Anellated cabamoylazaheterocycles, focused library, pharmaceutical composition and method for its preparing

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anellated carbamoylazaheterocycles of the general formula (1) that possess inhibitory property of kinase activity and eliciting, for example, an anticancer activity. Also, compounds can be used as agonists, antagonists, receptor modulating agents, antiparasitic and antibacterial agents. Also, invention relates to a method for synthesis of compounds of the formula (1), a pharmaceutical composition based on thereof and a focused library for assay of leader-compounds. In compounds of the general formula (1) W represents 6-oxopiperazine, [1,4]-thiazepane, [1,4]-oxazepane or [1,4]-diazepane cycle anellated with at least one optionally substituted and optionally condensed heterocycle or carbocycle Q; Q represents optionally substituted thiophene, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted thiazole, optionally substituted pyrrolidine, optionally substituted indole, optionally substituted benzofuran, optionally substituted pyridine, optionally substituted quinoline, optionally substituted benzene or optionally substituted naphthalene cycle; R1, R2 and R represent independently of each another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

EFFECT: improved preparing method, valuable biological and medicinal properties of compounds and pharmaceutical composition.

15 cl, 5 tbl, 6 ex

 

This invention relates to the synthesis of new chemicals, the search for new physiologically active substances, compounds leaders and drug candidates that can be derived from the combinatorial or screening of focused libraries of compounds, and to pharmaceutical compositions, methods for their preparation and use.

More specifically, the present invention relates to novel fused to carbamoylaspartate of interest as a potential physiologically active substances (agonists, antagonists and modulators of receptors, enzyme inhibitors, oncolytic, antibacterial and antiparasitic agents and so on), to the focused library, including kannelirovannye carbamoylaspartate, pharmaceutical compositions containing as active substance kannelirovannye carbamoylaspartate, to methods for their preparation and use.

There are a large number of natural and synthetic physiologically active compounds whose molecules are kannelirovannye azaheterocycle. Among the natural it should be noted antineoplastics and antibacterial alkaloids languid, languid In and facilitative isolated from the marine sponge Agelas genus, Homaxinella sp. and Phakellia mauritiana [Cafieri, F., et.al. J.Nat.Prod. 1998, 61: 122. Umeyama, A., et.al. J.Nat.Prod. 1998, 61: 1433. Poullennec K., Romo D. SoC. 003, 125:6344].

Among synthetic annelated of carbamoylaspartate having inhibitory action on the activity of protein kinases, have recently become known compounds, including:

fragment 1-oxo-1,2,3,4,6,8A-hexahydro-pyrrolo[1,2-a]pyrazin-3-carboxamide of the formula

fragment 1-oxo-1,2,3,4-tetrahydro-benzo[4,5]imidazo[1,2-a]pyrazin-6-carboxamide of the formula

fragment 4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-6-carboxamide of the formula

fragment 1-oxo-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline-3-carboxamide of the formula F

fragment 4-oxo-1-phenyl-1,4,5,6-tetrahydro-1,2,5,9a-tetraaza-cyclopent[f]azulene-6-carboxamide of the formula G;

fragment 6-oxo-9-chloro-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-carboxamide of the formula N;

fragment 6-oxo-5,6,7,8,9,10-hexahydro-4H-[1]benzothieno[3,2-f]pyrrolo[1,2-a][1,4]diazepin-4-carboxamide of the formula I;

[Il'in, A.P.; Kobak, V.V.; Kuzovkov, Y.A.; Kutepov, S.A.; Dmitrieva, I.G.; Zolotarev, D.A.; Trofimenko, FS; Mishenina, YU.S.; Gravce is to, D.V.; Tkachenko, S.E.; Perch, I.M.; Ivashchenko, A.V. Kannelirovannye carbamoylaspartate, focused library, pharmaceutical composition and method of production thereof. Application EN 2004113251, 2004, the priority of 29.04.2004, Navel, A.R.; Kuzovkova, J.A.; Potapov, V.V; Shkirando, A.M.; Kovrigin, D.I.; Tkachenko, S.E.; Ivachtchenko, A.V. An efficient synthesis of novel heterocycle-fused derivatives of 1-oxo-1,2,3,4-tetrahydropyrazine using Ugi condensation. Tetrahedron Lett. 2005, 46, 881-884. Ilyn, A.R.; Trifilenkov, A.S.; Kuzovkova, J.A.; Kutepov, S.A.; Nikitin, A.V.; Ivachtchenko, A.V. New Four-component Ugi-Type Reaction. Synthesis of 3-Oxo-2,3-dihydro-1H-pyrrolo[1,2-a][1,4]diazepine-1-Carboxylic Acid Amides. J. Org. Chem. (Lett.) 2005, 70,1478-1481].

Also known compounds, including the fragment 3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine-5-carboxamide of the formula To [Zhang, J.; Jacobson, A.; Rusche, J.R.; Herlihy, W.J. Org. Chem., 1999, 64(3), 1074-1076] and fragment 5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]diazepin-3-carboxamide of the formula L [Marcaccini, S.; Miguel, D.; Torroba, T.; Garcy'a-Valverde, M.J. Org. Chem. 2003, 68, 3315-3318] and fragment 2-methyl-7-nitro-5-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-3-carboxamide of the formula M [Tempest Paul et al., Tetrahedron Letters, 2003, 44(9), str-1950].

