Benzodiazepine compound and pharmaceutical composition

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzodiazepine compounds of general formula , wherein each R1, R2, R3 and R4 independently represent hydrogen or alkyl, or R2 and R3 together represent lower alkylene; A1 is lower alkylene optionally substituted by hydroxy; and R5 is a fragment of formula , wherein each R6 and R7 independently represents hydrogen, lower alkyl, cycloalkyl, phenyl, furyl, thienyl, pyrazolyl, etc.; each XA and XB independently represents a bond, lower alkylene, -CO-, -SO2- etc., a pharmaceutical composition containing them, and using the above compound as the pharmaceutical composition or for preparing the same.

EFFECT: new compounds may be used for preventing and treating cardiac arrhythmia.

8 cl, 1047 ex, 78 tbl

 

The text descriptions are given in facsimile form.

1. Connection benzodiazepine represented by the General formula (1)

or its pharmaceutically acceptable salt,
where R1, R2, R3and R4each independently is hydrogen or lower alkyl;
R2and R3may be associated with the formation of the lower alkylene;
And1is the lowest alkylene, optionally substituted by one or more hydroxy; and
R5is a group represented by

where R6and R7each independently is hydrogen, lower alkyl, lower cycloalkyl, phenyl, naphthyl, fullam, teinila, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pirrallo, triazolam, pyridium, pyrimidinium, pyridazinyl, pyrazinium, imidazo[2,1-b]what iatlian, thieno[2,3-b]pyrazinium, 2,3-dihydroimidazo[2,1-b]thiazolium, benzothiazolium, indolium, imidazo[1,2-a] pyridium, benzothieno, benzimidazolyl, 2,3-dihydrobenzo[b]fullam, benzofuran, indusrial, furo[2,3-C]pyridium, furo[3,2-C]pyridium, thieno[2,3-C]pyridium, thieno[3,2-C]pyridium, thieno[2,3-b]pyridium, benzo[1,3]dioxolan, benzisoxazole, pyrazolo[2,3-a]-pyridium, indolizinyl, 2,3-dihydroindole, ethanolism, 1,2,3,4-tetrahydro-1H-ethanolism, barbastella, 3,4-dihydroorotase, chinaillon, romaniam, 5,6,7,8-tetrahydroisoquinoline, 3,4-dihydro-1H-ethanolism, naphthyridine, 1,4-benzodioxane, cinnoline, khinoksalinona or 2,3-dihydrobenzo-1,4-oxazinyl, each of which is optionally substituted by one or more substituents selected from the group consisting of the following (4-1)to(4-32):
(4-1) cyano,
(4-2) hydroxy,
(4-3) halogen,
(4-4) lower alkyl, optionally substituted by one or more substituents selected from the group consisting of halogen, imidazolyl, morpholinyl and lower alkoxy,
(4-5) lower alkoxy, optionally substituted by one or more substituents selected from the group consisting of amino and lower alkylamino,
(4-6) pyridyl,
(4-7) tanila,
(4-8) piperazinil, optionally substituted by one or more lower alkyl,
(4-9) phenyl, optionally substituted by one or bol is e lower alkoxy,
(4-10) pyrazolyl, optionally substituted by one or more lower alkyl,
(4-11) pyrimidinyl, optionally substituted by one or more lower alkyl,
(4-12) piperidyl, optionally substituted by one or more lower alkyl,
(4-13) furil,
(4-14) carboxy,
(4-15) lower alkoxycarbonyl,
(4-16) amino, optionally substituted by one or more substituents selected from the group consisting of lower alkanoyl, lower alkylsulfonyl and lower alkyl,
(4-17) lower alkylthio,
(4-18) triazolyl,
(4-19) imidazolyl,
(4-20) pyrrolidinyl, optionally substituted by one or more oxo,
(4-21) lower alkylsulfonyl,
(4-22) lower alkylenedioxy, optionally substituted by one or more halogen,
(4-23) nitro,
(4-24) oxazolyl
(4-25) thiazolyl, optionally substituted by one or more lower alkyl,
(4-26) sulfo,
(4-27) pyridyloxy,
(4-28) lower alkylenedioxy,
(4-29) lower alkanolamine,
(4-30) oxo,
(4-31) morpholinyl and
(4-32) lower alkanoyl;
XAand XBeach is independently a bond, lower alkylene, lower Alcanena, -CO-, -SO2-, -SO2-lower alkylene, -CO-lower alkylene, -CO-lower Alcanena, lower alkylene-N(lower alkyl)-CO-lower alkylene, lower alkylene-N(lower alkyl)-, lower alkylene-M(lower alkyl)-CO - or lower alkylene-O-.

