Ligands of 5-ht6 receptors, pharmaceutical formulation, production method and medical product

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to application as ligands of 5-NT6 receptor azaheterocyclic compositions of general formula 1 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and/or hydrates , where R2 and R3 independently represent substitute of amides chosen from hydrogen; substituted carbonyl; substituted aminocarbonyl; substituted aminothiocarbonyl; substituted sulphonyl; C1-C5-alkyl, optionally substituted with C6-C10-aryl, optionally substituted with heterocyclil, C6-C10-arylaminocarbonyl, C6-C10- arylaminothiocarbonyl, C5-C10-azaheteroaryl, optionally substituted with carboxyl, nitrile group; optionally substituted with aryl; R1k are 1 to 3 independent substitutes to cyclic system chosen from hydrogen, optionally substituted C1-C5-alkyl, C1-C5-alkyloxy, C1-C5-alkenyl, C1-C5- alkenyl, halogen, trifluoromathyl, nitrile, carboxyl, optionally substituted heterocyclil, substituted sulphonyl, optionally substituted carboxyl; dashed line with accompanying continuous line () corresponds to single or double bond; n=1.2 or 3. Invention also concerns a pharmaceutical formulation, production method and tabletted, capsulated or injection medical product in pharmaceutically acceptable package.

EFFECT: agent has improved efficiency.

17 cl, 8 tbl, 5 ex, 1 dwg

 

This invention relates to new ligands serotonin 5-HT6receptors, to pharmaceutical compositions containing as active component new ligands serotonin 5-HT6receptor, to new medicines for humans and warm-blooded animals, used to treat diseases and conditions of the Central nervous system (CNS), the pathogenesis of which play an important role of neurotransmitter systems, modulated 5-HT6the receptors. The invention relates also to the creation of new molecular pharmacological tools for the study of in vitro and in vivo biochemical mechanisms of cognitive processes.

The development of effective means for the treatment and prevention of Alzheimer's disease (AD) and other neurodegenerative diseases is underway for many years, but still the main search direction remains attempt pharmacological correction of cholinergic deficit [Mayeux R, Sano M. Treatment of Alzhaimer′s disease. N. Engl. J. Med. 1999; 341: 1670-1679], leading to the establishment of a number of drugs based on acetylcholinesterase inhibitors (taken, amiridin, aricept etc), however, having very limited clinical applicability. In this regard, the search for highly effective means of treatment and early diagnosis of BA with brand new mechanics is the PTO's action becomes more urgent task [Jellinger K.A. Alzheimer's 100 - highlights in the history of Alzheimer's research. J Neural Transm. 2006 Oct 13; [Epub ahead of print].

One of the most promising approaches in this regard is the use of effective and selective antagonists of serotonin 5-HT6receptors for the treatment of diseases associated with the Central nervous system, in particular of ad and other neurodegenerative diseases [J. Holenz, Pauwels, P.J., J.L. Diaz, Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11: 283-299]. These receptors in mammals are found exclusively in the Central nervous system (CNS), mainly in areas of the brain responsible for learning and memory [Ge′rard C., Martres, M.-P., Lefe′vre K., Miquel, M.-C., Verge′ D., Lanfumey L., Doucet e, Hamon M., El Mestikawy S. Measurement localisation of serotonin 5-HT6receptor-like material in the rat central nervous system. Brain Research. 1997; 746: 207-219]. In addition, it is shown [Dawson L.A., Nguyen H.Q., Li P. The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology.. 2001; 25: 662-668]that 5-HT6the receptors are modulators of several neurotransmitter systems, including the cholinergic, noradrenergicheskoy, glutamatergic and dopaminergic. Given the fundamental role of these systems in normal cognitive processes, and their dysfunction in neurodegeneration, it is obvious exceptional role of 5-HT6receptors in shaping the AI normal or pathological memory. In a large number of modern studies have shown that blocking the 5-HT6receptors leads to a significant increase in memory consolidation in various animal models of learning-memory-playback [Foley A.G., Murphy K.J., Hirst W.D., H.C. Gallagher, J.J. Hagan, Upton N., F.S. Walsh, C.M. Regan The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology.. 2004; 29: 93-100. Riemer, S., E. Borroni, Levet-Trafit Century, Martin J.R., Poli, S., Porter, R.H., Bos M. Influence of the 5-NT receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine, a potent and selective 5-HT(6) receptor antagonist. J. Med. Chem. 2003; 46: 1273-1276. King M.V., M.L. Woolley, Topham LA., Sleight A.J., Marsden CA, Fone K.C. 5-HT(6) receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation e an effect sensitive to NMDA receptor antagonism. Neuropharmacology 2004; 47: 195-204]. Also shown significant improvement in cognitive function in aged rats in the model water maze Morrison when exposed to an antagonist of 5-HT6receptors [Foley A.G., Murphy K.J., Hirst W.D., H.C. Gallagher, J.J. Hagan, Upton N., F.S. Walsh, C.M. Regan The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology.. 2004; 29: 93-100]. Recently achieved not only a deeper understanding of the role of 5-HT6receptors in cognitive processes, but a clearer concept about possible pharmacophoric properties of their antagonists [Holenz j, Pauwels, P.J., J.L. Diaz, Merce R., Codony X., H. Buschmann Medicial chemistry strategies to 5-HT 6receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11: 283-299]. This led to the creation of selective high-affinity ligands ("molecular tools"), then and clinical candidates. At present, four antagonist 5-HT6receptors are in various stages of clinical trials as potential agents for the treatment of ad and other cognitive diseases [http://integrity.prous.com].

Another attractive property of antagonists of 5-HT6receptors is their ability to suppress the appetite, which can lead to the creation on their basis of fundamentally new means to reduce overweight and obesity [Vicker SP, Dourish C.T. Serotonin receptor ligands and the treatment of obesity. Curr. Opin. Investig. Drugs. 2004; 5: 377-388]. This effect is confirmed in many studies [J. Holenz, Pauwels, P.J., J.L. Diaz, Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11: 283-299. Davies, S.L. Drug discovery targets: 5-HT6receptor. Drug Of The Future. 2005; 30: 479-495], its mechanism is based on inhibition by antagonists of 5-HT6receptor signaling gamma-aminobutyric acid and the increase in the emission of alpha melanocytestimulating hormone, which ultimately reduces the need for food [M.L. Woolley 5-ht6 receptors. Curr. Drug Targets CNS Neurol. Disord. 2004; 3: 59-79].

Antagonists of 5-HT6receptor seem particularly promising as the potential remedies for the treatment of BA, other Central nervous system diseases and obesity due to their exclusive distribution in several regions of the brain, which eliminates the possibility of the manifestation of virtually any peripheral side effects.

It should be noted that in the scientific and patent literature, there are a significant number of examples of ligands of 5-HT6receptor belonging to different classes of organic compounds [J. Holenz, Pauwels, P.J., J.L. Diaz, Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11: 283-299], at the same time, there are only two substituted 3-(aminomethyl)indole as ligands of 5-HT6receptor: (a) - 1-benzazolyl and (b) - 1-(4-aminobenzenesulphonyl)-3-(dimethylaminomethyl)indole. [M.R.Pullagurla, M.Dukat, V.Setola, .Roth and R.A.Glennon. N1-Benzenesulfonylgramine and N1-Benzenesulfonylskatole: Novel 5-HT6Receptor Ligand Templates. Bioorganic & Medicinal Chemistry Letters, 2003, 13, 3355-3359.]

As a result of research aimed at finding new biologically active compounds, the inventors have found that azaheterocyclic compounds, including 3-(aminomethyl)indole fragment can effectively block the 5-HT6the receptors.

More specifically, the present invention relates to new ligands 5-hydroxytryptamine (5-HT6) receptor, pre the excitation of azaheterocyclic compounds, includes 3-(aminomethyl)indole fragment; to pharmaceutical compositions containing as active substances new antagonists of 5-HT6receptor, and to a method for producing the composition; the use of new pharmaceutical compositions for obtaining drugs; the method of treating and preventing various diseases of the CNS, such as illness BA, Parkinson's disease, Huntington's chorea, lathyrism, amyotrophic lateral sclerosis, schizophrenia and other neurological and neurodegenerative diseases and mental disorders; to reduce overweight and obesity, and others, as well as new ligands of 5-HT6receptor as a molecular pharmacological tools for studies (in vitro and in vivo biochemical mechanisms of cognitive processes.

Below are definitions of terms used in the description.

"Azaheterocycle" means an aromatic or non-aromatic monocyclic or polycyclic system containing a loop, at least one nitrogen atom, the value of which is determined in this section. Azaheterocycle can have one or more cyclic substituents" of the system.

"Aliphatic" radical, means the radical obtained by removing a hydrogen atom from neuroma the practical P-N connection. Aliphatic radical can optionally contain substituents is an aliphatic or aromatic radicals, as defined in this section. Representatives of aliphatic radicals include alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl, aralkyl, aralkylamines, uralelectromontrage, aralkyl, aralkyl, aralkylamines, heteroalkyl, heteroalkyl, heteroalicyclic, heteroalicyclic, heteroaryl, kannelirovannye aristically, kannelirovannye heteroalicyclic, kannelirovannye arylchloroalkanes, kannelirovannye heteroarylboronic, kannelirovannye arylheteroacetic, kannelirovannye heteroalicyclic, kannelirovannye arylheteroacetic, kannelirovannye heterooligomerization.

"Alkenyl" means aliphatic linear or branched hydrocarbon group containing 2 to 7 carbon atoms and including the carbon-carbon double bond. Branched means that linear alkenylphenol chain attached to one or more lower alkyl groups such as methyl, ethyl or propyl. The alkyl group may have one or more substituents, such as halogen, alkenylacyl, cycloalkyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, hetaeras is aralkylated, heterocyclyl, geterotsiklicheskikh, alkoxycarbonyl, arelaxation, heteroarylboronic or G1G2N-, G1G2NC(=O)-, G1G2NSO2-where G1and G2independently from each other represent a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or G1and G2together with the N atom to which they are bound, form a through G1and G24-7-membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, benzyloxycarbonylation and pyridinedicarboxylate. Preferred alkenylamine groups are ethynyl, propenyl, n-butenyl, ISO-butenyl, 3-methylbut-2-enyl, n-pentenyl and cyclohexylmethanol.

"Alkenylacyl" means alkenyl-O - group in which alkenyl defined in this section. The preferred alkenylamine groups are allyloxy and 3 butenyloxy.

"Alkenylacyl" means alkenyl-O-alkyl group in which the alkyl and alkenyl defined in this section.

"Alkyl" means an aliphatic hydrocarbon of linear or branched group with 1-12 carbon atoms in the chain. Branched means that as Celina chain has one or more "lower C 1-C4alkyl" substituents. The alkyl may have one or more identical or different substituents ("alkyl substituents including halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonates, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonyl, arelaxation, heteroarylboronic or G1G2N-, G1G2NC(=O)-, G1G2NC(=S)-, G1G2NSO2-where G1and G2independently from each other represent a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or G1and G2together with the N atom to which they are bound, form a through G1and G24-7-membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-PE is Teal, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylation, methoxycarbonylmethyl and pyridinedicarboxylate. Preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, Alcoxy, aryloxy, alkylthio, heteroaromatic, Uralkali, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arelaxation, heteroarylboronic or G1G2N-, G1G2NC(=O)-, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic.

