Bicyclic heterocycles and use thereof as hiv integrase inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I with anti-HIV activity , where R1 represents C1-6(Ar1)alkyl or C1-6(Ar1)oxyalkyl; R2 represents hydrogen or OR14; R3 represents hydrogen, halogen, hydroxyl, cyano, C1-6alkyl, C5-7cycloalkenyl, C1-6halogenalkyl, C1-6alkoxy, C1-6alkylthio, N(R8)(R9), NHAr2, N(R6)COR7, OCON(R8)(R9), OCH2CON(R9)(R9), CO2R6, CON(R8)(R9), SOR7, S(=N)R7, SO2R7, SO2N(R6)(R6), PO(OR6)2, C2-4(R12)alkynyl, R13, Ar2 or Ar3; R4 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; R5 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; R6 represents hydrogen or C1-6alkyl; R7 represents C1-7alkyl; R8 represents hydrogen or C1-6alkyl; R9 represents hydrogen, C1-6alkyl, C1-6hydroxyalkyl or C1-6(C1-6dialkylamino)alkyl; or N(R8)(R9) taken together represent azetidinyl, pyrrolydinyl, (R10)-piperidinyl, N-(R11)-piperazinyl, morpholinyl or dioxothiazinyl; R10 represents hydrogen; R11 represents hydrogen, C1-6alkyl, COR6 or CO2R6 ; R12 represents hydrogen, hydroxyl, N(R6)(R6), OSO2R7 or dioxothiazinyl; R13 represents dioxothiazinyl; R4 represents hydrogen or C1-6alkyl; Ar1 represents ,,, ,,,,,; or Ar2 represents tetrazolyl, triazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, furanyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl or indolyl, and is substituted with 0-2 substitutes selected from a group consisting of halogen, benzyl, C1-6alkyl, C1-6alkoxy, N((R8)(R9), CON(R8)(R9) and CO2R8; Ar3 represents phenyl substituted with 0-2 substitutes selected from a group consisting of halogen, cyano, hydroxy, C1-6alkyl, C1-6alkoxy, (C1-6alkoxy)methyl, C1-6halogenalkoxy, N(R8)(R9), CON(R6)(R6) and CH2N(R8)(R9), or represents dioxolanylphenyl; and X-Y-Z represents C(R14)2OC(R14)2C(R14)2, C(R14)2OC(R14)2C(R14)2C(R14)2; or pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition.

EFFECT: bicyclic heterocycles are disclosed, as well as their use HIV integrase inhibitors.

21 cl, 38 dwg, 8 tbl, 282 ex

 

The text descriptions are given in facsimile form.

1. The compound of the formula I

where R1represents a C1-6(AG1)alkyl or C1-6(Ar1)oxyalkyl;
R2represents hydrogen or or14;
R3represents hydrogen, halogen, hydroxy, cyano, C1-6alkyl, C5-7cycloalkenyl, C1-6halogenated, C1-6alkoxy, C1-6alkylthio, N(R8)(R9), NHAr2,
N(R6)COR7, OCON(R8)(R9), OCH2CON(R9)(R9), CO2R6, CON(R8)(R9), SOR7, S(=N)R7, SO2R7, SO2N(R6)(R6), PO(OR6)2C2-4(R12)quinil, R13, Ar2or Ar3;
R4represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy;
R5represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy;
R6represents hydrogen or C1-6alkyl;
R7represents a C1-7alkyl;
R8represents hydrogen or C1-6alkyl;
R9represents hydrogen, C1-6alkyl, C1-6hydroxyalkyl or C1-6(C1-6dialkylamino)alkyl; or
N(R8)(R9), taken together, represent azetidinol, pyrrolidinyl, (R10-piperidinyl, N-(R11)-piperaz the Nile, morpholinyl or dissociating;
R10represents hydrogen;
R11represents hydrogen, C1-6alkyl, COR6or CO2R6;
R12represents hydrogen, hydroxy, N(R6)(R6), OSO2R7or dissociating;
R13is dissociating;
R14represents hydrogen or C1-6alkyl;
AG1represents a
,,,,,
,,,,,
;
or
Ar2represents tetrazolyl, triazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, furanyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridinyl, chinoline or indolyl, and is substituted with 0-2 substituents selected from the group consisting of halogen, benzyl, C1-6of alkyl, C1-6alkoxy, N(R8)(R9), CON(R8)(R9and CO2R6;
Ar3represents phenyl, substituted with 0-2 substituents selected from the group consisting of halogen, cyano, hydroxy, C1-6of alkyl, C1-6alkoxy, (C 1-6alkoxy)methyl,
C1-6halogenoalkane, N(R8)(R9), CON(R6)(R6and CH2N(R8)(R9), or is DIOXOLANYL; and
X-Y-Z represents C(R14)2OC(R14)2C(R14)2C(R14)2OC(R14)2C(R14)2C(R14)2;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R1represents a C1-6(AG1)alkyl.