Synthetic kannelirovannye carbamoylaspartate exhibit an exceptionally wide range of physiological activity. For example, 4-methyl-2-(3-triptoreline)-hexahydropyrazino[1,2-a]pyrazin-3-he manifests the properties of anxiolytic and antidepressant [Silvestrini, B., Baiocchi, L. ACRAF SpA. WO 8705022. 1987], 3-[1-oxo-2-[2-(piperidine-1-ileti]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-7-ylcarbonyl]propionic acid is an antagonist fibrinogenesis gpIIb/IIIa receptor, and thus inhibits platelet aggregation [Askew, B.C. et al. J.Med.Chem. 1997, 40(12):1779], and [6S-[6α([R*(TRANS),8Aα]]]-N-[1-(4-aminocyclohexane)-2-(2-benzothiazolyl)-2-oxoethyl]-1,4-dioxo-2-(3-phenylpropyl)-perritopiloto[1,2-α]pyrazin-6-carboxamide anticoagulant by inhibiting serine protease thrombin and Factoria. [Berryman, K.A.; Doherty, A.M.; Edmunds, J.J.; Siddiqui, M.A. Pfizer Inc. WO 9748706, 1997].

Antibacterial properties shows 3-isopropylideneglycerol[1,2-α]pyrazin-1,4-dione [O. Kwon, et.al. J.Antibiot. 2001, 54(2): 179], and N-[4-(3-oxo-3,5-dihydro-1,4,8b-createanimation-4-yl)butyl]triftormetilfullerenov is an inhibitor of PDGF receptor kinase and consequently a potential tool for the treatment of renal failure, hyperlipidemia, and hypertension [Ikemoto, T. et al. Tetrahedron, 2000, 56(40): 7915]. High Antiprotozoal activity manifests 3,4,7,8-tetrahydro-2H-pyrazino[1,2-a]indol-1,6,9-Trion [Tapia, R., et.al. Eur.J.Org.Chem. 2002, 23: 4005], and 2-{4-[4-(3-triptoreline)piperazine-1-yl]butyl}hexahydropyrazino[1,2-a]pyrazin-1,4-dione is a highly efficient ligand serotonin 5-Ht1a receptor [Lopez-Rodriguez, M., et.al. J.Med.Chem. 2001, 44(2): 186].

Recently it became known that amides 2,3,4,5-tetrahydrobenzo[1][1,4]oxazepine-5-carboxylic to the slots are effective hibitory gamma secretase, of interest for the treatment of Alzheimer's disease [Peters, J.U.; Goodnow, R.A. Jr.; Galley, G. US 2004235819, 2004; WO 04100958, 2004].

Given that the search for highly effective inhibitors of protein kinases is currently one of the main directions of the development of new pharmacological agents for the treatment of a wide and diverse range of diseases [Cohen P. The development and therapeutic potential of protein kinase inhibitors. Curr. Opin. Chem. Biol. 1999, 3, 459-65], including cancer [a) Bridges A.J. Chemical Inhibitors of Protein Kinases. Chem. Rev. 2001, 101, 2541-2571. b) Paul M.K., A.K. Mukhopadhyay Tyrosine kinase - Role and significance in Cancer. Int. J. Med. Sci. 2004, 1(2), 101-115], neurodegeneration [a) Milton N.G. Phosphorylated amyloid-beta: the toxic intermediate in Alzheimer's disease neurodegeneration. Subcell. Biochem. 2005, 38, 381-402. b) Nakagami Y. Inhibitors beta-amyloid-induced toxicity by modulating the Akt signaling pathway. Drug News Perspect. 2004, 17(10), 655-660], metabolic [Barnes B.R., J.R. Zierath Role of AMP-activated protein kinase in the control of glucose homeostasis. Curr. Mol. Med. 2005, 5(3), 341-348] disease, inflammatory [Tas S.W., Remans P.H., Reedquist K.A., Tak P.P. Signal transduction pathways and reduced factors as therapeutic targets in inflammatory disease: towards innovative antirheumatic therapy. Curr. Pharm. Des. 2005, 11(5), 581-611.] and autoimmune [Berton G., Mocsai, A., C.A. Lowell Src and Syk kinases: key regulators of phagocytic cell activation. Trends Immunol. 2005, 26(4), 208-214] processes, and infection [Klebl V.M., A. Kurtenbach, Salassidis K., H. Daub, Herget So ost cell targets in HCV therapy: a novel strategy or proven practice. Antivir. Chem.Chemother. 2005, 16(2), 69-90].

Given the high potential and a wide range of physiological activity of annelated azaheterocycles, including their ability of inhibiting the activity of protein kinases, it is important to develop new compounds of this type, focused libraries and pharmaceutical compositions comprising these compounds and methods of their preparation and use.

As a result of research aimed at finding new physiologically active substances, compounds leaders, inventors received previously unknown kannelirovannye carbamoylaspartate, which possess physiological activity, focused library and pharmaceutical composition comprising these compounds, have developed methods for their preparation and use.

Below are definitions of terms used in the description of this invention:

"Combinatorial library" means a collection of compounds obtained by parallel synthesis, designed to search for connections-hit or 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.

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

"Connection-hit" ("hit") means a compound expressed during primary screening desired physiological activity.

"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.

"Parallel synthesis" means a method of doing combinatorial chemical synthesis library.