"Alkyloxyalkyl" means alkyl-O-alkyl group in which the alkyl groups are independent of each other and defined in this section. Preferred alkyloxyalkyl groups are methoxyethyl, ethoxymethyl, n-butoxymethyl, methoxypropyl and ISO-propylacetate.

"Alkylthio" means alkyl-S-group in which the alkyl group defined in this section.

"Alkoxy" means alkyl-O-group in which alkyl is defined in this section. The preferred alkyloxyaryl are methoxy, ethoxy, n-propoxy, ISO-propoxy and n-butoxy.

"Alkoxycarbonyl" means alkyl-O-C(=O)- group in which alkyl is defined in this section. Preferred alkoxycarbonyl groups are methoxycarbonyl, etoxycarbonyl and tert-bout oxycarbonyl.

"Alkoxycarbonyl" means alkyl-O-C(=O)-alkyl group, in which alkyl is defined in this section. Preferred alkoxycarbonylmethyl groups are methoxycarbonylmethyl and ethoxycarbonylmethyl and methoxycarbonylethyl and ethoxycarbonylethyl.

"Amino group"means G1G2N - group, substituted or unsubstituted "Deputy amino group" G1and G2whose value is defined in this section, for example, amino (H2N-), methylamino, diethylamino, pyrrolidine, morpholine, benzylamine or phenethylamine.

"Annelirovannymi cycle" (condensed cycle) means of bi - or polycyclic system, where annelirovannymi cycle and cycle or politics, with whom he "annylirovan have at least two common atom.

"Annelirovannymi arylheteroacetic" means kannelirovannye aryl and geteroseksualen, the value of which is determined in this section. Annelirovannymi arylheteroacetic can be contacted through any possible atom of the cyclic system. The prefix "Aza", "oxa" or "thia" before "geteroseksualen" means the presence in the cyclic system of nitrogen atom, oxygen atom or sulfur atom, respectively. Annelirovannymi arylheteroacetic may have one or more "cyclic system substituents"which may be the same or different. the volumes of nitrogen and sulfur, in heterocyclyl part, can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of annelated allgemeinreaktion are indolinyl, 1H-2-oxopyrrolidin 2N-1-oxoethylidene, 1,2-dihydroquinoline etc.

"Annelirovannymi arylheteroacetic" means kannelirovannye aryl and heteroseksualci, the value of which is determined in this section. Annelirovannymi arylheteroacetic can be contacted through any possible atom of the cyclic system. The prefix "Aza", "oxa" or "thia" before "heterocyclization" means the presence in the cyclic system of nitrogen atom, oxygen atom or sulfur atom, respectively. Annelirovannymi arylheteroacetic may have one or more "cyclic system substituents"which may be the same or different. Atoms of nitrogen and sulfur, in heterocyclyl part, can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of annelated analgeticalkie are indolyl, 1,2,3,4-tetrahydroisoquinoline, 1,3-benzodioxol etc.

"Annelirovannymi arylchloroalkanes" means kannelirovannye aryl and cycloalkenyl, the value of which is determined in this section. Annelirovannymi arylchloroalkanes can be contacted through any possible atom of the cyclic system. Annelirovannymi arylchloroalkanes can and who know one or more "cyclic system substituents", which may be the same or different. Representatives of annelated arylcyclohexylamines are 1,2-dihydronaphthalene, inden, etc.

"Annelirovannymi aristically" means kannelirovannye aryl and cycloalkyl, the value of which is determined in this section. Annelirovannymi aristically can be contacted through any possible atom of the cyclic system. Annelirovannymi aristically may have one or more "cyclic system substituents"which may be the same or different. Representatives of annelated arylcyclohexylamines are indanan, 1,2,3,4-tetrahydronaphthalen, 5,6,7,8-tetrahedronal-1-yl, etc.

"Annelirovannymi heteroarylboronic" means kannelirovannye heteroaryl and cycloalkenyl, the values of which are defined in this section. Annelirovannymi heteroarylboronic can be contacted through any possible atom of the cyclic system. The prefix "Aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of nitrogen atom, oxygen atom or sulfur atom, respectively. Annelirovannymi heteroalicyclic may have one or more "cyclic system substituents"which may be the same or different. The nitrogen atom located in the heteroaryl portion may be oxidized to N-oxide. Representatives of annelated heteroa is illlooking are 5,6-dihydroxyindoline, 5,6-dihydroisoquinolyl, 4,5-dihydro-1H-benzimidazolyl etc.

"Annelirovannymi heteroalicyclic" means kannelirovannye heteroaryl and cycloalkyl, the values of which are defined in this section. Annelirovannymi heteroalicyclic can be contacted through any possible atom of the cyclic system. The prefix "Aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of nitrogen atom, oxygen atom or sulfur atom, respectively. Annelirovannymi heteroalicyclic may have one or more "cyclic system substituents"which may be the same or different. The nitrogen atom located in the heteroaryl portion may be oxidized to N-oxide. Representatives of annelated heteroarylboronic are 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, 4,5,6,7-tetrahydro-1H-benzimidazolyl etc.

"Annelirovannymi heterooligomerization" means kannelirovannye heteroaryl and heterocyclyl, the values of which are defined in this section. Annelirovannymi heterooligomerization can be contacted through any possible atom of the cyclic system. The prefix "Aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of nitrogen atom, oxygen atom or sulfur atom, respectively. Annelirovannymi heterooligomerization can methodin or more "cyclic system substituents", which may be the same or different. The nitrogen atom located in the heteroaryl portion may be oxidized to N-oxide. Atoms of nitrogen and sulfur, in heterocyclyl part, can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of annelated heteroarylboronic are 1,2-dihydro[2,7]naphthyridines, 7,8-dihydro[1,7]naphthyridine, 6,7-dihydro-3H-imidazo[4,5-C]pyridyl and the like,

"Kannelirovannye heteroalicyclic" means kannelirovannye heteroaryl and heterocyclyl, the values of which are defined in this section. Annelirovannymi heteroalicyclic can be contacted through any possible atom of the cyclic system. The prefix "Aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of nitrogen atom, oxygen atom or sulfur atom, respectively. Annelirovannymi heteroalicyclic may have one or more "cyclic system substituents"which may be the same or different. The nitrogen atom located in the heteroaryl portion may be oxidized to N-oxide. Atoms of nitrogen and sulfur, in heterocyclyl part, can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of annelated heteroarylboronic are 2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-2-yl, 2,3-dihydro-1H-pyrrolo[3,4-b]indol-2-yl, 1,2,3,4-tetrahed what about the[1,5]naphthyridine etc.

"Aralkyl" means arylalkyl group, in which values of aryl and alkenyl defined in this section. For example, 2-pentenyl is aralkylamines group.

"Aralkyl" means an alkyl group substituted by one or more aryl groups, in which values of aryl and alkyl are defined in this section. Examples Uralkalij groups are benzyl, 2,2-diphenylether or phenethyl.

"Aralkylamines" means arylalkyl-NH-, in which values of aryl and alkyl are defined in this section.

"Aralkylamines" means aralkyl-SO - group, which is aralkyl defined in this section.

"Aralkylamines" means aralkyl-SO2the group, which is aralkyl defined in this section.

"Uralkali" means aralkyl-S - group in which the value of aralkyl defined in this section.

"Arakaki" means aralkyl-O - group in which the value of aralkyl defined in this section. For example, benzyloxy or 1 - or 2-naphthalenyloxy are Uralkalij groups.

"Alcoxialchil" means aralkyl-O-alkyl group, in which values of aralkyl and alkyl are defined in this section. An example of aralkyl-O-alkyl group is benzyloxyethyl.

"Arelaxation" means aralkyl-O-C(=O)- group in which the value of aralkyl defined in this section. An example of aralex the carbonyl group is benzyloxycarbonyl.

"Alcoxycarboxylates" means aralkyl-O-C(=O)-alkyl group, in which values of aralkyl and alkyl are defined in this section. Example alcoxycarboxylates group is benzyloxycarbonyl or benzyloxycarbonyl.

"Aryl" means an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, predominantly from 6 to 10 carbon atoms. Aryl can contain one or more "cyclic system substituents"which may be the same or different. Representatives of aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. The aryl may be annylirovan with non-aromatic cyclic system or heterocycle.

"Arylcarbamoyl" means aryl-NHC(=O)- group, where aryl is defined in this section.

"Aryloxy" means aryl-O - group, where aryl is defined in this section. Representatives of aryloxy are phenoxy and 2 naphthyloxy.

"Aryloxyalkyl" means aryl-O-C(=O)- group, where aryl is defined in this section. Representatives aryloxyalkyl groups are phenoxycarbonyl and 2-mattoxicator.

"Arylsulfonyl" means aryl-SO - group, where aryl is defined in this section.

"Arylsulfonyl" means aryl-SO2group in which the Oh is aryl is defined in this section.

"Aristeo" means an aryl-S - group, where aryl is defined in this section. Representatives of aricioglu are phenylthio and 2 naphthylthio.

"Aroylamino" means aroyl-NH - group, which is aroyl defined in this section.

"Aroyl" means an aryl-C(=O)- group, where aryl is defined in this section. Examples rolnych groups are benzoyl, 1 - and 2-naphtol.

"Aromatic" radical, means the radical obtained by removing hydrogen atom from the aromatic C-H connection. "Aromatic" moiety includes aryl and heteroaryl cycles defined in this section. Aryl and heteroaryl cycles can optionally contain substituents is an aliphatic or aromatic radicals, as defined in this section. Representatives of aromatic radicals include aryl, annelirovannymi cycloalkenyl, annelirovannymi cycloalkenyl, annelirovannymi heterocyclisation, annelirovannymi heterocultural, heteroaryl, annelirovannymi cycloalkylcarbonyl, annelirovannymi cycloalkylcarbonyl, annelirovannymi heterocyclisation and annelirovannymi heterocyclisation.

"Aromatic cycle" means a planar cyclic system in which all the atoms of the cycle involved in the formation of a unified system of conjugation, including, according to the hückel rule, (4n+2)π -electrons (n is a nonnegative integer). Examples of aromatic cycles are benzene, naphthalene, anthracene, etc. In the case of heteroaromatic cycles in the system of the pairing involved πelectrons and p-electrons of heteroatoms, their total number is also equal to (4n+2). Examples of such cycles include pyridine, thiophene, pyrrole, furan, thiazole, etc. Aromatic cycle can have one or more cyclic substituents" of the system and can be annylirovan with non-aromatic cycle, heteroaromatic or heterocyclic system.

"Acyl" means an H-S(=O)- or alkyl-C(=O)-, cycloalkyl-C(=O)-, heterocyclyl-C(=O)-, geterotsiklicheskikh-C(=O)-, aryl-C(=O)- arylalkyl-C(=O)- or heteroaryl-C(=O)-, heteroallyl-C(=O)- group in which alkyl, cycloalkyl-, heterocyclyl, geterotsiklicheskikh, aryl, arylalkyl heteroaryl, heteroaromatic defined in this section.

"Acylamino" means acyl-NH - group in which the value of acyl defined in this section.

"1,2-Vinyl radical" means-CH=CH - group, which contains one or more identical or different "alkyl substituents", which is defined in this section.

