5-2 hours, then add methylene-active compound of 3 (0.09 mol). The resulting reaction mass was stirred at room temperature for 8-12 hours, acidified while cooling, concentrated hydrochloric acid to pH=5 and 1.5-2 hours the precipitate is filtered off. Receive, with the release of 55-87%, 6-sulfo-quinoline-3,4-dicar is about acid of formula 4, containing data LC MS more than 95% of the basic substance (table 5).

Example 6. A common way of obtaining a quinoline-3,4-dicarboxylic acids of the formula 4 (scheme 8).

in which R1, R2and R3have the above value.

To a suspension of isatin 2 (45 mmol) in water (100 ml) was added to the nitrogen atmosphere of KOH (30 g). The reaction mass is stirred at room temperature until complete dissolution of isatin 2, then add methylene-active compound 3 (126 mmol) and stirred for another 8-12 hours. To the reaction mass gradually added while cooling, concentrated hydrochloric acid (40 ml) to pH=5. The precipitate is filtered off and dried in vacuum at 70°C. Receive, with the release of 60-87%, acid 4, containing according to LC-MS, more than 95% of the basic substance (table 5).

Example 7. A common way of obtaining 6-sulfo-quinoline-3,4-dicarboxylic acids of the formula 4 (scheme 9).

in which R1and R3have the above value.

To a mixture of sodium salt of 2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonic 2 (45 mmol) or sodium in water (110 ml) was added LiOH × 1H2O (22,0 g, 536 mmol) under stirring in nitrogen atmosphere. To the resulting solution was added at room temperature methylene-active compound of 3 (126 mmol). The reaction mass is maintained at AC is shivani and room temperature for 12-24 hours, acidified under stirring with concentrated hydrochloric acid to pH=5, the precipitate is filtered off, washed with water and dried in vacuum. Get 6 sulfo-quinoline-3,4-dicarboxylic acid 4, with the release of 80-95%, containing according to LC MS more than 95% of the basic substance (table 5).

Example 8. A common way to obtain 1,3-dioxo-1,3-dihydrofuro[3,4-C]quinoline 5 (scheme 10).

in which R1, R2and R3have the above value.

Suspension 3.66 g (10 mmol) quinoline-3,4-dicarboxylic acid 4 in acetic anhydride (25 ml) is heated under stirring on an oil bath at 120°until complete dissolution of the acid, and then additionally heated with stirring 30 minutes, the Reaction mixture was cooled for 12 hours at 4°C. the precipitation 1,3-dioxo-1,3-dihydrofuro[3,4-C]quinoline 5 filtered off, washed with a small amount of acetic anhydride and anhydrous ether. An additional quantity of 1,3-dioxo-1,3-dihydrofuro[3,4-C]quinoline 5 is obtained from the filtrate, and the filtrate was diluted 3 times with ether, maintained at the cooling 40-60 hours at 4°S, sediment 5 filtered and washed with ether. Receive 1,3-dioxo-1,3-dihydrofuro[3,4-C]quinoline 5, with a total output of 78-90% (table 6).

Example 9. A common way to obtain 1,3-dioxo-1,3-dihydro-furo[3,4-C]quinoline-6-sulfonates pyridinium 5 (scheme 11).

in which R1and R3have the above value.

To a suspension of 6-sulfoxidation-3,4-dicarboxylic acid of formula 4 (30 mmol) in pyridine (30 ml), was added acetic anhydride (50 ml) and stirred the reaction mass for 3 hours at 50-60°C. the Product is filtered, washed on the filter with acetone or ether and dried in vacuum. Receive, with the release of 71-95%, pyridinium 1,3-dioxo-1,3-dihydrofuro[3,4-C]quinoline-6-sulfonates 5 (table 6).

Example 10. Pyridine 1,3-dioxo-4-phenyl-1,3-dihydrofuro[3,4-C]quinoline-8-sulfonate 5(8) (scheme 12).

It heated up to 80°With a solution of 6.23 g (0.025 mol) of sodium salt of isatin-5-sulfonic 2 in 60 ml of 5N NaOH solution was added with stirring 9.6 g (0.05 mol) of ethyl benzoylacetate 3. The mixture is stirred at this temperature for 4 hours, cooled and intensivnom stirring, acidified with 2N Hcl to pH=2-3 and leave in the refrigerator over night. The precipitate is filtered off, washed thoroughly with chilled 2N Hcl, cold water, isopropanol, carefully dried, get 8.26 g (88%) pyridinium salts 2-phenyl-6-sulfo-3,4-hinolincarbonova acid 4(12) (LC / MS m/z 374 (M+1)), which without further purification suspended in 100 ml of acetic anhydride to the mixture are added 20 ml of anhydrous pyridine. The resulting mixture was heated under stirring at 80°to dissolve the precipitate, and then advanced, 3 hours. The reaction mixture is cooled, the precipitate is filtered off, washed on the filter with acetic anhydride, anhydrous ether, obtain 6.1 g (56%) pyridine 1,3-dioxo-4-phenyl-1,3-dihydrofuro[3,4-C]quinoline-8-sulfonate 5(8) (table 6). LC-MS (solution in methanol), m/z: 388(M+1), which corresponds to the methyl ether of 2-phenyl-6-sulfo-3,4-hinolincarbonova acid.

Example 11. Parallel synthesis of amides 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline 1 (scheme 1).

A. Parallel synthesis of quinoline-3,4-dicarboxylic acid 4.

Parallel synthesis of quinoline-3,4-dicarboxylic 4 was performed in the synthesizer "CombiSyn-012-3000". In each of the 12 reactors synthesizer upload 0.97 g (10.21 mmol) of KOH in a mixture of 15 ml of water and 10 ml of ethanol, successively added under stirring at room temperature for 5.11 mmol of the corresponding isatin 2 and 6.13 mol methylene-active carbonyl compounds 3, pre-dissolved in 5 ml of ethanol. The reaction mixture is boiled for 5-18 hours until the disappearance of the original isatin 2. Control is carried out using thin-layer chromatography (TLC) on silica gel, as additionally separated by using a mixture of chloroform with ethanol in a volume ratio of 19:1. For TLC control 0.1 ml of the reaction mixture is dissolved in 1 ml of water. Obtained in each reactor, the solutions are neutralized with 5% hydrochloric acid to pH=3 and extracted with 0.25 ml of ethyl acetate. Organic SL is separated and chromatographic on the plates “Silufol UV 254” firm Kavalier (Czech Republic). After the process of the reaction mixtures is distilled off in vacuum, the alcohol, the remains of filtered and evaporated to dryness. The resulting residual was dissolved in minimum amount of water and add 10% hydrochloric acid to pH=2-3. The amount of precipitation is filtered off and dried in vacuo over calcium chloride. The resulting crystalline products extracted with ethyl acetate, chloroform or methylene chloride, the extracts are dried with anhydrous sodium sulfate, filtered and evaporated in vacuum. Remains is recrystallized from a suitable solvent. Get a quinoline-3,4-dicarboxylic acid 4, a crystalline substance, soluble in ethyl acetate, chloroform, methylene chloride, sparingly soluble in ethanol and acetone, slightly soluble in ether and insoluble in hexane (table 5).