2. Connection benzodiazepine represented by the General formula (1) or its pharmaceutically acceptable salt according to claim 1,
where R6and R7each is one of (1)to(52):
(1) hydrogen,
(2) lower alkyl,
(3) lower cycloalkyl,
(4) phenyl, optionally substituted by one or more substituents selected from the group consisting of (4-1)to(4-25):
(4-1) cyano,
(4-2) hydroxy,
(4-3) halogen,
(4-4) lower alkyl, optionally substituted by one or more substituents selected from the group consisting of halogen, imidazolyl and morpholinyl,
(4-5) lower alkoxy, optionally substituted by one or more substituents selected from the group consisting of amino and lower alkylamino,
(4-6) pyridyl,
(4-7) tanila,
(4-8) piperazinil, optionally substituted by one or more lower alkyl,
(4-9) phenyl,
(4-10) pyrazolyl, optionally substituted by one or more lower alkyl,
(4-11) pyrimidinyl, optionally substituted by one or more lower alkyl,
(4-12) piperidyl, optionally substituted by one or more lower alkyl,
(4-13) furil,
(4-14) carboxy,
(4-15) lower alkoxycarbonyl,
(4-16) amino, optionally substituted by one or more substituents selected from the group consisting of lower alkanoyl and lower alkylsulfonyl,
(4-17) lower alkylthio,
(4-18) triazolyl,
(4-19) them is Azolla,
(4-20) pyrrolidinyl, optionally substituted by one or more oxo,
(4-21) lower alkylsulfonyl,
(4-22) lower alkylenedioxy, optionally substituted by one or more halogen,
(4-23) nitro,
(4-24) oxazolyl, and
(4-25) thiazolyl, optionally substituted by one or more lower alkyl,
(5) naphthyl,
(6) furil, optionally substituted by one or more substituents selected from the group consisting of lower alkyl, optionally substituted with halogen, carboxy, sulfo, pyridyloxy, lower alkoxycarbonyl and phenyl,
(7) tanila, optionally substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkylenedioxy, carboxy, halogen, pyridyl, lower alkoxy, lower alkoxycarbonyl, oxazolyl and Furie,
(8) imidazolyl, optionally substituted by one or more substituents selected from the group consisting of phenyl, lower alkyl and halogen,
(9) pyrazolyl, optionally substituted by one or more substituents selected from the group consisting of lower alkyl, optionally substituted with halogen, halogen, phenyl, optionally substituted lower alkoxy, purile and tanila,
(10) oxazolyl, optionally substituted by one or more substituents selected from the group consisting of lower alkyl and phenyl,
(11) isoxa olila, optionally substituted by one or more substituents selected from the group consisting of phenyl, lower alkyl, tanila and Furie,
(12) thiazolyl, optionally substituted by one or more substituents selected from the group consisting of lower alkyl, optionally substituted lower alkoxy, phenyl and lower alkanolamine,
(13) pyrrolyl, optionally substituted by one or more substituents selected from the group consisting of lower alkyl and lower alkoxycarbonyl,
(14) triazolyl, optionally substituted by one or more lower alkyl,
(15) pyridyl, optionally substituted by one or more substituents selected from the group consisting of lower alkyl, optionally substituted with halogen, oxo, hydroxy, lower alkoxy, halogen, pyrrolidinyl, morpholinyl and tanila,
