Substituted derivatives of benzoquinolisine

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula: I, where R1 is selected from hydrogen or methoxy; R2 is selected from a group consisting of hydroxy, lower alkoxy, provided that R2 does not denoe methoxy when R1 denotes methoxy, lower alkoxy, mono- or di-substituted with a hydroxy group, benzyloxy, amino, alkylamino, dialkylamino, cyano group, unsubstituted phenyl or tetrazolyl, -O-(CH2)m-C(O)-NR8R9, where m equals 1 or 2, and where R8 and R9 are independently selected from hydrogen, lower alkyl or tetrazolyl, or R8 and R9 together with the nitrogen atom with which they are bonded form morpholinyl or piperazinyl, -O-(CH2)n-COOR10, where n equals 1 or 2 and R10 denotes hydrogen or lower alkyl, -O-(CH2)p-NH-C(O)-OR11, where p equals 1 or 2,and where R11 denotes lower alkyl, -O-SO2-R12, where R12 denotes lower alkyl, -NR13R14, where R13 denotes hydrogen or lower alkyl, and R14 denotes lower alkyl or benzyl, and -NH-CO-(CH2)q-R15, where q equals 1 or 2, and where R5 denotes tetrazolyl; R3 is selected from a group consisting of hydrogen, hydroxy, lower alkoxy, lower alkoxy which is mono- or di-substituted with a hydroxy group, alkoxy or unsubstituted phenyl, and -O-(CH2)m-C(O)-NR8R9, where m equals 1 or 2, and where R8 and R9 are independently selected from hydrogen or lower alkyl, or R8 and R9 together with the nitrogen atom with which they are bonded form morpholinyl or piperazinyl, which can be substituted with lower alkyl; R4 is or , where R5 is selected from lower alkyl; or R5 can also denote hydrogen when selected from a group consisting of -(CH2)m-C(O)-NR8R9, -O-(CH2)p-NH-C(O)-OR11, -O-SO2-R12, -NR13R14, -NH-CO-(CH2)q-R15 and lower alkoxy which is mono- or di-substituted with a group selected from hydroxy, benzyloxy, amino or cyano; R6 is selected from a group consisting of hydrogen and lower alkyl; R7 is selected from a group consisting of lower alkyl and lower halogenalkyl; and to pharmaceutically acceptable salts of said compounds. The invention also pertains to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having DPP-IV enzyme inhibiting activity.

22 cl, 50 ex

 

The text descriptions are given in facsimile form.

1. Compounds of General formula

where R1selected from hydrogen or methoxy;
R2selected from the group consisting of
hydroxy,
lower alkoxy, provided that R2does not mean methoxy, in the case when R1represents methoxy,
lower alkoxy, mono - or disubstituted by hydroxy-group, benzyloxy, amino, alkylamino, dialkylamino, cyano, unsubstituted phenyl or tetrazolyl,
-O-(CH2)m-C(O)-NR8R9where m is 1 or 2, and where R8and R9independently selected from hydrogen, lower alkyl or tetrazolyl, or R8and R9together with the nitrogen atom to which they are attached, form morpholinyl or piperazinil,
-O-(CH2)n-COOR10where n is 1 or 2, and R10represents hydrogen or lower alkyl,
-O-(CH2)p-NH-C(O)-OR11where p denotes 1 or 2, and where R11represents lower alkyl,
-O-SO2-R12where R12represents lower alkyl,
-NR13R14where R13represents hydrogen or lower alkyl, and R14represents lower alkyl or benzyl, and
-NH-CO-(CH2)q-R15where q denotes 1 or 2, and where R15represents tetrazolyl;
R3selected from the group consisting of
hydrogen
hydroxy,
the bottom is his alkoxy,
lower alkoxy, mono - or disubstituted by hydroxy-group, alkoxy or
unsubstituted phenyl, and
-O-(CH2)m-C(O)-NR8R9where m is 1 or 2, and where R8and R9independently selected from hydrogen or lower alkyl, or R8and R9together with the nitrogen atom to which they are attached, form morpholinyl or piperazinil, which may be substituted by lower alkyl;
R4represents a
or
where R5selected from lower alkyl; or
R5may also represent hydrogen when R2selected from the group consisting of -(CH2)m-C(O)-NR8R9, -O-(CH2)p-NH-C(O)-OR11, -O-SO2-R12, -NR13R14, -NH-CO-(CH2)q-R15and lower alkoxy which is mono - or disubstituted by a group selected from hydroxy, benzyloxy, amino or cyano;
R6selected from the group consisting of hydrogen and lower alkyl;
R7selected from the group consisting of lower alkyl and lower halogenoalkane;
and pharmaceutically acceptable salts of these compounds.

