Sulphonamidethiazole pyridine derivatives as glucokinase activators, suitable for treating type-2 diabetes

FIELD: chemistry.

SUBSTANCE: invention relates to novel sulphonamidethiazole pyrimidine derivatives of formula (I)

, which are glucokinase activators or to their enantiomers, mixture of enantiomers or pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on the novel compounds, use of the compounds to prepare a medicinal agent and to a method of activating glucokinase. In formula (I) R1 denotes (C1-C10)alkoxy, R2 denotes (C3-C6)cycloalkyl, R3 denotes hydrogen, and values of substitutes R4 and R5 are given in the formula of invention.

EFFECT: more effective use of the compounds.

33 cl, 166 ex

 

The text descriptions are given in facsimile form.

1. The compound of the formula

where R1means (C1-C10)alkoxy;
R2means (C3-C6)cycloalkyl;
R3means hydrogen;
R4means hydrogen; optionally substituted (C1-C10)alkyl, where the substituents selected from the group comprising hydroxy, cyano, (C1-C10)alkoxy, carboxy, (C1-C10)alkoxycarbonyl, carbarnoyl, phenyl, tetrahydrofuranyl, pyrrolidin, pyridinyl, amino, N,N-(C1-C10)dialkylamino, oxo, N-methylpiperazine and (C1-C10)alkoxycarbonyl; or (C3-C6)cycloalkyl;
R5means -(CR6R7)m-W-R8,
where R6and R7means independently hydrogen, (C1-C10)alkyl or (C3-C6)cycloalkyl;
m denotes 0 or an integer from 1 to 2;
W means-NR9-,
where R9means hydrogen or (C1-C10)alkyl; or
R9means-C(O)OR10,
where R10means (C1-C10)alkyl;
or W is absent;
R8means hydrogen; and (C1-C7)alkyl, (C3-C6)cycloalkyl; phenyl, optionally substituted (C1-C10 )alkoxy, halogen, carboxy, N,N-(C1-C10)dialkylamino, piperidine-1-elmetron, N,N-(C1-C10)dialkylaminoalkyl; 4-6-membered heterocycles with one heteroatom selected from N, O and S, optionally substituted (C1-C10)alkoxycarbonyl, hydroxy, tetrahydropyranyl, phenyl(C1-C10)alkyl, (C1-C10)alkyl, optionally substituted hydroxy, -C(O)R15where R15represents hydrogen or (C1-C10)alkyl; or a 5-6-membered heterocycle with two heteroatoms, selected from O and N, optionally substituted (C1-C10)alkyl;
or
R8and R9connected with the formation of alkylene, which together with the nitrogen atom to which they are attached, form a 4-7-membered ring; or R5and R4connected with the formation of alkylene, which together with the nitrogen atom to which they are attached, form a 4-7-membered ring, which can optionally contain another heteroatom selected from nitrogen and oxygen, where a 4-7-membered ring may be optionally replaced with N,N-diethylamino; pyrrolidinyl; piperazinil, replaced by stands; and (C3-C8)cycloalkyl; phenyl, optionally substituted (C1-C10)alkoxy, halogen, (C1-C10)alkyl; 6-9-membered heteroaryl with one or two heteroatoms, selected the from N and O; phenyl-(C1-C6)alkyl; -C(O)R15or-C(O)OR15where R15means hydrogen or optionally substituted (C1-C10)alkyl, where the substituents are selected from piperidyl, halogen and N,N-diethylamino; allyl; amino;
-NH-C(O)O-tert-bootrom; -NH-CH2-C(O)O-ethyl; -NH-CH2-C(O)OH; N-(isopropyl)amino; piperidinyl, optionally substituted stands, -C(O)O-ethyl or-C(O)IT; or (C1-C7)alkyl, optionally substituted hydroxy, halogen, cyano, (C1-C6)alkoxy, (C3-C6)cycloalkyl, phenyl, aminocarbonyl, carboxyla, etoxycarbonyl, (C1-C6)dialkylamino, (C1-C6)alkylsulfonyl, pyridium or imidazolium; or
R5and R4together with the nitrogen atom to which they are attached, form an 8-10-membered condensed, containing bridging fragment or Spiro-bicyclic ring which may be optionally substituted benzyl or hydroxy, and which may contain 1-2 other heteroatom selected from oxygen and nitrogen;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

2. The compound according to claim 1,
where R1means (C1-C10)alkoxy;
R2means (C3-C6)cycloalkyl;
R3means hydrogen;
R4means hydrogen or (ness.)alkyl;
Rsub> 5means -(CR6R7)m-W-R8,
where R6and R7means independently hydrogen or (ness.)alkyl;
m denotes 0 or an integer from 1 to 2;
W means-NR9-,
where R9means hydrogen or (ness.)alkyl; or
R9means-C(O)OR10,
where R10means (C1-C10)alkyl;
or W is absent;
R8means hydrogen; and (C1-C7)alkyl, (C3-C6)cycloalkyl; phenyl, optionally substituted (C1-C10)alkoxy, halogen, carboxy, N,N-(C1-C10)dialkylamino, piperidine-1-elmetron, N,N-(C1-C10)dialkylaminoalkyl; or a 4-6-membered heterocycles with one heteroatom selected from N, O and S; or
R8and R9connected with the formation of alkylene, which together with the nitrogen atom to which they are attached, form a 5-7-membered ring;
R5and R4connected with the formation of alkylene, which together with the nitrogen atom to which they are attached, form a 5-7-membered ring;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