(16) pyrimidinyl, optionally substituted by one or more substituents selected from the group consisting of lower alkyl and phenyl,
(17) pyridazinyl,
(18) pyrazinyl,
(19) imidazo[2,1-b]thiazolyl, optionally substituted by one or more halogen,
(20) thieno[2,3-b]pyrazinyl,
(21) 2,3-dihydroimidazo[2,1-b]thiazolyl, optionally substituted by one or more phenyl,
(22) benzothiazolyl, optionally substituted by one or more lower alkyl,
(23) indolyl, optionally substituted by one who does more substituents, selected from the group consisting of lower alkyl, lower alkanoyl and halogen,
(24) imidazo[1,2-a]pyridyl, optionally substituted by one or more lower alkyl,
(25) benzothieno, optionally substituted by one or more lower alkyl,
(26) benzimidazolyl, optionally substituted by one or more lower alkyl,
(27) 2,3-dihydrobenzo[b]Furie,
(28) benzofuran, optionally substituted by one or more halogen,
(29) indazole, optionally substituted by one or more lower alkyl,
(30) furo[2,3-C]pyridyl, optionally substituted by one or more substituents selected from the group consisting of oxo and lower alkyl,
(31) furo[3,2-C]pyridyl, optionally substituted by one or more substituents selected from the group consisting of oxo, lower alkyl, optionally substituted with halogen, halogen, furil, pyridyl and phenyl, optionally substituted by one or more lower alkoxy,
(32) thieno[2,3-e]pyridyl, optionally substituted by one or more substituents selected from the group consisting of a carbonyl group and lower alkyl,
(33) thieno[3,2-C]pyridyl, optionally substituted by one or more substituents selected from the group consisting of oxo and lower alkyl,
(34) thieno[2,3-b]pyridyl,
(35) benzo[1,3]dioxole, optionally substituted by one or more halogen,br/> (36) benzisoxazole,
(37) pyrazolo[2,3-a]pyridyl,
(38) indolizinyl,
(39) 2,3-dihydroindole, optionally substituted by one or more substituents selected from the group consisting of oxo, lower alkyl and lower alkanoyl,
(40) izochinolina, optionally substituted by one or more substituents selected from the group consisting of lower alkyl, halogen and oxo,
(41) 1,2,3,4-tetrahydro-1H-izochinolina, optionally substituted by one or more oxo,
(42) barbastella, optionally substituted by one or more lower alkoxy,
(43) 3,4-dihydroorotase, optionally substituted by one or more lower alkoxy,
(44) chinoline, optionally substituted by one or more substituents selected from the group consisting of amino, optionally substituted by one or two lower alkyl, lower alkoxy, lower alkyl and oxo,
(45) Romania, optionally substituted by one or more lower alkyl,
(46) 5,6,7,8-tetrahydroisoquinoline, optionally substituted by one or more oxo,
(47) 3,4-dihydro-1H-izochinolina, optionally substituted by one or more oxo,
(48) naphthyridine,
(49) 1,4-benzodioxane,
(50) cinnoline,
(51) khinoksalinona, or
(52) 2,3-dihydrobenzo-1,4-oxazinyl, optionally substituted by one or more substituents selected from the group consisting of lower alkyl and the CSR.