3. The compound according to claim 1, where R1represents a

4. The compound according to claim 1, where R1represents a

5. The compound according to claim 1, where R2represents hydrogen.

6. The compound according to claim 1, where R3represents hydrogen, halogen, N(R8)(R9), N(R6)COR7, OCON(R8)(R9), CON(R8)(R9), SOR7, SO2R7, SO2N(R6)(R6), PO(OR6)2, R13or Ar2.

7. The compound according to claim 1, where X-Y-Z represents C(R14)2OCH2CH2or C(R14)2OCH2CH2CH2.

8. The compound according to claim 1, where X-Y-Z represents CH2Och2CH2, (CH3)NON2CH2, (CH3)2Och2CH2CH2Och2CH2CH2, (CH3)NON2CH2sub> 2or(CH3)2Och2CH2CH2.

9. The compound according to claim 1, selected from the group including
N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
9,9-diethyl-N - [[4-fluoro-2-(1H-1,2,4-triazole-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
9,9-diethyl-N-[[4-fluoro-2-(methylsulphonyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[2-[(dimethylamino)sulfonyl]-4-forfinal]methyl]-9,9-diethyl-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-(2-oxo-1-azetidine)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
9,9-diethyl-N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-(2-oxo-3-oxazolidinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-(methylsulphonyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-(1H-1,2,4-triazole-1-yl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-6N-pyrimido[2,1-C][1,4]oxazepine-2-carboxamide;
N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazole-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-is hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-(2-oxo-1-pyrrolidinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-(1H-1,2,4-triazole-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-6N-pyrimido[2,1-C][1,4]oxazepine-2-carboxamide;
9,9-diethyl-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-N-[[2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-(1,2,3-thiadiazole-4-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-airymida[2,1-C][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-(methylsulphonyl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-6N-pyrimido[2,1-C][1,4]oxazepine-2-carboxamide;
N-[[4-fluoro-2-(1-methyl-1H-tetrazol-5-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazole-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-(2-oxo-1-piperidinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[2-[(dim is thylamino)sulfonyl]-4-forfinal]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[(4-forfinal)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(2-oxo-3-oxazolidinyl)phenyl]methyl]-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-[(methylamino)sulfonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[2-(acetylamino)-4-forfinal]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-[3-[(4-methyl-1-piperazinil)carbonyl]-1H-1,2,4-triazole-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1C][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-(4-morpholinylcarbonyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-[[(2-hydroxyethyl)amino]carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-[3-(4-morpholinylcarbonyl)-1H-1,2,4-triazole-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(2-oxo-1-azetidine)phenyl]methyl]-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-(1H-pyrazole-5-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[2-[3-[(dimethylamino)carbonyl]-1H-1,2,4-triazole-1-yl]-4-is terphenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[(4-forfinal)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[3-fluoro-2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(methylsulphonyl)phenyl]methyl]-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
N-[[4-fluoro-2-(4-morpholinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide;
5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimidine[2,1-C][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl ether N,N-dimethylcarbamyl acid;
N-[[2-(aminosulfonyl)-4-forfinal]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide; and
[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimidine[2,1-C][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]phosphonic acid dimethyl ester;
or its pharmaceutically acceptable salt.

10. The compound according to claim 1, which represents the

or its pharmaceutically acceptable salt.

11. The compound according to claim 1, which represents the

or its pharmaceutically acceptable salt.

12. The compound according to claim 1, which represents the

or its pharmaceutically acceptable salt.

13. With the Association according to claim 1, representing

or its pharmaceutically acceptable salt.

14. The compound according to claim 1, which represents the

or its pharmaceutically acceptable salt.

15. The compound according to claim 1, which represents the

or its pharmaceutically acceptable salt.

16. The compound according to claim 1, which represents the

or its pharmaceutically acceptable salt.

17. The compound according to claim 1, which represents the

or its pharmaceutically acceptable salt.

18. The compound according to claim 1, which represents the

or its pharmaceutically acceptable salt.

19. The compound according to claim 1, which represents the

or its pharmaceutically acceptable salt.