3. The compound according to claim 2,
where R4means hydrogen or (ness.)alkyl;
R5means -(CR6R7)m-W-R8,
where R6and R7means independently hydrogen or (ness.)alkyl;
m means 2;
W means-NR9-,
g is e R 9means hydrogen or (ness.)alkyl; or
R9means-C(O)OR10,
where R10means (C1-C10)alkyl;
R8means hydrogen; and (C1-C7)alkyl, (C3-C6)cycloalkyl; phenyl, optionally substituted (C1-C10)alkoxy, halogen, carboxy, N,N-(C1-C10)dialkylamino, piperidine-1-elmetron, N,N-(C1-C10)dialkylaminoalkyl; or a 4-6-membered heterocycles with one heteroatom selected from N, O and S; or
R8and R9connected with the formation of alkylene, which together with the nitrogen atom to which they are attached, form a 5-7-membered ring;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

4. The compound according to claim 3,
where R1means (C1-C4)alkoxy;
R2means (C3-C5)cycloalkyl;
R3means hydrogen;
R6and R7mean hydrogen;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

5. The compound according to claim 4 of the formula

where R1means (C1-C4)alkoxy;
R2means (C3-C5)cycloalkyl;
R4means hydrogen or (ness.)alkyl;
R8means hydrogen; and (C1-C7)alkyl, (C3-C6)cycloalkyl; phenyl, optional C is displaced (C 1-C10)alkoxy, halogen, carboxy, N,N-(C1-C10)dialkylamino, piperidine-1-elmetron, N,N-(C1-C10)dialkylaminoalkyl; go 4-6-membered heterocycles with one heteroatom selected from N, O and S;
R9means hydrogen or (ness.)alkyl; or
R9means-C(O)OR10,
where R10means (C1-C10)alkyl;
R9and R8connected with the formation of alkylene, which together with the nitrogen atom to which they are attached, form a 5-7-membered ring;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

6. The compound according to claim 5,
where R1means methoxy;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

7. The compound according to claim 5,
where R2means cyclopentyl;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

8. The compound according to claim 5,
where R1means methoxy;
R2means cyclopentyl;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

9. The compound according to claim 1,
where R5and R4connected with the formation of alkylene, which together with the nitrogen atom to which they are attached, form a 5-7-membered ring, where 5-7-membered ring may be optionally substituted (C3-C6)cycle is an alkyl; by phenyl; 6-9-membered heteroaryl with one or two heteroatoms, selected from N and O; phenyl-(C1-C6)alkyl; -C(O)R15or-C(O)OR15where R15means optionally substituted (C1-C10)alkyl, where the substituents are selected from piperidyl, halogen and N,N-diethylamino; or (C1-C7)alkyl, optionally substituted hydroxy, halogen, cyano, (C1-C6)alkoxy, (C3-C6)cycloalkyl, phenyl, aminocarbonyl, carboxyla, etoxycarbonyl, (C1-C6)dialkylamino, (C1-C6)alkylsulfonyl, pyridium or imidazolium;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

10. The connection according to claim 9 of the formula

where R1means (C1-C4)alkoxy;
R2means (C3-C5)cycloalkyl;
R12means hydrogen; and (C1-C7)alkyl, optionally substituted with halogen, hydroxy, cyano, (C1-C6)alkoxy, (C3-C6)cycloalkyl, phenyl, aminocarbonyl, carboxyla, etoxycarbonyl, (C1-C6)dialkylamino, (C1-C6)alkylsulfonyl, pyridium or imidazolium; and (C3-C6)cycloalkyl; phenyl; 6-9-membered heteroaryl with one or two heteroatoms, selected from N and O; or phenyl-(C1-C6)Ala is l; or
R12means-C(O)R15or-C(O)OR15,
where R15means optionally substituted (C1-C10)alkyl, where the substituents are selected from piperidyl, halogen and N,N-diethylamino;
R13and R14means independently hydrogen or (C1-C7)alkyl;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

11. The connection of claim 10,
where R1means methoxy;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

12. The connection of claim 10,
where R2means cyclopentyl;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

13. The connection of claim 10,
where R1means methoxy;
R2means cyclopentyl;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

14. The connection of claim 10,
where R12means methyl;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

15. The connection of claim 10,
where R1means methoxy;
R2means cyclopentyl;
R13and R14means independently hydrogen or methyl;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

16. The connection according to claim 9 of the formula

where R1OSN which includes ( 1-C4)alkoxy;
R2means (C3-C5)cycloalkyl;
R12means hydrogen; and (C1-C7)alkyl, optionally substituted with halogen, hydroxy, cyano, (C1-C6)alkoxy, (C3-C6)cycloalkyl, phenyl, aminocarbonyl, carboxyla, etoxycarbonyl, (C1-C6)dialkylamino, (C1-C6)alkylsulfonyl, pyridium or imidazolium; and (C3-C6)cycloalkyl; phenyl; 6-9-membered heteroaryl with one or two heteroatoms, selected from N and O; or phenyl-(C1-C6)alkyl; or
R12means-C(O)R15or-C(O)OR15,
where R15means optionally substituted (C1-C10)alkyl, where the substituents are selected from piperidyl, halogen and N,N-diethylamino;
R19, R20, R21and R22means independently hydrogen or (C1-C7)alkyl, optionally substituted by hydroxy;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

17. Connection P16,
where R1means methoxy;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

18. Connection P16,
where R2means cyclopentyl;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

19. Connection P16,
where R1Osnach the em methoxy;
R2means cyclopentyl;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