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

"Nucleophilic" means electron-excess reagent.

"Electrophilic" means electron-deficient reagent.

"Deputy" means a chemical moiety that is attached to scaffold or polypody is the synthesis in the process of their synthesis, for example, "nucleophilic Deputy", "electrophilic Deputy", "NH-protective Deputy" or "inert Deputy".

"Optionally substituted radical" means a radical without substituents or with one or more substituents, including: "nucleophilic Deputy", "electrophilic Deputy", "NH-protective Deputy" and/or "inert Deputy".

"Nucleophilic Deputy" 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 thiophenols.

"Electrophilic Deputy" 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 halides (optionally substituted C1-C7alkyl halides, optionally substituted aryls1-C7alkyl halides, optionally substituted heterocyclyl1-C7alkyl halides, optionally substituted aryl halides, optionally substituted heterocyclyl halides), organic acids or their derivatives (anhydrides, imidazolides, halides, esters of organic sulfonic acids or organic sulfochlorides, organic is loginformation, organic isocyanates and organic isothiocyanatobenzene.

"NH-Protective Deputy" 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 (such as trichloroacetyl, TRIFLUOROACETYL 3-phenylpropionyl and others), optionally substituted benzoyl and others; urethane Deputy, such as optionally substituted C1-C7allyloxycarbonyl, for example, methyloxycarbonyl, 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 "NH-Protective substituents" described in the book: 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.

"Inert Deputy" (or "not interfering", "Non-interfering substituent"means low or directionspanel radical, including, but not limited to C1-C7alkyl, C2-C7alkenyl, C2-C7quinil, C1-C7alkoxy, C 7-C12aralkyl substituted with inert substituents, aralkyl, C7-C12geterotsiklicheskikh substituted with inert substituents, geterotsiklicheskikh, C7-C12alkaryl, C3-C10cycloalkyl, C3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C2-C12alkoxyalkyl, C2-C10alkylsulfonyl, C2-C10alkylsulfonyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted with 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, C7-C12alkaryl, C3-C10cycloalkyl, C3-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 with inert substituents aryl, heterocyclyl and substituted with inert substituents Goethe is iillil.

"Aryl" means one or more aromatic cycles, each of which contains 5 or 6 carbon atoms. "Aryl" may be condensed political, such as naphthalene, or unfused, such as biphenyl. "Substituted aryl" has one or more substituents.

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

"Heterocycle" means one or more saturated, unsaturated or aromatic cycles with 5, 6 or 7 atoms, at least one of which is a heteroatom. Preferred heteroatoms are sulfur, oxygen and nitrogen. "Heterocycle" may be condensed political, such as benzimidazole, benzoxazole, benzthiazole, quinoline or unfused, for example as bipyridyl.

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

"Substituted heterocycle" means a heterocycle having one or more substituents.

"Substituted azaheterocycle" means azaheterocycle with one or more substituents.

The aim of the present invention are new kannelirovannye carbamoylaspartate.

This goal is achieved annulated by carbamoylaspartate General formula 1

where

W is a 6-oxopiperidine, [1,4]diazepambuy, [1,4]oxazepines or [1,4]diazepambuy cycle, annelirovannymi at least one optionally substituted and optionally condensed heterocycle or carbocycle Q;

Q represents an optionally substituted titanovyi pyrrole, optionally substituted imidazole, optionally substituted thiazole, optionally substituted pyrolidine, optionally substituted indole, optionally substituted benzofuranyl, optionally substituted pyridine, optionally substituted quinoline, optionally substituted benzene ring or optionally substituted naphthalene cycle;

R1, R2and R3represent independently each other a hydrogen atom, an inert Deputy, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; excluding compounds including: fragment 1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-3-carboxamide formula A, a fragment of 8-oxo-5,6,7,6-tetrahydro-imidazo[1,2-a]pyrazin-6-carboxamide formulas, fragment 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-6-carboxamide of the formula, fragment 1-oxo-1,3,4,6,11,11a-hexahydro-2H-what iresine[1,2-b]isoquinoline-3-carboxamide of the formula F, fragment 4-oxo-1-phenyl-1,4,5,6-tetrahydro-1,2,5,9a-tetraaza-cyclopent[f]azulene-6-carboxamide of the formula G, fragment 6-oxo-9-chloro-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-carboxamide of General formula H, fragment 6-oxo-5,6,7,8,9,10-hexahydro-4H-[1]benzothieno[3,2-f]pyrrolo[1,2-a][1,4]diazepin-4-carboxamide of the formula I, the fragment 3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine-5-carboxamide of the formula and To fragment 5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]diazepin-3-carboxamide of the formula L and fragment 2-methyl-7-nitro-5-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-3 - carboxamide of the formula M.

According to the invention the most preferred annulated by carbamoylaspartate are also substituted 8-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-6-carboxamide General formula 1.1

where R1, R2, R3have the above meaning; R4represents a hydrogen atom or optionally substituted C1-C6alkyl; R5represents a hydrogen atom, carboxyethyl, carboxy, optionally substituted carbarnoyl.