B. Parallel synthesis of 1,3-dihydrofuro[3,4-C]quinoline-1,3-diones 5. Parallel synthesis of 1,3-dihydrofuro[3,4-C]quinoline-1,3-diones 5 spend synthesizer "CombiSyn-012-3000". In each of the 12 reactors synthesizer upload 3.43 mmol dicarboxylic acid 4 and 15 ml of acetic anhydride. The reaction mass is stirred until complete dissolution at 100°C. the resulting solution is cooled to 0°C and maintained at this temperature for 3-4 hours. The amount of precipitation is filtered off, washed on the filter with ether and hexane and dried in HAC the mind at 50-60° C. Get 5, with the release of 50-80%, which without additional purification is used to produce amides of 2,3-dihydro-1,3-dioxo-1H-pyrrolo[3,4-C]quinoline 1.

C. Parallel synthesis of amides of 2,3-dihydro-1,3-dioxo-1H-pyrrolo[3,4-C]quinoline 1. Parallel synthesis of combinatorial libraries were performed with synthesizers "CombiSyn-012-3000". In each of the 12 reactors synthesizer download the appropriate 1,3-dihydrofuro[3,4-C]quinoline-1,3-diones 5, one of the amines 6 and triethylamine in a molar ratio of 1:1:0.1 To 1 g 5 using 20 ml of toluene. The reaction mass is stirred at boiling of the reaction mass 20-48 hours before the end of the reaction. A control reaction carried out using LC-MS and/or TLC (silica gel, chloroform : methanol=19:1). After completion of the reaction, the toluene is distilled off in vacuum to dryness, the residues in each reactor synthesizer add methylene chloride, stirred and filtered precipitation. The three filtrates are washed with 3% aqueous sodium hydroxide solution, water, 10% hydrochloric acid and again with water. Dried with anhydrous sodium sulfate, filtered, the solvent is distilled off in vacuum and the remaining chromatographic on silica gel, methylene chloride, and then with a mixture of methylene chloride : methanol=99:1. Receive, with the release of 11-55%, 2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-1,3-dione 1, presented in Table 7.

Example 12. A common way to obtain 1,3-dioxo-1,3-dihydro-2H-pyrrolo[3,4-C]hee is Olya 3 (scheme 12).

in which R1, R2, R3and R4have the above value.

To a solution of 3,4-quinoline-3,4-dicarboxylic acid 4 (2.0 mmol) in NMP (1 ml) was added carbodiimides (4.2 mmol) and stirred until the termination of allocation of CO2. To the mixture was added amine 6 (2.0 mmol) and, if necessary, triethylamine (4.0 mmol). The reaction mass incubated 20 min at 80-100°C, cooled, diluted with water, extracted the reaction product dichloromethane. The extract evaporated and the residue chromatographic on silica gel with a mixture of dichloromethane-THF. Receive, with the release of 35-91%, 1,3-dioxo-1,3-dihydro-2H-pyrrolo[3,4-C]quinoline 1, presented in Table 7.

Example 13. A common way to obtain 1,3-dioxo-1,3-dihydro-2H-pyrrolo[3,4-C]quinoline-8-sulfonates pyridinium 1 (scheme 13).

in which R1, R3and R4have the above value.

Refluxed for 3-5 hours a mixture of the corresponding anhydride 5 (60 mmol) and primary amine 6 (60 mmol) in 50 ml of acetic acid. The reaction mass is evaporated in vacuum, the residue is washed with isopropanol and dried. Receive, with the release of 75-97%, 1,3-dioxo-1,3-dihydro-2H-pyrrolo[3,4-C]quinoline-8-sulfonates pyridinium 1, presented in Table 7.

Example 14. A common way to obtain 8-sulfamoyl-1,3-dioxo-1,3-dihydro-2-pyrrolo[3,4-C]quinoline 1.1 (scheme 14).

in which R1, R3, R4and R6, R7N have the above meaning.

Stirred for 3 hours a mixture of the corresponding 6-sulfamoyl-quinoline-3,4-dicarboxylic acid 4 (0.2 mmol) and CDI (0.44 mmol) in 1 ml NMP. To the mixture was added the appropriate amine 6 (0.2 mmol), stirred for 1 hour at room temperature, then for 2 hours at 80°C. the Reaction mass is then cooled with stirring to room temperature, add 2 ml of water and 1 ml of a saturated solution of NaHCO3and stirred for 30 minutes Precipitated precipitate was separated, washed with saturated solution of NaHCO3three times with water, isopropanol and crystallized from the minimum amount of isopropanol. Get connection 1.1, with the release of 45-92%, are presented in Table 7.

Example 15. A common way to obtain 1,3-dioxo-1,3-dihydro-2H-pyrrolo[3,4-C]quinoline 1 (scheme 15).

To the mixture of anhydride 5 (0.2 mmol) and 1 M solution of amine 6 in N-organic (0.2 ml) is added 1.1 M solution of carbonyldiimidazole in N-organic (0.4 ml). The reaction mass is stirred for 1 hour at room temperature and 2 hours at 80°C, cooled and added with stirring, 2.5 ml of water, then 1 ml of saturated sodium bicarbonate solution. The resulting mixture was stirred for 30 min, the precipitated precipitate is centrifuged, washed nasy the military sodium bicarbonate solution, three times with water and isopropanol. If necessary, the product is crystallized from a minimum amount. Receive, with the release of 25-85%, compound 1, is presented in Table 7.

Example 16. A common way to obtain 8-sulfamoyl-1,3-dioxo-1,3-dihydro-2H-pyrrolo[3,4-C]quinoline 1.1 (scheme 16).