"Halogen" means fluorine, chlorine, bromine and iodine. Preferred are fluorine, chlorine and bromine.

"Heterogeneously cycle" means a cycle, which is attached (Anneliese or con is insinuate) to another cycle or polycycle, contains at least one heteroatom.

"Heteroalkyl" means heteroaryl-alkenylphenol group, in which heteroaryl and alkenyl defined in this section. Preferably heteroalkyl includes lower alkenylphenol group. Representatives of heteroarylboronic are 4-pyridalyl, trilateral, imidazolidinyl, personalemail etc.

"Heteroalkyl" means heteroaryl-alkyl group, in which heteroaryl and alkyl are defined in this section. Representatives of heteroalkyl are pyridylmethyl, thienylmethyl, furylmethyl, imidazolidinyl, personality etc.

"Heteroaromatics" means heteroallyl-O - group in which heteroaromatic defined in this section. The preferred heteroalicyclic are 4 pyridylmethylene, 2-thienylmethyl etc.

"Heteroaryl" means an aromatic monocyclic or polycyclic system containing from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms replaced by a heteroatom or heteroatoms, such as nitrogen, sulfur or oxygen. The prefix "Aza", "oxa" or "thia" before "heterocyclization" means the presence in the cyclic system of nitrogen atom, oxygen atom or sulfur atom, respectively. The nitrogen atom located in heteroaryl, can be oxidized to N-oxide. Heteroa the l may have one or more "cyclic system substituents", which may be the same or different. Representatives of heteroaryl are pyrrolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, isooxazolyl, isothiazolin, tetrazolyl, oxazolyl, thiazolyl, pyrazolyl, furutani, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, honokalani, phthalazine, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofuranyl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, chinoline, imidazolyl, cyanopyridyl, hintline, thienopyrimidines, pyrrolopyridine, imidazopyridine, ethenolysis, benzoxazinones, 1,2,4-triazinyl, thienopyrrole, properaly and other

"Heteroarylboronic" means heteroaryl-SO2-NH-C(=O)- group in which heterooligomerization in this section.

"Heteroaryl" means heteroaryl-C(=O)- group in which heteroaryl defined in this section. The preferred heteroaromatic are nicotinoyl, thienoyl, pyrazolyl etc.

"Heterocycle" means an aromatic or non-aromatic monocyclic or polycyclic system containing a loop, at least one heteroatom, which is defined in this section. Preferred heteroatoms are nitrogen, oxygen and sulfur. The heterocycle may have one or more cyclic substituents" of the system.

"Heterocyclyl" means nonaromatic monocyclics the Yu or polycyclic system, comprising from 3 to 13 carbon atoms, mainly from 5 to 13 carbon atoms, in which one or more carbon atoms replaced by a heteroatom, such as nitrogen, oxygen, sulfur, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. The prefix "Aza", "oxa" or "thia" before heterocyclyl means the presence in the cyclic system of nitrogen atom, oxygen atom or sulfur atom, respectively. Heterocyclyl may have one or more "cyclic system substituents"which may be the same or different. Atoms of nitrogen and sulfur, in heterocyclyl can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of heterocyclyl are 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridines, 1,4-dihydropyridines, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 2-pyrazoline, dihydrofurane, dihydrothiophene etc.

"Heterocyclyl" means the radical formed from the heterocycle.

"Heterocyclic" means heterocyclyl-O - group in which heterocyclyl defined in this section.

"Hydrate" means the MES, in which water is a molecule or molecules of solvent.

"Hydroxyalkyl" means BUT is an alkyl group in which alkyl is defined in this section.

"Deputy" means a chemical moiety that is attached scaffold (fragment), for example, "Deputy alkyl", "Deputy amino group", "Deputy carboxyl", "Deputy carbamoyl", "Deputy cyclic system, the values of which are defined in this section.

"Deputy alkyl" means a Deputy, attached to the alkyl, alkenyl, the value of which is determined in this section. Deputy alkyl represents hydrogen, alkyl, halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonates, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonyl, arelaxation, heteroarylboronic or G1G2N-, G1G2NC(=O)-, G1G2NSO2-where G1and G2independently from each other represent a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or G1and G2together with the N atom to which they are bound, form a through G1and Gsup> 24-7-membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylation, methoxycarbonylmethyl and pyridinedicarboxylate. Preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, Alcoxy, aryloxy, alkylthio, heteroaromatic, Uralkali, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arelaxation, heteroarylboronic or G1G2N-, G1G2NC(=O)-, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic. The significance of the "alkyl substituents" defined in this section.

"Deputy amino group" means the Deputy attached to the amino group. Deputy amino group represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylaminocarbonyl, allumination, heteroarylboronic, heterocyclization, alkylaminocarbonyl, allumination, heteroarylboronic, heterocyclization, annelia the config heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonylmethyl, alcoxycarboxylates, heteroarylboronic.

"Deputy carbamoyl" means the Deputy attached to carbamoyl group, the value of which is defined in this section. Deputy carbamoyl represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonyl, alcoxycarboxylates, heteroarylboronic or G1G2N-, G1G2NC(=O)-alkyl, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic. Preferred substituents carbamaepine" are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonyl, alcoxycarboxylates, heteroarylboronic or G1G2N-, GlG2NC(=O)-alkyl, annelirovannymi arylheteroacetic, anneliesa the hydrated arylheteroacetic. The value of "Vice carbamoyl" is defined in this section.

"Deputy carboxyl" means the Deputy attached to the oxygen of the carboxylic group, the value of which is defined in this section. Deputy carboxyl represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonyl, alcoxycarboxylates, heteroarylboronic or G1G2N-, G1G2NC(=O)-alkyl, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic. Preferred carboxyl substituents are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonyl, alcoxycarboxylates, heteroarylboronic or G1G2N-alkyl, G1G2NC(=O)-alkyl, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic.

"Deputy nucleophilic" means a chemical moiety that is attached to scaffold in the reaction with the nucleophilic reagent, for example, selected from the group of primary or secondary amines, alcohols, phenols, mercaptans and thio is of enols.

"Deputy cyclic system" means the Deputy attached to aromatic or non-aromatic cyclic system, including hydrogen, alkylaryl, quinil, aryl, heteroaryl, aralkyl, heteroalkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, acyl, aroyl, halogen, nitro, cyano, carboxy, alkoxycarbonyl, aryloxyalkyl, arelaxation, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylthio, aaltio, heteroaromatic, Uralkali, heteroalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl, amidino, G1G2N-, G1G2N-alkyl-, G1G2NC(=O) -, or G1G2NSO2-where G1and G2represent independently from each other hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroalkyl, or Deputy G1G2N-, in which one of the G1and G2can be acyl or aroyl, and is different from G1and G2defined above, or "Deputy cyclic system are G1G2NC(=O) -, or G1G2NSO2-in which G1and G2together with the nitrogen atom to which they are bound, form a through G1and G24-7-membered heterocyclyl or heteros is clenil. Preferred "cyclic system substituents" are alkoxycarbonyl, alkoxy, halogen, aryl, Alcoxy, alkyl, hydroxy, aryloxy, nitro, cyano, alkylsulfonyl, heteroaryl or G1G2N-. If the cyclic system is saturated or partially saturated, the "Deputy of the cyclic system may be set to a methylene (CH2=), oxo(O=) or thioxo(S=).

"Deputy electrophilic" means a chemical moiety that is attached to scaffold as a result of reaction with an electrophilic reagent, for example, selected from the group of organic acids or their derivatives (anhydrides, imidazolides, halides, esters of organic sulfonic acids or organic sulfochlorides, organic halogenfree, organic isocyanates and organic isothioscyanates.

"Protective group" (PG) means a chemical moiety that is attached to scaffold or semi-synthesis for the temporary protection of amino groups in multifunctional compounds, including, but not limited to amide Deputy, such as formyl, optionally substituted acetyl (for example, trichloroacetyl, TRIFLUOROACETYL, 3-phenylpropionyl and others), optionally substituted benzoyl and others; urethane Deputy, such as optionally substituted C1-C7allyloxycarbonyl, for example, metalaxyl ronil, ethoxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc), and others; optionally substituted C1-C7alkyl substituent, such as tert-butyl, benzyl, 2,4-dimethoxybenzyl, 9-phenylfluorene and others; sulfanilic Deputy, for example benzazolyl, p-toluensulfonyl and other More "Protective groups described in Protective groups in organic synthesis, Third Edition, Greene, T.W. and Wuts, P.G.M. 1999, p.494-653. Publisher John Wiley & Sons, Inc., New York, Chichester, Weinheim, Brisbane, Toronto, Singapore.

"Protected primary or secondary amine" means a group of the formula G1G2N-, in which one of the G1and G2represents a protective group PG, and is different from G1and G2represents hydrogen, alkenyl, alkyl, aralkyl, aryl, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, heterocyclyl or heterocyclyl.

"Inert Deputy" (or "not interfering", "Non-interfering substituent"means low or directionspanel radical, including, but not limited to C1-C7alkyl, C2-C7alkenyl, 2-C7quinil, C1-C7alkoxy, C7-C12aralkyl substituted with inert substituents, aralkyl, C7-C12geterotsiklicheskikh substituted with inert substituents, 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 by Halogens, inert substituents aryl, substituted with inert substituents, alkoxy, foralkyl, aryloxyalkyl, heterocyclyl substituted with inert substituents heterocyclyl and nitroalkyl; where m and n have a value from 1 to 7. Preferred inert substituents are C1-C7alkyl, C2-C7alkenyl, C2-C7quinil, C1-C7alkoxy, C7-C12aralkyl,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl substituted with inert substituents C1-C7alkyl, phenyl, substituted by inert substituents phenyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted inert replaces the representatives aryl, heterocyclyl and substituted with inert substituents heterocyclyl.

"Carbarnoyl" means G1G2NC(=O)- group. Carbarnoyl may have one or more identical or different "Vice carbamoyl" G1and G2including alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the value of which is determined in this section.

"Carbamoylaspartate" means azaheterocycle containing as a substituent of a cyclic system, at least one karbamoilnuyu group, is "azaheterocycle", "Deputy cyclic system" and "carnemolla group" is defined in this section.

"Carboxy" means the NOSE(=O)- (carboxyl) group.

"Carboxylic" means the NOSE(=O)-alkyl group, where alkyl is defined in this section.

"Carbocycle" means a mono - or polycyclic system composed only of carbon atoms. Carbocycle can be aromatic, and alicyclic. Alicyclic politicly can have one or more common atoms. In the case of a single atom formed zerocarboncity (for example, Spiro[2.2]pentane), in the case of two - a variety of condensed matter systems (for example, decalin), in the case of three - bridge systems (for example, bicyclo[3.3.1]nonan), in case a greater number of different polyhedral systems (e.g., adamantane). Alicycle mo the ut to be "saturated", for example, as cyclohexane, or partially saturated, for example, as tetralin.

"Combinatorial library" means a collection of compounds obtained by parallel synthesis, designed to search for connections-hit or connection-leader, as well as to optimize the physiological activity of hit or leader, each compound of the library meets the General scaffold and the library is a collection of related homologues or analogues.

"Methylene radical" means-CH2group, which contains one or two identical or different "alkyl substituents", which is defined in this section.