3. Connection benzodiazepine represented by the General Formula (1) or its pharmaceutically acceptable salt according to claim 2,
where R6and R7each is one of (4A), (6A), (7a), (15A), (30A), (31A), (32A), (33a), (40A) and (44a):
(4A) phenyl, optionally substituted by one or more substituents selected from the group consisting of (4A-1), (4A-4) and (4A-6):
(4A-1) cyano,
(4A-4) lower alkyl, optionally substituted by one or more halogen, and
(4A-6) pyridyl,
(6A) furil,
(7a) tanila,
(15A) pyridyl, optionally substituted by one or more lower alkyl,
(30A) furo[2,3-C]pyridyl, optionally substituted by one or more oxo,
(31A) furo[3,2-C]pyridyl, optionally substituted by one or more substituents selected from the group consisting of oxo and lower alkyl,
(32A) thieno[2,3-C]pyridyl, optionally substituted by one or more oxo,
(33a) thieno[3,2-C]pyridyl, optionally substituted by one or more oxo,
(40A) izochinolina, optionally substituted by one or more oxo, and
(44a) chinoline, optionally substituted by one or more oxo.

4. Connection benzodiazepine represented by the General formula (1) or its pharmaceutically acceptable salt according to claim 2, which is chosen from the group consisting of the following compounds:
trihydrochloride 1-ethyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-retil)pyridine-4-ylmethylamino]propoxy}-15-dihydrobenzo[b][1,4]diazepin-2,4-dione,
trihydrochloride 3,3,5-trimethyl-1-propyl-7-{3-[(2-pyridin-3-retil)pyridine-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
trihydrochloride 1,5 - diethyl-3,3-dimethyl-7-{3-[(2-pyridin-3-retil)pyridine-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
trihydrochloride 1,3,3,5-tetramethyl-7-{3-[(2-pyridin-3-retil)pyridine-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
the dihydrochloride of 1-ethyl-3,3,5-trimethyl-7-(3-{[2-(1-oxo-1H-isoquinoline-2-yl)ethyl]pyridine-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
the dihydrochloride of 1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-oxo-7H-furo[2,3-C]pyridine-6-yl)ethyl]pyridine-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
the dihydrochloride of N-methyl-N-(2-{pyridin-4-ylmethyl-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]amino}ethyl)benzamide,
the dihydrochloride 1,3,3,5-tetramethyl-7-{3-[(2-methylbenzyl)-(2-pyridin-3-retil)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
trihydrochloride 1,3,3,5-tetramethyl-7-{3-[(2-pyridin-3-retil)-(quinoline-4-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
trihydrochloride 1-ethyl-3,3,5-trimethyl-7-{3-[(3-methylpyridin-4-ylmethyl)-(2-pyridin-3-retil)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
the dihydrochloride of 1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-oxo-2H-quinoline-1-yl)ethyl]pyridine-4-ylmethylamino}propoxy)-1,5-Digue is drobenko[b][1,4]diazepin-2,4-dione,
the dihydrochloride of 1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-oxo-7H-thieno[2,3-C] pyridine-6-yl)ethyl] pyridine-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
4-({[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4] diazepin-7-yloxy)propyl]-[2-(1-oxo-1H-isoquinoline-2-yl)ethyl]amino}methyl)benzonitrile,
1-ethyl-3,3,5-trimethyl-7-(3-{[2-(1-oxo-1H-isoquinoline-2-yl)ethyl]thiophene-3-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
1-ethyl-7-(3-{furan-2-ylmethyl-[2-(1-oxo-1H-isoquinoline-2-yl)ethyl]amino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
7-{3-[benzyl-(2-pyridin-3-retil)amino]propoxy}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
3-{[[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-(2-pyridin-3-retil)amino]methyl}benzonitrile,
1-ethyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-ylbenzyl)-(2-pyridin-3-retil)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
4-({[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-[2-(7-oxo-7H-furo[2,3-C]pyridine-6-yl)ethyl]amino}methyl)benzonitrile,
1-ethyl-3,3,5-trimethyl-7-{3-[[2-(7-oxo-7H-furo[2,3-C]pyridine-6-yl)ethyl]-(4-trifloromethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
1-ethyl-3,3,5-trimethyl-7-(3-{(2-methylbenzyl)-[2-(7-oxo-7H-furo[2,3-C]pyridine-6-yl)ethyl]amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
1-ethyl-3,3,5-t is imethyl-7-(3-{[2-(7-oxo-7H-furo[2,3-C]pyridine-6-yl)ethyl]thiophene-2-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
the dihydrochloride of 1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-methyl-4-oxo-4H-furo[3,2-C]pyridine-5-yl)ethyl]pyridine-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-4H-furo[3,2-C]pyridine-5-yl)ethyl]pyridine-3-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-4H-thieno[3,2-C]pyridine-5-yl)ethyl]pyridine-3-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
1-ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-C]pyridine-5-yl)ethyl]-(4-methylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
1-ethyl-3,3,5-trimethyl-7-(3-{(2-methylpyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-C]pyridine-5-yl)ethyl]amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
1-ethyl-3,3,5-trimethyl-7-(3-{(4-methylpyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-e]pyridine-5-yl)ethyl]amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
1-ethyl-3,3,5-trimethyl-7-(3-{(2-methylpyridin-3-ylmethyl)-[2-(4-oxo-4H-thieno[3,2-C]pyridine-5-yl)ethyl]amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
the dihydrochloride of 1-ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-C]pyridine-5-yl)ethyl]-(2-propylpyridine-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
the hydrochloride of N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-(2-pyridin-3-retil)benzosulfimide,
the dihydrochloride of 7-(3-{(2,6-dimethylpyridin the n-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-C]pyridine-5-yl)ethyl]amino}propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione,
the hydrochloride of N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-(2-pyridin-3-retil)benzamide and
N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-[2-(1-oxo-1H-isoquinoline-2-yl)ethyl]benzosulfimide.

5. Pharmaceutical composition for prevention and/or treatment of arrhythmia, containing the compound of the benzodiazepine represented by the Formula (1), or its pharmaceutically acceptable salt according to claim 1 and a pharmacologically acceptable carrier.