Heated 2 hours at 60-80°With a mixture of 1,3-dioxo-1,3-dihydro-2H-pyrrolo[3,4-C]quinoline-8-sulfonates pyridinium 1 (50 mmol), tetramethylsilane (100 ml) and l3(35 ml). The reaction mass is then cooled to room temperature and poured on ice. The 1.2 product is extracted with methylene chloride. The extract is washed with water, dried with anhydrous sodium sulfate, filtered and evaporated in vacuum. The residue is dissolved in a minimum amount of dimethyl sulfoxide and poured into water. The precipitate is filtered off, washed on the filter with water and dried in leofiles drying. The resulting product, if necessary, is crystallized from a suitable solvent. Receive, with the release of 55-85%, 1,3-dioxo-1,3-dihydro-2H-pyrrolo[3,4-C]quinoline-8-sulfonyl chlorides 1.2. Dissolve sulfonyl chloride 1.2 (10 mmol) in dioxane (2 ml), the resulting solution was added N-methylmorpholine (20 mmol) and amine 10 (11 mmol). The reaction mass is heated at 60°3 hours, add water (3-5 ml), the precipitate was separated and, if necessary, recrystallized or purified flashr what matography on silica gel. Receive, with the release of 35-95%, compounds 1.1, presented in Table 7.

Example 17. 4-Methyl-1,3-dioxo-2-(1,3,5-trimethyl-1H-pyrazole-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-8-carbonitrile 1(452) (scheme 17).

Prepared in an inert atmosphere a mixture of 0.2 g (0.5 mmol) of 8-bromo-4-methyl-2-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1H-pyrrolo[3,4-C]quinoline-1,3(2H)-dione 1(451), 0,039 g (0.6 mmol) of potassium cyanide, 0,044 g (0.5 mmol) of N,N'-dimethylethylenediamine, 9.5 mg (0.05 mmol) CuI and 16 mg (0.1 mmol) KI in 3 ml of dimethoxyethane heated in a sealed the test tube in a microwave oven (300 W) at 190°C for 20 minutes, the Reaction mixture was poured into 5% Hcl solution, extracted twice with chloroform, the aqueous layer was washed with 5% Hcl solution, water, dried over Na2SO4and evaporated. Target product 1(452), obtained by separation of the residue preparative TLC (eluent - ethyl acetate, Rf=0.65), followed by crystallization from isopropanol. Get 0,045 g (26%) of nitrile 1(452) (table 7).

Example 18. Pyridine 1,3-dioxo-4-phenyl-2-(1,3,5-trimethyl-1H-pyrazole-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-8-sulfonate 1(453) (scheme 18).

A mixture of 2.78 g (6.4 mmol) of pyridine 1,3-dioxo-4-phenyl-1,3-dihydrofuro[3,4-C]quinoline-8-sulfonate 5(8) and 0.96 g of 1,3,5-1H-pyrazole-4-amine 13 in 20 ml of anhydrous pyridine is heated under stirring at 60°20 min, add 10 ml of acetic angeri is and continue stirring at 70° C for 1.5 hours. The mixture, up to 1/3 of the original volume, evaporated under reduced pressure, treated with ethyl acetate and leave overnight in the refrigerator. The solid is filtered off, washed with ethyl acetate and dried, yielding 3.2 g (92%) 1(453) (table 7).

Example 19. 8-[(3-Morpholino-3-oxopropyl)sulfonyl]-4-phenyl-2-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1H-pyrrolo[3,4-C]quinoline-1,3(2H)-dione 3(458) (scheme 19).

A. 3-[1,3-Dioxo-4-phenyl-2-(1,3,5-trimethyl-1 H-pyrazole-4-yl)-2,3-dihydro-1 H-pyrrolo[3,4-C]quinoline-8-sulfonanilide 1(454). To a mixture of 2.71 g (5 mmol) salt 1(453) and 15 ml of tetramethylsilane was added 0.91 ml (1.53 g, 10 mmol) l3the mixture is heated with stirring for 3.5 hours, poured on to ice, filtered the solid, washed on the filter with ice-cold water, lyophilizer day, get 2.5 g of the target sulfochloride 1(454). LC-MS (solution in a mixture of morpholine-DMSO 5:95), m/z: 532 [M+1] (which corresponds to the appropriate sulfonanilide).

B. 1,3-Dioxo-4-phenyl-2-(1,3,5-trimethyl-1H-pyrazole-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-8-Sultanova acid 14. To a solution of 0.126 g (1 mmol) of Na2SO3in 2 ml of water is added under stirring 0.096 g (0.2 mmol) of sulfochloride 1(454), then immediately sprinkled 0.084 g (1 mmol) and NaHCO3. The mixture is stirred for 1 hour, acidified with acetic acid to obtain a solution sulfinol acid 12, which is then used in sleduushem synthesis.

C. Methyl 3-[1,3-dioxo-4-phenyl-2-(1,3,5-trimethyl-1 H-pyrazole-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-8-yl]sulfonylamino 1(455). To a solution of sulfinol acid 14 obtained by the previous method, add 0.1 ml of methyl acrylate, the mixture is intensively stirred at room temperature for a day, acidified with 2N Hcl to pH 1-2 and leave overnight in the refrigerator. Dropped the precipitate was separated by centrifugation, washed three times with 5% sodium bicarbonate solution, three times with water, each time separating the precipitate from the wash water by centrifugation. Get 0.065 g (61%) of the target substance 1(455) (table 7).

, 8-[(3-(Morpholine-4-yl)-3-oxopropyl)sulfonyl]-4-phenyl-2-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1H-pyrrolo[3,4-C]quinoline-1,3(2H)-dione 1(458). To a solution of sulfinol acid 14 add 0.1 ml of acrylic acid, the reaction mixture is stirred for a day, the precipitation of acid 1(457) is separated by centrifugation, washed thoroughly with water, each time separating the precipitate from the wash water by centrifugation, day lyophilizer, to the obtained substance was added 1 ml of SOCl2and 1 drop of DMF, the mixture is stirred for 3 hours, treated with toluene. The solid is separated by centrifugation, then washed three times with toluene, separating the precipitate by centrifugation. Thus obtained substance is treated with a 10% solution of the research in dioxane, the mixture is stirred is 2 hours, then treated with water. Dropped the precipitate was separated by centrifugation, washed repeatedly with water, dried in vacuum. Get 0.036 mg (31%) 1(458) (table 7).