2. The compounds of formula I according to claim 1, where R2selected from the group consisting of hydroxy,
lower alkoxy, provided that R2does not mean methoxy in the case when R1is the th methoxy,
lower alkoxy, mono - or disubstituted by hydroxy-group, benzyloxy, amino, alkylamino, dialkylamino, cyano, unsubstituted phenyl or tetrazolyl,
-O-(CH2)m-C(O)-NR8R9where m is 1 or 2, and where R8and R9independently selected from hydrogen, lower alkyl or tetrazolyl, or R8and R9together with the nitrogen atom to which they are attached, form morpholinyl or piperazinil,
-O-(CH2)n-COOR10where n is 1 or 2, and R10represents hydrogen or lower alkyl,
-O-(CH2)p-NH-C(O)-OR11where p denotes 1 or 2, and where R11represents lower alkyl,
-O-SO2-R12where R12represents lower alkyl,
-NR13R14where R13represents hydrogen or lower alkyl, and R14represents lower alkyl or benzyl, and
-NH-CO-(CH2)q-R15where q denotes 1 or 2, and where R15represents tetrazolyl;
and R3selected from the group consisting of hydrogen, hydroxy and lower alkoxy.

3. The compounds of formula I according to claim 1, where R2selected from the group consisting of hydroxy,
lower alkoxy, mono - or disubstituted by hydroxy-group, benzyloxy, amino, cyano, phenyl or tetrazolyl,
-O-(CH2)m-C(O)-NR8R9where m is 1 or 2, and where R8and R9 is independently selected from hydrogen, lower alkyl or tetrazolyl, or R8and R9together with the nitrogen atom to which they are attached, form morpholinyl or piperazinil,
-O-(CH2)n-COOR10where n is 1 or 2, and R10represents hydrogen or lower alkyl,
-O-(CH2)p-NH-C(O)-OR11where p denotes 1 or 2, and where R11represents lower alkyl,
-O-SO2-R12where R12represents lower alkyl,
-NR13R14where R13represents hydrogen or lower alkyl, and R14represents lower alkyl or benzyl, and
-NH-CO-(CH2)q-R15where q denotes 1 or 2, and where R15represents tetrazolyl.

4. The compounds of formula I according to claim 1, where R2represents hydroxy or lower alkoxy, mono - or disubstituted by hydroxy-group, benzyloxy, amino, cyano, phenyl or tetrazolyl.

5. The compounds of formula I according to claim 1, where R2represents a
-O-(CH2)m-C(O)-NR8R9where m is 1 or 2, and where R8and R9independently selected from hydrogen, lower alkyl or tetrazolyl, or R8and R9together with the nitrogen atom to which they are attached, form morpholinyl or piperazinil.

6. The compounds of formula I according to claim 5, where R2represents a
-O-(CH2)mC(O)-NR8R9where m means 1 and the 2, and where R8and R9independently selected from hydrogen, lower alkyl or tetrazolyl.

7. The compounds of formula I according to claim 1, where R2represents a
-O-(CH2)n-COOR10where n is 1 or 2, and R10represents hydrogen or lower alkyl.

8. The compounds of formula I according to claim 1, where R is a
-O-SO2-R12where R12represents lower alkyl.

9. The compounds of formula I according to claim 1, where R2represents a
-NH-CO-(CH2)q-R15where q denotes 1 or 2, and where R15represents tetrazolyl.