"Nah cycle (saturated cycle or partially saturated cycle) refers to non-aromatic cyclic or polycyclic system, formally educated as a result of full or partial hydrogenation of unsaturated C=C or C=N bonds. Non-aromatic cycle can have one or more cyclic substituents" of the system and can be annylirovan with aromatic, heteroaromatic or heterocyclic systems. Examples of non-aromatic cycles are cyclohexane or piperidine, examples of partially saturated cycle - cyclohexen or piperideine.

"Optional aromatic cycle" means a cycle, which can be either aromatic cycle, and n is an aromatic cycle, the value which is defined in this section.

"Optionally substituted radical" means a radical without substituents or with one or more substituents.

"Optional annelirovannymi (condensed) cycle" means a condensed or unfused cycle, the values of which are defined in this section.

"Lower alkyl" means a linear or branched alkyl with 1-4 carbon atoms.

"Connection-leader (leader) means the connection is outstanding (maximum) physiological activity associated with a specific biomechani relating to a particular (or several) of pathology or disease.

"Connection-hit (hit) refers to the compound shown in the primary screening process the desired physiological activity.

"Altamarena group" means G1G2NSO2group, substituted or unsubstituted "Deputy amino group", G1and G2values are defined in this section.

"Sulfonyl" means G3-SO2- the group in which G3represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi arils cloaker, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, the value of which is determined in this section.

"Template" means the General structural formula of a group of compounds or compounds included in "combinatorial library".

"Thiocarbamoyl" means G1G2NC(=S)- group. Thiocarbamoyl may have one or more identical or different "Vice thiocarbamoyl" G1and G2including alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the value of which is determined in this section.

"Cycloalkyl" means a radical derived from nonaromatic mono - or polycyclic system comprising 3 to 10 carbon atoms. Cycloalkyl may have one or more "cyclic system substituents"which may be the same or different. Representatives cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalin, norbornyl, adamant-1-yl, etc. Cycloalkyl can be annylirovan with aromatic cycle or a heterocycle. Preferred "cyclic system substituents" are alkyl, Alcoxy, hydroxy or G1G2N, the value of which is determined in this section.

"Cycloalkylcarbonyl" means cycloalkyl-C(=O)- group in which the value of cycloalkyl defined in this section. Representatives of cycloalkylcarbonyl the selected groups are cyclopropanecarbonyl or cyclohexylcarbonyl.

"Cycloalkane" means cycloalkyl-O - group in which the value of cycloalkyl defined in this section.

"Pharmaceutical composition" means a composition comprising at least one biologically active compound (substance) and at least one component selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, distributing and perceiving means, means of delivery, such as preservatives, stabilizers, fillers, shredders, moisturizers, emulsifiers, suspendresume agents, thickeners, sweeteners, flavors, fragrances, antibacterial agents, fungicides, lubricants, regulators prolonged delivery, choice and value which depend on the nature, method of appointment and dosage. Examples suspendida agents are ethoxylated isostearoyl alcohol, polyoxyethylene, sorbitol and sorbitol ester, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant, as well as mixtures of these substances. Protection from the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid and the like soy is inane. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be achieved with agents that slow the absorption of the active agent, such as aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohol, and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as etiloleat). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of shredders and distributes funds are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulphate, talc, and polyethylene with high molecular weight. Pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration, the active principle, one or in combination with other active early, can be introduced animals and people in the standard form of administration, mixed with conventional pharmaceutical carriers. Usable standard form of introduction include oral forms such as tablets is etki, gelatin capsules, pills, powders, granules, chewing gum and oral solutions or suspensions, sublingual and transbukkalno forms of administration, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.

"Pharmaceutically acceptable salt" refers to the relatively non-toxic organic and inorganic salts of acids and bases, as claimed in the present invention. These salts can be obtained in situ during the synthesis, separation, or purification of compounds or prepared. In particular, salts of bases can be obtained specifically on the basis of the purified free base of the claimed compounds and a suitable organic or inorganic acid. Examples of the thus obtained salts are hydrochloride, hydrobromide, sulphates, bisulfate, phosphates, nitrates, acetates, oxalates, valeriote, oleates, palmitate, stearates, laurate, borate, benzoate, lactates, tozilaty, citrates, maleate, fumarate, succinate, tartratami, mesylates, malonate, salicylates, propionate, econsultancy, bansilalpet, sulfamate and the like. (For a detailed description of the properties of these salts is given in S.M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66: 1-19). Salts of the stated acids can also be specially receiving the s by the reaction of purified acid with a suitable base, this can be synthesized metal salts and amines. The metal include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum, the most desirable of which are sodium and potassium salts. Suitable inorganic bases which can be obtained metal salts are the hydroxide, carbonate, bicarbonate and sodium hydride, hydroxide and bicarbonate of potassium, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases, of which can be obtained salts of the stated acids, selected amines and amino acids with sufficient basicity to form a stable salt, and suitable for use in medical purposes (in particular, they should have a low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, Tris(hydroxymethyl)aminomethane and the like. In addition, for the salt formation can be used tetraalkylammonium hydroxide, such as choline, Tetramethylammonium, tetraethylammonium and the like. As amino acids can be used basic amino acids such as lysine, ornithine and arginine.

"Fragment" (scaffold) means structural formula cha is ti molecules, characteristic of a group of compounds or molecular frame, characteristic of a group of compounds or compounds included in "combinatorial library".

"1,2-Ethylene radical" sachet-CH2-CH2- the group that contains one or more identical or different "alkyl substituents", which is defined in this section.

The aim of the present invention is the creation of new ligands of 5-HT6the receptor.

This goal is achieved by the application as ligands of 5-HT6receptor azaheterocyclic compounds of General formula 1 or their racemates, or optical isomers or geometrical isomers, or their pharmaceutically acceptable salts and/or hydrates

where R2and R3independently from each other represent a Deputy amino group selected from hydrogen; substituted carbonyl; substituted aminocarbonyl; substituted aminothiazole; substituted sulfonyl; C1-C5-alkyl, optionally substituted C6-C10-aryl, heterocyclyl,6-C10-arylenecarborane,6-C10-arylaminothiourea,5-C10-azaheterocycles, optionally substituted carboxyla, nitrile group; optionally substituted aryl;

R1k/sub> represents from 1 to 3 substituents cyclic systems are independent from each other and selected from hydrogen, optionally substituted C1-C5-alkyl, C1-C5-alkyloxy,1-C5-alkenyl,1-C5-quinil, halogen, trifloromethyl, nitrile, carboxyl, optionally substituted aryl, optionally substituted heterocyclyl, substituted sulfonyl, optionally substituted carboxyl;

the dotted line with its accompanying solid line (represents a single or double bond; n=1, 2, or 3.

According to the invention preferred azaheterocyclic compounds as ligands of 5-HT6receptor are substituted pyrrolo[4,3-b]indoles of General formula 1.1 or their racemates, or optical isomers or geometrical isomers, or their pharmaceutically acceptable salts and/or hydrates

where R1k, R2, R3and the dotted line with its accompanying solid line (have the above values.

According to the invention preferred azaheterocyclic compounds as ligands of 5-HT6receptor are substituted 1,2,3,4-tetrahydropyrrolo[4,3-b]indole of General formula 1.2 or a racemate is, or their optical isomers or geometrical isomers, or their pharmaceutically acceptable salts and/or hydrates

where R1k, R2and R3have the above values.

According to the invention preferred azaheterocyclic compounds as ligands of 5-HT6receptor are substituted CIS-1,2,3,3A,4,8b-hexahydropyrazino[4,3-b]indole of General formula 1.3 or their racemates, or optical isomers or geometrical isomers, or their pharmaceutically acceptable salts and/or hydrates

where R1k, R2and R3have the above values.

According to the invention preferred azaheterocyclic compounds as ligands of 5-HT6receptor are replaced by γ-carboline General formula 1.4 or their racemates, or optical isomers or geometrical isomers, or their pharmaceutically acceptable salts and/or hydrates.

where R1k, R2, R3and the dotted line with soprovojdaya its solid line (have the above values.

According to the invention preferred azaheterocyclic compounds as ligands of 5-HT6is eceptor are substituted 1,2,3,4-tetrahydro-γ -carboline General formula 1.5 or their racemates, or optical isomers or geometrical isomers, or their pharmaceutically acceptable salts and/or hydrates

where R1k, R2and R3have the above values.

According to the invention preferred azaheterocyclic compounds as ligands of 5-HT6receptor are substituted 1,2,3,4,4A,9a-hexahydro-γ-carboline General formula 1.6 or their racemates, or optical isomers or geometrical isomers, or their pharmaceutically acceptable salts and/or hydrates

where R1k, R2and R3have the above value.

According to the invention preferred azaheterocyclic compounds as ligands of 5-HT6receptor are substituted CIS-1,2,3,4,4A,9a-hexahydro-γ-carboline General formula 1.7 or their racemates, or optical isomers or geometrical isomers, or their pharmaceutically acceptable salts and/or hydrates

where: R1k, R2and R3have the above values.

According to the invention preferred azaheterocyclic compounds as ligands of 5-HT6receptor for amennye TRANS-1,2,3,4,4A,9a-hexahydro-7-carboline General formula 1.8 or their racemates, or their optical isomers or geometrical isomers, or their pharmaceutically acceptable salts and/or hydrates

where R1k, R2and R3have the above values.

According to the invention preferred azaheterocyclic compounds as ligands of 5-HT6receptor are substituted azepino[4,3-b] indoles of General formula 1.9 or their racemates, or optical isomers or geometrical isomers, or their pharmaceutically acceptable salts and/or hydrates

where R1k, R2, R3and the dotted line with its accompanying solid line (have the above values.

According to the invention preferred azaheterocyclic compounds as ligands of 5-HT6receptor are substituted 1,2,3,4,5,6-hexahydroazepin[4,3-b]indoles of General formula 1.10 or their racemates, or optical isomers or geometrical isomers, or their pharmaceutically acceptable salts and/or hydrates

where R1k, R2and R3have the above values.

According to the invention preferred azaheterocyclic compounds as ligands of 5-HT6R is Ceptor are substituted 1,2,3,4,5,5A,6,10b-octahydrate[4,3-b]indoles of General formula 1.11 or their racemates, or their optical isomers or geometrical isomers, or their pharmaceutically acceptable salts and/or hydrates

where R1k, R2and R3have the above values.

According to the invention preferred azaheterocyclic compounds as ligands of 5-HT6receptor are substituted CIS-1,2,3,4,5,5A,6,10b-octahydrate[4,3-b]indoles of General formula 1.12 or their racemates, or optical isomers or geometrical isomers, or their pharmaceutically acceptable salts and/or hydrates

where R1k, R2and R3have the above values.

According to the invention preferred azaheterocyclic compounds as ligands of 5-HT6receptor are substituted TRANS-1,2,3,4,5,5A,6,10b-octahydro-azepino[4,3-b]indoles of General formula 1.13 or their racemates, or optical isomers or geometrical isomers, or their pharmaceutically acceptable salts and/or hydrates

where R1k, R2and R3have the above values.

The aim of the present invention is the creation of a pharmaceutical composition for treating and preventing various diseases of the Central nervous system of warm-blooded animals alive is different and people the pathogenesis of which is associated with 5-HT6the receptors.