According to the invention the most preferred annulated by carbamoylaspartate are also substituted 6-oxo-4,5,6,7-tetrahydro-1H-8-thia-1,2,5-triaza-azulene-4-carboxamide General formula 1.2

where R1, R2, R3and R 4have the above meaning; R6represent a hydrogen atom, carboxyethyl, carboxy, optionally substituted carbarnoyl; R6and R7independently from each other represent inert Deputy, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

According to the invention the most preferred annulated by carbamoylaspartate are also 7-oxo-5,7,8,10-tetrahydro-6H-9-thia-6,10-diaza-benzo[a]azulene-5-carboxamide General formula 1.3, 7-oxa-7,8,9,10-tetrahydro-6H-5-thia-8,10-diaza-benzo[a]azulene-9-carboxamide General formula 1.4 and 9-oxo-7,8,9,10-tetrahydro-6H-5-thia-8,10-diaza-benzo[a]azulene-7-carboxamide General formula 1.5

where R1, R2, R3and R4have the above meaning; R9represents a hydrogen atom, an inert Deputy, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; and R10represents a hydrogen atom, halogen atom, optionally replacing the " C 1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted C1-C5alkoxy group, carboxyethyl, carboxy, optionally substituted carbarnoyl.

According to the invention the most preferred annulated by carbamoylaspartate are also substituted 9-oxo-6,7,8,9-tetrahydro-10-oxa-5-thia-8-Aza-benzo[a]azulene-7-carboxamide General formula 1.6

where R1, R2, R3, R4and R10have the above value.

According to the invention the most preferred annulated by carbamoylaspartate are also substituted 7-oxo-5,6,7,8-tetrahydro-9-thia-1,6-diaza-benzocycloheptene-5-carboxamide General formula 1.7 and 8-oxo-7,8,9,10-tetrahydro-6-thia-5,9-diaza-cyclopent[b]naphthalene-10-carboxamide General formula 1.8

where R1, R2, R3, R4and R10have the above value.

According to the invention the most preferred annulated by carbamoylaspartate are also substituted 8-oxo-5,6,7,8-tetrahydro-4-oxa-1-thia-7-Aza-azulene-6-carboxamide General formula 1.9

where: R1, R2, R3and R4have the above meaning; R11and R12independently from each other represent a hydrogen atom, acyl, carboxyethyl, carboxy, optionally substituted carbarnoyl, inert Deputy, such as C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; R11and R12together with the carbon atoms to which they are attached, form an optionally substituted, and Carbo - or heterocycle.

According to the invention the most preferred annulated by carbamoylaspartate are also substituted 8-oxo-5,6,7,8-tetrahydro-4-oxa-1-thia-3,7-diaza-azulene-6-carboxamide General formula 1.10

where R1R2, R3and R4have the above meaning; R13represents a hydrogen atom, an inert Deputy, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

According to the invention the most preferred annulated by carbamoylaspartate are also substituted 9-oxo-6,7,8,9-tetrahydro-510-dioxa-8-Aza-benzo[a]azulene-7-carboxamide General formula 1.11

where R1, R2, R3, R4and R10have the above value.

According to the invention the most preferred annulated by carbamoylaspartate are also substituted 9-oxo-8,9,10,11-tetrahydro-7-oxa-10-Aza-cyclopent[a]naphthalene-11-carboxamide General formula 1.12

where R1and R2have the above value.

According to the invention the most preferred annulated by carbamoylaspartate are also substituted 4-oxo-2,3,3A,4,5,6-hexahydro-1H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-6-carboxamide General formula 1.13, (3aS)-4-oxo-2,3,3A,4,5,6-hexahydro-1H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-6-carboxamide General formula 1.14 (3S,6S)-4-oxo-2,3,3A,4,5,6-hexahydro-1H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-6-carboxamide General formula a and (3S,6R)-4-oxo-2,3,3A,4,5,6-hexahydro-1H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-6-carboxamide General formula 1.14b

where R1and R2have the above meaning; R14represents a hydrogen atom or an optionally substituted hydroxy group; R15a hydrogen atom, NO2, CF3CN, carboxyethyl, carboxy, optionally substituted the carbs the sludge, optionally substituted amino group.

According to the invention the most preferred annulated by carbamoylaspartate are substituted 6-oxo-5,6-dihydro-4H-benzo[1]pyrrolo[1,2-a][1,4]diazepin-4-carboxamide General formula 1.15

where R1, R2, R3and R15have the above meaning; R16, R17and R18independently from each other represent a hydrogen atom, an inert substitute, such as optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl, or acetyl, or C1-C6alkoxycarbonyl1-C4-alkyl, or R16and R17together with the carbon atoms to which they are attached, or R17and R18together with the carbon atoms to which they are attached, form an optionally substituted benzene, cycloalkane or a heterocycle, for example, azaheterocycle, thiophene, furan, 2,3-dihydrofuran, 3,6-dihydro-2H-peranovic or 3,6-dihydro-2H-Tierney.

The purpose of the present invention is a method of obtaining new annelated of carbamoylaspartate General formula 1.

This goal is achieved by a method of obtaining new annelated of carbamoyl is heterocycles General formula 1 by condensation of the corresponding isonitrile General formula 2, the corresponding primary amine of General formula 3 and a corresponding heterocyclic bifunctional reagent of General formula 4 or 5

where R1, R2, R3and Q have the above significance;

Q1and Q2have a different value Q.

The aim of the present invention are new focused library to identify compounds leaders.

This goal is achieved by the focused library to identify compounds leaders, including at least one annulirovano carbamoylaspartate compound of General formula 1.

