3-cyclyl-2-(4-sulphamoylphenyl)-n-cyclylpropionamide derivatives applicable for treating impaired glucose tolerance and diabetes

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula in which Q together with carbon and nitrogen atoms whereto attached forms a 9-10-member bicyclic heterocycle, and R1 and R2, R3, R4, R5 and R6 are as specified in cl.1 of the patent claim, or to its enantiomers, or a mixture of its enantiomers, or to its pharmaceutically acceptable salt. Also, an invention refers to a method for activation of glucokinase activity in mammals, by introduction of the compound described above, to a method of treating the pathological conditions associated with glucokinase activity and impaired glucose tolerance by means of introduction of the compound of formula I, to a pharmaceutical composition on the basis of the presented compounds, and also to application of the compounds of formula I for preparing the pharmaceutical composition.

EFFECT: there are produced and described new compounds which are activators of glucokinase activity and can be used as therapeutic agents for preventing and treating impaired glucose tolerance, insulin-independent diabetes and obesity.

14 cl, 4 ex

 

The text descriptions are given in facsimile form.

1. The compound of the formula

in which Q, together with the atoms to the carbon and nitrogen, to which it is attached, forms a 9-10-membered ring of the bicyclic heterocycle selected from the group consisting of
;;;;
;;;;
;;;;
;;;and;
R1and R2independently of one another denote hydrogen; a halogen; a cyano; a nitro-group; alkoxygroup, replaced by carbamoyl, carboxypropyl or one or more halogen; alkyl, optionally substituted by phenyl or by one or more halogen; sulfonyl; free or esterified carboxypropyl; carbarnoyl; the amino group, optionally substituted by one or more Deputy independently selected from alkyl or alkoxyalkyl; aryl, optionally substituted dialkylamino; 6-membered heteroaryl containing 1-2 heteroatoms, optionally substituted by alkyl, or a 3-6-membered cycloalkyl; or 6-membered heterocyclyl containing 1-2 heteroatoms, optionally substituted by alkyl; or
2no;
R3stands With3-C6cycloalkyl;
R4denotes hydrogen, halogen or halogenated;
R5denotes hydrogen, cycloalkyl or alkyl, optionally substituted by alkoxygroup;
R6means -(CR7R8)m-W-R9where
R7and R8independently of one another denote hydrogen, alkyl or cycloalkyl; or
R7and R8together denote alkylene, which together with the carbon atom to which it is attached, form a 3-7-membered ring;
m is 0 or an integer from 1 to 5;
W represents-NR10-where
R10denotes hydrogen, alkyl or heterocyclyl; or
R10denotes-C(O)R11-C(O)OR11or-C(O)NR12R13where
R11and R12independently of one another denote alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl or heteroaromatic;
R13denotes hydrogen or lower alkyl; or
R13and R12together denote alkylene, which together with the nitrogen atom to which it is attached, form a 4-7-membered ring; or
W is absent;
R9denotes hydrogen, C1-C7alkyl, cycloalkyl, aryl or heterocyclyl; or
R9and R10together denote alkylene, which together with the nitrogen atom to which it is attached, form a 4-7-membered ring; or
R6/sub> and R5together denote alkylene, which together with the nitrogen atom to which it is attached, form a 4-7-membered ring, which optionally may be substituted or may contain 1-3 other heteroatom selected from oxygen, nitrogen and sulfur, or may be part of another ring;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which
R1denotes hydrogen; halogen; cyano; nitro-group; alkoxygroup, replaced by carbamoyl, carboxypropyl or one or more halogen; alkyl, optionally substituted by phenyl or by one or more halogen; sulfonyl; free or esterified carboxypropyl; carbarnoyl; the amino group, optionally substituted by one or more Deputy independently selected from alkyl or alkoxyalkyl; aryl, optionally substituted dialkylamino; 6-membered heteroaryl containing 1-2 heteroatoms, optionally substituted by alkyl, or a 3-6-membered cycloalkyl; or 6-membered heterocyclyl containing 1-2 heteroatoms, optionally substituted by alkyl; or
R2no;
R3denotes cyclopentyl;
R4denotes hydrogen;
R5denotes hydrogen or lower alkyl;
R6means -(CR7R8)m-W-R9where
R7and R8 independently represent hydrogen or lower alkyl;
m is 0 or an integer from 1 to 5;
W represents-NR10-where
R10denotes hydrogen or lower alkyl; or
R10denotes-C(O)R11-C(O)OR11or-C(O)NR12R13where
R11and R12independently of one another denote alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl or heteroaromatic;
R13denotes hydrogen or lower alkyl; or
R13and R12together denote alkylene, which together with the nitrogen atom to which it is attached, forms a 5-7-membered ring; or
W is absent;
R9denotes hydrogen, C1-C7alkyl, cycloalkyl, aryl or heterocyclyl; or
R9and R10together denote alkylene, which together with the nitrogen atom to which it is attached, forms a 5-7-membered ring; or
R6and R5together denote alkylene, which together with the nitrogen atom to which it is attached, form a 4-7-membered ring, which optionally may be substituted or may contain 1-3 other heteroatom selected from oxygen, nitrogen and sulfur, or may be part of another ring;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