This goal is achieved by a pharmaceutical composition for obtaining a medicinal product for treating and preventing diseases and conditions of the Central nervous system (CNS), the pathogenesis of which is associated with 5-HT6receptors containing as active substance pharmaceutically effective amount azaheterocyclic compounds of General formula 1 or its racemate, or optical isomer, or its geometric isomer, or its pharmaceutically acceptable salt and/or hydrate

where R1k, R2, R3, dotted line with its accompanying solid line (and n have the above values.

The aim of the present invention is also a method of obtaining a pharmaceutical composition.

This goal is achieved by a method of obtaining a pharmaceutical composition, which consists in mixing at least one of azaheterocyclic compounds of General formula 1 or its racemate, or optical isomer, or its geometric isomer, or its pharmaceutically acceptable salt and/or hydrate with an inert filler and/or diluent.

Under inert fillers and/or solvents (experiencemy) podrazumeva the tsya used in the field of pharmaceutical diluents, auxiliary agents and/or carriers. Azaheterocyclic compounds of General formula 1 according to the present invention can be used in combination with other active ingredients provided that they do not cause unwanted effects, such as allergic reactions.

When using the pharmaceutical compositions of the present invention in clinical practice it can be mixed with various fillers and diluents. For the production of different forms it can contain conventional pharmaceutical carriers; for example, oral formulations such as tablets, gelatin capsules, pills, solutions or suspensions); forms for injection (such as solutions or suspensions for injection or dry powder for injection, which requires only the addition of water for injection before use); local forms such as ointments or solutions).

The media used in the pharmaceutical compositions of the present invention, are media that are used in the pharmaceutical industry to obtain common forms, including: oral forms are used binders, lubricating agents, disintegrators, solvents, diluents, stabilizers, suspendresume agents, colorless agents, korrigentami taste; the forms are used for injections ant the septic agents, soljubilizatory, stabilizers; local forms are used bases, diluents, lubricating agents, antiseptic agents. The pharmaceutical preparations can be administered orally or parenterally (e.g. intravenously, subcutaneously, intraperitoneally or topically). If any of the medicinal substance in the conditions of the stomach is not stable, you can use it for the manufacture of tablets, film-coated substance, soluble in the stomach or intestines.

The aim of the present invention is also a drug for the treatment and prevention of diseases and conditions of the Central nervous system (CNS), the pathogenesis of which is associated with 5-HT6the receptors.

This goal is achieved medicinal product in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing for the treatment and prevention of diseases and conditions of the Central nervous system (CNS), the pathogenesis of which is associated with 5-HT6receptors, including in its composition a pharmaceutical composition comprising at least one ligand of General formula 1.

The clinical dosage of the pharmaceutical composition or drug containing as an active ingredient of azaheterocyclic compounds of General formula 1, patients may be adjusted depending on tera is eticheskoi efficiency and bioavailability of the active ingredients in the body, the speed of their metabolism and excretion from the body, and depending on age, gender and stage of disease of the patient, the daily dose in adults is usually 10˜500 mg, preferably 50˜300 mg. Therefore, during the preparation of pharmaceutical compositions of the present invention in the form of dosage units it is necessary to consider the above-mentioned effective dosages, each unit dosage of the drug should contain 10˜500 mg of azaheterocyclic compounds of General formula 1, preferably 50˜300 mg. In accordance with the instructions of the doctor or pharmacist these medications can be taken several times during a defined time period (preferably from one to six times).

Azaheterocyclic compounds of General formula 1 or their racemates, or optical isomers or geometrical isomers, or their pharmaceutically acceptable salts and/or hydrates are known compounds [Welch, W.M., Harbert, C.A., Weissman, A.J. Med. Chem. 1980, 23, 704-707. N.Barbulescu, .Bornaz, C.si Greff - Rev. Chim. (Bucuresti), 1971, v.22, p.269. Lermontova N.N., Lukoyanov NV, Serkova T.P., Lukoyanova E.A., Bachurin S.O. Dimebon improves learning in animals with experimental Alzheimer's′s disease. Bull Exp Biol Med. 2000, 129 (6), 544-546. Zefirov, N.S.; Afanasiev, A.Z.; Afanasievf, S.V.; Bachurin, S.E.; Tkachenko, S.E.; Grigoriev, V.V.; Jurovskaya, M.A.; Chetverikov, V.P.; Bukatina, E.E,; Grigoriev, I.V. US 6187785, 2001], many of which are commercially available from the American firm ChemDiv, Inc. (San Diego, CA: ww.chemdiv.com).

The drawing shows the concentration dependences of the degree of interaction of azaheterocyclic compounds of General formula 1 with 5-HT6receptor:

- 1.5 (20),- 1.10 (50),- 1.10 (51),- 1.10 (53),- 1.13 (13).

The following are specific examples which illustrate, but not limit the invention.

Example 1. The study of ligand activity by 5-HT6receptor azaheterocyclic compounds of General formula 1. Focused library, including 3537 azaheterocyclic compounds of General formula 1, their geometric isomers and their pharmaceutically acceptable salts, felt on ligand activity by 5-HT6the receptor. Some examples of proven azaheterocyclic compounds of General formula 1 are presented in tables 1-3, including pyrrolo[4,3-b]indoles 1.2, 1.3 (table 1), γ-carboline 1.5, 1.6, 1.7 (table 2) and azepino[4,3-b]indoles 1.10, 1.12, 1.13 (table 3). Ligand activity was determined by the ability of azaheterocyclic compounds of General formula 1 of competitively tritium-labeled diethyl ether lysergic acid diethylamide ([3H]LSD), specifically bind to the serotonin 5-HT6receptors expressed in the membranes of HeLa cells [Monsm FJ Jr, Shen Y, Ward RP, Hamblin MW and Sibley DR (1993). Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol Pharmacol. 43: 320-327]. Cell membranes were incubated with 1.5 nm [3H]LSD for 2 hours at 37°From without and in the presence of 10 μm concentrations of the tested compounds in a medium containing 50 mm Tris-HCl, pH 7.4, 150 mm NaCl, 2 mm ascorbic acid and 0.001% bovine serum albumin. Nonspecific binding of [3H]LSD was determined in the presence of 5 μm serotonin (5-HT). After incubation, the membrane suspension was filtered through a glass microfibre filters GF/A (Millipor, USA) and the remaining radioactivity was measured by scintillation counter Microbeta 1840 (PerkinElmer). The investigated compounds will effectively interact with 5-HT6the receptor. Table 4 shows the efficiency of the interaction of some of the tested compounds of General formula 1 with 5-HT6the receptor.

td align="center"> 76
Table 4
Examples of the efficiency of interaction azaheterocyclic compounds of General formula 1 with 5-HT6receptor
No. of azaheterocyclic compounds of General formula 1The efficiency of interaction of the compounds of General formula 1 with 5-HT6receptor, %
12
1.2 (39)77
1.3 (9)27
1.5 (18)71
1.5 (20)100
1.6 (6)52
1.6 (22)82
1.7 (1)47
1.10 (49)88
1.10 (50)84
1.10 (51)84
1.10 (53)79
1.12 (12)84
1.12 (13)
1.13 (3)93
1.13 (13)93

Example 2. The measurements were carried out under the conditions described in example 1, except that compound were taken at various concentrations and the percent displacement of [3H] LSD was plotted on a graph as a function of the concentration of the compound (see drawing), from which expected values IC50(concentration premaxillae blocking the binding of [3H] LSD)characterizing the apparent affinity of substituted azaheterocyclic compounds of General formulae 1 to 5-HT6the receptor (see table 5).

Table 5
The magnitude of the apparent affinity azaheterocyclic compounds of General formula 1 (IC50to 5-HT6receptor
ConnectionIC50that μM
1.5 (20)0.074
1.10 (50)1.250
1.10 (51)1.060
1.10 (53)0.738
1.13 (13)0.787

Example 3. An example illustrating the preparation of tablets containing 100 mg of active ingredient. Mix 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg of azaheterocyclic is soedineniya 1.5 (20) or 1.10 (49), or 1.10 (53) 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 560 mg each. According to the invention likewise receive pharmaceutical composition in the form of tablets containing as active ingredient other azaheterocyclic compounds of General formula 1.

Example 4. Capsules containing 200 mg of azaheterocyclic compounds 1.5 (20) or 1.10 (49), or 1.10 (53) according to the invention can be obtained by thorough mixing of the compound 1.5 (20) or 1.10 (49), or 1.10 (53) with lactose powder in a 2:1 ratio. The obtained powder mixture is Packed 300 mg in gelatin capsules of suitable size.

Example 5. Injectable compositions for intramuscular, intraperitoneal or subcutaneous injection can be prepared by mixing 500 mg of the active ingredient with suitable solvents, such as hydrochloride of azaheterocyclic compounds 1.10 (53) with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injectable water. The resulting solution is filtered and placed in 1 ml ampoules which are sealed and sterilized in an autoclave.

1. Use as ligands of 5-HT6receptor azaheterocyclic compounds of General formula 1 or their racemates, or opt the ical isomers, or their pharmaceutically acceptable salts and/or hydrates

where R2and R3independently from each other represent a Deputy amino group selected from hydrogen; substituted carbonyl; substituted aminocarbonyl; substituted aminothiazole; substituted sulfonyl; C1-C5-alkyl, optionally substituted C6-C10-aryl, optionally substituted heterocyclyl,6-C10-arylenecarborane,6-C10-arylaminothiourea,5-C10-azaheterocycles, optionally substituted carboxyla, nitrile group; optionally substituted aryl;

R1k- represent from 1 to 3 substituents cyclic systems are independent from each other and selected from hydrogen, optionally substituted C1-C5-alkyl, C1-C5-alkyloxy,1-C5-alkenyl,1-C5-quinil, halogen, trifloromethyl, nitrile, carboxyl, optionally substituted aryl, optionally substituted heterocyclyl, substituted sulfonyl, optionally substituted carboxyl; dotted line with its accompanying solid line (represents a single or double bond; n=1, 2, or 3.

2. The use according to claim 1, distinguished by the Eesa fact, as azaheterocyclic compounds used substituted pyrrol o [4,3-b] indoles of General formula 1.1

where R1k, R2, R3and the dotted line with its accompanying solid line (have the above value.

3. The use according to claim 1, characterized in that the quality of azaheterocyclic compounds use of substituted 1,2,3,4-tetrahydro-pyrrolo[4,3-b]indoles of General formula 1.2

where R1k, R2, R3have the above value.

4. The use according to claim 1, characterized in that the quality of azaheterocyclic compounds use of substituted CIS-1,2,3,3A,4,8b-hexahydro-pyrrolo[4,3-b]indoles of General formula 1.3

where R1k, R2, R3have the above value.

5. The use according to claim 1, characterized in that the quality of azaheterocyclic compounds used replaced by γ-carbolines, which General formula 1.4

where R1k, R2, R3and the dotted line with its accompanying solid line (have the above value.

6. The use according to claim 1, characterized in that the quality of azaheterocyclic compounds use of substituted 1,2,3,4-tetrahydro-γ -carboline General formula 1.5

where R1k, R2, R3have the above value.