10. The compounds of formula I according to claim 1, where R3represents hydrogen.

11. The compounds of formula I according to claim 1, where R3selected from the group consisting of hydroxy,
lower alkoxy,
lower alkoxy, mono - or disubstituted by hydroxy-group, alkoxy or unsubstituted phenyl, and
-O-(CH2)m-C(O)-NR8R9where m is 1 or 2, and where R8and R9independently selected from hydrogen or lower alkyl, or R8and R9together with the nitrogen atom to which they are attached, form morpholinyl or piperazinil, which may be substituted by lower alkyl, and
R2represents hydroxy or lower alkoxy.

12. The compounds of formula I according to claim 1, where R3represents hydroxy or lower alkoxy, mono - or disubstituted by the hydroxy-group, alkoxy or phenyl.

13. The compounds of formula I according to claim 1, where R3represents a
-O-(CH2)m-C(O)-NR8R9where m is 1 or 2, and where R8and R9independently selected from hydrogen and lower alkyl, or R8and R9together with the nitrogen atom to which they are attached, form morpholinyl or piperazinil, which may be substituted by lower alkyl.

14. The compounds of formula I according to claim 1, where R2represents methoxy.

15. The compounds of formula I according to claim 1, where R4represents a
,
R5selected from lower alkyl; and
R6selected from the group consisting of hydrogen and lower alkyl.

16. The compounds of formula I according to claim 1, where R4represents a
,
and R7represents a lower alkyl or lower halogenated.

17. The compounds of formula I according to claim 1, where R7represents lower alkyl.

18. Compounds according to claim 1, selected from the group consisting of
(2S,3S,11bS)- and (2R,3R,11bR)-9-(2-amino-ethoxy)-3-(2,5-dimetilfenil)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ylamine,
(2S,3S,11bS)- and (2R,3R,11bR)-2-amino-3-(2,5-dimetilfenil)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-ol,
hydrochloride (2S,3S,1bS)- and (2R,3R,11bR)-3-(2,5-dimetilfenil)-10-methoxy-9-[2-(1H-tetrazol-5-yl)ethoxy]-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]ethanol is n-2-ylamine,
(2S,3S,11bS)- and (2R,3R,11bR)-3-[2-amino-3-(2,5-dimetilfenil)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]propionitrile,
hydrochloride of 2-amino-3-(2,5-dimetilfenil)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-silt of ester (2S,3S,11bS)- and (2R,3R,11bR)methanesulfonic acid,
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-2-[2-amino-3-(2,5-dimetilfenil)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]ethanol,
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-[2-amino-3-(2,5-dimetilfenil)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]acetic acid,
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-2-[2-amino-3-(2,5-dimetilfenil)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]-N-(1H-tetrazol-5-yl)acetamide", she
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-2-[2-amino-3-(2,5-dimetilfenil)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]ndimethylacetamide,
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-2-[2-amino-3-(2,5-dimetilfenil)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]-N-methylacetamide,
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-N-[2-amino-10-methoxy-3-(4-methylpyridin-2-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yl]-2-(1H-tetrazol-5-yl)acetamide", she
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-10-methoxy-9-methylamino-3-(4-methylpyridin-2-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diamine,
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-[2-amino-10-methoxy-3-(4-methylp ridin-2-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]acetic acid,
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-2-[2-amino-10-methoxy-3-(4-methylpyridin-2-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]N-(2H-tetrazol-5-yl)acetamide", she
2-amino-10-methoxy-3-phenyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-silt ester (2S,3S,11bS)- and (2R,3R,11bR)methanesulfonic acid,
(2S,3S,11bS)- and (2R,3R,11bR)-2-(2-amino-10-methoxy-3-phenyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy)-N-methylacetamide,
(2S,3S,11bS)- and (2R,3R,11bR)-2-(2-amino-10-methoxy-3-phenyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy)-N,N-dimethylacetamide,
(2S,3S,11bS)- and (2R,3R,11bR)-2-amino-10-methoxy-3-m-tolyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-ol,
(2S,3S,11bS)- and (2R,3R,11bR)-2-(2-amino-10-methoxy-3-m-tolyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy)ethanol,
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-2-(2-amino-10-methoxy-3-m-tolyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy)ndimethylacetamide,
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-2-(2-amino-10-methoxy-3-m-tolyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy)-1-morpholine-4-ratanana,
(2S,3S,11bS) and (2R,3R,11bR)-2-amino-10-methoxy-3-(4-methylpyridin-2-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-ol,
(2S,3S,11bS)- and (2R,3R,11bR)-2-[2-amino-10-methoxy-3-(4-methylpyridin-2-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]ethanol,
(2S,3S,11bS)- and (2R,3R,11bR)-2-[2-amino-10-methoxy-3-(4-methylpyridin-2-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]p is open-1,3-diol,
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-2-[2-amino-10-methoxy-3-(4-methylpyridin-2-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]-1-morpholine-4-yl-ethanone,
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-2-[2-amino-10-methoxy-3-(4-methylpyridin-2-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1A]isoquinoline-9-yloxy]ndimethylacetamide,
methyl ester (2S,3S,11bS)- and (2R,3R,11bR)-2-amino-3-(4-formatieren-2-yl)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]acetic acid,
rat-(2S,3S,11bS)-2-amino-9-methoxy-3-m-tolyl-l,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-8-ol,
rat-2-(2-amino-9-methoxy-3-m-tolyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-8-yloxy)ndimethylacetamide, (2S,3S,11bS) and (2R,3S,11bS)diastereomers,
rat-2-((2S,3S,11bS)-2-amino-9-methoxy-3-m-tolyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-8-yloxy)-N,N-dimethylacetamide,
rat-9-methoxy-8-(2-methoxy-ethoxy)-3-m-tolyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ylamine, (2S,3S,11bS) and (2R,3S,11bS)diastereomers,
rat-2-(2-amino-9-methoxy-3-m-tolyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-8-yloxy)ethanol, (2S,3S,11bS) and (2R,3S,11bS)diastereomers,
and their pharmaceutically acceptable salts.