20. Pharmaceutical composition having anti-HIV activity, containing a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

21. The pharmaceutical composition according to claim 20, in which the compound according to claim 1 is N-[(4-forfinal)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-C][1,4]oxazin-2-carboxamide.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention relates to benzopyran derivatives of formula or

or their pharmaceutically acceptable salts, where R1 and R2 independently represent a hydrogen atom or a C1-6alkyl group, R3 is a hydroxyl group, R4 is a hydrogen atom, m is an integer ranging from 1 to 4, n is an integer ranging from 0 to 4, V is a single bond, CR7R8 or NR9, R5 is a hydrogen atom, R6 is a hydrogen atom, C1-6alkyl group, C3-8cycloalkyl group, C3-8cycloalkenyl group, amino group, C1-6alkylamino group, C6-14aryl group, C2-9heteroaryl group or C2-9heterocyclic group, A is a 5- or 6-member ring condensed with a benzene ring, and the ring can contain an oxygen atom, a nitrogen atom or a sulphur atom numbering from 1 to 3 or separately, or combined, the number of unsaturated bonds in the ring equals 1, 2 or 3, including the unsaturated bond in the condensed benzene ring, carbon atoms in the ring can represent carbonyl or thiocarbonyl.

EFFECT: compounds can be used as antiarrhythmic agents.

47 cl, 1 tbl, 98 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on HsEg5. In formula (I) A is C=O or CH2; B is optionally substituted C1-6alkyl, D is O or N, where O is substituted with one R8, and where N is substituted with one or more R8, R1 and R2 together with the carbon atoms with which they are bonded form optionally substituted isothiazole or isoxazole, condensed with a pyrimidine ring, optionally substituted with a substitute which is C1-6 alkyl. Values of the rest of the radicals are given in the formula of invention.

EFFECT: invention relates to use of disclosed compounds in making medicinal agents with inhibitory effect on HsEg5, to a method of obtaining inhibitory effect on HsEg5, to a pharmaceutical composition which contains the disclosed compound as an active ingredient.

22 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 2,3-dihydro-6-nitroimidazo[2,1-b]oxazol of general formula (1), as well as to their optically active forms and pharmacologically acceptable salts: where values of R1, R2 and n are given in i.1 of invention formula.

EFFECT: development of compounds, which have bactericidal action against Mycobacterium tuberculosis, polyresistant Mycobacterium tuberculosis and can be applied as antituberculosis medication.

3 cl, 16 ex, 183 tbl, 1515 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new annelated azaheterocyclic amides, including a pyrimidine fragment, with the general formula 1, method of obtaining them and their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of P13K kinase, in compounds with the general formula 1: , where: X represents an oxygen atom, sulphur atom or not necessarily substituted at the nitrogen NH group, where the substitute is selected from lower alkyls and possibly a substituted aryl; Y represents an atom of nitrogen or substituted at the carbon atom CH group, where the substitute is selected from lower alkyls; Z represents an oxygen atom; R1 represents a hydrogen atom or not necessarily substituted C1-C6alkyl, or Z represents a nitrogen atom, which is together with a carbon atom, with which it is joined, form through Z and R1 annelated imidazole cycle; R2 and R3 independently from each other represent hydrogen, not necessarily substituted with C1-C6alkyl, C3-C6cycloalkyl, not necessarily substituted with phenyl, not necessarily substituted with 6-member aza-heteroaryl, under the condition, when Y represents a nitrogen atom, or R2 and R3 independently from each other represent not necessarily substituted C1-C6alkyl, not necessarily substituted with phenyl, not necessarily substituted with 5-7-member heterocycle with 1-2 heteroatoms, selected from nitrogen and oxygen, and possibly annelated with a phenyl ring, under the condition, when Y does not necessarily represent a substituted carbon atom at the CH group, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents a substituted aminoC1-C6alkyl and not necessarily substituted 5-6-member aza-heterocycloalkyl, under the condition, when Y represents a group which is substituted at the CH atom, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents phenyl which is not necessarily substituted, pyridyl which is not necessarily substituted, pyrimidinyl which is not necessarily substituted, under the conditions, when R1 represents a substituted aminoC1-C6alkyl, substituted C2-C3hydroxyalkyl and aza-heterocycloalkyl not necessarily substituted, Y represents a group with CH substituted, and X represents an oxygen atom, sulphur, and the substitute of the above indicated substituted alkyl, phenyl, heterocycle, pyridyl, pyrimidyl are selected from groups of hydroxyl-, cyano-groups, hydrogen, lower alkyls, possibly mono- or di-substituted lower alkyl sulfamoyl, carbamoyl, C1-C6alkoxycarbonyl, amino, mono- or di-lower alkyl-amine, N-(lower alkyl), N-(phenylC1-C6alkyl)amine, phenyl, possibly substituted with a halogen atom, C1-C6alkyl, haloid-C1-C6alkyl; phenylC1-C6alkyl, saturated or non-saturated 5-6-member heterocycle containing 1-2-heteroatoms, selected from nitrogen, oxygen and sulphur, and possible condensation with a benzene ring R4 represents hydrogen or a lower alkyl.