7. The use according to claim 1, characterized in that the quality of azaheterocyclic compounds use of substituted 1,2,3,4,4A,9a-hexahydro-γ-carboline General formula 1.6

where R1k, R2, R3have the above value.

8. The use according to claim 1, characterized in that the quality of azaheterocyclic compounds use of substituted CIS-1,2,3,4,4A,9a-hexahydro-γ-carboline General formula 1.7

where R1k, R2, R3have the above value.

9. The use according to claim 1, characterized in that the quality of azaheterocyclic compounds use of substituted TRANS-1,2,3,4,4A,9a-hexahydro-γ-carboline General formula 1.8

where R1k, R2, R3have the above value.

10. The use according to claim 1, characterized in that the quality of azaheterocyclic compounds used substituted azepino[4,3-b]indoles of General formula 1.9

where R1k, R2, R3and the dotted line with soprovojdalos the th its solid line ( have the above value.

11. The use according to claim 1, characterized in that the quality of azaheterocyclic compounds used substituted 1,2,3,4,5,6-hexahydro-azepino[4,3-b]indoles of General formula 1.10

where R1k, R2, R3have the above value.

12. The use according to claim 1, characterized in that the quality of azaheterocyclic compounds used substituted 1,2,3,4,5,5A,6,10b-octahydro-azepino[4,3-b]indoles of General formula 1.11

where R1k, R2, R3have the above value.

13. The use according to claim 1, characterized in that the quality of azaheterocyclic compounds use of substituted CIS-1,2,3,4,5,5A,6,10b-octahydro-azepino[4,3-b]indoles of General formula 1.12

where R1k, R2, R3have the above value.

14. The use according to claim 1, characterized in that the quality of azaheterocyclic compounds used substituted TRANS-1,2,3,4,5,5A,6,10b-octahydro-azepino[4,3-b]indoles of General formula 1.13

where R1k, R2, R3have the above value.

15. Pharmaceutical composition for obtaining a medicinal product for treatment and prevention of diseases and conditions of the Central nervous system (CNS), the pathogenesis of which is associated with 5-HT6receptors containing as active substance pharmaceutically effective amount of a ligand according to any one of claims 1 to 14.

16. A method of obtaining a pharmaceutical composition according to item 15, which consists in mixing at least one ligand according to any one of claims 1 to 14 with an inert filler and/or diluent.

17. The drug is in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing for the treatment and prevention of diseases and conditions of the Central nervous system (CNS), the pathogenesis of which is associated with 5-HT6receptors, which includes in its membership at least one ligand according to any one of claims 1 to 14 or a pharmaceutical composition according to item 15.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to the novel inhibitor of phosphodiesterase (PDE) IV and/or to the tumor necrosis factor (TNF) production inhibitor, which corresponds to the compound with formula (I), where R1 is: (1) mono- or di(inferior)alkylamino, (2) phenyl, (3) saturated or unsaturated 5-or 6-membered heteromonocyclic group, selected from a group which includes pyrrolidinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thienyl and piridinyl, or (4) inferior alkyl not necessarily substituted with (i) inferior alkoxi or (ii) saturated 5- or 6-membered heteromonocyclic group, selected from the group, consisting of piperazinyl and morpholinyl, where the inferior alkoxi is not necessarily substituted with cyclo(inferior)alkyl or piridinyl, R2 corresponds to R7 or - A2R7 , where A2 is -(CH2)n- or -(CH=CH)m- [where n is an even number within 2 to 6, and m is an even number 1 or 2], and R7 is a hydrogen, inferior alkylsulfonyl, carboxy, etherificated carboxy or piridinyl; R3 is: (1) phenyl, not necessarily substituted with inferior alkyl, cyclo(inferior)alkyl, inferior alkoxi, halogen, cyano or carbamoyl; or (2) quinolinyl; or piridinyl, substituted with inferior alkyl, cyclo(inferior)alkyl, inferior alkoxi, carbamoyl or halogen, and R4 corresponds to the inferior alkyl, or its pharmaceutically acceptable salt. The application of the compound with formula is invented, for producing the therapeutic agent with the PDE IV and/or TNF production inhibiting activity and the pharmaceutical composition containing the effective amount of compounds with formula (I) mixed with the pharmaceutically acceptable carriers. The method for prevention and treatment of the diseases where the application of the PDE IV and/or TNF production inhibitor is considered to be reasonable, including the administration of the therapeutically effective amount of the compound with formula (I). The method for prevention and treatment of asthma, chronic obstructive pulmonary disease, fibrous disorders, acute and fulminant hepatitis, hepatic steatosis, chronic hepatitis, cirrhosis, autoimmune hepatitis, autoimmune inflammatory intestine disease, atopic dermatitis, Alzheimer's disease or viral infection, including the administration of the therapeutically or preventively effective amount of the compound with formula (I).

EFFECT: compound with the PDE IV and/or TNF production inhibiting activity.

11 cl, 2 tbl, 672 ex

FIELD: chemistry.

SUBSTANCE: invention relates to producing the novel compounds with dipeptidyl peptidase IV (DPP-IV) inhibiting activity and particularly, it relates to the compounds with the condensed 1,3-dihydroimidazole cycle. The invention relates to the compounds represented by the common formula (II), or their pharmaceutically acceptable salts, where, Z3a means nitrogen atom or the group with formula -CR2a=; X3a means oxygen atom or sulfur atom; T1a means piperazine-1-yl group, 3-amino-piperidine-1-yl group, 3-methylamino-piperidine-1-yl group; X1a means oxygen atom hydrogen, C2-6-alkenyl group, C2-6-alkynyl group or benzyl group; each of R1a and R2a independently means hydrogen atom, halogenatom, C1-6-alkyl group, cyanogroup or group, represented with formula-A0a-A1a; A0a means oxygen atom, sulfur atom or group, represented with formula-NA2a-; Ala means hydrogen atom, C1-6-alkyl group, C1-6-alkenyl group, C2-6-alkynyl group, phenyl group, cyanophenyl group, carbamoylphenyl group, benzyl group; A2a means hydrogen atom or C1-6-alkyl group; X2a means hydrogen atom, C2-6-alkenyl group, C2-6-alkynyl group, 1H-piridine-2-onyl group, 1-methyl-1H-piridine-2-onyl group, C1-6-alkyl group, which can have a group, selected from the substitutes group specified below B, phenyl group, which can have a group, selected from the substitutes group specified below B, 5- or 6-membered heteroarylgroup, containing one or two nitrogen atoms, oxygen or sulfur, which can have a group, selected from the substitutes group specified below B, phenylC1-6-alkyl group, which can have a group, selected from the substitutes group specified below B: <Substitutes group B> substitutes group B is group, including chlorine atom, bromine atom; cyanogroup, C1-b-alkyl group, C2-b-alkenyl group, C2-6-alkynyl group, C3-8-cycloalkyl group, C1-6alcoxigroup, carbamoyl groupcarboxyl group and C1-6-alcoxicarbonyl group.

EFFECT: research and revealing compounds with DPP-IV inhibiting activity, useful as pharmaceutical agents which can be used as therapeutic and preventing medicines in such diseases as diabetes, obesity and hyperlipidemia.

12 cl, 84 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the novel compounds with formula I or their pharmaceutically acceptable salts and based on them pharmaceutics with the CRF (corticotrophin releasing factor) related activity. In the common formula I , X1 means (CH2)n, where n equal to 0-2, R1 means (1)C1-C10alkyl or C1-C10alkenyl, not necesserily substituted with substitute, selected from the group, including hydroxy, cyano, (C1-C3alkyl)arylamino and phenyl, and said phenyl not necesserily substituted with one-three substitutes, independently selected from the group including C1-C6alkyl, C1-C6alkoxi, halogen, (2) C3-C7cycloalkyl, not necesserily substituted with hydroxy,(3) C3-C7cycloalkyl(C1-C3)alkyl or C3-C7cycloalkenyl(C1-C3)alkyl,(4) C4-C12tricyclic alkyl,(5)C3-C7heterocycloalkyl or C3-C7heterocycloalkyl(C1-C3)alkyl, where each of the heterocyclic rings contains in the ring 1-2 heteroatoms, selected from nitrogen, oxygen or sulfur, and not necesserily can be substituted with the group C1-C3alkyl, phenyl or phenyl(C1-C6)alkyl, or the CH2 group in the heterocycloalkyl residue is substituted with C=O,(6) benzo-condensed (C5-C7)cycloalkyl,(7) phenyl, and said phenyl is not necesserily substituted with one-three substitutes, independently selected from the group including C1-C6alkyl, C1-C6alkoxi, methylendioxy, halogen, (8) naftyl, (9) heteroaryl(C1-C6)alkyl, and said heteroaryl(C1-C6)alkyl has 5-6 atoms in the ring and contains 1-2 heteroatoms, selected from nitrogen, oxygen or sulfur, can be condensed with the benzene ring and not necesserily substituted with one-three substitutes, selected from the group, including C1-C6alkyl, (10) 1,2-diphenylethyl,(12) C1-C3alkoxi(C1-C6)alkyl or (13) aryloxy(C1-C6)alkyl, R2 means C1-C6alkyl, R3 means (1) hydrogen,(2) C1-C6alkyl, not necesserily substituted with the group C1-C3acyloxy,(3) C3-C6alkenyl,(8) benzene, and R4 means phenyl, not necesserily substituted with one-three substitutes, independently selected from the group including C1-C6alkyl, halogen.

EFFECT: compounds can be used in treatment of phobias, stress dependent disorders, mental disorders, gastro-intestine disfunctions, neurodegenerative and other psychoneurologic disease.

19 cl, 2 dwg, 2 tbl, 8 ex

FIELD: medicine; pharmacology.

SUBSTANCE: new discovered pyrimidine compounds of formula where R1-R9 are those as specified are selective inhibitors of group Src of nonreceptor tyrosine kinases. These compounds and their pharmaceutically acceptable salts are antiproliferative agents applied for treatment and fight against solid tumours, specifically breast tumours, rectum tumours, liver and pancreatic tumours.

EFFECT: applicable for cancer treatment.