19. Compounds according to claim 1, selected from the group consisting of
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-3-(2,5-dimetilfenil)-10-methoxy-9-[2-(1H-tetrazol-5-yl)ethoxy]-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ylamine,
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-[2-amino-3-(2,5-dimetilfenil)-1-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]acetic acid,
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-2-[2-amino-3-(2,5-dimetilfenil)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy] -N-(1H-tetrazol-5-yl)acetamide", she
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-2-[2-amino-3-(2,5-dimetilfenil)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]ndimethylacetamide,
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-2-[2-amino-3-(2,5-dimetilfenil)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]-N-methylacetamide,
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-N-[2-amino-10-methoxy-3-(4-methylpyridin-2-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yl]-2-(1H-tetrazol-5-yl)acetamide", she
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-[2-amino-10-methoxy-3-(4-methylpyridin-2-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]acetic acid,
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-2-[2-amino-10-methoxy-3-(4-methylpyridin-2-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]-N-(2H-tetrazol-5-yl)acetamide", she
2-amino-10-methoxy-3-phenyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-silt of ester (2S,3S,11bS)- and (2R,3R,11bR)-methanesulfonic acid,
(2S,3S,11bS)- and (2R,3R,11bR)-2-amino-10-methoxy-3-m-tolyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-ol,
(2S,3S,11bS)- and (2R,3R,11bR)-2-(2-amino-10-methoxy-3-m-tolyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy)ethanol,
hydrochloride (2S,3S,11bS)- and (2R,3R,11bR)-2-(2-amino-10-methoxy-3-m-tolyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-ylox is)ndimethylacetamide,
(2S,3S,11bS) and (2R,3R,11bR)-2-amino-10-methoxy-3-(4-methylpyridin-2-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-ol,
(2S,3S,11bS)- and (2R,3R,11bR)-2-[2-amino-10-methoxy-3-(4-methylpyridin-2-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-yloxy]ethanol,
rat-2-((2S,3S,11bS)-2-amino-9-methoxy-3-m-tolyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-8-yloxy)-N,N-dimethylacetamide,
and their pharmaceutically acceptable salts.

20. The pharmaceutical composition having inhibitory activity against the enzyme DPP-IV, comprising the compound according to any one of claims 1 to 19 and a pharmaceutically acceptable carrier and/or excipient.