The aim of the present invention are a new pharmaceutical composition having anticancerous activity.

This goal is achieved by a pharmaceutical composition having anticancer activity, including at least one annulirovano carbamoylaspartate compound of General formula 1 or its pharmaceutically acceptable salt.

Below the invention is described using examples, illustrating, but not limiting the invention.

Example 1. A common way to obtain annelated carbamoylaspartate compounds of General formula 1. Re exively at room temperature for 48-56 hours a mixture of 3 mmol of the corresponding isonitrile General formula 2, 3 mmol of the corresponding primary amine of General formula 3 and 3.1 mmol of the corresponding heterocyclic bifunctional reagent of General formula 4 or 5 in 5 ml of dry methanol or other suitable solvent. The precipitate was filtered, if necessary, recrystallized from a suitable solvent. Received compound 1 in form of a mixture of enantiomers with the release of 40-95% (tables 1-4). If necessary, the compound 1 was subjected to chromatographic separation of the optical isomers.

Example 2. Test the biological activity of the compounds of General formula 1.

Was focused library comprising compounds of General formula 1, are presented in tables 1-4, and tested its ability to inhibit the activity of protein kinase, which was determined as follows. The solution of the polypeptide (Calbiochem, USA), consisting of a random sequence of glutamic acid and tyrosine in the proportion 4:1, respectively, was maintained in the wells of 96 well plates with optically transparent bottom during the night. During this time, the polypeptide firmly sorbirovtsa on the surface of the hole. Adsorbed polypeptide served as substrate for the kinase, which was fosfaurilirovania tyrosine in this polypeptide.

Added 100 microliters 1U kinase (Calbiochem, USA, 1U is defined as the concentration of this enzyme is able to attach to the substrate picomole phosphate for 1 minute) in wells with adcor the new the polypeptide without the test compounds (control activity) or in the presence of different concentrations of these compounds. After 30 minutes of incubation, the solutions were removed by shaking out from the wells, and the wells were washed twice with saline. The wells were filled with 100 microlitres solution anti-phosphotyrosine monoclonal IGg antibodies conjugated with horseradish peroxidase from horseradish (Sigma, USA). The amount of bound peroxidase antibodies was determined by the activity of peroxidase, which, in turn, was determined by conversion speed peroxidase substrate (OPD, phenolenediamine dihydrochloride, Sigma) into a colored product. The concentration of the product formed in 30 minutes the reaction was determined by optical density at 490 nm measured using a parallel 96-well reader VICTOR2V (PerkinElmer, USA).

To calculate the percentage inhibition of kinase activity, each 96-well plate contained the following control wells: 1) the reaction solution containing all components except kinase; 2) the reaction solution together with the kinase. The optical density measured in control wells (1), was taken as zero activity (OD0), and the optical density measured in control wells (2), 100% (OD100). The optical density measured in the presence of test compounds (ODi), was expressed as a percentage of the maximum activity. The percentage inhibition of kinase activity was calculated on the trail is the fact that the formula:

The magnitude of inhibition of ABL-kinase obtained from testing focused libraries vary in the interval (30%-100%) and confirm the biological activity of the compounds of General formula 1.

Example 3. Test the biological activity of the compounds of General formula 1.

Was focused library comprising compounds of General formula 1, are presented in tables 1-4, and tried it on anticancerous activity. Anticamara activity of the compounds was determined by their ability to kill concerne cells in tissue culture. For this purpose, we chose three cell lines representing three types of cancer: DLD-1 (adenocarcinoma of the rectum), DU-145 (carcinoma of the brain) and T-47D (a tumor of the breast). All cell cultures were obtained from the American collection of tissue cultures (ATSS).

Evaluation of the effectiveness of the compounds was carried out by measuring the amount of dead cells after treatment of the studied substances within 48 hours. Cells were sowed at a concentration of 5×103cells/well of a standard 96-well card and was left overnight to attach the cells to the bottom of the hole. After that, the cells were added to the substance at a final concentration of 30μM and cards were left for 48 hours in the incubator at 37°supporting 5%CO2/95% without the SCE environment with 100% humidity. At the end of the experiment environment with connections was aspirated from all wells and the wells were washed twice with saline. To each well was added 50μM solution of Alamar Blue was measured by fluorescence (λex=531 nm, λem=589 nm) immediately after it is added and after 2 hours. The rate of increase in fluorescence is proportional to the number of cells remaining alive after their incubation with the target substances [John O'brien, lan Wilson, Terry Orton and Fran9ois Pognan, Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity. Eur. J. Biochem. 2000,6 267, 5421-5426]. The percentage of suppression of cell growth was determined by the following equation

% Growth inhibition = ((Δfto-Δfi)/Δfto)×100%,

where Δf represents an increase of fluorescence for two hours after addition of Alamar Blue solution; subscripts K and i denote, respectively, the control (grown without chemicals) and experienced (grown in the presence of the tested substances) cells. Data for some of the tested substances are given in table 5. From the data presented in table 5, it can be seen that the tested substances showed good activity in suppressing the growth of tumor cells.

Example 4. A method of obtaining a pharmaceutical composition in tablet form.