6. Connection benzodiazepine represented by the Formula (1)or its salt according to claim 1 for use in pharmaceutical compositions for the prevention and/or treatment of arrhythmia.

7. Application connection benzodiazepine represented by the Formula (1), or its pharmaceutically acceptable salt according to claim 1 as a pharmaceutical composition for prevention and/or treatment of arrhythmia.

8. Application connection benzodiazepine represented by the Formula (1), or its pharmaceutically acceptable salt according to claim 1 to obtain a pharmaceutical composition for prevention and/or treatment of arrhythmia.



 

Same patents:

Iap inhibitors // 2491276

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula: U1-M-U2, where U1 and U2 have general formula (I), where: G stands for: IVb IVd ive, and values M, X1, X2, R2, R3, R3', R4, R4', R5, R5', R6, R6', R7, Z7, Z2, Z3, Z4, Q2 are given in item 1 of the formula.

EFFECT: compounds can be applied for induction of apoptosis in cell.

37 cl, 13 dwg, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and salts thereof wherein R1 represents -A11-A12-; R2 represents tetrahydrofurylmethyl, tetrahydropyranylmethyl or tetrahydropyranyl; A11 represents a single bond, methylene or 3,2-ethylene; A12 represents C1-6 alkyl, C3-6 cycloalkyl or C3-6 cycloalkyl containing methyl; R3 represents methoxy, cyano, cyclobutyloxymethyl, methoxymethyl or ethoxymethyl; and R4 represents methoxy or chlorine. Also, the invention also refers to a pharmaceutical composition possessing corticotrophin-releasing factor (CRF) receptor antagonist activity, containing a compound of formula (I), to a therapeutic/preventive agent, and a method of treating the diseases specified in the patent claim.

EFFECT: there are presented the compounds of formula (I) as corticotropin-releasing factor (CRF) receptor antagonists.

20 cl, 2 dwg, 2 tbl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1 , where X and T are N or C, Q is a (3-7)-member aromatic ring which contains 0-3 nitrogen atoms as ring members, and which is optionally benzo-condensed and is substituted with oxo; C1-C6-alkyl; halogen- C1-C6-alkyl; hydroxy-C1-C6-alkyl; C1-C6-alkoxy; C6-C10-aryl; or a (3-7)-member heteroaryl containing 1-3 oxygen atoms, P is C1-C6-alkyl, optionally substituted with a halogen, and R is a group selected from: (i) -C1-C6-alkyl-R1, (ii) -NR2R3, (iii) -O-R4, (iv) -S-R5, (v) -C (=O))-R6, (vi) optionally substituted (3-7)-member heteroaryl containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (vi) optionally substituted (3-7)-member heteroatom containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (vii) optionally substituted, saturated or partially unsaturated, separate or condensed (3-10)-member heterocyclic ring containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (viii) azido; where each R1, R2, R3, R4, R3, R6, is as described in the claim. The invention also relates to a pharmaceutical composition for preventing and treating a vascular disease, which contains a compound of formula 1.

EFFECT: compounds of formula 1 with inhibitory activity with reference to aggregation of thrombocytes.

7 cl, 7 dwg, 2 tbl, 519 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a 2-aza-bicyclo[3.3.0]octane derivative of formula , with stereogenic centres in a (1S,3S,5S)-configuration, where A is a thiazolyl which is unsubstituted or monosubstituted, where the substitute is independently selected from a group comprising C1-4alkyl, C3-6cycloalkyl and NH2; B is phenyl which is unsubstituted or mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, trifluoromethyl, NHC(O)CH3 and halogen; and R1 is an imidazo[2,1·b]thiazolyl or benzoisoxazolyl group, where said groups are independently unsubstituted or monosubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl; or R1 is a 2,3-dihydrobenzofuranyl group; or a pharmaceutically acceptable salt. The 2-aza-bicyclo[3.3.0]octane derivative of formula (I) is as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: obtaining novel 2-aza-bicyclo[3,3,0]octane derivatives as orexin receptor antagonists.