21. The compounds of formula I according to claim 1, having inhibitory activity against the enzyme DPP-IV.

22. The compounds of formula I according to claim 1 for use as therapeutically active substances for the treatment and/or prevention of diseases mediated by the enzyme DPP-IV.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives of general formula , where R is an optional ortho- or meta-substitute selected from halogen and (C1-4)alkyloxy; R1 is halogen or CF3; R2 is H, (C1-4)alkyloxy or halogen; R3 is H or (CH2)n-NR5R6; R4 is H or (C1-6)alkyl, optionally substituted COOR7 or NR8R9; R5 and R6 independently denote H, (C3-8)cycloalkyl, quinuclidin-3-yl, (C2-6)alkenyl or (C1-6)alkyl, optionally substituted mono-substituted with CF3, (C3-8)cycloalkyl, (C6)aryl, a 5- or 6-member heteroaryl group, OH, (C1-6)alkyloxy, (C6-10)aryloxy, CONR11R12, NR13R14 or NR13SO2(C1-4)alkyl; or R5 and R6 together with a nitrogen atom to which they are bonded form a 4-8-member saturated heterocyclic ring which also contains 1 heteroatom selected from O, SO2 and NR15, where the ring is optionally mono-substituted or di-substituted with oxo, (C1-4)alkyl, (C3-8)cycloalkyl, NR16R17 or CONR18R19; R7 is H or (C1-4)alkyl; R8 and R9 independently denote H, (C1-4)alkyl (optionally substituted di(C1-4)alkylamino) or (C3-8)cycloalkyl; or R8 and R9 together with a nitrogen atom with which they are bonded form a 4-8-member saturated heterocyclic ring which also contains one heteroatom which is O; R11 and R12 independently denote H or (C1-4)alkyl; R13 and R14 independently denote H or (C1-4)alkyl; R15 is H, (C1-4)alkyl (optionally mono-substituted OH, (C1-4)alkyloxy or di(C1-4)alkylamino), phenyl, pyridyl or COR20; R16 and R17 denote (C1-4)alkyl; or R16 and R17 together with a nitrogen atom with which they are bonded from a 4-8-member saturated heterocyclic ring; R18 and R19 denote H; R20 is (C1-4)alkyl, (C3-8)cycloalkyl or furyl; and n equals 0 or 1; or its pharmaceutically acceptable salt. The invention also relates to use of formula I compounds to prepare a medicinal agent and to a pharmaceutical composition based on formula I compound.

EFFECT: novel derivatives have catepsin S and K inhibitory activity.

9 cl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound which exhibits inhibitory effect on the FAAH enzyme having formula I , where n denotes an integer from 1 to 6; A denotes a group X; where when n equals an integer from 2 to 6, groups A are identical or different; X denotes C1-2-alkylene; R1 denotes a hydrogen atom; R2 denotes a hydrogen atom or a group selected from the following groups: phenyl, phenyloxy; R3 denotes either 2,2,2-trifluoroethyl or phenyl, if necessary substituted with one or more halogen atoms or C1-3-alkyl, C1-3-alkoxy, trifluoromethyl; provided that: the formula 1 compound is not 2,2,2-trifluoroethyl benzylcarbamate, when R3 denotes 2,2,2-trifluoroethyl and group -[A]n- denotes a -CH2- group, when R3 denotes phenyl, if necessary substituted, and group -[A]n-denotes a -CH2-, -CH2CH2-,-CH2CH2CH2- group, then R2 is not a hydrogen atom and is in form of a base, an addition salt with a pharmaceutically acceptable acid, as well as to a method for synthesis of the formula I compound and a pharmaceutical composition having inhibitory effect on FAAH, containing at least one formula I compound.

EFFECT: improved method.

5 cl, 6 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to novel pyrrolo[3,2-b]pyridine derivatives of formula I , where values of radicals R1-R5 are given in the description. The invention also covers pharmaceutically acceptable salts of these compounds, methods of producing these compounds and pharmaceutical compositions containing these compounds. Pyrrolo[3,2-b]pyridine derivatives and their pharmaceutically acceptable salts can provide proton pump reversible inhibitory effect.