Mix 80 mg of starch, 800 mg powdered lactose 200 mg of talc and 500 mg cyclohexylamin metalguy ether 6-cyclohexylcarbonyl-7-(4-methoxybenzyl)-6-methyl-8-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-carboxylic acid 1.1 (4) and pressed in the bar. The resulting block is crushed into granules and sieved through a sieve, collecting graneli size 14-16 mesh. The obtained granules tabletirujut in a suitable form tablets weighing 280 mg each. Similarly receive pharmaceutical composition in the form of tablets containing as active ingredient other 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinoline of General formula 1.

Example 5. A method of obtaining a pharmaceutical composition in capsule form. Thoroughly mix connection 1.1 (4) with lactose powder in a 2:1 ratio. Received poroshkoobraznuju mix pack 300 mg in gelatin capsules of suitable size.

Example 6. A method of obtaining a pharmaceutical composition in the form of injection for intramuscular, intraperitoneal or subcutaneous injection. Mix 500 mg of hydrochloride of compound 1.1 (4) 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. Kannelirovannye carbamoylaspartate General formula 1, where

W of t is made by a 6-oxopiperidine, [1,4]diazepambuy, [1,4]oxazepines or [1,4]diazepambuy cycle, annelirovannymi at least one optionally substituted and optionally condensed heterocycle or carbocycle Q;

Q represents an optionally substituted titanovyi, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted thiazole, optionally substituted pyrolidine, optionally substituted indole, optionally substituted benzofuranyl, optionally substituted pyridine, optionally substituted quinoline, optionally substituted benzene ring or optionally substituted naphthalene cycle;

R1, R2and R3represent independently each other a hydrogen atom, an inert Deputy, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; excluding compounds including fragments, specified in the application: part 1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-3-carboxamide formula A, a fragment of 8-oxo-5,6,7,6-tetrahydroimidazo[1,2-a]pyrazin-6-carboxamide formulas, fragment 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-6-carboxamide of the formula, fragment 1-oxo-1,3,,6,11,11a-hexahydro-2H-pyrazino [1,2-b]isoquinoline-3-carboxamide of the formula F, fragment 4-oxo-1-phenyl-1,4,5,6-tetrahydro-1,2,5,9a-tetraazacyclooctane[e]azulene-6-carboxamide of the formula G, fragment 6-oxo-9-chloro-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-carboxamide of the formula N, fragment 6-oxo-5,6,7,8,9,10-hexahydro-4H-[1] benzothieno [3,2-f]pyrrolo [1,2-a] [1,4]diazepin-4-carboxamide of the formula I, the fragment 3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxamide of the formula To fragment 5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]diazepin-3-carboxamide of the formula L and fragment 2-methyl-7-nitro-5-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-3-carboxamide of the formula M

2. Compounds according to claim 1 represents a substituted 8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-6-carboxamide General formula 1.1

where R1, R2, R3have the above meaning; R4represents a hydrogen atom or optionally substituted C1-C6alkyl; R5represents a hydrogen atom, carboxyethyl, carboxy, optionally substituted carbarnoyl.

3. Compounds according to claim 1, which represents a substituted 6-oxo-4,5,6,7-tetrahydro-1H-8-thia-1,2,5-triaza-azulene-4-carboxamide General formula 1.2

where R1, R2, R3and R4have the above meaning; R6represent a hydrogen atom, carboxyethyl, carboxy, not necessarily samewe the hydrated carbarnoyl; R6and R7independently from each other represent inert Deputy, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

4. Compounds according to claim 1, which represents a substituted 7-oxo-5,7,8,10-tetrahydro-6N-9-thia-6,10-diaza-benzo[a]azulene-5-carboxamide General formula 1.3, substituted 7-oxo-7,8,9,10-tetrahydro-6N-5-thia-8,10-diaza-benzo[a]azulene-9-carboxamide General formula 1.4 and substituted 9-oxo-7,8,9,10-tetrahydro-6N-5-thia-8,10-diaza-benzo[a]azulene-7-carboxamide General formula 1.5

where R1, R2, R3and R4have the above meaning; R9represents a hydrogen atom, an inert Deputy, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; and R10represents a hydrogen atom, halogen atom, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted aryl, not battelino substituted heterocyclyl, optionally substituted C1-C5alkoxygroup, carboxyethyl, carboxy, optionally substituted carbarnoyl.

5. Compounds according to claim 1, which represents a substituted 9-oxo-6,7,8,9-tetrahydro-10-oxa-5-thia-8-Aza-benzo[a]azulene-7-carboxamide General formula 1.6

where R1, R2, R3, R4and R10have the above value.

6. Compounds according to claim 1, which represents a substituted 7-oxo-5,6,7,8-tetrahydro-9-thia-1,6-diaza-benzocycloheptene-5-carboxamide General formula 1.7 and substituted 8-oxo-7,8,9,10-tetrahydro-6-thia-5,9-diaza-cyclopent[b]naphthalene-10-carboxamide General formula 1.8

where R1, R2, R3, R4and R10have the above value.

7. Compounds according to claim 1, which represents a substituted 8-oxo-5,6,7,8-tetrahydro-4-oxa-1-thia-7-Aza-azulene-6-carboxamide General formula 1.9

where R1, R2, R3and R4have the above meaning; R11and R12independently from each other represent a hydrogen atom, acyl, carboxyethyl, carboxy, optionally substituted carbarnoyl, inert Deputy, such as C1-C6alkyl, optionally substituted C3-C8cycloalkyl,optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; R11and R12together with the carbon atoms to which they are attached form an optionally substituted Carbo - or heterocycle.