EFFECT: obtaining new annelated aza-heterocyclic amides, including a pyrimidine fragment, with the general formula with the possibility of their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of PI3K kinase.

16 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: novel chemical compounds of formula (I) or their pharmaceutically acceptable salts possess inhibiting activity with respect to kinase p-38 MAP and kinase FGFR, and can be used in treatment of such diseases as arthritis, obstructive lung disease, Alzheimer's disease or oncological and other diseases. In general formula (I) , R1 is hydrogen, R2 is 6-member oxygen-containing heterocyclyl, aryl, selected from unsubstituted phenyl or phenyl substituted with aliphatic acyl group which contains 1-6 carbon atoms, halogen cyano, hydroxyl, C1-6alkylsulfinyl, C1-6alkylsulfonyloxy, C1-6alkylsulfonyl, C1-6alkylsulfanyl, tret-butydimethylsilanyloxy, 6-member heterocyclyl, containing 1-2-heteroatoms, selected from nitrogen and oxygen, R3 is C1-6alkyl, Ar1 is phenyl, substituted with 1-2 substituents, selected from atoms of halogen, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, X1 is oxygen and X2 is chemical bond.

EFFECT: efficient application of invention compounds in pharmaceutical composition.

13 cl, 1 tbl, 64 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: medicine.

SUBSTANCE: present invention concerns lysine compounds of formula (I) or its pharmaceutically acceptable salts, a based pharmaceutical compositions and application for treatment or prevention of HIV-infection. The compounds of formula (I) where n is equal to 3 or 4, where X and Y identical or different are chosen from the group consisting of H, F, Cl, Br, I and -NR4R5, where R6 is chosen from the group consisting of unbranched alkyl group, containing 1 to 6 carbon atoms, and branched alkyl group containing 3 to 6 carbon atoms, where R3 is chosen from the group consisting of the group of formula R3A-CO-, and R3a is chosen from the group consisting of unbranched or branched alkyl group containing 1 to 6 carbon atoms, alkyloxygroup containing 1 to 6 carbon atoms, and 4-morpholinyl, where R4 and R5 are identical and represent H, where R2 is chosen from the group consisting of diphenylmethyl group, naphthyl-1-CH2-group, and naphthyl-2-CH2-group, where X' and Y' are identical and represent H, and where R1 is chosen from the group consisting of from (HO)2P(O) and (MO)2P(O), where M represents alkaline metal.

EFFECT: lysine compounds representing effective inhibitors of aspartyl-protease.

15 cl, 3 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely medical products for HIV/AIDS infection therapy. There is offered application of Glimurid as a drug for HIV-infection treatment.

EFFECT: application of said drug ensures to increase the clinical effectiveness due to viral load reduction and immunocorrection.

1 ex, 2 dwg

FIELD: pharmacology.