Example 20. A method of obtaining a pharmaceutical composition in tablet form. Mix 800 mg of starch, 800 mg of powdered lactose 200 mg of talc and 500 mg of methyl 2-[4-methyl-8-(4-metilprednisolone)-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-2-yl] acetate 1(101) and pressed 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. Similarly receive pharmaceutical composition in the form of tablets containing as active ingredient other 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline of General formula 1.

Example 21. A method of obtaining a pharmaceutical composition in capsule form. Thoroughly mix of compound 1(101) with lactose powder in a 2:1 ratio. Received poroshkoobraznuju mix pack 300 mg in gelatin capsules of suitable size.

Example 22. A method of obtaining a pharmaceutical composition in the form of injection for intramuscular, intraperitoneal or subcutaneous injection. Mix 500 mg of hydrochloride of compound 1(101), with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injectable water. Received RA the solution is filtered and placed in 1 ml ampoules, which are sealed and sterilized in an autoclave.

Example 23. Be focused library, including the famous antiprotease ligands and 505 2,3-dihydro-1,3-dioxo-1H-pyrrolo[3,4-C]quinoline of formula 1, are presented in Table 7. Antiprotease activity focused libraries determine 9 the serine proteases (Caspase 1-9), which are involved in the regulation of programmed cell death (apoptosis) and inflammatory processes. Recombinant Caspase were purchased from the company Sigma (USA). The Caspase activity was determined by the rate of cleavage of the corresponding substrate, representing a peptide specific for each used cassy the amino acid sequence with attached fluorescent group (methylcoumarin). The method described in [H.R. Stennicke and Salvesen G.S. Biochemical Characteristics of Caspase-3, -6, -7 and-8. The Journal of Biological Chemistry, 1997, 272(41) 25719-25723]. Removal methylcoumarin from the peptide molecules in the proteolytic reaction of the enzyme is accompanied by increased fluorescence intensity measurements which are produced using 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 using optical 96-hole of the blade. Caspase 1, 4, 5, 6, and 9 were purchased from Calbiochem (USA); caspase 2, 7 and 8 in R&D Systems (US) and caspase 3 was obtained from UPSTATE (USA). Fluorescent substrates for each of these caspases were also purchased from the respective companies. The composition of the medium used to carry out the enzymatic reaction was universal for all caspases and included the following components: 25 mm HEPES pH=7.5, 50 mm KCl, 0.1% CHAPS, 5 mm DTT. The original solutions of the test compounds prepared by dissolution in DMSO (dimethyl sulfoxide) to a concentration of 10 mm. The original solutions of the compounds further diluted in distilled water to a concentration of 300 μM working mortar joints). From the working solution of the compounds prepared a series of 3-fold dilutions in 3.3% DMSO/N2About2, 10μl each connection corresponding concentration is placed in the corresponding cells in 96-cell optical card in duplicate and add 90 μl solutions of the respective kinases at a final concentration of 1 U by definition manufacturers kinases. After incubation of the compounds with the enzyme for 10 minutes in each cell type 50 μl of the substrate solution, and measuring the fluorescence produced in the kinetic mode. The rate of change in fluorescence over time is calculated using the software package Prism 4.0 (Graphpad, USA). Inhibition of the reaction rate at each concentration of the compound is calculated by the formula

where (F100- the speed of the PE the work of this caspase in the absence of compounds;

Fi- speed kinase reaction in the presence of this (i) compounds at a given concentration.

From dependency speed kinase reaction at various concentrations of this compound calculate the concentration of compound that causes premaxillae inhibition (IC50for each kinase. Most experienced 2,3-dihydro-1,3-dioxo-1H-pyrrolo[3,4-C]quinoline of formula 1 have shown the ability of inhibition, while depending on their structure values IC50ranged from a few PM to tens μM

Example 24. Be focused library, including the famous antiprotease ligands and 505 2,3-dihydro-1,3-dioxo-1H-pyrrolo[3,4-C]quinoline of formula 1, are presented in Table 7. Anti-apoptotic activity focused libraries to determine cell lines T obtained from ATS (American Type Culture Collection) by the method described in [Burchiel SW, Edwards BS, Kuckuck FW, Lauer FT, Prossnitz ER, Ransom JT, Sklar LA. Analysis of free intracellular calcium by flow cytometry: multiparameter and pharmacologic applications. Methods, 2000, 21(3), 221-230]. Cells grown on microscope slides in complete DMEM medium, and cell morphology evaluated under a microscope Nikon Eclips TS100. Cells treated with 20 nm staurosporine for 24 hours without and in presence of different concentrations of the compounds showed inhibitory activity Caspase-3. Treatment of cells with staurosporine leads to the initiation of glue is full of apoptosis, which is manifested in the rounding of cells. The effect of the compounds expressed in the prevention of apoptosis, was assessed by the proportion of cells that retained fibroblast-like morphology in the presence of this compound, staurosporine. Cytotoxic effect of the compounds of formula 1 were determined using standard methods described in [Thomas P. Misko, Maureen K. Highkin, Amy W. Veenhuizen, Pamela T. Manning, Michael K. Stem, Mark G. Currie, and Daniela Salvemini. Characterization of the Cytoprotective Action of Peroxynitrite Decomposition Catalysts. J. Biol. Chem., 1998, Vol. 273, Issue 25, 15646-15653]. TET cells were seeded in 96-well card at a cell concentration of approximately 2×105cells/cell and grow in an environment Earle's MEM (without phenol red)containing 10% calf serum and 2 mm L-glutamine. Before adding the tested compounds Board is washed in physiological solution Dulbecco with phosphate buffer. Compounds were then added to each well containing 200 μl saline Dulbecco with phosphate buffer and leave on Board a rocking chair for 15 minutes at room temperature. After 15 min incubation, the cells washed once with saline and the cell type 200 μl of 10% Alamar Blue in full Earle''s MEM medium and incubated for 1-2 hours at 37°C in an atmosphere of 5% CO2. 100 μl aliquots are transferred into an optical card, and the fluorescence intensity of the product formed in resolutionstate resazurin (Alamar Blue) measured on a fluorescent reader boards Victo 2V at the wavelength of excitation 545 nm and the wavelength of emission 575 nm. The cells assessed by the ability of mitochondria in living cells to restore resazurin. Toxicity is expressed as the percentage of Alamar Blue signal produced by cells treated with a substance, relative to the signal of untreated control cells.