8. Compounds according to claim 1, which represents a substituted 8-oxo-5,6,7,8-tetrahydro-4-oxa-1-thia-3,7-diaza-azulene-6-carboxamide General formula 1.10

where R1, R2, R3and R4have the above meaning; R13represents a hydrogen atom, an inert Deputy, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

9. Compounds according to claim 1, which represents a substituted 9-oxo-6,7,8,9-tetrahydro-5,10-dioxa-8-Aza-benzo[a]azulene-7-carboxamide General formula 1.11

where R1, R2, R3, R4and R10have the above value.

10. Compounds according to claim 1, which represents a substituted 9-oxo-8,9,10,11-tetrahydro-7-oxa-10-Aza-cyclopent[a]naphthalene-11-carboxamide General formula 1.12:

where R1and R2have the above value.

11. Compounds according to claim 1, which represents Sames is installed 4-oxo-2,3,3A,4,5,6-hexahydro-1H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-6-carboxamide General formula 1.13, substituted (3S)-4-oxo-2,3,3A,4,5,6-hexahydro-1H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-6-carboxamide General formula 1.14, substituted (3aS,6S)-4-oxo-2,3,3a,4,5,6-hexahydro-1H-benzo[1]pyrrolo[1,2-a][1,4]diazepin-6-carboxamide General formula a and substituted (3S,6R)-4-oxo-2,3,3A,4,5,6-hexahydro-1H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-6-carboxamide General formula 1.14b:

where R1and R2have the above meaning; R14represents a hydrogen atom or optionally substituted by a hydroxy-group; R15a hydrogen atom, NO2, CF3CN, carboxyethyl, carboxy, optionally substituted carbarnoyl, optionally substituted amino group.

12. Compounds according to claim 1, which represents a substituted 6-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-carboxamide General formula 1.15:

where R1, R2, R3and R15have the above meaning; R16, R17and R18independently from each other represent a hydrogen atom, an inert substitute, such as optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted aryl, it is certainly substituted heterocyclyl, or acetyl, or1-C6alkoxycarbonyl1-C4-alkyl, or R16and R17together with the carbon atoms to which they prisoedinenii or R17and R18together with the carbon atoms to which they are attached form an optionally substituted benzene, cycloalkane or a heterocycle, for example, azaheterocycle, thiophene, furan, 2,3-dihydrofuran, 3,6-dihydro-2H-Piran or 3,6-dihydro-2H-thiopyran.

13. The method of obtaining annelated of carbamoylaspartate General formula 1 according to claim 1 by condensation of the corresponding isonitrile General formula 2, the corresponding primary amine of General formula 3 and a corresponding heterocyclic bifunctional reagent of General formula 4 or 5

where R1, R2, R3and Q have the above significance;

Q1and Q2have a different value Q.

14. Focused library to identify compounds leaders, including at least one annulirovano carbamoylaspartate compound of General formula 1 according to claim 1.

15. Pharmaceutical composition having anti-cancer activity comprising at least one annulirovano carbamoylaspartate the compound of General formula 1 according to claim 1 or its pharmaceutically acceptable salt.

.....



 

Same patents:

FIELD: medicine, pharmacology, organic chemistry.

SUBSTANCE: invention relates to using 2-amino-4-acetyl-8b-hydroxy-3a,8b-dihydrothiazole[5,4-d]indole as a substance protecting body against hypoxia effect. Invention provides enhanced effectiveness of the protection effect.

EFFECT: enhanced effectiveness of effect of agent.

1 tbl, 1 ex

FIELD: medicine, pharmacology, organic chemistry.

SUBSTANCE: invention relates to using 2-amino-4-acetylthiazolo[5,4-d]indole for protection of body against effect of hemic and hypercapnic hypoxia. Invention proves high effectiveness of the protection effect.

EFFECT: enhanced effectiveness of agent.

2 tbl

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

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

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

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

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

SUBSTANCE: invention relates to novel heterocyclic compounds comprising 2-aminopyridin-3-sulfonic fragment of the general formula (1) or their pharmaceutically acceptable salts, N-oxides or hydrates possessing properties of antagonists of glutamate-induced calcium ions transport, in particular, neuroprotective effect. Also, invention relates to the focused library for the search of biologically active leader-compounds comprising at least one heterocyclic compound of the general formula (1) and to pharmaceutical composition if form of tablets, capsules or injections placed into pharmaceutically acceptable package containing compounds of invention as an active substance. In compound of the general formula (1) R1 represents hydrogen atom; R2 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; or R1 and R2 in common with nitrogen and sulfur atoms to which they are bound form optionally substituted and optionally condensed with other cycles 1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazine or optionally substituted and optionally condensed with other cycles 5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triazabenzocyclohepten-8-one. Also, invention discloses methods for preparing different compounds of the general formula (1).

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

10 cl, 4 sch, 4 tbl, 9 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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

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

and (1.2):

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

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

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

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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

EFFECT: valuable medicinal and biochemical properties of azoles.

27 cl, 8 tbl

FIELD: organic chemistry, madicine.