EFFECT: obtaining novel pharmaceutically acceptable salts which can provide proton pump reversible inhibitory effect.

5 cl, 2 tbl, 289 ex

FIELD: medicine.

SUBSTANCE: invention refers to compounds having anxiolytic and antidepressant activity, which are derivatives of the formula 1 (a-b), or formula 2 (a-b) at that compounds of formula 2 (a-b) are intermediate products in synthesis of compounds of the formula , where R-Cl is a compound 1a or R'=COOC2H5 - compound 1b, , where R=COOC2H5 and R'=C1 - compound 2a; R=R-COOC2H5 - compound 2b.

EFFECT: obtaining new biologically active compounds that differ from analogues as intended in low toxicity and lack of side effects.

5 cl, 3 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. The disclosed compounds have CDK1 and/or CDK2 kinase inhibiting activity. In formula R1 is selected from hydrogen, hydroxy-lower alkyl, C3-C6 cycloalkyl and R2-(X)n; X is selected from lower alkylene, hydroxy-lower alkylene, lower cycloalkylene or lower alkanoyloxy-lower alkylene; R2 is and is selected from phenyl and a 5- or 6-member heteroaromatic ring containing 1 or 2 heteroatoms selected from a group consisting of sulphur and nitrogen; R5 and R6 are independently selected from a group consisting of hydrogen, lower alkyl, halogen and lower alkoxy; and n equals 0 or 1.

EFFECT: design of a pharmaceutical composition for treating and preventing diseases whose condition can be improved by inhibiting CDK1 and/or CDK2 kinase, containing an effective amount of formula I compounds.

47 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula where L1 and L2 independently denote a bond, -S-, -NH- or unsubstituted C1-C5alkylene; A1 denotes a 6-member substituted aryl or unsubstituted heteroaryl; A2 denotes aryl or heteroaryl; R1 denotes halogen, -OR5, -NR6R7, -C(Z)R8, -S(O)wR9, -CN, -NO2, -S(O)2NH2, alkyl, aryl or heteroaryl; X1 denotes -C(R2)=, -C(R2)(R3)-, -N(R4)- or -O-; R2 and R3 independently denote hydrogen, -OR5 or alkyl; R4 denotes hydrogen or alkyl; Z denotes O or NH; w is integer from 0 to 2; R5 independently denotes hydrogen or alkyl; R6 and R7 independently denote hydrogen, -S(O)2R11 alkyl or heteroalkyl; R11 denotes hydrogen or alkyl; R8 independently denotes hydrogen, -NR14R15, -OR16, heteroalkyl or cycloalkyl; R14, R15 and R16 independently denote hydrogen, alkyl, cycloalkyl, heteroalkyl or heterocycloalkyl; R9 independently denotes hydrogen or alkyl; and where R6 and R7, R14 and R15 independently and optionally together with the nitrogen atom to which they are bonded form a substituted or unsubstituted heterocycloalkyl. The invention also relates to a method of modulating protein kinase activity, as well as to use of compounds in paragraph 1 and a pharmaceutical composition based on the said compounds.

EFFECT: new compounds which can be useful in treating diseases mediated by kinase activity are obtained and described.

47 cl, 2 ex, 40 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and their pharmaceutically acceptable salts of formula (I) where n equals 0, 1 or 2, A is a five- or six-member aromatic ring which optionally contains one or two heteroatoms independently selected from nitrogen, oxygen or sulphur, B is a 5-9-member ring containing 0 or 1 double bonds and optionally contains an additional heteroatom selected from nitrogen and oxygen; where the ring optionally contains one or two substitutes independently selected from a group comprising C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkyl, carboxy, cyano, hydroxy, hydroxy-C1-C6-alkyl, di-C1-C6-alkylamino-C1-C6-alkyl, (NR4R5)-carbonyl or oxo; R1 is selected from -C(O)NR4R5 - CO2R4, 5-tetrazolyl, cyano; each R2 is independently selected from a group comprising C1-C6-alkyl, amino, benzyloxy, halogen, hydroxyl; R3 is a 5-7-member cycloalkyl ring; values of the rest of the radicals are given in the formula of invention. The invention also relates to a method for synthesis of the said compounds, a method of inhibiting HCV replicon function and a method of inhibiting functioning of the HCV NS5B protein.