20. Connection P16,
where R12means methyl;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

21. Connection P16,
where R1means methoxy;
R2means cyclopentyl;
R19, R20, R21and R22means methyl;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

22. The compound according to claim 1,
where R4and R5together with the nitrogen atom to which they are attached, form an 8-10-membered condensed, containing bridging fragment or Spiro-bicyclic ring which may be optionally substituted benzyl and which may contain 1-2 other heteroatom selected from oxygen and nitrogen;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

23. Connection p.22 formula

where R1means (C1-C4)alkoxy;
R2means (C3-C5)cycloalkyl;
R23means hydrogen or (C1-C7)alkyl, optionally substituted by phenyl;
R25and R24connected with the formation of alkylene, which together with the carbon atom to which they are connec the us, forms a 3-membered ring;
R26and R27means independently hydrogen or (C1-C7)alkyl, optionally substituted by hydroxy;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

24. Connection item 23,
where R1means methoxy;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

25. Connection item 23,
where R2means cyclopentyl;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

26. Connection item 23,
where R1means methoxy;
R2means cyclopentyl;
or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

27. The compound according to claim 1, selected from
3-cyclopentyl-2-(4-cyclopropanesulfonyl)-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-[4-(2-methoxyethanol)phenyl]-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-[4-(3-methoxybenzenesulfonyl)phenyl]-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-(4-phenylsulfanyl-phenyl)propionamide;
2-[4-(2-carbamoyltransferase)phenyl]-3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-(4-diisopropylaminoethyl)-N-(5-methoxythiazole[5,4-b]pyridin-yl)propionamide;
3-cyclopentyl-2-{4-[(furan-2-ylmethyl)sulfamoyl]phenyl}-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(phenylpropyl-sulfamoyl)phenyl]propionamide;
3-cyclopentyl-2-(4-dimethylaminophenyl)-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-(4-diethylaminophenyl)-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-(4-dipropylamino)-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[(pyridine-3-ylmethyl)-sulfamoyl]phenyl}propionamide;
2-(4-cyclohexylsulfamate)-3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(piperidine-1-sulfonyl)phenyl]propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(morpholine-4-sulfonyl)phenyl]propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[(thiophene-2-ylmethyl)-sulfamoyl]phenyl}propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(pyridine-3-ylsulphonyl)phenyl]propionamide;
3-cyclopentyl-2-[4-(2-perpenicular)phenyl]-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-[4-(4-methoxybenzenesulfonyl)phenyl]-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
2-(4-benzylcarbamoyl)-3-cyclopentyl-N-(5-IU oxitosona[5,4-b]pyridine-2-yl)propionamide;
2-[4-(enzymatically)phenyl]-3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
3-cyclopentyl-2-(4-dibutylaminoethanol)-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-[4-(4-ethylpiperazin-1-sulfonyl)phenyl]-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
2-[4-(4-acetylpiperidine-1-sulfonyl)phenyl]-3-cyclopentyl-N-(5-methoxy-thiazolo [5,4-b] pyridine-2-yl)propionamide;
hydrochloride 3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(piperazine-1-sulfonyl)phenyl]propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(4-phenylpiperazin-1-sulfonyl)phenyl]propionamide;
3-cyclopentyl-2-{4-[4-(2-methoxyphenyl)piperazine-1-sulfonyl]phenyl}-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
2-{4-[4-(3-chlorophenyl)piperazine-1-sulfonyl]phenyl}-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
2-[4-(4-benzylpiperazine-1-sulfonyl)phenyl]-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-[4-(4-isopropylpiperazine-1-sulfonyl)phenyl]-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(4-o-tailpipes-1-sulfonyl)phenyl]propionamide;
methyl ester of N-[2-(2-{4-[4-(2-chlorophenyl)piperazine-1-sulfon the l]phenyl}-3-cyclopentylpropionyl)thiazol-5-yl]acetamido acid;
3-cyclopentyl-2-{4-[4-(4-forfinal)piperazine-1-sulfonyl]phenyl}-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(4-pyridin-2-yl-piperazine-1-sulfonyl)phenyl]propionamide;
3-cyclopentyl-2-{4-[(2-hydroxyethyl)methylsulfinyl]phenyl}-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(4-pyridin-4-yl-piperazine-1-sulfonyl)phenyl]propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(2-piperidine-1-yl-ethylsulfanyl)phenyl]propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(2-pyrrolidin-1-yl-ethylsulfanyl)phenyl]propionamide;
hydrochloride 3-cyclopentyl-2-{4-[(2-dimethylaminoethyl)ethylsulfanyl]phenyl}-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
hydrochloride 3-cyclopentyl-2-[4-(2-dimethylaminoethanol)phenyl]-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-{4-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]phenyl}-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
hydrochloride 3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[methyl-(2-pyrrolidin-1-retil)sulfamoyl]phenyl}propionamide;
hydrochloride 3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[methyl-(2-piperidine-1-retil)sulfamoyl]phenyl}propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[IU the Il-(2-morpholine-4-retil)sulfamoyl]phenyl}propionamide;
ethyl ester of 4-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}piperazine-1-yl)acetic acid;
3-cyclopentyl-2-{4-[(2-diethylaminoethyl)methylsulfinyl]phenyl}-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-[4-(2-hydroxyethylsulphonic)phenyl]-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
2-[4-(4-carbamoyltransferase-1-sulfonyl)phenyl]-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(pyrrolidin-1-sulfonyl)phenyl]propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(pyridine-2-ylsulphonyl)phenyl]propionamide;