2,3-dihydro-1,3-dioxo-1H-pyrrolo[3,4-C]quinoline of formula 1 exhibit anti-apoptotic activity in the concentration range from tens of microns to hundreds of microns at the same time, the cytotoxic effect of some active compounds of formula 1 appears at a concentration of 100 μM and above.

Example 25. Prophylactic treatment of apoptosis of brain and yolk SAC Zebra-fish (zebrafish). The use of a pharmaceutical composition comprising 2,3-dihydro-1,3-dioxo-1H-pyrrolo[3,4-C]quinoline of formula 1 for prophylactic treatment, the apoptosis of nerve cells in the brain caused by pathological impact of adverse environmental factors were tested on whole body (Zebra-fish) in accordance with the methodology described in [U.S. Pat. USA 6299858 and 6656449]. 24-hour fry zebrafish were placed in the wells (10 fry in each well) 96-well card and to each well was added or the test substance and inducer of apoptosis or inducer of apoptosis, or nothing (control). After 24 hours incubation in the wells is obavljale dye, staining dead cells. After 8 hours of incubation with the dye fish were subjected to microscopic examination.

Supervisory experience - keeping Zebra-fish in a 1% aqueous solution DMS does not lead to any changes in the field of brain and yolk SAC. Keeping within 24 hours, Zebra-fish in a 1% aqueous solution DMS containing 2,3-dihydro-1,3-dioxo-1H-pyrrolo[3,4-C]quinoline and inducer of apoptosis, does not lead to noticeable changes in the brain and yolk SAC.

Impact proapoptotic substance (inducer of apoptosis) in Zebra-fish cause mass destruction of nerve cells in the brain. Recent evidence about effective preventive treatment induced death of neuronal cells and strain the egg bag by using a pharmaceutical composition comprising 2,3-dihydro-1,3-dioxo-1H-pyrrolo[3,4-C]quinoline.

1. Substituted 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline of General formula 1

or their pharmaceutically acceptable salts, N-oxides or hydrates, in which

R1, R2and R3independently selected from hydrogen atom, halogen atom, CF3, CN, NO2inert substituent selected from the group comprising low - or directionspanel radical With1-C7alkyl, C2-C7alkenyl,2-C7quinil,1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, ALWIL, xylenyl, biphenyl,2-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 has a value from 1 to 7, n has a value from 1 to 2; optionally substituted hydroxyl group, optionally substituted carboxy-C2-C6alkyl group, optionally substituted karbamoilnuyu group, provided that two of R1, R2and R3mean hydrogen;

R4represents a hydrogen atom, a halogen atom, an inert Deputy, substituted C1-C7alkyl, substituted C2-C7alkenyl, optionally substituted by an amino group or optionally substituted hydroxyl group;

R5represents a hydrogen atom, an inert Deputy selected from the group comprising low - or directionspanel radical With1-C7alkyl, C2-C7alkenyl,2-C7quinil,1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl 3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-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 has a value from 1 to 7, n has a value from 1 to 2; optionally substituted hydraxis1-5alkyl, optionally substituted by an amino group, optionally substituted hydroxyl group, substituted C1-C7alkyl, substituted C2-C7alkenyl, substituted C2-C7quinil substituted in the alkyl or aryl fragment With7-C12aralkyl substituted in the alkyl or heterocyclic fragment With7-C12geterotsiklicheskikh substituted in the alkyl or aryl fragment With7-C12alkaryl, substituted C3-C10cycloalkyl, substituted C3-C10cycloalkenyl, substituted phenyl, substituted aryl, substituted heterocyclyl; R8represents a group

or

R8means a hydrogen atom, halogen atom, CF3, CN, NO2inert Deputy selected and the group, incorporating low or directionspanel radical With1-C7alkyl, C2-C7alkenyl,2-C7quinil,1-C7alkoxy, C7-C12aralkyl, substituted aralkyl, C7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh, C7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-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 has a value from 1 to 7, n has a value from 1 to 2; optionally substituted hydroxyl group, optionally substituted With carboxy1-C6alkyl group, optionally substituted karbamoilnuyu group;

R6and R7independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted amino With1-C7alkyl, optionally substituted by an amino group, optionally substituted hydroxyl group

or

R6and R7together with the nitrogen atom to which they are attached, provided the amount 3-10-membered cycle, optional extras including a heteroatom selected from the group oxygen, nitrogen or sulfur, optionally condensed and optionally substituted;

excluding N-oxide 2-methyl or 2-phenyl)-3,4-chinainternational; 2-(2-dimethyl (or diethyl)aminoethyl)or 2-(3-dimethylaminopropyl)-4-methyl-1H-pyrrolo[3,4-C]quinoline-1,3(2H)-dione and 8-bromo-2-(2-dimethyl (or diethyl)aminoethyl)or 8-bromo-2-(3-dimethylaminopropyl)-4-methyl-1H-pyrrolo[3,4-with]quinoline-1,3(2H)-diones and connection 1, in which both R1= R2= R3= R8= R5= H, a R4= N or CH3; connection 1, in which both R1= R2= R3= R8= N, a R4= CH3, 2-(3,4-dichlorophenyl)-vinyl, NH2, NHC(O)CH3and R5= 2-(dibutylamino)ethyl, 2-pyrrolidin-1-yl-ethyl, 2-piperidine-1-yl-ethyl; compound 1, in which one of R1- R3Is h, CL, Br, and the other two are H, R8= Cl, Br, NO2, R4= CH3, ADHD2, phenyl, R5= N, CH3; connection 1, in which at the same time two of R1- R3mean hydrogen and one of R1- R3and R8are the same or different hydrogen atom, halogen atom, CF3, CN, IT, alkyl, cycloalkyl, alkoxy, alkylthio, R4= H, alkyl, phenyl; R5= H, alkyl, cycloalkyl, alkoxy, cycloalkane, benzyl, phenyl, 2-(1-metalpro the-2-yl)ethyl, 2-morpholine-4-yl-ethyl, 2-(4-perbenzoate)-ethyl; compound 1, in which both R1= H, R8= substituted Altamarena group, R4= CH3, R5= inert Deputy; R1- R3is hydrogen, R4still, R5- p-tolyl, p-methoxyphenyl, phenyl, R8is hydrogen, chlorine, bromine, methyl, nitro; R1= R2= R3= R5= H, a R4- aminocarbonyl group.