EFFECT: wider field of use of the compounds.

16 cl, 4 tbl, 29 ex

FIELD: medicine.

SUBSTANCE: integrated treatment of diabetes mellitus type two involves a complex of biologically active factors separately, consecutively between meals. It includes 20% propolis butter, aqueous solution of ursine bile 1:10, ursine fat, aspen bark tincture, cowberry water, cramp water, bilberry water, vitamin herbal tea, flower pollen. Honey is introduced 1/3 teaspoons 3 times a day; propolis butter - 1-2 g 3 times a day; ursine fat - 2 teaspoons 3 times day, aspen bark tincture - 100 to 150 ml 3 times a day; vitamin herbal tea 200 ml 3 times a day, cowberry, cramp and bilberry water - 50 ml 3 times a day; flower pollen 2 g in the morning. And aspen bark tincture is introduced 1.5 before meals, ursine fat - 1 hour before meals, propolis butter - immediately after meal, ursine bile - 3-5 minutes before meals. The course of the introduction of biologically active factors is 20-24 days daily.

EFFECT: method provides the stable carbohydrate metabolism compensation, prevents the progression of the related complications.

7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel crystalline modifications of [6-methoxy-5-(2-methoxyphenoxy)-2-pyridin-4-ylpyrimidin-4-yl]amide-5-methylpyridine-2-sulfonic acid, which produces an endothelial antagonistic effect and is suitable for treating diseases associated with abnormal vascular tone and endothelial dysfunction, such as heart failure, pulmonary hypertension etc. The crystalline modification which is denoted modification B is characterised by a powder X-ray diffractogram with characteristic peaks expressed through the d-parametre value (interplanar distance) () obtained on a conventional X-ray powder diffractometre using Cuka radiation: 10.7 (m), 9.4 (m), 8.6 (vs), 8.3 (m), 7.6 (m), 6.7 (m), 6.4 (m), 6.0 (m), 5.69 (m), 5.30 (m), 5.17 (m), 4.95 (vs), 4.76 (m), 4.56 (m), 4.43 (s), 4.13 (vs), 3.80 (s), 3.45 (s), 3.41 (s), 3.37 (s) and 3.03 (m). The invention also relates to crystalline pseudopolymorphous modifications of [6-methoxy-5-(2-methoxyphenoxy)-2-pyridin-4-ylpyrimidin-4-yl]amide-5-methylpyridine-2-sulfonic acid selected from: a) pseudopolymorphous modification, solvate with ethanol, denoted modification D; b) pseudopolymorphous modification, polysolvate with acetone, denoted modification E; c) pseudopolymorphous modification, solvate with tetrahyrofuran, denoted modification F; d) pseudopolymorphous modification, solvate with methanol, denoted modification G; e) pseudopolymorphous modification, solvate with isopropanol, denoted modification H; f) pseudopolymorphous modification, solvate with dichloromethane, denoted modification I; and g) pseudopolymorphous modification, solvate with 2-butanol, denoted modification J. The invention also relates to a method of obtaining crystalline modification B, a pharmaceutical composition and use.

EFFECT: wider field of use of the compounds.

8 cl, 9 dwg, 9 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: invention relates to chemical-pharmacological industry, namely to creation of preparation for controlling glycemia level and prevention of vascular complications in patients with disorders of carbohydrate metabolism and type 2 diabetes mellitus. As said preparation, applied is BAA to food "Carb blocker Phase2/Phasa2".

EFFECT: preparation has good tolerance and does not have side effects, allows prevention or considerably slow down of development of vascular complications at reaching state of compensation/subcompensation of carbohydrate metabolism.

4 tbl, 1 dwg

FIELD: medicine.

SUBSTANCE: invention relates to pharmacology and is intended for extension of arsenal of plants, which influence correction of metabolic disorders of brain in case of diabetes mellitus. Claimed is application of Vaccinium hirtum Thunb shoots as medicine for correction of metabolic disorders of brain in case of diabetes mellitus.