3. The compound according to claim 2, in which
Q together with the carbon atoms and the nitrogen to which it is connected is inen, forms a 9-10-membered ring of the bicyclic heterocycle selected from the group consisting of
;;;;
;;;;
;;;;
;;;and;
R5denotes hydrogen or lower alkyl;
R6means -(CR7R8)m-W-R9where
R7and R8represent hydrogen;
m is an integer from 2 to 5;
W represents-NR10-where
R10denotes hydrogen or lower alkyl; or
R10denotes-C(O)R11-C(O)OR11or-C(O)NR12R13where
R11and R12independently of one another denote alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl or heteroaromatic;
R13denotes hydrogen or lower alkyl; or
R13and R12together denote alkylene, which together with the nitrogen atom to which it is attached, forms a 5-7-membered ring; or
W is absent;
R9denotes hydrogen, C1-C7lcil, cycloalkyl, aryl or heterocyclyl; or
R9and R10together denote alkylene, which together with the nitrogen atom to which it is attached, forms a 5-7-membered ring;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

4. The compound according to claim 3 of the formula

in which R1denotes hydrogen; halogen; cyano; trifluoromethyl; alkoxygroup, replaced by carbamoyl, carboxypropyl or one or more halogen; or carboxypropyl;
R2no;
R5denotes hydrogen or lower alkyl;
R9denotes hydrogen, C1-C7alkyl, cycloalkyl, aryl or heterocyclyl;
R10denotes hydrogen or lower alkyl; or
R10denotes-C(O)R11-C(O)OR11or-C(O)NR12R13where
R11and R12independently of one another denote alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl or heteroaromatic;
R13denotes hydrogen or lower alkyl; or
R13and R12together denote alkylene, which together with the nitrogen atom to which it is attached, forms a 5-7-membered ring; or
R10and R9together denote alkylene, which together with the nitrogen atom to which it is attached, forms a 5-7-membered ring;
or its enantiomer, or a mixture of it EN is tomarow, or its pharmaceutically acceptable salt.

5. The compound according to claim 4, in which
Q together with the carbon atoms and the nitrogen to which it is attached, forms a 9-10-membered ring of the bicyclic heterocycle selected from the group consisting of
;and;
or its pharmaceutically acceptable salt.

6. The compound according to claim 2, in which
Q together with the carbon atoms and the nitrogen to which it is attached, forms a 9-10-membered ring of the bicyclic heterocycle selected from the group consisting of
;;;;
;;;;
;;;;
;;;and;
R6and R5together denote alkylene, which together with the nitrogen atom to which it is attached, form a 4-7-membered ring, which optionally may be substituted or may contain 1-3 other heteroatom selected from oxygen, nitrogen and sulfur, or may be the part of the other ring;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

7. The connection according to claim 6 of the formula

in which R1denotes hydrogen; halogen; cyano; trifluoromethyl; alkoxygroup, replaced by carbamoyl, carboxypropyl or one or more halogen; or carboxypropyl;
R2no;
R14denotes hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl or heteroaromatic; or
R14denotes-C(O)R19, -C(O)OR19or-C(O)NR20R21where
R19and R20independently of one another denote alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl or heteroaromatic;
R21denotes hydrogen or lower alkyl; or
R21and R20together denote alkylene, which together with the nitrogen atom to which it is attached, forms a 5-7-membered ring;
R15, R16, R17and R18independently of one another denote hydrogen, halogen, a hydroxy-group, alkoxygroup, free or esterified carboxylate, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroaromatic or heterocyclic;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

8. The connection according to claim 7, in which
Q together with the carbon atoms and the nitrogen to which he pries the United, forms a 9-10-membered ring of the bicyclic heterocycle selected from the group consisting of
;and;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

9. The connection of claim 8, in which R14denotes methyl; or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

10. The connection of claim 8, in which R14, R15, R16, R17and R18independently of one another denote hydrogen or methyl; or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

11. The connection according to claim 6 of the formula

in which R1denotes hydrogen; halogen; cyano; trifluoromethyl; alkoxygroup, replaced by carbamoyl, carboxypropyl or one or more halogen; or carboxypropyl;
R2no;
R22denotes hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl or heteroaromatic; or
R22denotes-C(O)R19, -C(O)OR19or-C(O)NR20R21where
R19and R20independently of one another denote alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl or heteroaromatic;
R21denotes hydrogen or lower alkyl; or
R21and R20together is the mean alkylen, which together with the nitrogen atom to which it is attached, forms a 5-7-membered ring;
R23, R24, R25and R26independently of one another denote hydrogen, halogen, a hydroxy-group, alkoxygroup, free or esterified carboxylate, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroaromatic or heterocyclyl; or
R22and R25together denote alkylene, which together with the nitrogen atoms and the carbon to which it is attached, form a 4-7-membered ring; or
R25and R26together denote alkylene, which together with the carbon atom to which it is attached, form a 3-7-membered ring;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

12. Connection by claim 11, in which
Q together with the carbon atoms and the nitrogen to which it is attached, forms a 9-10-membered ring of the bicyclic heterocycle selected from the group consisting of
;and;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

13. The activation of glucokinase in a mammal, which includes an introduction to the needy in the mammal the compound according to claim 1 in a therapeutically effective amount.

14. A method for the treatment of PA is ideological States, associated with the activity of glucokinase in a mammal, which includes an introduction to the needy in the mammal the compound according to claim 1 in a therapeutically effective amount.

15. A method of treating impaired glucose tolerance, type 2 diabetes and obesity, which includes an introduction to the needy in the mammal the compound according to claim 1 in a therapeutically effective amount.

16. Pharmaceutical composition having an activating effect on glucokinase, including a connection according to claim 1 or its pharmaceutically acceptable salt in a therapeutically effective amount in combination with one or more pharmaceutically acceptable carriers.

17. The pharmaceutical composition according to item 16, intended for the treatment of impaired glucose tolerance, type 2 diabetes and obesity.

18. The pharmaceutical composition according to item 16, having an activating effect on glucokinase intended for use as a medicine.