4-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzosulfimide}piperidine-1-carboxylic acid;
tert-butyl ester 4-({4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzosulfimide}methyl)piperidine-1-carboxylic acid;
3-cyclopentyl-2-{4-[(1-ethylpyrrolidin-2-ylmethyl)sulfamoyl]phenyl}-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(piperidine-4-ylsulphonyl)phenyl]propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[(piperidine-4-ylmethyl)sulfamoyl]phenyl}propionamide;
ethyl ether (4-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine--ylcarbonyl)ethyl]benzazolyl}piperazine-1-yl)acetic acid;
3-cyclopentyl-2-{4-[(3-hydroxy-5-hydroxymethyl-2-methylpyridin-4-ylmethyl)-sulfamoyl]phenyl}-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
tert-butyl ester 3-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzosulfimide}azetidin-1-carboxylic acid;
tert-butyl methyl ether (1-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}azetidin-3-yl)carbamino acid;
tert-butyl ether 3-({4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzosulfimide}methyl)azetidin-1-carboxylic acid;
1-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]-benzazolyl}pyrrolidin-2-carboxylic acid;
2-[4-(azetidin-3-ylsulphonyl)phenyl]-3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
2-[4-(3-aminoamides-1-sulfonyl)phenyl]-3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
2-{4-[(azetidin-3-ylmethyl)sulfamoyl]phenyl}-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-(4-sulfamoylbenzoyl)-propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[(pyridine-4-ylmethyl)-sulfamoyl]phenyl}propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[(pyridine-2-ylmethyl)-sulfamoyl]phenyl}propionamide;
4-{4-[2-cyclopenta is-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]-benzosulfimide}benzoic acid;
3-cyclopentyl-2-[4-(4-dimethylaminomethylphenol)phenyl]-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
2-[4-(4-cyclohexylpiperazine-1-sulfonyl)phenyl]-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(1,2,2,6,6-pentamethyl-piperidine-4-ylsulphonyl)phenyl]propionamide;
3-cyclopentyl-2-[4-(1,1-dimethyl-2-morpholine-4-reticulator)phenyl]-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
tert-bouteloua ether (S)-3-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzosulfimide}piperidine-1-carboxylic acid;
2-[4-([1,4']bipyridinyl-1'-sulfonyl)phenyl]-3-cyclopentyl-N-(5-methoxy-thiazolo [5,4-b] pyridine-2-yl)propionamide;
3-cyclopentyl-2-[4-(4-diethylaminophenyl-1-sulfonyl)phenyl]-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(4-pyrrolidin-1-yl-piperidine-1-sulfonyl)phenyl]propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(octahedrite[1,2-a]pyrazin-2-sulfonyl)phenyl]propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(pyridine-4-ylsulphonyl)phenyl]propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-((5)-piperidine-3-ylsulphonyl)phenyl]propionamide;
3-cyclopentyl-2-[4-(1-ethylpiperidine-3-ylsulphonyl)phenyl]-N-(5-methoxy-ti is gold[5,4-b]pyridine-2-yl)propionamide;
2-{4-[4-(2-cyanoethyl)piperazine-1-sulfonyl]phenyl}-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(4-piperidine-1-ilmatieteenlaitos)phenyl]propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(1-phenyl-2-pyrrolidin-1-reticulator)phenyl]propionamide;
2-[4-(4-cyclohexylpiperazine-1-sulfonyl)phenyl]-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-[4-(2-dimethylamino-2-pyridin-3-reticulator)phenyl]-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[methyl-(1-methyl-piperidine-4-yl)sulfamoyl]phenyl}propionamide;
2-[4-(4-cyclooctylmethyl-1-sulfonyl)phenyl]-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(4-feiticeira-1-sulfonyl)phenyl]propionamide;
tert-butyl ether (R)-3-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzosulfimide}piperidine-1-carboxylic acid;
3-cyclopentyl-2-{4-[4-(2-ethoxyethyl)piperazine-1-sulfonyl]phenyl}-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-{4-[4-(2-diethylaminoethyl)piperazine-1-sulfonyl]phenyl}-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-the l)-2-[4-((R)-piperidine-3-ylsulphonyl)phenyl]propionamide;
ethyl ether (1-{4-[2-cyclopentyl-1-(5-methoxythiazole [5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}azetidin-3-ylamino)acetic acid;
ethyl ester of [3-({4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzosulfimide}methyl)azetidin-1-yl]acetic acid;
3-cyclopentyl-2-[4-(hexahydropyrazino[1,2-a]pyrazin-2-sulfonyl)phenyl]-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
ethyl ester of 4-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzosulfimide}piperidine-1-carboxylic acid;
3-cyclopentyl-2-{4-[cyclopropyl-(1-methylpiperidin-4-yl)sulfamoyl]phenyl}-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
2-[4-(4-benzyl-4,7-diazaspiro[2.5]octane-7-sulfonyl)phenyl]-3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[4-(4-methylpiperazin-1-yl)piperidine-1-sulfonyl]phenyl}propionamide;
3-cyclopentyl-2-[4-(4-cyclopentylpropionyl-1-sulfonyl)phenyl]-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-[4-(4,7-diazaspiro[2.5]octane-7-sulfonyl)phenyl]-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
tert-bouteloua ester 3-({4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]-benzosulfimide}methyl)piperidine-1-carboxylic acid;
(S)-1-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]PI is one-2-ylcarbonyl)ethyl]-benzazolyl}pyrrolidin-2-carboxylic acid;
(R)-1-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]-benzazolyl}pyrrolidin-2-carboxylic acid;
3-cyclopentyl-2-{4-[4-(2-diethylaminoethyl)piperazine-1-sulfonyl]phenyl}-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[(piperidine-3-ylmethyl)sulfamoyl]phenyl}propionamide;
2-(4-butylsulfonyl)-3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
2-[4-(4-cinematelevision-1-sulfonyl)phenyl]-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