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

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzoxazepine and describes derivative of benzoxazepine of the general formula (I): wherein X represents -CO or -SO2; R1, R2, R3 and R4 are chosen independently from hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkyloxy-(C1-C4)-alkyl, -CF3, halogen atom, nitro-group, cyano-group, -NR8R9, -NR8COR10 and -CONR8R9; R5, R6 and R7 represent independently hydrogen atom (H) or (C1-C4)-alkyl; R8 and R9 represent independently hydrogen atom (H) or (C1-C4)-alkyl; or R8 and R9 in common with nitrogen atom to which they are bound form 5- or 6-membered saturated heterocyclic ring comprising optionally the additional heteroatom chosen from oxygen atom (O), sulfur atom (S) or the group -NR11; R10 represents (C1-C4)-alkyl; R11 represents (C1-C4)-alkyl; A represents residue of 4-7-membered saturated heterocyclic ring comprising optionally oxygen atom wherein ring is substituted optionally with 1-3 substitutes chosen from (C1-C4)-alkyl, (C1-C4)-alkoxy-, hydroxy-group, halogen atom and oxo-group, or to its pharmaceutically acceptable salt under condition that compounds of the formula (I) are excluded wherein X represents -CO, and each among R1-R7 represents hydrogen atom (H), and A represents -(CH2)3 or -(CH2)4; compounds of the formula (I) wherein X represents -CO; R1 represents hydrogen atom (H); R2 represents methyl (CH3); each among R3-R7 represents hydrogen atom (H), and A represents -(CH2)3; compounds of the formula (I) wherein X represents -CO; R1 and R2 represent hydrogen atom (H); R3 represents methyl; each among R4-R7 represents hydrogen atom (H), and A represents -(CH2)3; compounds of the formula (I) wherein X represents -CO; each among R1-R3 represents hydrogen atom (H); R4 represents methyl; each among R5-R7 represents hydrogen atom (H), and A represents -(CH2)3, and compounds of the formula (I) wherein X represents -CO; each among R1-R4 represents hydrogen atom (H); R5 represents methyl; R6 and R7 represent hydrogen atom (H), and A represents -(CH2)3. Also, invention describes pharmaceutical compositions comprising indicated derivatives and using these benzoxazepine derivatives in treatment of neurological diseases and psychotic disorders sensitive to enhancing responses mediated by AMPA receptors in the central nervous system. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 31 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new amide derivatives of carboxylic acid that are antagonists of NMDA receptors of the formula (I): , wherein one radical among R1, R2, R3 and R4 represents -OH or NH2-group and others are hydrogen atoms; or two adjacent groups R1, R2, R3 and R4 in this case in common with one or more similar or different additional heteroatoms and -CH= and/or -CH2-groups form 5-6-membvered homo- or heterocyclic ring but preferably pyrrole, pyrazole, imidazole, oxazole, oxooxazolidine or 3-oxo-1,4-oxazine ring; two other groups among R1, R2, R3 and R4 radicals represent hydrogen atoms; R5 and R6 in common with nitrogen atom between them form saturated or unsaturated 4-6-membered heterocyclic ring that is substituted with phenoxy-, phenyl-[(C1-C4)-alkoxy]-, phenoxy-[(C1-C4)-alkyl]-, benzoyl-group optionally substituted in aromatic ring with one or more halogen atoms, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; X and Y mean independently oxygen, nitrogen atom or group -CH=, and to their salts formed with acids and bases. Also, invention relates to a method for preparing compounds of the formula (I) and pharmaceutical compositions showing activity as selective antagonists of NR2B receptor based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of the following diseases: chronic neurodegenerative diseases, chronic painful states, bacterial and viral infections.

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

11 cl, 2 tbl, 27 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacology.

SUBSTANCE: invention relates to gyrase inhibitors that reduce amount of microorganisms in biological sample by contacting the indicated sample with compound of the formula (I): , to a method for treatment of bacterial infection by using compounds of the formula (I), compounds of the formula (I) and a pharmaceutical composition comprising compounds of the formula (I). Invention provides the enhanced effectiveness of treatment.

EFFECT: valuable medicinal properties of gyrase.

54 cl, 5 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

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

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

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

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, madicine.

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

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

The invention relates to the field of organic chemistry, namely to new individual compounds of class benzoxazines that exhibit fluorescent properties and can be used as starting products for the synthesis of new heterocyclic systems, as well as substances for sample labeling and additives for reflective paints

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention relates to new compounds of the formula (I) wherein R1 and R2 can be similar or different and represent independently (C1-C6)-alkyl that are selective inhibitors of enzyme phosphodiesterase, and to their pharmaceutically acceptable salts or stereoisomers. Also, invention involves a method for preparing the preferable compound, i. e. 5-[[2-ethoxy-5-(cis-2,6-dimethylpiperazin-4-ylsulfonyl)phenyl]]-1-methyl-3-n-propyl-7,6-dihydro-1H-pyrazolo[4,3-d]pyrimidine-7-one. Also, invention proposes new intermediate compounds used in method for synthesis of this compound. Compounds of the formula (I) show very high effectiveness in treatment of diseases associated with impotence, such as the male erectile sterility but they exhibit such features as prolonged therapeutic effectiveness and lower toxicity. Also, invention relates to a pharmaceutical composition used in treatment of impotence and using compound of the formula (I) in preparing the medicinal preparation designated for treatment of diseases associated with impotence.

EFFECT: valuable medicinal properties of compound.

8 cl, 7 ex

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