SUBSTANCE: present invention refers to compounds of formula (I) , to its N-oxides, salts, stereoisomer forms where n is equal 1, 2 or 3; R1 means cyano group; X means bivalent radical NR2 or O; R2 means hydrogen or C1-10alkyl, each Q1 independently stands for direct coupling, -CH2- or -CH2-CH2-; each R4 independently means hydrogen or C1-4alkyl; each R5a, R5b, R5c independently means hydrogen, C1-4alkyl or arylC1-4alkyl; each R5e, R5f independently means hydrogen, C1-4alkyl or arylC1-4alkyl, or R5e and R5f together can form bivalent alkandiyl radical of formula -CH2-CH2- or -CH2-CH2-CH2-; R11 means aryl, arylC1-4alkyl, C1-4alkylcarbonyl, arylcarbonyl, arylC1-4alkylcarbonyl, C1-4alkyloxycarbonyl, arylC1-4alkyloxycarbonyl, R5aR5bN-carbonyl, hydroxyC1-4alkyl, C1-4alkyloxyC1-4alkyl, arylC1-4alkyloxyC1-4alkyl, aryloxyC1-4alkyl, pyridyl; -a1=a2-a3=a4- means a bivalent radical of formula -CH=CH-CH=CH- (c-1); where one or two hydrogen atoms in (c-1) are substituted by radical C1-6alkyl, C1-4alkoxy, halogen, hydroxy group, (R5g)(R5h)N-(C1-4alkandiyl)-O-trifluoromethyl, cyano group, radical -COOR4, (R5a)(R5b)N-sulphonyl, pyrrolidinyl-sulphonyl, piperidinyl sulphonyl, radical N(R5a)(R5b), radical (a-1), (a-7), morpholinyl, (R5g)(R5h)N-(C1-4alkandiyl)-N(R5c)-, C1-6alkylcarbonylamino, C1-6alkyloxycarbonylamino, C1-6alkylsulphonylamino, (R5a)(R5b)N-C1-4alkyl; R20 means hydrogen, spiro (C2-4alkylenedioxy), spiro (diC1-4alkyoxy) or -NR5gR5h; each R5g or R5h independently means either hydrogen, or C1-4alkyl, or R5g and R5h together with nitrogen atom whereto attached form pyrrolidinyl, piperidinyl or morpholinyl; R3 means nitro group, cyano group, amino group, halogen, hydroxy group or C1-4alkoxy; aryl means phenyl optionally substituted with one or more substitutes chosen from the group consisting of C1-6alkyl, C1-4alkoxy, halogen, hydroxy, amino and trifluoromethyl. Besides it relates to the pharmaceutical composition with antiviral activity, and method for making said compounds.

EFFECT: there are prepared and described new compounds with antiviral activity.

9 cl, 15 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: salts of di- and/or trinicotinates of glycyrrhizic acid are inhibitors of human immunodeficiency virus reproduction, including salts of di- and/or trinicotinates of glycyrrhizic acid.

EFFECT: derivatives of glycyrrhizic acid display properties of highly efficient and water-soluble inhibitor of human immunodeficiency virus reproduction.

2 cl, 5 ex, 2 tbl, 2 dwg

Amide derivatives // 2375352

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I, to its pharmaceutically acceptable salts exhibiting properties of inhibitors of cytokine production, such as TNF (tumour necrosis factor) and various members of interleukins (IL) family, and properties of kinase inhibitors, particularly p38α kinase. The invention also concerns methods for producing; pharmaceutical compositions and application thereof for making the medicines for treating diseases affected by the compound of the invention with specified activity. In formula I , m represents 0, 1 or 2; R1 represents halogeno, hydroxy, (1-6C) alkyl, (1-6C)alkoxy, (2-6C)alkenyl, (2-6C) alkinyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, amino-(2-6C) alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, N-(1-6C)alkylcarbamoyl - (1-6C)alkoxy, di[(1-6C) alkyl]amino-(1-6C)alkyl, hydroxy-(2-6C)alkylamino, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyloxy and heterocyclyl-(1-6C)alkoxy and wherein any heteroaryl or heterocyclyl group in substitute representing R1, can probably have 1 or 2 substitutes chosen from hydroxy, halogeno, (1-6C) alkyl, (2-6C)alkinyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxycarbonyl, (2-6C) alkanoyl, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, carboxy- (1-6C)alkyl and methylsulphonyl and wherein any said substitute representing R1 which contains group CH2 attached to 2 carbon atoms, or group CH3 attached to carbon or nitrogen atom, can probably have with each specified group CH2 or CH3, one or two substitutes chosen from halogeno, hydroxy, amino, triflouromethyl, oxo, carboxy, acetamido, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkyamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, halogen-(1-6C)alkyl, (1-6C)alkoxycarbonyl, carbamoyl, N, N-di-[(1-6)alkyl]carbamoyl, (1-6C)alkylsulphonyl, heteroaryl, heteroaryl-(1-6)alkyl and heterocyclyloxy and wherein any heterocyclyl group in substitute representing R1, can probably have 1 oxo-subsitute; R2 represents trifluoromethyl or (1-6C)alkyl; R3 represents hydrogen or (1-6C)alkyl; and R4 represents (3-6C)cycloalkyl, and R4 can be optionally substituted with one or more substitutes chosen from (1-6C)alkyl; and wherein heteroaryl represents aromatic 5- or 6-merous monocyclic ring containing one or two heteroatoms chosen from oxygen, nitrogen and sulphur; heterocyclyl represents saturated 3-10-merous monocyclic or bicyclic ring, each containing one or two heteroatoms chosen from oxygen, nitrogen and sulphur.