19. The use of the pharmaceutical composition according to item 16 for preparing a medicinal product intended for the treatment of pathological conditions associated with the activity of glucokinase.

20. The use of compounds according to claim 1 or its pharmaceutically acceptable salts for the preparation of pharmaceutical compositions intended for the treatment of PA is ideological States, associated with the activity of glucokinase.

21. The application of claim 19 or 20, where the pathological condition associated with the activity of glucokinase, selected from impaired glucose tolerance, type 2 diabetes and obesity.

22. The compound according to claim 1, having an activating effect on glucokinase intended for use as a medicine.

23. The compound of the formula

in which Q, together with the carbon atoms and the nitrogen to which it is attached, forms a 9-10-membered ring of the bicyclic heterocycle selected from the group consisting of
;;;;
;;;;
;;;;
;;;and;
R1and R2independently of one another denote hydrogen; a halogen; a cyano; a nitro-group; alkoxygroup, replaced by carbamoyl, carboxypropyl or one or more halogen; alkyl, optionally substituted by phenyl or by one and the or more halogen; alkenyl; quinil; sulfonyl; free or esterified carboxypropyl; carbarnoyl; the amino group, optionally substituted by one or more Deputy independently selected from alkyl or alkoxyalkyl; aryl, optionally substituted dialkylamino; fenoxaprop; 6-membered heteroaryl containing 1-2 heteroatoms, optionally substituted by alkyl, or a 3-6-membered cycloalkyl; or 6-membered heterocyclyl containing 1-2 heteroatoms, optionally substituted by alkyl;
R3stands With3-C6cycloalkyl;
R4denotes hydrogen, halogen or halogenated;
R5denotes hydrogen, cycloalkyl or alkyl, optionally substituted by alkoxygroup;
R6means -(CR7R8)m-W-R9where
R7and R8independently of one another denote hydrogen, alkyl or cycloalkyl; or
R7and R8together denote alkylene, which together with the carbon atom to which it is attached, form a 3-7-membered ring;
m is 0 or an integer from 1 to 5;
W represents-NR10-where
R10denotes hydrogen, alkyl or heterocyclyl; or
R10denotes-C(O)R11-C(O)OR11or-C(O)NR12R13where
R11and R12independently of one another denote alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl or heteroaryl the sludge;
R13denotes hydrogen or lower alkyl; or
R13and R12together denote alkylene, which together with the nitrogen atom to which it is attached, form a 4-7-membered ring; or
W is absent;
R9denotes hydrogen, C1-C7alkyl, cycloalkyl, aryl or heterocyclyl; or
R9and R10together denote alkylene, which together with the nitrogen atom to which it is attached, form a 4-7-membered ring; or
R6and R5together denote alkylene, which together with the nitrogen atom to which it is attached, form a 4-7-membered ring, which optionally may be substituted or may contain 1-3 other heteroatom selected from oxygen, nitrogen and sulfur, or may be part of another ring;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