ethyl ester of 3-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzosulfimide}propionic acid;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[methyl-(1-methyl-1H-imidazol-2-ylmethyl)sulfamoyl]phenyl}propionamide;
3-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]-benzosulfimide}propionic acid;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[3-(4-methylpiperazin-1-yl)-3-oxopropionate]phenyl}propionamide;
3-cyclopentyl-2-{4-[2-(4-hydroxypiperidine-1-yl)ethylsulfanyl]phenyl}-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
2-[4-(4-cyclobutylmethyl-1-sulfonyl)phenyl]-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
2-[4-(4-arylpiperazine-1-sulfonyl)phenyl]-3-cyclopentyl-N-(5-m is toxicity[5,4-b]pyridine-2-yl)propionamide;
(1-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]-benzazolyl}azetidin-3-ylamino)acetic acid;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(2-piperidine-1-ilmatieteenlaitos)phenyl]propionamide;
3-cyclopentyl-2-{4-[4-(2-dimethylaminoethyl)phenylsulfonyl]phenyl}-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-(4-propanesulfonyl-phenyl)propionamide;
[3-({4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]-benzosulfimide}methyl)azetidin-1-yl]acetic acid;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[4-(2,2,2-Cryptor-acetyl)piperazine-1-sulfonyl]phenyl}propionamide;
3-cyclopentyl-2-[4-(3-isopropylaminomethyl-1-sulfonyl)phenyl]-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-[4-(1-isopropylpyridine-3-ylsulphonyl)phenyl]-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-{4-[(1-isopropylpyridine-3-ylmethyl)sulfamoyl]phenyl}-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[(oxazol-2-ylmethyl)-sulfamoyl]phenyl}propionamide;
3-cyclopentyl-2-{4-[4-(2-methanesulfonyl)piperazine-1-sulfonyl]phenyl}-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
2-{4-[4-(3-cyanopropyl)piperazine-1-sulfonyl]phenyl}-3-cyclopent is-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(tetrahydropyran-4-ylsulphonyl)phenyl]propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[1-(tetrahydropyran-4-yl)azetidin-3-ylsulphonyl]phenyl}propionamide;
tert-bouteloua ether 4-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-3-hydroxyethylpiperazine-1-carboxylic acid;
tert-butyl ether (S)-2-tert-butoxycarbonylamino-4-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzosulfimide}butyric acid;
(S)-2-amino-4-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)-ethyl]benzosulfimide}butyric acid;
3-cyclopentyl-2-{4-[4-(2-imidazol-1-retil)piperazine-1-sulfonyl]phenyl}-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-[4-(2-hydroxyethylpiperazine-1-sulfonyl)phenyl]-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
(4-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]-benzazolyl}piperazine-1-yl)acetic acid;
3-cyclopentyl-2-{4-[(2-methoxyethyl)-(1-methylpiperidin-4-yl)sulfamoyl]phenyl}-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
hydrochloride 3-cyclopentyl-2-{4-[(2-methoxyethyl)pyridine-2-ylmethylamino]phenyl}-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-{4-[(2-hydroxyethyl)-(1-methylpiperid the Jn-4-yl)sulfamoyl]phenyl}-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
2-[4-(4-benzooxazol-2-reparation-1-sulfonyl)phenyl]-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-[4-(furan-2-eletronically)phenyl]-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-[4-(3-hydroxy-4,7-dihydro-5H-isoxazole[5,4-C]pyridine-6-sulfonyl)phenyl]-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
2-[4-((S)-1-benzylpiperidine-3-ylsulphonyl)phenyl]-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[4-(2,2,2-triptorelin)-piperazine-1-sulfonyl]phenyl}propionamide;
hydrochloride ethyl ester ({4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}pyridine-2-ylmethylamino)acetic acid;
hydrochloride 3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(4-pyridine-3-iletileri-1-sulfonyl)phenyl]propionamide;
the hydrochloride of the ethyl ester of 1'-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-[1,4']bipyridinyl-4-carboxylic acid;
hydrochloride of 1'-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-[1,4']bipyridinyl-4-carboxylic acid;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[2-(1-methylpyrrolidine-2-yl)ethylsulfanyl]phenyl}propionamide;
({4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]is iridin-2-ylcarbonyl)ethyl]-benzazolyl}pyridine-2-ylmethylamino)acetic acid;
ethyl ester of 3-({4-[2-cyclopentyl-1-(5-methoxythiazole [5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}furan-2-ylmethylamino)propionic acid;
2-{4-[(2-cyanoethyl)furan-2-ylmethylamino]phenyl}-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-{4-[(3-methoxypropyl)-(1-methylpiperidin-4-yl)sulfamoyl]-phenyl}-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-{4-[(2-diethylaminoethyl)-(1-methylpiperidin-4-yl)sulfamoyl]-phenyl}-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-cyclopentyl-2-{4-[(3-diethylaminopropyl)-(1-methylpiperidin-4-yl)sulfamoyl]-phenyl}-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
3-({4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]-benzazolyl}furan-2-ylmethylamino)propionic acid;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(3-phenylpiperazin-1-sulfonyl)phenyl]propionamide;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(3,3,4-trimethyl-piperazine-1-sulfonyl)phenyl]propionamide;
3-cyclopentyl-2-[4-(3,3-dimethylpiperazine-1-sulfonyl)phenyl]-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide;
1-tert-butyl ester 4-{4-[2-cyclopentyl-1-(5-methoxythiazole [5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}piperazine-1,3-dicarboxylic acid;
3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-[4-(4-methyl-3-phenyl-piperazine-1-sulfo who yl)phenyl]propionamide; and
3-cyclopentyl-2-[4-(2,5-diazabicyclo[2.2.1]heptane-2-sulfonyl)phenyl]-N-(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)propionamide, or its enantiomer, or a mixture of enantiomers or its pharmaceutically acceptable salt.