2. Pharmaceutical composition in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing with by (caspase) activity intended for the treatment and prevention of the development of various human and animal diseases associated with increased activation of apoptosis, containing as active substance pharmaceutically effective amount of the compounds of General formula 1 according to claim 1.

3. A method of obtaining a pharmaceutical composition according to claim 2, mixture of inert diluent and/or excipient and active substance, characterized in that the active substance use compounds of General formula 1 according to claim 1.

4. Pharmaceutical composition in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing with by (caspase) activity designed to treat and prevent the development of various diseases the animals and people associated with increased activation of apoptosis, containing as active substance pharmaceutically effective amount of 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline of General formula 1

or their pharmaceutically acceptable salt, N-oxide or hydrate, in which

R1, R2and R3independently selected from hydrogen atom, halogen atom, CF3, CN, NO2inert substituent selected from the group comprising low - or directionspanel radical With1-C7alkyl, C2-C7alkenyl,2-C7quinil,1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-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 has a value from 1 to 7, n has a value from 1 to 2; optionally substituted hydroxyl gr the PPU, optionally substituted carboxy-C2-C6alkyl group, optionally substituted karbamoilnuyu group, provided that two of R1, R2and R3mean hydrogen;

R4represents a hydrogen atom, a halogen atom, an inert Deputy, substituted C1-C7alkyl, substituted C2-C7alkenyl, optionally substituted by an amino group or optionally substituted hydroxyl group;

R5represents a hydrogen atom, an inert Deputy selected from the group comprising low - or directionspanel radical With1-C7alkyl, C2-C7alkenyl,2-C7quinil,1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-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 has a value from 1 to 7, n is C Uchenie from 1 to 2; optionally substituted hydraxis1-5alkyl, optionally substituted by an amino group, optionally substituted hydroxyl group, substituted C1-C7alkyl, substituted C2-C7alkenyl, substituted C2-C7quinil substituted in the alkyl or aryl fragment With7-C12aralkyl substituted in the alkyl or heterocyclic fragment With7-C12geterotsiklicheskikh substituted in the alkyl or aryl fragment With7-C12alkaryl, substituted C3-C10cycloalkyl, substituted C3-C10cycloalkenyl, substituted phenyl, substituted aryl, substituted heterocyclyl;

R8represents a group

or

R8means a hydrogen atom, halogen atom, CF3, CN, NO2inert Deputy selected from the group comprising low - or directionspanel radical With1-C7alkyl, C2-C7alkenyl,2-C7quinil,1-C7alkoxy, C7-C12aralkyl, substituted aralkyl, C7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh, C7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-C12Ala is cialkis, With2-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 has a value from 1 to 7, n has a value from 1 to 2; optionally substituted hydroxyl group, optionally substituted With carboxy1-C6alkyl group, optionally substituted karbamoilnuyu group;

R6and R7independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted amino With1-C7alkyl, optionally substituted by an amino group, optionally substituted hydroxyl group

or

R6and R7together with the nitrogen atom to which they are attached, represent a 3-10-membered cycle, optionally including additional heteroatom selected from the group oxygen, nitrogen or sulfur, optionally condensed and optionally substituted.

5. A method of obtaining a pharmaceutical composition according to claim 4, mixture of inert diluent and/or excipient and active substance, characterized in that the active substance use compounds of General formula 1 according to claim 4.

6. A method of treating or prophylact the key diseases or conditions in animals and humans, associated with increased activation of apoptosis, which is to assign patients in need of treatment, an effective amount of the pharmaceutical composition according to claim 4.

7. Method for the treatment or prevention of diseases or conditions in animals and humans, the pathogenesis of which involves caspase, which is to assign patients in need of treatment, an effective amount of the pharmaceutical composition according to claim 4.

8. The use of 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline of General formula 1

or its pharmaceutically acceptable salt, N-oxide or hydrate as inhibitron caspases, which can be used to obtain drugs and experimental (in vivo, in vitro) studies of apoptosis as pharmacological tools in which

R1, R2and R3independently selected from hydrogen atom, halogen atom, CF3, CN, NO2inert substituent selected from the group comprising low - or directionspanel radical With1-C7alkyl, C2-C7alkenyl,2-C7quinil,1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh,7-C12alkaryl,3-C0 cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-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 has a value from 1 to 7, n has a value from 1 to 2; optionally substituted hydroxyl group, optionally substituted carboxy-C2-C6alkyl group, optionally substituted karbamoilnuyu group, provided that two of R1, R2and R3mean hydrogen;

R4represents a hydrogen atom, a halogen atom, an inert Deputy, substituted C1-C7alkyl, substituted C2-C7alkenyl, optionally substituted by an amino group or optionally substituted hydroxyl group;

R5represents a hydrogen atom, an inert Deputy selected from the group comprising low - or directionspanel radical With1-C7alkyl, C2-C7alkenyl,2-C7quinil,1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, zamestnavatelsky, With7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-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 has a value from 1 to 7, n has a value from 1 to 2; optionally substituted hydraxis1-5alkyl, optionally substituted by an amino group, optionally substituted hydroxyl group, substituted C1-C7alkyl, substituted C2-C7alkenyl, substituted C2-C7quinil substituted in the alkyl or aryl fragment With7-C12aralkyl substituted in the alkyl or heterocyclic fragment With7-C12geterotsiklicheskikh substituted in the alkyl or aryl fragment With7-C12alkaryl, substituted C3-C10cycloalkyl, substituted C3-C10cycloalkenyl, substituted phenyl, substituted aryl, substituted heterocyclyl;

R8represents a group

or

R8means a hydrogen atom is, halogen atom, CF3, CN, NO2inert Deputy selected from the group comprising low - or directionspanel radical With1-C7alkyl, C2-C7alkenyl,2-C7quinil,1-C7alkoxy, C7-C12aralkyl, substituted aralkyl, C7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh, C7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-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 has a value from 1 to 7, n has a value from 1 to 2; optionally substituted hydroxyl group, optionally substituted carboxy1-C6alkyl group, optionally substituted karbamoilnuyu group;