24. A compound selected from the group consisting of:
(R)-3-cyclopentyl-N-isoquinoline-1-yl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
(R)-3-cyclopentyl-N-(1-methyl-1H-benzimidazole-2-yl)-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]-N-quinoline-2-ylpropionic;
tert-butyl ester 2-[(R)-3-cyclopentyl-2-(4-diethylaminophenyl)propionamido]-6,7-dihydro-4H-thiazolo[5,4-C]pyridine-5-carboxylic acid;
(R)-3-Cyclops is ntil-2-(4-diethylaminophenyl)-N-(4,5,6,7-tetrahydro-thiazolo[5,4-C]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-2-(4-diethylaminophenyl)-N-(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-N-(1H-indazol-3-yl)-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
(R)-N-(5-bromothiazole[5,4-b]pyridine-2-yl)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
(R)-N-benzothiazol-2-yl-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
(R)-N-(6-bromobenzimidazole-2-yl)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
(R)-3-cyclopentyl-N-(6-metasulphobenzoate-2-yl)-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]-N-(5-phenoxethanol[5,4-b]pyridine-2-yl)propionamide;
ethyl ester of 2-{(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide}benzothiazole-6-carboxylic acid;
2-{(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide}benzothiazole-6-carboxylic acid;
2-{(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide}benzothiazole-6-carboxylic acid;
2-{(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)-3-triptoreline]propionamide}benzothiazole-6-carboxylic acid;
(2-methoxyethyl)amide 2-{(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide}benzothiazole-6-carboxylic acid;
3-[(2-{(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-sulfonyl)phenyl]propionamide}-benzothiazole-6-carbonyl)amino]propionic acid;
(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]-N-(6-cryptomaterial-2-yl)propionamide;
(R)-N-(5-chlorothiazole[5,4-b]pyridine-2-yl)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
(2-{(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide}thiazolo[5,4-b]pyridine-5-yloxy)acetic acid;
(R)-3-cyclopentyl-N-(5-portasilo[5,4-b]pyridine-2-yl)-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]-N-(5-vinylthiazole[5,4-b]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-N-(5-utilizalo[5,4-b]pyridine-2-yl)-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]-N-(5-morpholine-4-iltiazem[5,4-b]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]-N-(5-pyridin-3-iltiazem[5,4-b]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]-N-(5-phenylthiazole[5,4-b]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)-3-triptoreline]-N-(5-pyridin-4-iltiazem[5,4-b]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-N-[5-(2-methoxyethoxy)thiazolo[5,4-b]pyridine-2-yl]-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
4-(2-{(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide}thiazolo[5,4-b]pyridine-5-yloxy)butyric acid;
(R)-3-qi is lipantil-N-{5-[(2-methoxyethyl)methylamino]thiazolo[5,4-b]pyridine-2-yl}-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
3-(2-{(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide}thiazolo[5,4-b]pyridine-5-yloxy)-2,2-dimethylpropionic acid;
(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]-N-[5-(4-methylpiperazin-1-yl)thiazolo[5,4-b]pyridine-2-yl]propionamide;
(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]-N-(5-piperidine-1-iltiazem[5,4-b]pyridine-2-yl)propionamide;
(2-methoxyethyl)methylamide 2-{(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)-phenyl]propionamide}thiazolo[5,4-b]pyridine-5-carboxylic acid;
(R)-3-cyclopentyl-N-[5-((2R,6S)-2,6-dimethylmorpholine-4-yl)thiazolo[5,4-b]pyridine-2-yl]-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]-N-[5-(2-methylpyridin-4-yl)thiazolo[5,4-b]pyridine-2-yl]propionamide;
(R)-3-cyclopentyl-N-(5-amenitiesa[5,4-b]pyridine-2-yl)-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]-N-(5-pyrimidine-5-iltiazem[5,4-b]pyridine-2-yl)propionamide;
(2-methoxyethyl)amide 2-{(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide}thiazolo[5,4-b]pyridine-5-carboxylic acid;
dimethylamide 2-{(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide}thiazolo[5,4-b]pyridine-5-carboxylic acid;
(R)-3-cyclopentyl-N-[5-(2-hydroxyethoxy)thiazolo[5,4-b]pyridine-2-yl]-2-[4-(4-methylpiperazin-1-sulfonyl)f the Nile]propionamide;
(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]-N-(5-pyridin-4-iltiazem[5,4-b]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]-N-[5-(morpholine-4-carbonyl)thiazolo[5,4-b]pyridine-2-yl]propionamide;
(R)-3-cyclopentyl-N-(5-isopropoxyethanol[5,4-b]pyridine-2-yl)-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
(R)-N-(5-benzilate[5,4-b]pyridine-2-yl)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
(R)-N-(5-aminothiazolo[5,4-b]pyridine-2-yl)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
(R)-3-cyclopentyl-N-[5-(2-methoxyethylamine)thiazolo[5,4-b]pyridine-2-yl]-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
(R)-2-[3-chloro-4-(4-methylpiperazin-1-sulfonyl)phenyl]-N-(5-chlorothiazole[5,4-b]pyridine-2-yl)-3-cyclopentylpropionate;
(R)-N-(5-bromothiazole[5,4-b]pyridine-2-yl)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)-3-triptoreline]propionamide;
(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)-3-triptoreline]-N-[5-(4-methylpiperazin-1-yl)thiazolo[5,4-b]pyridine-2-yl]propionamide;