28. Method for activating glucokinase including the introduction of a therapeutically effective amount of a compound according to claim 1.

29. The use of compounds according to claim 1 for preparing a medicinal product intended for treating conditions associated with the activity of glucokinase.

30. The use of compounds according to claim 1 for preparing a medicinal product intended for the treatment of impaired glucose tolerance, type 2 diabetes and obesity.

31. Pharmaceutical composition having the properties of a glucokinase activator comprising a therapeutically effective amount of a compound according to claim 1 in combination with one or more therapeutically acceptable carriers.

32. The pharmaceutical composition according p intended for the treatment of impaired glucose tolerance, type 2 diabetes and obesity.

33. The compound according to claim 1 for use as a medicinal product having the properties of a glucokinase activator.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to derivatives of 5,7-disubstituted [1,3]thiazolo[4,5-d]pyrimidine-2(3H)-one of formula (I) where R1 represents CH3 or CH3CH2; R2 represents H, 3-CN, 2-CF3, 2-F, 3-F, 3-CF3, 3-CONH2 or SO2CH3; R3 represents H; R4 represents H or CH3; and R5 represents H; or, when R4 represents CH3, R5 represents H or F; and to its pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition exhibiting properties of CX3CR1 receptor antagonist containing compound (I) of formula or its pharmaceutically acceptable salt mixed with a pharmaceutically acceptable diluent or carrier.

EFFECT: enabled administration of the derivatives of 5,7-disubstituted [1,3]thiazolo[4,5-d]pyrimidine-2(3H)-one as selective CX3CR1 receptor antagonists.

13 cl, 1 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 3-cyclohexylaminomethylthiazole[3,2-a]benzimidazole dihydrochloride of formula I: , having immunotropic and anti-aggregation activity.

EFFECT: novel compounds have useful biological properties.

2 cl, 8 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds which possess inhibiting properties with respect to PI3-kinase of general formula (1), where R1 is selected from group, including -NHRC, -NHC(O)Rc, -NHC(O)ORc, -NHC(O)NRcRc and -NHC(O)SRc, R2 stands for residue, optionally substituted with one or two substituents R4, selected from group, including C1-C6alkyl, C3-C8cycloalkyl, 5-6-member heterocycloalkyl with one heteroatom, selected from nitrogen and sulphur, phenyl, benzyl and 5-6-member heteroaryl, including 1-2 nitrogen atoms, R3 stands for optionally substituted with one or several substituents Re and/or Rf residue, selected from group, including phenyl and 5-6-member heteroaryl with 1-3 heteroatoms, selected from nitrogen and oxygen, R4 represents residue, selected from group, including Ra, Rb, and substituted with one or several identical or different substituents Rc and/or Rb , Ra in each case is independently selected from group, including C1-C6alkyl, phenyl, 4-7-member heterocycloalkyl with 1-2 heteroatoms, selected from nitrogen and oxygen, and 9-member heteroaryl with one atom of nitrogen as heteroatom, Rb in each case is independently selected from group, including =O, -ORc, -NRCRC, halogen, -CF3, -CN, -S(O)Rc, -C(O)Rc, -C(O)ORc, -C(O)NRcRc, -C(O)N(Rg)NRcRc, -N(Rg)C(O)Rc, -N(Rg)S(O)2Rc, -N(Rg)S(O)2NRcRc, -N(Rg)C(O)ORc and -N(Rg)C(O)NRcRc, RC in each case independently represents hydrogen or optionally substituted with one or two identical or different substituents R and/or Re residue, selected from group, including C1-C6alkyl, C3-C8cycloalkyl, C6-C9aryl, 4-7-member heterocycloalkyl with 1-2 heteroatoms, selected from nitrogen and oxygen, and 5-6-member heteroaryl with 1-2 heteroatoms, selected from nitrogen, oxygen and sulphur, Rd in each case independently represents hydrogen or optionally substituted with one or two identical or different substituents Re and/or Rf residue, selected from group, including C1-C6alkyl, C3-C8cycloalkyl, phenyl, 4-7-member heterocycloalkyl with 1-2 heteroatoms, selected from nitrogen and oxygen, and 5-10-member heteroaryl with one atom of nitrogen, Re in each case is independently selected from group, including =O, -ORf, -SRf, -NRfRf, -CN, -S(O)2Rf, -C(O)Rf, -C(O)ORf, -C(O)NRfRf and -OC(O)Rf, Rf in each case independently represents hydrogen or optionally substituted with one or two identical or different substituents Rg residue, selected from group, including C1-C6alkyl, C3-C8cycloalkyl, phenyl, 4-7-member heterocycloalkyl with 1-2 heteroatoms, selected from nitrogen and oxygen and 5-6-member heteroaryl with one heteroatom, selected from nitrogen and sulphur, Rg in each case independently represents hydrogen, C1-C6alkyl, C3-C8cycloalkyl and 4-7-member heterocycloalkyl with one nitrogen as heteroatom, as well as to their pharmaceutically harmless acid-additive salts. Invention also relates to compounds, used as intermediate products of synthesis of formula (I) compounds, pharmaceutical composition and application of compounds for preparation of medication, possessing properties of PI3-kinase inhibitor.