R6and R7independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted amino1-C7alkyl, optionally substituted by an amino group, optionally substituted hydroxyl group

or

6and R7together with the nitrogen atom to which they are attached, represent a 3-10-membered cycle, optionally including additional heteroatom selected from the group oxygen, nitrogen or sulfur, optionally condensed and optionally substituted;

or R8means a hydrogen atom, halogen atom, CF3, CN, NO2inert Deputy, optionally substituted hydroxyl group, optionally substituted carboxy1-C6alkyl group, optionally substituted karbamoilnuyu group.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

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

SUBSTANCE: invention relates to a new improved method for preparing 6-methyl-2-(4-methylphenyl)-imidazolo[1,2-a]pyridine-3-(N,N-dimethylacetamide) of the formula (I) or its pharmaceutically acceptable acid additive salts. Method involves interaction of ester of the general formula (II) (wherein R is a lower alkyl or phenyl-lower alkyl) with dimethylamine in polar aproton solvent and if necessary conversion of synthesized compound of the formula (I) to pharmaceutically acceptable acid additive salt. Compound of the formula (I) is the known effective sedative agent used in therapy. Also, invention relates to intermediate compounds of the general formula (II) wherein R is a lower alkyl or phenyl-lower alkyl using in this method. Method provides preparing highly pure product for a single stage being without applying harmful and toxic reagents.

EFFECT: improved method for preparing.

16 cl, 15 ex

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 proposes compound of the formula (I): wherein cycle A represents imidazo[1,2-a]pyrid-3-yl or pyrazole[2,3-a]pyrid-3-yl; R2 is joined to cyclic carbon atom and taken among halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkyl-S(O)a wherein a = 0, phenyl, phenylthio- or (heterocyclic group)-thio-group wherein any (C1-C6)-alkyl, phenyl or heterocyclic group can be substituted optionally by carbon atom with one or some G wherein heterocyclic group represents saturated, partially saturate or unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least atom is taken among nitrogen, sulfur or oxygen atom that can be bound if another variants are not specified with unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least one atom is taken among nitrogen, sulfur or oxygen atoms that can be bound if another variants are not specified with carbon or nitrogen atom wherein group -CH2- can be substituted optionally with -C(O)- and cyclic atom can carry optionally (C1-C6)-alkyl group and to form quaternary compound, or cyclic atom of nitrogen and/or sulfur can be oxidized to form N-oxide and/or S-oxides; m = 0-2 and R2 values can be similar or different; R1 means halogen atom, (C1-C3)-alkyl-S(O)a wherein a = 0 wherein any (C1-C3)-alkyl can be substituted optionally by carbon atom with one or some J; n = 0-1; cycle B represents phenyl or phenyl condensed with (C5-C7)-cycloalkyl cycle; R3 means halogen atom or sulfamoyl; p = 0-2 and R3 values can be similar or different; R4 means group A-E- wherein A is taken among (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heterocyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl wherein (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heteroccyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl can be substituted optionally by carbon atom with one or some D and wherein above mentioned heterocyclic group comprises fragment -NH- then nitrogen atom can be substituted optionally with group taken among R; E means a simple bond or -O-, -C(O)-, -N(Ra)C(O)- or -N(Ra)SO2-, -S(O)r wherein Ra means hydrogen atom or (C1-C6)-alkyl and r = 0-2; D is taken independently among hydroxy-, amino- (C1-C6)-alkoxy-, N-(C1-C6-alkyl)-amino-, N,N-(C1-C6-alkyl)-amino-, (C1-C6)-alkoxycarbonylamino- and benzyloxycarbonylamino-group wherein any (C1-C6)-alkyl or phenyl can be substituted optionally by carbon atom with one or some K; q = 0-1; G, J and K are taken independently among hydroxy-, dimethylamino-, diethylamino-group; R is taken among (C1-C4)-alkyl; or its pharmaceutically acceptable salt. Invention proposes applying pyrimidine compounds for inhibition of activity of kinases CDK2, CDK4 and CDK6 in cellular cycle eliciting anti-proliferative properties. Indicated properties have value in treatment of cancer diseases (solid tumors and leukemia), fibroproliferative and differential disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial repeated stenosis, osseous and ophthalmic diseases with proliferation of cellular tissue in vessels.

EFFECT: valuable medicinal properties of compounds.

22 cl, 99 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new imidazoquinolines of the formula (1): wherein R, R1, R2 and n have values given in the description. Compounds elicit effect of immunomodulating agents inducing biosynthesis of cytokines in animals in treatment of different pathologies, among them viral and neoplastic diseases. Also, invention relates to a pharmaceutical preparation used for inducing interferon-α or tumor necrosis α-factor, to a method for inducing biosynthesis of cytokines in animals and to methods for treatment of viral diseases and neoplasm pathologies in animals. Invention provides preparing new biologically active compounds.

EFFECT: improved inducing method, valuable properties of compounds and pharmaceutical preparation.

23 cl, 10 tbl, 231 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes 8-cyclo-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I):

in crystalline modification D and a medicinal agent based on thereof eliciting effect against pathogenic microorganisms. The prepared crystalline form of compound of the formula (I) shows low hygroscopicity and can be processed to galenic preparations easily and it has the highest filled density and satisfied fluidity.

EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 ex

FIELD: organic chemistry, medicine pharmacy.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid in the crystalline modification C of the formula (I):

and a medicinal agent eliciting effect against pathogenic microorganisms. This crystalline modification of compound of the formula (I) elicits low hygroscopicity, satisfied friability and can be processed easily to galenic preparations.

EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 tbl, 1 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I):

in the crystalline modification B and a medicinal agent based on thereof that elicits effect against pathogenic microorganisms. Indicated modification of compound of the formula (I) shows stability and insignificant absorption of air moisture ant doesn't convert to another crystalline modification or amorphous form being even in the prolonged storage.

EFFECT: valuable properties of agent.

4 cl, 4 dwg, 6 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S)-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I): with the crystalline modification A and a drug eliciting effect against pathogenic microorganisms. The prepared crystalline modification shows stability and doesn't transform to another crystalline modification or amorphous form being even at prolonged storage.

EFFECT: improved and valuable properties of compound.