(R)-2-[3-chloro-4-(4-methylpiperazin-1-sulfonyl)phenyl]-3-cyclopentyl-N-(5-pyridin-4-iltiazem[5,4-b]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-N-[5-(2-cyclopropylamino-4-yl)thiazolo[5,4-b]pyridine-2-yl]-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide;
(R)-N-(5-chlorothiazole[5,4-b]piridin-2-yl)-3-cyclohexyl-2-[4-(4-methylpiperazin the-1-sulfonyl)phenyl]propionamide;
(R)-2-[3-chloro-4-(4-methylpiperazin-1-sulfonyl)phenyl]-3-cyclopentyl-N-[5-(4-methylpiperazin-1-yl)thiazolo[5,4-b]pyridine-2-yl]propionamide;
(R)-3-cyclopentyl-2-[4-((S)-3,4-dimethylpiperidin-1-sulfonyl)phenyl]-N-(5-pyridin-4-iltiazem[5,4-b]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-2-[4-((S)-3,4-dimethylpiperidin-1-sulfonyl)phenyl]-N-(5-morpholine-4-iltiazem[5,4-b]pyridine-2-yl)propionamide;
methyl ester of (R)-4-{4-[2-cyclopentyl-1-(5-pyridin-4-iltiazem[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-1-methylpiperazin-2-carboxylic acid;
(R)-4-{4-[2-cyclopentyl-1-(5-pyridin-4-iltiazem[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-1-methylpiperazin-2-carboxylic acid;
2-{(R)-3-cyclopentyl-2-[4-(2-methoxyethanol)phenyl]propionamide}benzothiazole-6-carboxylic acid;
2-((R)-3-cyclopentyl-2-{4-[(2-methoxyethyl)methylsulfinyl]phenyl}propionamide)benzothiazole-6-carboxylic acid;
(R)-N-(5-chlorothiazole[5,4-b]pyridine-2-yl)-3-cyclopentyl-2-[4-(2-methoxyethanol)phenyl]propionamide;
(R)-N-(5-bromothiazole[5,4-b]pyridine-2-yl)-3-cyclopentyl-2-[4-(4-methyl-4,7-diazaspiro[2,5]Octan-7-sulfonyl)phenyl]propionamide;
(R)-3-cyclopentyl-2-[4-(4-methyl-4,7-diazaspiro[2,5]Octan-7-sulfonyl)phenyl]-N-(5-pyridin-4-iltiazem[5,4-b]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-2-[4-(4-methyl-4,7-diazaspiro[2,5]Octan-7-sulfonyl)phenyl]-N-[5-(4-methylpiperazin-1-yl)thiazolo[5,4-b]pyridine-2-yl]propionamide;
(R)-3-cyclo is entil-2-[4-(4-methyl-4,7-diazaspiro[2,5]Octan-7-sulfonyl)phenyl]-N-(5-pyridin-4-iltiazem[5,4-b]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-N-(5-pyridin-4-iltiazem[5,4-b]pyridine-2-yl)-2-[4-(3,3,4-trimethylpyrazine-1-sulfonyl)phenyl]propionamide;
(R)-2-(4-butylsulfonyl)-3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)-2-{4-[4-(2-oxo-2-piperidine-1-retil)piperazine-1-sulfonyl]-phenyl}propionamide;
(R)-3-cyclopentyl-2-{4-[4-(isopropylaminomethyl)piperazine-1-sulfonyl]phenyl}-N-(5-methoxythiazole[5,4-b]pyridine-2-yl)propionamide;
1-{4-[(R)-2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}piperidine-4-carboxylic acid;
1-{4-[(R)-2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}piperidine-3-carboxylic acid;
4-{4-[(R)-2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}piperazine-2-carboxylic acid;
1-{4-[(R)-2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-4-methylpiperazin-2-carboxylic acid;
1-{4-[(R)-2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}piperazine-2-carboxylic acid;
1-{4-[(R)-2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}pyrrolidin-3-carboxylic acid;
4-{4-[(R)-2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-1-methylpiperazin-2-carboxylic acid;
{2-[()-3-cyclopentyl-2-(4-diethylaminophenyl)propionamido]thiazolo[5,4-b]pyridine-5-yloxy}acetic acid;
(R)-N-(5-carbamoyloximes[5,4-b]pyridine-2-yl)-3-cyclopentyl-2-(4-diethylaminophenyl)propionamide;
3-(4-{4-[(R)-2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzosulfimide}piperidine-1-yl)propionic acid;
(R)-1-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}piperidine-2-carboxylic acid;
3-(4-{4-[(R)-2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}piperazine-1-yl)propionic acid;
4-(4-{4-[(R)-2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}piperazine-1-yl)-4-oxomethane acid;
(R)-3-cyclopentyl-2-[4-((S)-3-methylpiperazin-1-sulfonyl)phenyl]-N-(5-morpholine-4-iltiazem[5,4-b]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-2-[4-((S)-3-methylpiperazin-1-sulfonyl)-phenyl]-N-(5-pyridin-4-iltiazem[5,4-b]pyridine-2-yl)-propionamide;
(R)-3-cyclopentyl-N-[5-(2-methoxyethylamine)thiazolo[5,4-b]pyridine-2-yl]-2-[4-(piperazine-1-sulfonyl)phenyl]propionamide;
(R)-3-cyclopentyl-2-[4-(piperazine-1-sulfonyl)phenyl]-N-(5-vinylthiazole[5,4-b]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-2-[4-(piperazine-1-sulfonyl)phenyl]-N-(5-pyridin-4-iltiazem[5,4-b]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-N-(5-morpholine-4-iltiazem[5,4-b]pyridine-2-yl)-2-[4-(piperazine-1-sulfonyl)phenyl]propionamide;
(R)-3-cyclopentyl-2-[4-(piperazine-1-sulfonyl)phenyl]-N-(5-piperazine-1-iltiazem[5,4-b]is iridin-2-yl)propionamide;
(R)-3-cyclopentyl-N-[5-(4-methylpiperazin-1-yl)thiazolo[5,4-b]pyridine-2-yl]-2-[4-(piperazine-1-sulfonyl)phenyl]propionamide;
(R)-3-cyclopentyl-2-[4-(piperazine-1-sulfonyl)phenyl]-N-(5-pyridin-3-iltiazem[5,4-b]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-2-[4-(4,7-diazaspiro[2,5]Octan-7-sulfonyl)phenyl]-N-(5-pyridin-4-iltiazem[5,4-b]pyridine-2-yl)propionamide.
(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]-N-(5-cryptomaterial[5,4-b]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]-N-(5-(tetrahydropyran-4-ylamino)thiazolo[5,4-b]pyridine-2-yl)propionamide;
(R)-3-cyclopentyl-N-[5-(4-dimethylaminophenyl)thiazolo[5,4-b]pyridine-2-yl]-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide; and
4-(2-{(R)-3-cyclopentyl-2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]propionamide}thiazolo[5,4-b]pyridine-5-yl)benzoic acid
or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I), which can be used as a medicinal agent having PI3-kinase inhibiting properties. In general formula (I)