17 cl, 5 dwg, 16 ex, 1 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new condensed derivatives of azolpyrimidine of formula (I), their tautomeric or stereoisomeric form and their physiologically accepted salts. Compounds of this invention have improved activity of phosphatidyl inositol-3-kinase (P13K) inhibiting, specifically of P13K-γ inhibiting, and can be applied for production of medicinal agents for prevention and treatment of P13K- and P13K-γ activity based diseases. Those diseases are inflammatory and immunoregulatory diseases such as asthma and others. In compounds of formula (I) . X means CR5R6 or NH; Y1 means CR3 or N; chemical bond between means single bond or double bond, as long as means double bond, then Y2 and Y3 mean CH, and as long as mean single bond, then Y2 and Y3 mean regardless CR3R4; Z1, Z2, Z3 and Z4 mean redardless CH , CR2 or N; R1 means phenyl, optionally containing 1 to 3 substitutes selected from group including R11, C3-8cycloalkyl, optionally containing 1 to 3 substitutes selected from group including R11, C1-6alkyl, optionally containing as substitutes one or more halogen atoms, or 3-15-component mono- or bicyclic heterocyclic ring being saturated or non-saturated, optionally containing 1 to 3 substitutes selected from group including R11, and containing 1 to 3 heteroatoms selected from group including N, O and S, where R11 means halogen, nitro-, hydroxyl-, cyano-, carboxy-, amino-, N-(C1-6alkyl)amino-, K-(hydroxyC1-6alkyl)amino-, N,N-di(C1-6alkyl)amino-, N(C1-6acyl)amino-, N-(formyl)-N-(C1-6 alkyl) amino-, N-(C1-6alkansulphonyl)amino-, N-(carboxy C1-6 alkyl)-N-(C1-6 alkyl) amino-, N-(C1-6 alkansulphonyl)amino-, N-[N,N-di(C1.6 alkyl)aminomethylene] amino-, N-[N,N-di(C1-6 alkyl)amino(C1-6 alkyl)methylene]amino-, N-[N,N-di(C1-6 alkyl)aminoC1-6alkenyl]amides, aminocarbonyl, N-(C1-6 alkyl)aminocarbonyl, N,N-di(C1-6 alkyl)aminocarbonyl, C3-8 cycloalkyl, C1-6alkylthio, C1-6 alkansulphonyl, sulphamoyl, C1-6alkoxycarbonyl, phenylC1-6alkoxycarbonyl, where specified phenylic fragment optionally contains 1 to 3 substitutes selected from group including R101, C1-6alkyl, optionally containing as substitutes 1, 2 or 3 halogen atoms, C1-6alkoxy, optionally containing as substitutes 1, 2 or 3 halogen atoms, or 5- 7-component saturated or non-saturated ring containing 1 to 3 heteroatoms selected from group containing N, and optionally containing 1 to 3 substitutes selected from group including and R101, where R101 means halogen, carboxy, amino-, N-(C1-6alkyl)amino-, N,N-di(C1-6alkyl)amino-, aminocarbonyl, N-(C1-6alkyl)aminocarbonyl, N,N-di(C1-6alkyl)aminocarbonyl, C1-6alkyl, and C1-6alkoxy; R2 mean hydroxy, halogen, nitro-, cyano-, amino-, N-(C1-6alkyl)amino-, N,N-di(C1-6alkyl)amino-, N-(hydroxyC1-6alkyl)amino-, N-(hydroxyC1-6alkyl)-N-(C1-6alkyl)amino-, C1-6 acoxy, aminoC1-6 acoxy, C2-6alkenyl, phenyl, 5-7-compound saturated or non-saturated heterocyclic ring containing 1 to 2 heteroatoms selected from group including O and N, and optionally containing as substitutes: hydrohy, d-balkyl, N-(C1-6acyl)amino-, phenyl, phenylC1-6alkyl, C1-6alkyl, optionally containing as substitutes R21, or C1-6alkoxy, optionally containing as substitutes R21, where R21 means cyano group, 1, 2 or3 halogen atoms, hydroxy, amino-, N-(C1-6alkyl)amino-, N,N-di(C1-6alkyl)amino-, C1-6alkoxy, hydroxyC1-6alkoxy, -C(O)-R201, -NHC(O)-R201, C3-8 cycloalkyl, phthalymidil, 2-oxo-1,3-oxazolidinyl, phenyl or 5- or 6-compound saturated or non-saturated heterocyclic ring containing 1 to 4 heteroatoms selected from group including O and N, and optionally containing as substitutes hydroxy, C1-6alkyl, N-(C1-6acyl)amides or benzyl, where R201 means hydroxyl, amino-, N-(C1-6alkyl)amino-, N,N-di(C1-6alkyl)amino-, N-(halogenphenylC1-6 alkyl)amides, C1-6alkyl, aminoC1-6alkyl, C1-6alkoxy, 5- or 6-compound saturated or non-saturated heterocyclic ring containing 1 to 2 heteroatoms selected from group including O and N; R3 means hydrogen, halogen, aminocarbonyl or C1-6alkyl, optionally containing as substitutes phenylC1-6alkoxy or 1, 2 or 3 halogen atoms; R4 means hydrogen or C1-6alkyl; R5 means hydrogen or C1-6alkyl; and R means halogen, hydrogen or C1-6alkyl. Invention also refers to medicinal agent, inhibition method and compound application.

EFFECT: compounds under this invention have improved activity.

16 cl, 2 tbl, 18 ex

Asaindoles // 2326880

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to pharmaceutical formulation inhibiting protein kinase, containing inhibiting selective kinase compound amount of general formula (I): , where: R means aryl or indolyl, and the latter is optionally substituted with one or more groups selected from R4, -C(=O)-R, -C(=O)-OR5, -C(=O)-NY1Y2 and -Z2R; R2 means H; R3 means H; R4 means C1-C6 alkyl, optionally substituted with one substitute -C(=O)-NY1Y2; R5 means H; R7 means C1-C6 alkyl; R means C1-C6 alkyl; X1 means C-aryl, C-heteroaryl, such as pyridile or isoxasolyl, and the latter is optionally substituted with one or two C1-C6 alkyls, C-heterocycloalkyl, such as morpholinile or peperidynil, C-halogen, C-CN, C-OH, C-Z2R, C-C(=O)-OR5, C-NYlY2, C-C(=O)-NY1Y2; Y1 and Y2 means redardless H, aryl, C3-C6 cycloaryl, C1-C6 alkyl, optionally substituted with one group selected from phenyl, halogen, heterocyclil, such as morpholinile, phurile, hydroxyl, -C(=O)-OR5, OR7; or group-NY1Y2 can form morpholinile, peperidynil, optionally substituted with one or two substitutes selected from OH, C1-C6 alkyl; Z means O; where aryl as group or part of group means optionally substituted with one or two substitutes monocyclic aromatic C6carbocyclic fragment, where substitute is selected from halogen or C1-C6 alkoxy, C(=O)-OR5; except compounds: 4-chlorine-2-(4-tert-butylphenyl)-1H-pyrrole[2,3-b]pyridine, 2-(5-methoxy-1 -methyl-1 H-indole-3-il)-4-phenyl-1H- pyrrole[2,3-b]pyridine, 2-(5- methoxy-1 -methyl-1 H-indole-3-il)-1H- pyrrole[2,3-b] pyridine-4-carbonitrile, 4-chlorine-2-(5- methoxy-1 -methyl-1H-indole-3-il)-1H- pyrrole[2,3-b]pyridine, or 2-(5- methoxy-1H-indole-3-il)-1H- pyrrole[2,3-b]pyridine -4- carbonitrile.

EFFECT: application of compound for production of medicinal agent for inflammatory disease.

51 cl, 9 tbl, 148 ex

FIELD: chemistry.

SUBSTANCE: described is the compound of the general formula , where R1, R2, R3, R4, R5, R6, R7, R8 can be identical or different represent independently hydrogen, halogen, percahalogenalkyl, (C1-C3)alkyl or (C1-C3)alkoxy; R9, R10, R11, R12 R13 and R14 can be identical or different and represent independently hydrogen or (C1-C3)alkyl; "n" is equal to 1 or 2, it is preferable that n be equal to 1; not obligatorily R13 and R14 together with nitrogen atom cab form a 6- term heterocyclic ring, where heterocycle can also be substituted by (C1-C3)alkyl that can have "additional heretoatoms", selected from N and O. Described also are intermediate compounds, the method of their production, pharmaceutical composition and the use of pharmaceuticals intended for treatment of the cases when modulation of the 5-HT receptor activity.

EFFECT: compounds as per this invention are applicable in treatment of disturbances of nervous system.

16 cl, 34 ex

FIELD: medicine; pharmacology.

SUBSTANCE: this invention describes new crystal forms of tryazol[4,5-d]pyrimidine formula I , composition methods and based pharmaceutical formulations. Compounds develop high efficiency as antagonist P2T, can be applied for medical prevention and treatment of arterial thrombotic complication, as well as tumour growth and extension.

EFFECT: compounds show high metabolic stability and bioavailability.

22 cl, 5 ex, 6 dwg

FIELD: chemistry.

SUBSTANCE: invention refers to organic substances production and can be applied for production of herbicides and other bioactive compounds. Production of 2-sulphanilamine-1,2,4-triazolo[1,5-a]pyrimidine of general formula , where R1 is metal, phenylic, 4-methyl phenylic, 4-chlorophenylic group, R is phenylic, 4-methyl phenylic, 4-chlorophenylic, methoxyphenylic group, R is metal, phenylic, 4-methyl phenylic, 4-chlorophenylic group is sulphurization of 2-amino-4,7-dihydro-1,2,4-triazolo [1,5-a]pyrimidines (II) by sulphochlorides (III) in pyrimidine and oxidation of produced 2-sulphanilamine-4,7-dihydro-1,2,4-triazolo[1,5-a] pyrimidines (IV) by bromine in acetic acid with sodium acetate occurrence.

EFFECT: method allows to produce compounds using low-price and reasonable raw materials without any complicated processing steps applied.

1 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of heterocyclic compounds, which contain pyrrolo[1,2-а][1,4]diazepine fragment, annelated to aromatic and heteroaromatic ring. Method for preparation of derivatives of pyrrolo[1,2-а][1,4]diazepine of general formula I, where А =

, is described. The said derivatives may be of use as substances with potential CNS activity, or with analgesic, antimicrobial and antifungal effect. Method implies recyclization of furan ring of 5-methyl-furfurylamides of general formula 2, , where А stands for above shown groups, by exposure to temperature of 60-70°С in the mixture of glacial acetic acid and strong hydrochloric acid in volumetric ratio 1:0.15 for 10-15 minutes.

EFFECT: provides for simultaneous formation of pyrrole and diazepine rings and improves yield of end products due to less number of process steps.

The invention relates to new chemical substances suitable for use as medicaments, in particular to the xanthine derivative of General formula I

R3where R1and R2lower alkyl;

R3the rest of the group, including tetrahydrofurane, thiophene, dithiolane, dithienyl, furan, optionally substituted by a group: -CH2OH, CHO, COOH,

-CH=where Alk denotes alkyl with 1-4 carbon atoms,

-CH=CH-CO-NO,

-CONHN-CH< / BR>
-CH=C< / BR>
-CH=C< / BR>
-CONH-(CH2)2N(Alk)2where Alk has the specified value, tetrahydrofuran, optionally substituted lower alkyl or the group-CH2CH2-CO-NO, or furan or thiophene, substituted lower alkyl or nitro-group or the unsubstituted cycloalkyl with 6-8 carbon atoms, cycloalkane or ticlea, alseny of Gruppman2,N,NH-phenyl, whereby phenyl may be substituted,NOH, -OCONH-phenyl, and phenyl may be samisens-COOCH3, -CH2COOCH3, -CH2CH2NH2, -OC(C6H5)3, -OALK, where Alk has the specified value, ОСОR4where R4matter: the rest campanulas acid, lower alkyl, phenyl, substituted lower alkoxyl, phenyl, methoxymethyl, six-membered nitrogen-containing heterocycle; cyclohexane, substituted cyanomethylene or oxyalkyl1-C4or hydroxy-group, or cyclopentane, substituted lower alkyl or phenyl, which may have as a second Deputy in genialnom position relative to the first hydroxyl group or ketal formula

or R3residue selected from the group:

(CH2)1,2< / BR>
ororin VI

FIELD: chemistry.