8 cl, 1 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of general formula:

or its pharmaceutically acceptable salt wherein the ring A represents a phenyl group which can contain 1-3 substitutes specified in a group of substitutes, or a thienyl group which can contain 1-3 substitutes specified in a group of substitutes α; L represents a single bond or a group of formula -NRC CO- (wherein Re represents a hydrogen atom), the ring B represents C6-14 aryl group which can contain 1-3 substitutes specified in a group of substitutes α, or a 5-10-member heterocyclic group which can contain 1-3 substitutes specified in a group of substitutes α; the X, Y, Z , R1 and R2 , R3, R4, R5 and R6 radical values are presented in cl.1 of the patent claim which possess an effect of Aβ protein production inhibition or an effect of BACE1 inhibition.

EFFECT: preparing the compound which is applicable as a preventive or therapeutic agent for neurodegenerative disease caused by Aβ.

13 cl, 35 tbl, 285 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bicyclosulphonyl acid (BCSA) compounds of formula: where: where each of -Rpw, -Rpx, -RPY, and -RPZ independently denotes H or -RRS1; each -RRS1 independently denotes -F, -Cl, -Br, -I, -RA1, -CF3, -OH, -OCF3 or -ORA1; where each RA1 independently denotes C1-4alkyl, phenyl or benzyl; and additionally, two neighbouring -RRS1 groups can together form -OCH2O-, -OCH2CH2O- or -OCH2CH2CH2O-; -RAK independently denotes a covalent bond, -(CH2)- or -(CH2)2-; -RN independently denotes -RNNN, or -LN-RNNN; the rest of the values of the radicals are given in claim 1, which act as inhibitors of inhibitors of tumor necrosis factor-α converting enzyme (TACE).

EFFECT: compounds are useful in treating TNF-α mediated conditions.

36 cl, 303 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 3-aza-bicyclo[3.3.0]octane derivatives of formula , where R1 and R2 are hydrogen, C1-4alkyl or fluorine; R3 is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl, trifluoromethoxy group and halogen; 2,3-dihydrobenzofuranyl; 2,3-dihydrobenzo[1,4]dioxynyl; or isoxazolyl, pyridyl, indazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, pyrrolo[2,1b]thiazolyl, imidazo[ 1,2-a]pyridinyl or imidazo[2,1-b]thiazolyl, where said groups are unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, halogen and trifluoromethyl; A is or ; R4 is C1-4alkyl or -NR6R7; R6 is hydrogen or C1-4alkyl; R7 is hydrogen or C1-4alkyl; and D is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl and halogen; or a pharmaceutically acceptable salt of such a compound. 3-aza-bicyclo[3.3.0]octane derivatives or a pharmaceutically acceptable salt thereof are used as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: novel 3-aza-bicyclo[3,3,0]octane derivatives as nonpeptide antagonists of human orexin receptors.

9 cl, 1 tbl, 85 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: medicine.

SUBSTANCE: invention refers to an agent for activation of lipoprotein lipase containing a benzene derivative of general formula (1) which is used for preventing and treating hyperlipidemia and obesity. The invention also refers to the benzene derivatives of general formula (1a).

EFFECT: composition improvement.

8 cl, 6 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (I): and pharmaceutically acceptable salts, diastereoisomers and enantiomers thereof, wherein D is specified in a group consisting of , and , M is ; Z is -O-; Ar is a 6-member aromatic ring system substituted by 0 to 4 R2 groups; and G is or ; the other radical values are presented in cl.1 of the patent claim, as well as to using them for inhibiting protein tyrosine kinase inhibition.

EFFECT: preparing the new compounds.

14 cl, 33 tbl, 191 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to thienopyridazine compounds of formula (I) and to pharmaceutically acceptable salts and hydrates thereof, wherein R1 and R2 independently mean H or C1-4 alkyl; R3 means a saturated or unsaturated 5- or 6-members ring containing N, S or O, or optical isomers thereof, R4 means phenyl, monosubstituted or disubstituted halogen. The invention also refers to a method for preparing the above compounds and to a pharmaceutical composition for treating and preventing tumour diseases containing the above compounds.

EFFECT: there are prepared new compounds that may be used in medicine for treating anti-tumour diseases, particularly cancer.