,

A denotes N, Ra denotes C1-C8alkyl, phenyl substituted with 1-2 residues selected from a group comprising halogen and C1-C6halogenalkyl, Rb denotes hydrogen, R1 denotes hydrogen or C1-C8alkyl, R2 denotes hydrogen or a substitute selected from a group comprising: C1-C8alkyl, substituted with one substitute selected from C1-C6alkoxy group, -(CO)-O-C1-C6alkyl, N(C1-C6alkyl)2; 6-member heterocycloalkyl containing a nitrogen atom as a heteroatom, substituted with 1-2 substitutes selected from an oxo group and phenyl; (5-6-member heterocycloalkyl containing 1-2 heteroatoms selected from nitrogen and oxygen)-C1-C4alkyl, optionally substituted with 1-2 substitutes independently selected from -(CO)-O-C1-C6alkyl, C1-C6alkyl, -(CO)-O-benzyl, oxo group, benzyl substituted with C1-C6alkyl, 6-member heteroaryl containing 2 nitrogen atoms as heteroatoms; phenyl which is optionally substituted with 1 substitute selected from a 6-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, optionally substituted with -(CO)-O-C1-C6alkyl, (5-6-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, substituted with C1-C6alkyl)-C1-C4alkyl, optionally substituted with an oxo group, -(C1-C4alkyl)-NR7-(CO)O-C1-C6alkyl; phenyl-C1-C5alkyl, optionally substituted with 1-2 substitutes selected from NH2, N(C1-C6alkyl)2, C1-C6alkyl, N(C1-C6alkyl)2-C1-C6alkyl, OR7, OCF3, haloC1-C6alkyl, CN, SO2R7, NR7COR8, CONH2, NR7-(CO)O-C,-C6alkyl; -(C1-C4alkyl)-NR7-(CO)O-C1-C6alkyl, 5-member heteroaryl containing 2 nitrogen atoms as heteroatoms, (5-6-member heterocycloalkyl containing 1-2 heteroatoms independently selected from nitrogen and oxygen), optionally substituted with an oxo group, (5-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms substituted with 1-3 substitutes independently selected from oxo group, C1-C6alkyl)-C1-C4alkyl, -C(O)-NH-(C3-C8cycloalkyl), -C(O)-NH-(C1-C6alkyl), -C(O)-N(C1-C6alkyl)2, COR7, NR7(CO)NR8R9; (5-6-member heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, sulphur and oxygen)-C1-C6alkyl, optionally substituted with 1-2 substitutes selected from C1-C6alkyl, C3-C8cycloalkyl, CN and OH; (9-member heteroaryl containing a nitrogen atom as a heteroatom)-C1-C4alkyl; C3-C8cycloalkyl, optionally substituted with a 5-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, substituted with an oxo group; C3-C8cycloalkyl-C1-C4alkyl, optionally substituted with 1 substitute selected from C1-C4alkyl-(CO)OR8, NR (CO)OR8; 1,3-benzodioxole-C1-C4alkyl; 1,4-benzodioxane-C1-C4alkyl; isoindoline-C1-C4alkyl substituted with 1 CO-NH2 substitute; or R1 and R2 together form a 5- or 6-member saturated ring which optionally contains an additional heteroatom selected from oxygen and nitrogen, and optionally substituted with 1-3 substitutes independently selected from OH, C1-C6alkyl, (CO)OR8, (C1-C4alkyl)-(CO)OR8, NR7(CO)OR8, -(C1-C4alkyl)-NR7(CO)OR8, NR7COR8, -(C1-C4alkyl)-NR7COR8, -NH-C(O)CF3, -CH(OH)-phenyl, NR7(CO)NR8R9, NR7(CO)CH2NR8R8, -NR7(SO2)R8, phenyl, optionally substituted C1-C6alkoxy, OH, 9-10-member bicyclic heteroaryl containing 1-2 nitrogen atoms as heteroatoms, optionally substituted with a phenyl oxo group, substituted with a hydroxy group, -CH2-isoquinoline, substituted with an oxo group, 5-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, substituted with an oxo group, -CH2-O-(phenyl, substituted with 3 substitutes independently selected from halogen and amino); or R1 and R2 together form a saturated 9-11-member spirocyclic system with 1-2 additional nitrogen heteroatoms, substituted with 1-2 substitutes independently selected from -C1-C6alkyl, OH, oxo group and phenyl; or R2 denotes a residue selected from a group of residues of general formulae:

, , , , , and , where X denotes C1-C7alkylene, Q denotes C1-C7alkylene, R3, R4 have identical or different values and denote hydrogen or a substitute selected from a group comprising C1-C8alkyl, 9-member bicyclic heteroaryl containing 2 nitrogen atoms as heteroatoms, substituted with C1-C6alkyl, phenyl substituted with C1-C4alkyl, 6-member heteroaryl containing 2 nitrogen atoms as heteroatoms, 5-member heterocyclyl containing 1 nitrogen atom as a heteroatom, (C3-C8cycloalkyl)-C1-C4alkyl-, or R3, R4 together form a 6-member saturated ring containing an oxygen atom as an additional heteroatom, R7, R8, R9 have identical or different values and denote hydrogen or a substitute selected from a group comprising C1-C8alkyl, 5-6-member heterocycloalkyl containing 1-2 heteroatoms independently selected from nitrogen and oxygen, C3-C8cycloalkyl, C1-C6haloalkyl, C3-C8cycloalkyl- C1-C4alkyl-, C1-C4alkoxy-C1-C4alkyl-.

EFFECT: high efficiency of using the disclosed compounds in preparing a medicinal agent.

10 cl, 1 tbl, 299 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

, where R1 denotes a lower alkyl; R2 denotes phenyl or a 5- or 6-member heteroaryl containing 1-2 N atoms or 1 N atom and 1 S atom as heteroatoms, which may be unsubstituted or substituted with a substitute selected from halogen or lower alkyl; R3 denotes hydrogen, phenyl or a 5-6-member heteroaryl containing 1-2 N atoms and 1 O atom as heteroatoms, which can be unsubstituted or substituted with a substitute selected from 1-2 halogen atoms, lower alkyl or a S(O)2-lower alkyl group; as well as pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, having metabotropic glutamate receptor mGluR5 antagonist properties, which contains the compound of formula (I) as active component and pharmaceutically acceptable excipients.

EFFECT: possibility of using said derivatives as mGluR5 receptor antagonists.

25 cl, 2 dwg, 1 tbl, 30 ex

FIELD: chemistry.

SUBSTANCE: described are novel substituted naphthyridines of general formula E: (radicals R1 and R3 are described in the claim), pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds, and use of the novel compounds to prepare a medicinal agent for treating or preventing malignant tumours in mammals.

EFFECT: compounds inhibit Akt acitivity, in particular, the compounds selectively inhibit one or two isoforms of Akt and can be used in medicine.