SUBSTANCE: invention relates to producing the novel compounds with dipeptidyl peptidase IV (DPP-IV) inhibiting activity and particularly, it relates to the compounds with the condensed 1,3-dihydroimidazole cycle. The invention relates to the compounds represented by the common formula (II), or their pharmaceutically acceptable salts, where, Z3a means nitrogen atom or the group with formula -CR2a=; X3a means oxygen atom or sulfur atom; T1a means piperazine-1-yl group, 3-amino-piperidine-1-yl group, 3-methylamino-piperidine-1-yl group; X1a means oxygen atom hydrogen, C2-6-alkenyl group, C2-6-alkynyl group or benzyl group; each of R1a and R2a independently means hydrogen atom, halogenatom, C1-6-alkyl group, cyanogroup or group, represented with formula-A0a-A1a; A0a means oxygen atom, sulfur atom or group, represented with formula-NA2a-; Ala means hydrogen atom, C1-6-alkyl group, C1-6-alkenyl group, C2-6-alkynyl group, phenyl group, cyanophenyl group, carbamoylphenyl group, benzyl group; A2a means hydrogen atom or C1-6-alkyl group; X2a means hydrogen atom, C2-6-alkenyl group, C2-6-alkynyl group, 1H-piridine-2-onyl group, 1-methyl-1H-piridine-2-onyl group, C1-6-alkyl group, which can have a group, selected from the substitutes group specified below B, phenyl group, which can have a group, selected from the substitutes group specified below B, 5- or 6-membered heteroarylgroup, containing one or two nitrogen atoms, oxygen or sulfur, which can have a group, selected from the substitutes group specified below B, phenylC1-6-alkyl group, which can have a group, selected from the substitutes group specified below B: <Substitutes group B> substitutes group B is group, including chlorine atom, bromine atom; cyanogroup, C1-b-alkyl group, C2-b-alkenyl group, C2-6-alkynyl group, C3-8-cycloalkyl group, C1-6alcoxigroup, carbamoyl groupcarboxyl group and C1-6-alcoxicarbonyl group.

EFFECT: research and revealing compounds with DPP-IV inhibiting activity, useful as pharmaceutical agents which can be used as therapeutic and preventing medicines in such diseases as diabetes, obesity and hyperlipidemia.

12 cl, 84 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the novel compounds with the formula (I) or their pharmaceutically or veterinary-acceptable salts: where: R1 and R3 independently represent H; F; Cl; Br; C1-C6alkyl; R2 represents H or C3-C7cycloalkyl; Y represents -S- or -N(R5)-, where R5 represents H; X represents the bind; R4 represents -C(=O)NR6R7, where R6 represents H or radical of formula -(Alk)b-Q, where b is equal to 0 or 1, and Alk is not necessarily substituted with C1-C6alkyl, C1-C6alkoxi, F, Cl, Br, oxo, COOH, bivalent C1-C12alkylen, C2-C12alkenylen with direct or ramified chain, which can be disconnected with one ore several non-adjacent -O-, -S- or -N(R8)-, where R8 represents H or C1-C4alkyl, C3-C4alkenyl or C3-C6cycloalkyl, and Q represents H; -SH; -NR8R8, where each R8 can be similar or different; the complex ether group; or not necessarily substituted with C1-C6alkyl, C1-C6alkoxi, phenyl, benzyl, phenoxy, C3-C8cycloalkyl, amino, fluor, bromine, oxo, -COOH, -CORA, -COORA, NHRA, -NRARB, where RA and RB are independent (C1-C6)alkyl group, phenyl, C3-C7cycloalkyl, C5-C7cycloalkenyl or heterocyclilc ring containing 5 to 8 ring atoms; and R7 represents H or C1-C6alkyl; or, taken together with atom or atoms, they are bound with, R6 and R7 form not necessarily substituted with (C1-C6)alkyl, COORA, where RA is the (C1-C6)alkyl group, phenyl, not necessarily substituted with F, Cl, Br, heterocyclilc ring containing 5 to 8 ring atoms. The invention also relates to N-(3-dimethylaminopropyl)-4-(4-cyclopropyl-3-oxo-3,5-dihydropirazol[4,3-c]quinoline-2-il]benzamide; to application of the compounds; to the immunomodulation method and to the pharmaceutical and veterinary composition.

EFFECT: production of novel immunobiologic compounds.

14 cl, 173 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the novel substituted indoline phemylsulfamide derivatives with the common formula , where A means C-R11 group or nitrogen, and R11 means hydrogen or alkyl with 1-4 carbon atoms, X means oxygen, R1 means aryl with 6-10 carbon atoms, unsubstituted or once-triple substituted with the similar or different substitutes, selected from the group which includes halogen, zyano, alkyl with 1-6 carbon atoms, alkoxi with 1-6 carbon atoms, phenoxi, benziloxi, trifluoromethyl, trifluorometoxi, alkenil with 2-6 carbon atoms, phenyl, alkylthio with 1-6 carbon atoms, mono- and dialkylamino with 1-6 carbon atoms in each alkyl group, or means the group with formula , R2 and R3 similar or different and independently from each other mean hydrogen or alkyl with 1-6 carbon atoms, or with the carbon atom they are bound to form the 3-7-membered spiro-compound cycloalkylic ring, R4 means hydrogen or alkyl with 1-6 carbon atoms, R5 R4 means hydrogen or alkyl with 1-6 carbon atoms, R6 means hydrogen or alkyl with 1-6 carbon atoms, R7 means hydrogen, alkyl with 1-6 carbon atoms, R8 - R10 mean hydrogen; as well as to their pharmaceutically compatible salts.

EFFECT: compounds are designated for prevention and/or treatment of cardio-vascular diseases, particularly dislipidemia and ischemic heart disease.

4 cl, 1 dwg, 96 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention pertains to derivatives of 7-phenylpyrazolopyridine with formula (I) ,where R1, R5, R6, R40, R41 and R42 represent different hydrocarbon substitutes or functional groups, its salts or hydrates, and especially to salts of N-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyradin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine. The compound with formula (I), especially salts of N-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyradin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine, act as antagonists of the receptor of corticotrophin release factor and can be used in medicine for treating various diseases of the nervous system and the gastrointestinal tract.

EFFECT: obtaining of new biologically active substances.

162 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of indole with general formula 1: where R is unsubstituted or substituted quinolyl, pyridopyrazinyl, indazolyl or pyridyl and which is directly bonded to nitrogen of the amide group; R1 is unsubstituted or substituted alkly-aryl; R2 represents hydrogen; R3-R6 represent hydrogen, R7 represents (C1-C6)-alkylcarbonyl or (C1-C6)- alkoxycarbonyl, and X, Y represent oxygen or sulphur, under the condition that, when R is an unsubstituted or substituted 2-, 3-, 4-, 5- and 6-pyridyl group and R1-R6 have the above mentioned values, R7 is not an acetyl radical or tert-butyloxycarbonyl group. The invention also relates to physiologically tolerant salts of the indole derivatives, as well as to pharmaceutical compositions based on them and their use in obtaining medicinal preparations.

EFFECT: obtaining of medicinal preparations, used as medicines for curing tumorous diseases, especially in case of resistance to other drugs and metastasising carcinomas.

14 cl, 7 tbl, 6 dwg, 25 ex

Asaindoles // 2326880

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to pharmaceutical formulation inhibiting protein kinase, containing inhibiting selective kinase compound amount of general formula (I): , where: R means aryl or indolyl, and the latter is optionally substituted with one or more groups selected from R4, -C(=O)-R, -C(=O)-OR5, -C(=O)-NY1Y2 and -Z2R; R2 means H; R3 means H; R4 means C1-C6 alkyl, optionally substituted with one substitute -C(=O)-NY1Y2; R5 means H; R7 means C1-C6 alkyl; R means C1-C6 alkyl; X1 means C-aryl, C-heteroaryl, such as pyridile or isoxasolyl, and the latter is optionally substituted with one or two C1-C6 alkyls, C-heterocycloalkyl, such as morpholinile or peperidynil, C-halogen, C-CN, C-OH, C-Z2R, C-C(=O)-OR5, C-NYlY2, C-C(=O)-NY1Y2; Y1 and Y2 means redardless H, aryl, C3-C6 cycloaryl, C1-C6 alkyl, optionally substituted with one group selected from phenyl, halogen, heterocyclil, such as morpholinile, phurile, hydroxyl, -C(=O)-OR5, OR7; or group-NY1Y2 can form morpholinile, peperidynil, optionally substituted with one or two substitutes selected from OH, C1-C6 alkyl; Z means O; where aryl as group or part of group means optionally substituted with one or two substitutes monocyclic aromatic C6carbocyclic fragment, where substitute is selected from halogen or C1-C6 alkoxy, C(=O)-OR5; except compounds: 4-chlorine-2-(4-tert-butylphenyl)-1H-pyrrole[2,3-b]pyridine, 2-(5-methoxy-1 -methyl-1 H-indole-3-il)-4-phenyl-1H- pyrrole[2,3-b]pyridine, 2-(5- methoxy-1 -methyl-1 H-indole-3-il)-1H- pyrrole[2,3-b] pyridine-4-carbonitrile, 4-chlorine-2-(5- methoxy-1 -methyl-1H-indole-3-il)-1H- pyrrole[2,3-b]pyridine, or 2-(5- methoxy-1H-indole-3-il)-1H- pyrrole[2,3-b]pyridine -4- carbonitrile.

EFFECT: application of compound for production of medicinal agent for inflammatory disease.

51 cl, 9 tbl, 148 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new compounds of and formula: I II those developing antiviral activity allowing application in pharmaceutical formulations and for antiviral medicines production.

EFFECT: new compounds have useful biological properties.

5 cl, 3 dwg, 6 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the formula I compounds or its pharmaceutically acceptable salt or hydrate where Z means N; X1 means O or S, R1 means alkyl containing one to six carbon atoms; R2 designates hydrogen or alkyl containing one to six carbon atoms; and R3 designates hydrogen or alkyl containing one to six carbon atoms substituted with the -ORa group where Ra means alkyl containing one to six carbon atoms; saturated nonaromatic cyclic radical containing 3 to 8 atoms in a cycle where one atom in a cycle is a heteroatom selected from N or O, whereas the rest of the atoms in the cycle are carbon atoms, one or two of these carbon atoms being not necessarily substituted by nitrogen atom with the groups -C(O)(C1-C6alcoxy) or -SO2-C1C6alkyl. Invention also relates to pharmaceutical composition.

EFFECT: compounds possess inhibiting activity.

13 cl, 1 tbl, 8 ex

FIELD: CHEMISTRY.

SUBSTANCE: invention relates to novel method for preparation of compounds of formula IX or IXа, which implies reaction of compound of formula Va, in solvent, with compound of formula VII or formula VIIa, in the presence of palladium catalyst and phospho ligand, in the presence of amine base, resulting in compound of formula VIII or VIIIa. The method also implies reaction of compound of formula VIII or VIIIa, in solvent, with cyclopropylamine, not necessarily in the presence of catalyst. Also, invention relates to method for purification of compound of formula IX or IXa.

Va - R1 may be either С1-8alkyl, aryl or heteroaryl, not necessarily aryl- and/or С1-8alkyl-substituted; and

.

EFFECT: method for preparation of biologically useful compounds is described.

17 cl, 3 tbl, 77 ex

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