EFFECT: infusion of Vaccinium hirtum Thunb shoots limits disorders of carbohydrate metabolism and activation of free-radical oxidation in case of diabetes mellitus.

2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, cardiology and endocrinology, and concerns normalisation of the blood microvesicle level in arterial hypertension, abdominal obesity and type II diabetes mellitus. That is ensured by the specific low-calorie diet combined with graduated physical activity. In addition, Valsartan 80 mg once in the morning and Pioglitazone 30 mg once in the morning are prescribed. The length of treatment is at least 6 weeks.

EFFECT: method ensures the correction of the blood microvesicle level in the case patients, and consequently, reduced risk of thrombotic complications, such as infarction and stroke.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, cardiology and endocrinology, and concerns normalisation of the blood microvesicle level in arterial hypertension, abdominal obesity and impaired glucose tolerance. That is ensured by the administration of Irbesartan 150 mg once in the morning combined with Metformin 500 mg twice a day. In addition, the patients perform graduated physical activity, including morning hygienic gymnastics, therapeutic gymnastics and graduated physical exercises throughout a day. The length of treatment is at least 5 weeks.

EFFECT: method ensures the correction of the blood microvesicle level in the case patients, and consequently, reduced risk of thrombotic complications, such as infarction and stroke.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, cardiology, endocrinology, and can be used for correction of the blood microvesicle level in the patients with arterial hypertension with dyslipidemia and type II diabetes mellitus. That is ensured by graduated physical exercises and the administration of Valsartan 80 mg once in the morning, Lovastatin 40 mg once a day in the evening at mealtimes and Metformin 500 mg twice a day. The length of treatment is at least 6 weeks.

EFFECT: method ensures reduced risk of thrombotic complications, higher clinical effectiveness and improved prognosis in the case patients due to the rating correction of the blood microvesicle level.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, cardiology and endocrinology, and can be used for correction of the blood microvesicle level in the patients with abdominal obesity and impaired glucose tolerance. That is ensured by the administration of Pioglitazone 30 mg once in the morning with underlying individual low-calorie diet and graduated physical activity for at least 9 weeks.

EFFECT: method ensures reduced risk of thrombotic complications, higher clinical effectiveness and improved prognosis in the case patients due to the rating correction of the blood microvesicle level and decrease in the blood haemocoagulation potential.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, cardiology, endocrinology, and can be used for correction of the blood microvesicle level in the patients with arterial hypertension, dyslipidemia and abdominal obesity. That is ensured by the administration of Irbesartan in dosage 150 mg once in the morning and Metformin 500 mg twice a day with underlying graduated physical activity for at least 5 weeks.

EFFECT: method ensures reduced risk of thrombotic complications, higher clinical effectiveness and improved prognosis in the case patients due to the rating correction of the blood microvesicle level and decrease in the blood haemocoagulation potential.

1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or its pharmaceutically acceptable salt, where R1 and R2 each independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a hydroxyl group, a cyano group or a lower alkoxy; R3 independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, a hydroxyalkyl, trifluoromethyl, lower alkenyl or cyano group; R4 independently denotes a hydrogen atom, a lower alkyl, a lower alkoxy, a halogen atom, trifluoromethyl, hydroxyalkyl optionally substituted with a lower alkyl, aminoalkyl optionally substituted with lower alkyl, alkanoyl, carboxyl group, lower alkoxycarbonyl or cyano group; Q denotes a nitrogen atom; R5 and R6 each independently denotes a hydrogen atom, a lower alkyl, a halogen atom, a lower alkylsulfonyl, a lower alkylsulfanyl, alkanoyl, formyl, aryl, mono- or di-(lower) alkylcarbamoyl or mono- or di-(lower) alkylsulfamoyl; and further as indicated in the formula of invention. The invention also relates to a glucokinase activator containing the compound in paragraph 1 and to a therapeutic agent based on said compounds.

EFFECT: novel compounds which can be useful in treating and preventing diabetes and obesity are obtained and described.

29 cl, 227 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

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