5 cl, 14 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: in formula (I) , the ring A represents 6-members aryl or 5-6-members heteroaryl containing 1-2 heteroatoms selected from nitrogen and sulphur; Q means C3-8 cycloalkyl, 5-6-members heterocycle containing 1 heteroatom selected from oxygen, nitrogen or sulphur, C1-6 alkyl or C2-6 alkenyl; the ring T represents 5, 6, 9 or 10-members heteroaryl or 9-members heterocycle optionally additionally substituted by 1-3 heteroatoms independently selected from nitrogen or sulphur. The values of other substitutes are specified in the patent claim. Also, the invention refers to methods for preparing oxime derivatives of general formula (I), to pharmaceutical compositions containing the compound of the invention as an active ingredient and to applications of the compounds of the invention in preparing a drug.

EFFECT: compounds of the invention exhibit properties of a glucokinase activator.

33 cl, 1499 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein Q together with carbon and nitrogen atoms whereto attached forms a 5-6-members monocyclic heteroaromatic ring; or Q together with carbon and nitrogen atoms whereto attached forms a 9-10-members bicyclic heterocycle; R1 and R2 independently mean hydrogen, halogen, alkyl, alkyl substituted by one or more halogen, alkoxygroup, alkoxygroup substituted by alkoxygroup, alkylthiogroup, sulphonyl, free or etherified carboxygroup, carbamoyl, sulohamoyl, morpholinyl or pyridinyl; or R2 is absent; R3 means (C3-C6)cycloalkyl; R4 means hydrogen, halogen, lower alkyl or lowest alkyl substituted by one or more halogen; R5 means (C3-C6cycloalkyl, (C6-C10) aryl, (C3-C10)heterocyclyl or (C1-C6)alkyl optionally substituted by (C1-C6)alkoxygroup, (C3-C7)cycloalkyl, (C6-C10)aryl or (C3-C10)heterocyclyl; R6 means free or etherified carboxygroup; and n is an integer equal to 1-6; or to its enanthiomer, or a mixture of its enanthiomers, or its pharmaceutically acceptable salt. Besides, the invention refers to a method of glucokinase activation in mammals, to a method of treating pathological conditions associated with glucokinase activation in mammals and impaired glucose tolerance, as well as to a pharmaceutical composition based on these compounds and to application of said compositions for preparing a drug.

EFFECT: there are produced and described new compounds which are activators and can be used as therapeutic agents for treating the glucokinase mediated pathological conditions.

31 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a derivative of 5-substituted 7-amino-[1,3]thiazolo[4,5-d]pyrimidine of formula

and its optical isomers and pharmaceutically acceptable salts where R1 represents CH3 or CH3CH2; R2 represents H, 2-F, 2-Cl, 3-F, 3-OCN3, 3-CN, 3-CF3, 3-CONH2 or 3-SO2CH3; R3 represents H or CH3; R4 represents H or CH3; and R5 represents H; or when R4 represents CH3, R5 represents H or F. Also, the invention refers to methods for producing the compounds of formula (I) and to pharmaceutical compositions exhibiting CX3CR1 receptor antagonist properties containing the compounds of formula (I).

EFFECT: production of 5-substituted 7-amino-[1,3]thiazolo[4,5-d]pyrimidine as selective CX3CR1 receptor antagonists.

15 cl, 2 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds (la) of formula applied as tyrosine kinase c-Met inhibitors. , where: LA is selected from ,

or ; RA is selected from:

or each RA2 and RA6 represents hydrogen; RA3 represents RAr; or RA3, RA4 and carbon atoms whereto attached form 6-members aryl, optionally substituted, in the amount up to 4 by independent groups RAr, or a 5-6-members heterocyclyl or heteroaryl ring containing at least one O, N or S atom; R represents -OH; RA5 represents hydrogen or RAr; LB represents a covalent bond or -N(R*)-; RB represents halogen, NH2 or C1-8aliphatic group, optionally substituted by R; a 6-10-members aryl ring; a 3-7-members carbocyclyl ring, a 5-10-members heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms, where each said aryl or heteroaryl ring is optionally substituted, in the amount up to five by independent groups RAr; R represents halogen, -R°, -SR°, Ph, optionally substituted R° or -C(O)OR°; each RAr is independently selected from halogen, -R°, -OR°, -SR°, Ph, optionally substituted in the amount up to five by independent groups -R°, -CN, -N(R°)2 or -C(O)OR°; or two adjacent groups RAr taken together, represent 1,2-methylenedixy or 1,2-ethylenedixy; each R* represents hydrogen; and each R° represents independently hydrogen, an optionally substituted C1-6aliphatic radical or an unsubstituted 5-6-members heteroaryl or heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms.

EFFECT: invention refers to pharmaceutically acceptable compositions containing the compounds under the invention, and methods of application of the compositions in treatment of various proliferative disorders.

10 cl, 4 tbl, 548 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to azole derivatives of formula I , where: A denotes S, O; W denotes -(C=O)-; X are identical or different and denote =C(-R)- or =N-; Y denotes -O- or -NR1-; R denotes hydrogen, halogen, (C1-C6)-alkyl, nitro; R1 denotes hydrogen; R2 denotes (C5-C16)-alkyl, (C1-C4)alkyl-phenyl, where phenyl can be optionally mono- or poly-substituted with (C1-C6)-alkyl; R3 denotes hydrogen; or R2 and R3 together with the nitrogen atom bearing them can form a monocyclic saturated 6-member ring system, where separate members of this ring system can be substituted with 1 group selected from the following: -CHR5-, -NR5-; R5 denotes (C1-C6)-alkyl, trifluoromethyl; and physiologically acceptable salts thereof. The invention also pertains to methods of producing said compounds and a medicinal agent based on said compounds.