12 cl, 3 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely azepine derivatives of general formula (I) or pharmaceutically acceptable salts thereof, wherein X represents S; R1 and R2 are independently specified in a group of substitutes consisting of H, halogen, C1-8-alkyl, C1-8-alkylphenyl, C2-8-alkenyl, OR5, CON(R5)2, SO2N(R5)2, phenyl, if necessary containing up to three substitutes of C1-4alkyl, halogen or C1-4alkoxy-groups; R3 is specified in a group consisting of H, C1-8-alkyl, OR5; R3a represents H, or R2 and R3 together represent a five-merous saturated cycle; R4 is specified in a group consisting of H, C1-8-alkyl; R4a represents H, or R4 and R4a together represent the substitute -CH2CH2-; R5 is specified in a group consisting of C1-8-alkyl, or R5 together with the atom whereto attached represents pyrrolidinyl; or R1 represents 4-trifluoromethoxyphenyl or 2-trifluoromethylphenyl, then X represents S, and R2, R3, R3a, R4 and R4a represents hydrogen, provided a derivative is other than 8- phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-3-ol and 2-bromo-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-3-ol. Also, the invention refers to a pharmaceutical composition of the compounds of formula (I) and a method treating disorders on the basis of the use of the compound of formula (I).

EFFECT: there are produced new azepine derivatives effective in 5HT2C-receptor function modulation.

6 cl, 1 tbl, 49 ex

FIELD: medicine.

SUBSTANCE: invention describes crystals of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (prasugrel) hydrobromate, comprisions of crystals and pharmaceutical compositions containing them for preventing and treating the diseases associated with thrombus or embolism in an animal.

EFFECT: there are prepared new crystals of prasugrel hydrobromate which possess improved stability and solubility, and can find application in medicine.

13 cl, 7 dwg, 3 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1 , where X and T are N or C, Q is a (3-7)-member aromatic ring which contains 0-3 nitrogen atoms as ring members, and which is optionally benzo-condensed and is substituted with oxo; C1-C6-alkyl; halogen- C1-C6-alkyl; hydroxy-C1-C6-alkyl; C1-C6-alkoxy; C6-C10-aryl; or a (3-7)-member heteroaryl containing 1-3 oxygen atoms, P is C1-C6-alkyl, optionally substituted with a halogen, and R is a group selected from: (i) -C1-C6-alkyl-R1, (ii) -NR2R3, (iii) -O-R4, (iv) -S-R5, (v) -C (=O))-R6, (vi) optionally substituted (3-7)-member heteroaryl containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (vi) optionally substituted (3-7)-member heteroatom containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (vii) optionally substituted, saturated or partially unsaturated, separate or condensed (3-10)-member heterocyclic ring containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (viii) azido; where each R1, R2, R3, R4, R3, R6, is as described in the claim. The invention also relates to a pharmaceutical composition for preventing and treating a vascular disease, which contains a compound of formula 1.

EFFECT: compounds of formula 1 with inhibitory activity with reference to aggregation of thrombocytes.

7 cl, 7 dwg, 2 tbl, 519 ex

FIELD: chemistry.

SUBSTANCE: compound is N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl-N'-(3-fluorophenyl)urea, N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl-N'-[4-(difluoromethoxy)phenyl]urea, N-[4-(4-amino-7-{l-[(2S)-2-hydroxypropyl)-1H-pyrazol-4-yl}thieno[3,2-c]pyridin-3-yl)phenyl]-N'-(3-methylphenyl)urea, N-(4- {4-amino-7-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl-N'-(4-methoxyphenyl)urea, N-[4-(4-amino-7-{1-[(2S)-2,3-dihydroxypropyl)-1H-pyrazol-4-yl}thieno[3,2-c]pyridin-3-yl)phenyl]-N'-(4-methoxyphenyl) or therapeutically acceptable salts thereof. A pharmaceutical composition based on said compounds is also disclosed.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine for treating cancer.

13 cl, 5 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-acylated 3-amino-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxamides, which exhibit antidote activity on 2,4-dichlorophenoxyacetic acid on sunflower.

EFFECT: wider range of synthetic biologically active substances for use in agriculture as antidotes.