EFFECT: improved efficiency.

24 cl, 16 tbl, 66 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to inhibitor of reproduction of human immunodeficiency virus type 1. Inhibitor of reproduction of human immunodeficiency virus type 1, containing aqueous or water-alcohol extract of natural biologically active substances of basidium fungus Inonotus obliquus in specified concentration.

EFFECT: effective inhibitor of reproduction of human immunodeficiency virus type 1.

4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a compound of formula I , where X is C; W is N; V is C; R1 is hydrogen, methoxy or halogen; R2 is absent; R3 is methoxy or heteroaryl, each of which can be optionally independently substituted with one substitute, selected from G; where heteroaryl is triazolyl or pyrazolyl; E is hydrogen or its pharmaceutically acceptable mono or bis salt; Y is selected from a group which consists of and R10, R11, R12, R13, R14, R15, R16, R17 each independently represents H or methyl, under the condition that, not more than two of R10-R17 is methyl; R18 is selected from a group which consists of C(O)-phenyl and quinazolinyl; D is cyano; A is pyridinyl; G is (C1-6)alkyl. The invention also relates to methods of producing compounds of formula I.

EFFECT: obtaining new compounds with antiviral activity.

15 cl, 23 dwg, 48 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5'-phosphorus-containing derivatives of 2',3'-dideoxy-3'-thiacytidine with general structural formula given below , where R=H, NH2-C(O)-. The invented compounds can be used for inhibiting reproduction of the human immunodeficiency virus type 1 in an MT-4 cell culture.

EFFECT: increased antiviral activity of the compounds.

1 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to phenyl substituted pyrrolidones of formula: , where R1 and R5 represent substitutes, which are independently chosen from a group which contains H, CN, halogen, C1-C4alkyl and OR8, where R8 represents C1-C4alkyl, R2 and R4 represent substitutes, which are chosen from a group which contains H, halogen, CN and C1-C4alkyl, R3 represents H, R6 represents a condensed phenyl heterocyclic ring system, chosen from , where R16 represents a substitute, chosen from a group which contains H, C(O)NR18R19 and S(O)2R20, where R18 and R19 represent H or C1-C6alkyl; R20 represents C1-C6alkyl or phenyl; and R17 represents a substitute, which is chosen from a group which contains H, NH2, (CH2)mOH, C(O)NR21R22, SO2R23 and NHSO2R23; where R21 and R22 represent substitutes, which are independently chosen from a group which contains H and substituted or unsubstituted C1-C6alkyl, or, together with a nitrogen atom to which they are bonded, optionally form a ring; R23 represents C1-C6alkyl; and m equals 1; or R6 represents a group, where R9 and R11 represent substitutes, which are independently chosen from a group which contains H, halogen, CN, C(O)NR12R12, NR12R12 and OR12, where each R12 represents H or C1-C4alkyl, and under the condition that, at least one of substitutes R9 and R11 is not hydrogen; R10 represents CN, NR13R14, SO2NHR13, NHSO2R13, O(CH2)nSO2R15, SO2R15, SO2(CH2)nNR13R14 or C(O)NR13R14, where R13 and R14 represent H or C1-C4alkyl; R15 represents C1-C4alkyl, n equals 1-2, and R7 represents halogen, C1-C4alkyl, C2-C4alkenyl or C2-C4alkynyl.

EFFECT: design of compounds and a pharmaceutical composition for inhibiting HIV growth.

19 cl, 12 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention can be applied for blocking of chronic integration diseases caused by human immunodeficiency virus (HIV), bovine leucosis virus (BLV), bovine immunodeficiency virus (BIV), mouse leucosis virus (MuLV), equine infection anemia virus (EIA) and hepatitis B virus. Effect is achieved by application of live cells of Mycoplasma arginini microbe non-pathogenic to humans, used for superinfection of T lymphocyte infected with HIV.

EFFECT: enhanced specificity and efficiency of stepwise removal of integrated DNA provirus from cell genome preserving cell vitality, despite of any virus mutations.

5 dwg, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of pyrazolo[1,5-a]pyrimidine with general formula 1 (values of radicals are given in the formula of invention), a pharmaceutical composition containing said derivatives and use of the novel compounds for preparing a medicinal agent for treating one or more diseases associated with cyclin-dependant kinalse CDK2.

EFFECT: novel compounds have useful biological properties.

36 cl, 87 tbl, 607 ex

Up!