EFFECT: elaborated are novel compounds, which possess properties of PI3-kinase inhibitor.

11 cl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) and formula (II), their tautomers and pharmaceutically acceptable salts. In formula (I) and in formula (II), X - S; R1 - H; R2 - NR5R6; R3 - 5-6-member heteroaryl with 1 heteroatom, selected from N and S, or phenyl, optionally substituted with one or two substituents, selected from halogen, amino, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-halogenalkyl and C1-C6-halogenalkoxy; R4 - H, C1-C6 alkyl, C1-C6 alkoxy or XR3, where X and R3 are determined above; R5 - H; R6 - H; L - N or CR7, where R7 - H; M - S. Invention also relates to pharmaceutical composition, containing as active component invention compound, to method of inhibiting activity of caseinkinase lε and to method of obtaining compounds of formula (I) or formula (II).

EFFECT: compounds of claimed invention possess properties of casein kinase lε inhibitors.

13 cl, 5 tbl, 44 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described novel acylsulfonamide peri-substituted condensed bicyclic compounds of general formula (I), values of radicals are given in invention formula. Also described is pharmaceutical composition based on formula (I) compound.

EFFECT: compounds can be used for inhibition of prostaglandin E2 binding with receptor EP3.

30 cl, 371 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat diseases mediated by the nicotinic acetylcholine receptor, such as derangement of memory. In general formulae , and A is an indazolyl, benzothiazolyl or isobenzothiazolyl group which corresponds to structural formulae a) to c) respectively or X is O; R1 is H, F, Cl, Br, I, cycloalkyl containing 3-7 carbon atoms, alkoxy which contains 1-4 carbon atoms, fluorinated alkoxy which contains 1-4 carbon atoms, Ar or Het; ; R2 is H; R3 is H; R4 is H, F, Cl, Br, I, cycloalkyl which contains 3-7 carbon atoms, alkoxy which contains 1-4 carbon atoms, fluorinated alkoxy which contains 1-4 carbon atoms, Ar or Het; R5 is H; Ar is an aryl group containing 6 carbon atoms which is unsubstituted or substituted once or several times with halogen; and Het is a 5- or 6-member heteroaromatic group containing a heteroatom in the ring which is selected from N, O and S, or a 6-member saturated heterocyclic group which contains a heteroatom in the ring which is selected from N and O; and their pharmaceutically acceptable salts, where, if the said compound has formula I, the indazolyl group of group A is bonded through its 3rd, 4th or 7th position, the benzothiazole group of group A is bonded through the 4th or 7th position, the isobenzothiazole group of group A is bonded through the 3rd, 4th or 7th position.

EFFECT: obtaining compounds with properties of nicotinic acetylcholine receptor (nAChR) ligands, and pharmaceutical compositions based on the said compounds.

53 cl, 95 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: described is a bromohydrate of 4-methoxy-7,7-dimethyl-9-(5'-carboxyamyl)amino-6H-7,8-dihydropyrimido-(4,5-b)-1,4-benzthiazine (hereinafter methiazine) and a method for synthesis of the said compound. Methiazine has anti-tumour and anti-reductase activity, which has cytostatic and cytotoxic effect which inhibits synthesis of nucleic acids and can be used in medicine. Bromohydrate of 4-methoxy-7,7-dimethyl-9-(5'-carboxyamyl)amino-6H-7,8-dihydropyrimido-(4,5-b)-1,4-benzthiazine of formula I , is obtained by reacting dimedone with ω-amino caproic acid in a medium of boiling isopropanol to obtain enamine-ketone which is subjected to bromation with bromosuccinimide with further treatment with 4-methoxy-5-amino-6-mercaptopyrimidine in a medium of boiling isopropanol.

EFFECT: improved method.

2 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as a medicinal agent which modulates PPARδ (peroxisome proliferator-activated receptor δ). In formula I

, p is equal to 1; L2 is selected from a group which includes -XOX- and -XSX-, where X is independently selected from a group which includes a bond and C1-C4alkylene; R13 is selected from a group which includes halogen, C1-C6alkyl; R14 is selected from a group which includes -XOXC(O)OR17 and -XC(O)OR17, where X denotes a bond or C1-C4alkylene and R17 denotes hydrogen; R15 and R16 are independently selected from a group which includes -R18 and -YR18, where Y is selected from a group which includes C2-C6alkenylene, and R18 is selected from a group which includes C6-C10aryl, pyridinyl, pyrimidinyl, quinolinyl, benzo[b]furanyl, benzoxazolyl, 1,5-benzodioxanyl, 1,4-benzodioxanyl and 3,4-dihydro-2H-benzo[b][1,4]dioxepin; where any of phenyl, pyridinyl, pyrimidinyl, benzoxazolyl in R18 is independently substituted with 1-2 radicals, independently selected from a group which includes halogen, C1-C6alkyl, C2-C7alkenyl, C1-C6alkoxy group, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy group, C3-C12cycloalkyl, phenyl, morpholinyl, pyrrolidinyl, piperidinyl, -XNR17R17, -XC(O)NR17R17, -XC(O)R19 and -XOXR19, where X denotes a bond or C1-C4alkylene; R17 is selected from a group which includes C1-C6alkyl, and R19 is selected from a group which includes C3-C12cycloalkyl, piperidinyl and phenyl. The invention also relates to use of the disclosed compounds to prepare a medicinal agent which modulates PPARδ activity, a pharmaceutical composition having PPARδ activity modulating properties, which contains a therapeutically effective amount of the disclosed compound and to use of the pharmaceutical composition in preparing a medicinal agent which modulates PPARδ activity.