1 cl, 1 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a piperidine derivative of general formula (I)

,

where R1 denotes hydrogen or a substitute selected from the following (b)-(i): b) acrylic acid (including alkyl ester and hydroxyalkyl amide), (c) ureide, (d) alkenyl, (e) aminoalkyl which can be substituted with alkyl carbonyl or aminocarbonyl, (f) carbonyl alkyl, substituted with hydroxy, alkoxy or hydroxyalkylamino, (g) carbonyl, substituted with hydroxy, morpholino, alkoxy, hydroxyalkyl aminoalkoxy or cyclohexyloxy carbonyloxyalkoxy, (h) carbonylamino, substituted with alkyl or alkoxy, (i) aminocarbonyl which can be substituted with one or two substitutes selected from amino, hydroxy, alkoxy, alkenyl and alkyl (which can be substituted with halogen, thiol, piperidino, amino, alkoxy, alkoxycarbonyl, aminocarbonyl or one or two hydroxy); R2 denotes hydrogen or a substitute selected from the following (j)-(r): (j) cyano, (k) acrylic acid, (l) alkyl, substituted with hydroxy or piperidino, (m) carbonyl alkyl, substituted with hydroxy, alkoxy (which can be substituted with cyclohexyloxy carbonyloxy) or hydroxyalkylamino, (n) carbonyl, substituted with hydroxy or alkoxy, (o) carbonyl alkoxy, substituted with alkoxy, (p) carbonyl alkyl sulphanyl, substituted with hydroxy or alkoxy, (q) alkoxy, (r) halogen; and R3 denotes hydrogen or a substitute selected from the following (s)-(w): (s) alkyl which can be substituted with carboxy, cyano, pyrrolidyl, piperidino, alkoxy, alkyl sulphanyl or one or two hydroxy, (t) carbonyl, substituted with alkyl or alkoxy, (u) carbonyl alkoxyalkyl, substituted with hydroxy or alkoxy, (v) carbonyl alkyl, substituted with alkyl, alkoxy or alkylphenyl, (w) aminoalkyl, substituted with aminocarbonyl or alkane sulphonyl, where one of said R1 and R2 denotes a substitute other than hydrogen, A is unsubstituted or is an oxo, B denotes carbon or oxygen, one of X and Y denotes carbon and the other denotes sulphur, the dotted line denotes a single bond or a double bond, under the condition that when R2 denotes halogen or alkoxy, A is unsubstituted, R1 denotes a substitute other than hydrogen and B denotes oxygen. The invention also relates to an antihistamine which contains a compound of formula I and use of the described compound for treatment and production of a medicinal agent.

EFFECT: novel compounds having antagonistic action on histamine receptors are obtained and described and can be suitable as active ingredients of a pharmaceutical composition, especially an antihistamine composition.

17 cl, 40 ex, 21 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compound presented by Formula

or Formula ,

wherein A and B optionally represent CH2, CO; D represent S; the values R1, R2, R4, R4 are specified in cl. 1 of the patent claim, as well as to their pharmacologically acceptable salts or hydrates and methods for preparing them.

EFFECT: compounds are able to inhibit TNF-α recovering cells.

19 cl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A, J, R1, R4, X, Z are given in claim 1, and to a pharmaceutical composition containing such compounds, which modulate activity of store-operated calcium (SOC) channels. The present invention also describes methods of using such SOC channel modulators to treat diseases or conditions where inhibition of activity of SOC channels can be beneficial.

EFFECT: improved method.

17 cl, 5 tbl, 2 dwg, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely azepine derivatives of general formula (I) or pharmaceutically acceptable salts thereof, wherein X represents S; R1 and R2 are independently specified in a group of substitutes consisting of H, halogen, C1-8-alkyl, C1-8-alkylphenyl, C2-8-alkenyl, OR5, CON(R5)2, SO2N(R5)2, phenyl, if necessary containing up to three substitutes of C1-4alkyl, halogen or C1-4alkoxy-groups; R3 is specified in a group consisting of H, C1-8-alkyl, OR5; R3a represents H, or R2 and R3 together represent a five-merous saturated cycle; R4 is specified in a group consisting of H, C1-8-alkyl; R4a represents H, or R4 and R4a together represent the substitute -CH2CH2-; R5 is specified in a group consisting of C1-8-alkyl, or R5 together with the atom whereto attached represents pyrrolidinyl; or R1 represents 4-trifluoromethoxyphenyl or 2-trifluoromethylphenyl, then X represents S, and R2, R3, R3a, R4 and R4a represents hydrogen, provided a derivative is other than 8- phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-3-ol and 2-bromo-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-3-ol. Also, the invention refers to a pharmaceutical composition of the compounds of formula (I) and a method treating disorders on the basis of the use of the compound of formula (I).

EFFECT: there are produced new azepine derivatives effective in 5HT2C-receptor function modulation.

6 cl, 1 tbl, 49 ex

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