4 cl, 4 dwg, 6 ex

The invention relates to crystalline polyhydroxylated 8-cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid of formula (VI)

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes diazepane derivative of the general formula (I)

or its pharmaceutically acceptable salt wherein ring B means phenyl; ring A means pyridyl substituted with halogen atom optionally, or phenyl substituted optionally with lower alkyl, lower alkoxy-group or halogen atom; X1 represents -C(=O)-NR2- or -NR2-C(=O)- wherein R2 means hydrogen atom; X2 represents -C(=O)-NR3- or NR3-C(=O)- wherein R3 means hydrogen atom; R represents hydrogen atom or halogen atom; R1 means lower alkyl. Also, invention relates to a pharmaceutical composition and inhibitor of blood coagulation activated factor X that can be used for prophylaxis and treatment of patients suffering with thrombosis or embolism.

EFFECT: valuable medicinal properties of compound.

5 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes applying the known 2-imidazolyl-substituted carbinols as inhibitor of Na+/H+ exchange in treatment or prophylaxis of diseases caused by ischemia (myocardium infarction, stenocardia, heart ischemic state, ischemic state of peripheral and central nervous system, insult, shock state, hypoxic states of donor organs in removing, storage and transplantation in the recipient body). Also, compounds can be used as anti-arrhythmic agents with cardioprotective effect and for prophylaxis of high blood pressure genesis in essential hypertension.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compound of the formula (I) or its pharmaceutically acceptable salt or solvate wherein X represents CH or nitrogen atom (N); Z represents CH; R1 represents hydrogen atom; R2 and R3 can be similar or different and represent (C1-C6)-alkoxy-group that is optionally substituted with halogen atom, hydroxyl, (C1-C4)-alkoxycarbonyl, amino-group wherein one or two hydrogen atom are optionally replaced for (C1-C4)-alkyl that is optionally substituted with hydroxyl or (C1-C4)-alkoxy-group, the group R12R13N-C(=O)-O- wherein R12 and R13 can be similar or different and represent hydrogen atom or (C1-C4)-alkyl substituted optionally with (C1-C4)-alkoxy-group or the group R14-(S)m- wherein R14 represents phenyl or saturated or unsaturated 5-7-membered heterocyclic group substituted optionally with (C1-C4)-alkyl; m = 0 or 1; R4 represents hydrogen atom; R5, R6, R7 and R8 can be similar or different and represent hydrogen atom, halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy-group or nitro-group under condition that R5, R6, R7 and R don't represent hydrogen atom simultaneously; R9 represents hydrogen atom, (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl wherein alkyl fragment of indicated (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl is optionally substituted with (C1-C4)-alkoxy-group; R10 represents hydrogen atom or (C1-C6)-alkyl; R11 represents (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl (wherein each (C1-C6)-alkyl, (C2-C6)-alkenyl and (C2-C6)-alkynyl is substituted optionally with halogen atom or (C1-C6)-alkoxy-group), or R15-(CH2)n- wherein n is a whole number from 0 to 3; R15 represents naphthyl or 6-membered saturated or unsaturated carbocyclic or saturated or unsaturated 5-7-membered heterocyclic group that are substituted optionally with halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group. Also, invention relates to variants of compounds of the formula (I). Compounds elicit antitumor activity and don't effect on cytomorphosis. Also, invention relates to pharmaceutical composition based on above described compounds, to a method for treatment of such diseases as malignant tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma, and to a method for inhibition of vascular vessels angiogenesis.

EFFECT: valuable medicinal properties of compounds and composition.

22 cl, 4 tbl, 186 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

FIELD: medicine, surgery.

SUBSTANCE: medicinal mixture consisting of 10 ml 0.25%-novocaine, 1 ml 1%-emoxypin and 64 c.u. lidase should be injected strictly subcutaneously per 1 ml for each point of injection into the center of plantar surface of nail phalanx of every toe, and for the first inter-toe space - subcutaneously in plantar and rear directions, then, after injections, it is necessary to carry out massage in area if injection with stretching and stroking movements in proximal direction for 10-15 sec, moreover curative seances should be performed every other day , the course being of 5-10 procedures, at repeating this course 3-6 mo later. The present innovation enables to activate transcapillary exchange due to pathogenetically proved impact onto surface and deep lymphatic network of inferior limbs.

EFFECT: higher efficiency of therapy.

1 cl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves inducing angina pectoris attack on no medicament background. Provoking factor action time is measured to the moment the angina pectoris attack takes place. Nitroglycerine is administered in therapeutic dose to reach rapid relief of symptoms. The provoking factor action is repeated to reproduce attack of the same intensity. Provoking factor action time is measured once more. Prediction coefficient K value is calculated as ratio of the repeated provoking factor action time to the provoking factor action time to the moment the angina pectoris attack takes place. Prognosis is considered to be favorable, unfavorable or uncertain during the nearest year depending on K value.

EFFECT: high accuracy in evaluating coronary reserve.

2 tbl

FIELD: medicine, biochemistry.

SUBSTANCE: invention proposes applying CDP-choline (cytidinediphosphocholine) or its salt as a prophylactic agent for treatment of cerebral ischemia and a method for such prophylactic treatment. Invention found new and unknown early mechanism of action of CDP-choline or its salt: inhibition of activation of caspase cascade being the effectiveness of this effect is high in prophylactic intake of drug.

EFFECT: valuable medicinal properties of agent.

6 cl, 5 dwg, 4 ex

FIELD: medicine, cardiology.

SUBSTANCE: invention relates to treatment of patients with post-infarct cardiosclerosis with circulation insufficiency of functional class 2. Method involves using diltiazem with individual setting doses. Method involves carrying out the simplified 2 h oral tolerance test to glucose. Diltiazem is prescribed in the initial dose 90 mg and in the maintenance dose 45 mg in positive result of test. In negative result of test diltiazem is prescribed in the initial dose 180 mg and in the maintenance dose 90 mg. Method provides enhancing effectiveness in treatment of patients with post-infarct cardiosclerosis with circulation insufficiency due to the more precise individual setting dose of the preparation and reducing frequency in arising adverse effects.

EFFECT: improved method for setting, enhanced effectiveness of treatment.

2 tbl, 2 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention, in particular, relates to prolonged therapeutical form of domestic slow calcium channel blocker, namely ankardin-retard-AZIn (active principle 7,7-ethylenedioxybenzopyran-2,2-dione) in the form of 0.1% solution administered in dose 1 ml in the form of complex with poly(ethylene oxide) 400. Pre-clinical investigations indicated that Ankardin-retard-AZIn was a sufficiently active calcium ion antagonist and, after clinical investigations, it could be applied in medical practice for prevention and treatment of cardiovascular diseases.

EFFECT: extended choice of drugs.

6 tbl, 4 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

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