EFFECT: improved properties of compounds.

10 cl, 1 tbl, 69 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, namely to development of a pharmaceutical composition for blood sugar and fat control, to a method of manufacturing of said pharmaceutical composition, to administration thereof. The pharmaceutical composition contains the following Chinese herbs or their extracts in mass portions: 5-17 privet fruits (Ligustri lucidui), 3-12 locoweed roots (Radix Astragali Mongolia), 1-5 gold-thread rhizomes (Rhizoma Coptidis), 1-5 lychee seeds (Semen Litchi), optionally 1-6 laminarias (Thallus Laminariae Japonicae) and 1-6 turmeric rhizomes (Rhizoma Curcumae Longae).

EFFECT: manufacturing of the pharmaceutical composition to be applied for treating diabetes.

10 cl, 27 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacy, namely: to the development of a herbal drug exhibiting anorectic, hypoglycemic and hypolipidemic action. Object of the invention is worked out by developing an anorectic, hypoglycemic, hypolipidemic drug which represents an aqueous extract of black and brown leaves of Bergenia crassifolia collected after 1-2 winter stays which are dried at temperature 35-45°C before extraction to constant weight and crushed.

EFFECT: developing the herbal drug exhibiting hypoglycemic, hypolipidemic action and ability to suppress appetite with no by-effects.

1 cl, 5 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, and relates to peroral transmucosal pharmaceutical compositions, containing metformin or its pharmaceutically acceptable salt, in presence of at least one absorption intensifier, selected from alkylsulfate of alkaline metal, glycerin, bile acid or salt of bile acid, and also to methods for application of such compositions for treatment of diabetes in an individual, to method of compositions preparation.

EFFECT: composition provides for high bio-availability of metformin in an individual and fast therapeutic effect.

24 cl, 5 ex, 1 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to cocrystalline form of (1S)-1,5-anhydro-1-[3-(1-benzothiene-2-ylmethyl)-4-fluorophenyl]-D-glucitol (compound A) with L-proline. Proposed cocrystalline form is a promising anti-diabetes medicine.

EFFECT: cocrystalline form of compound is characterised with constant composition, improved stability in storage, and also low hygroscopicity, and is suitable for use as crystalline medicinal substance to produce pharmaceutical preparations.

11 cl, 1 ex, 2 tbl, 10 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-cyclopropyl-1 -{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate of formula:

. The invention also relates to salts and solvates of the said compound, a method of producing said compound, a pharmaceutical agent having angiotensin II antagonist activity, based on said compound.

EFFECT: compound can be used in medicine to prevent and treat blood circulatory system diseases.

18 cl, 1 dwg, 8 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and pharmaceutically acceptable salts thereof, where substitutes R1-R4 are as defined in claim 1. Said compounds have 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) enzyme inhibiting activity.

EFFECT: compounds can be used in form of a pharmaceutical composition.

15 cl, 1 tbl, 94 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazopyrazines of formula where Q1 and R1 have the values specified in the patent claim, and to their pharmaceutically acceptable salts showing IGF-1R enzyme inhibiting activity and applicable for treatment and/or prevention of various diseases and conditions which are sensitive to tyrosine kinase inhibition.

EFFECT: preparation of the compounds showing IGF-1R enzyme inhibiting activity.

27 cl, 294 ex

FIELD: medicine.

SUBSTANCE: invention belongs to medicine, notably to haematology and cardiology and refers to reduction of spontaneous erythrocytes aggregation in patients with arterial hypertension and dislipidemy. To achieve this, combination of hypolipidemic diet with dosed different physical exercises, daily swimming during at lest 40 minutes in the middle of the day is used. Additionally is administered 10 mg of lisinopril in the morning once daily and simvastatin 20 mg after supper once daily. Course of treatment is 2 months.

EFFECT: method ensures correction of spontaneous erythrocyte aggregation in this group of patents and results risk decrement of such thrombotic complications as myocardial infarction, insult and thromboses of different localisation.

1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medical and pharmaceutical industry. Buds of two types of Sophora - Sophora japonica and Sophora pachycarpa are soaked in 60% alcohol at the ratio of 1:2 between raw material and extractant for 14 days, then withdrawn, filtered and repeatedly poured with 90% alcohol at the ratio of 1:2 and soaked for 10 days. Extracted matter is filtered. Produced extracted matter is fraction No. 1. Fresh raw material of blossom clusters of Sophora pachycarpa and Sophora japonica is ground and poured with distilled water at the ratio of 1:10. 10% solution of ascorbic acid is added into the solution. Matter is left to soak for 24 hours, extracted matter is filtered, and fraction No.2 is produced. Two fractions are mixed to 60% concentration of alcohol.

EFFECT: invention makes it possible to increase product activity.

1 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to immunometabolic anthelmintic drug. Immunometabolic anthelmintic drug, including levamisole, succinic acid and water, taken in specified ratio.

EFFECT: medication possesses efficient immunometabolic, hepatoprotecting and anti-nematode action, without toxic effect.

5 tbl, 4 ex

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