EFFECT: novel compounds and a medicinal agent based on said compounds are obtained, which can be used as hormone-sensitive lipase (HSL) or endothelial lipase (EL) inhibitors.

12 cl, 11 ex

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

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: claimed invention relates to compound of formula (I), its pharmaceutically acceptable salt or solvate, in which R1 represents lower alkyl, Y represents -S(O)n-, where n equals 1 or 2, R2 represents hydrogen or lower alkyl, R1 and R2 together can form lower alkylene, R7 represents hydrogen, X represents group of formula: [formula 2], where R3, R4, R5 and R6 each independently represent hydrogen, group of formula: [formula 3] represents C5-C6-cvycloalkylene, p and q each independently equals integer number from 0 to 2, p or q is not equal 0, and Z represents optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyridasinyl, optionally substituted pyrasolyl, optionally substituted indanyl, optionally substituted benzothiazolyl, optionally substituted benzoxazolyl, optionally substituted thiazolopyridyl, optionally substituted oxazolopyridyl, optionally substituted benzimidasolyl, optionally substituted benzoxazinonyl, optionally substituted chinolyl, optionally substituted isochinolyl, optionally substituted benzoxazolinonyl, optionally substituted benzoxazolinonyl or optionally substituted ftalazinyl.

EFFECT: obtaining pharmaceutical composition, obtaining antagonistic activity with respect to receptor NPY Y5, based on said compounds.

14 cl, 1 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein Q together with carbon and nitrogen atoms whereto attached forms a 5-6-members monocyclic heteroaromatic ring; or Q together with carbon and nitrogen atoms whereto attached forms a 9-10-members bicyclic heterocycle; R1 and R2 independently mean hydrogen, halogen, alkyl, alkyl substituted by one or more halogen, alkoxygroup, alkoxygroup substituted by alkoxygroup, alkylthiogroup, sulphonyl, free or etherified carboxygroup, carbamoyl, sulohamoyl, morpholinyl or pyridinyl; or R2 is absent; R3 means (C3-C6)cycloalkyl; R4 means hydrogen, halogen, lower alkyl or lowest alkyl substituted by one or more halogen; R5 means (C3-C6cycloalkyl, (C6-C10) aryl, (C3-C10)heterocyclyl or (C1-C6)alkyl optionally substituted by (C1-C6)alkoxygroup, (C3-C7)cycloalkyl, (C6-C10)aryl or (C3-C10)heterocyclyl; R6 means free or etherified carboxygroup; and n is an integer equal to 1-6; or to its enanthiomer, or a mixture of its enanthiomers, or its pharmaceutically acceptable salt. Besides, the invention refers to a method of glucokinase activation in mammals, to a method of treating pathological conditions associated with glucokinase activation in mammals and impaired glucose tolerance, as well as to a pharmaceutical composition based on these compounds and to application of said compositions for preparing a drug.

EFFECT: there are produced and described new compounds which are activators and can be used as therapeutic agents for treating the glucokinase mediated pathological conditions.

31 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compound of formula pharmaceutically acceptable salt or solvate of a compound or salt (I), ring Q represents optionally substituted monocyclic or condensed (C6-C12)aryl or optionally substituted monocyclic or condensed heteroaryl where said substitutes are chosen from: halogen; (C1-C6)alkyl optionally substituted by 1-3 halogen atoms; (C1-C6)alkylsulphonyl; phenyl optionally substituted by 1 or 2 substitutes chosen from halogen, (C1-C6)alkyl which can be substituted by 1-3 halogen atoms, groups (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and (C1-C6)alkylthio; monocyclic or condensed heteroaryl optionally substituted by halogen; or oxo; Y1 represents a bond or -NR6-CO-, where R6 represents hydrogen, ring A represents optionally substituted a nonaromatic heterocyclyldiyl where said substitutes are chosen from (C1-C6)alkyl optionally substituted by groups hydroxy, (C1-C6)alkylamino, di(C1-C6)alkylamino, morpholino, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl; cyano; (C3-C6)cycloalkyl; (C1-C6)alkoxy; (C1-C6)alkoxy(C1-C6)alkyl; phenyl; benzyl; benzyloxymethyl; thienyl; 4-8-members monocyclic nonaromatic heterocycle having 1 or 2 heteroatoms chosen from N or O, and optionally substituted by 1 or 2 substitutes chosen from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and oxo; (C1-C6)alkylamino; di(C1-C6)alkylamino; a group of formula: -Y2Z'- represents a group of formula: [Formula 2] each R7 independently represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, each of R8 and R9 independently represents hydrogen or (C1-C6)alkyl, n is equal to an integer 0 to 3, Z1 represents a bond, -O-, -S- or-NR9 - where R9 represents hydrogen, (C1-C6)alkyl, acyl or (C1-C6)alkylsulphonyl, ring B represents optionally substituted aromatic carbocyclediyl or optionally substituted aromatic heterocyclediyl where said substitutes are chosen from (C1-C6)alkyl, halogen, (C1-C6)alkoxy and oxo; Y3 represents a bond optionally substituted (C1-C6)alkylene or (C3-C6)cycloalylene, optionally interrupted -O- or optionally substituted (C2-C6)alkenylene where said substitutes are chosen from (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen and (C1-C6)alkoxycarbonyl; Z2 represents COOR3; R3 represents hydrogen or (C1-C6)alkyl.

EFFECT: preparation of new compounds.

30 cl, 9 tbl, 944 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 2-hydroxy-4-oxo-4-phenyl-2-butenoate of benzothiazolylammonia, having hypoglycemic activity and formula:

.

EFFECT: high hypoglycemic activity.

1 cl, 1 tbl, 1 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: chemistry.

SUBSTANCE: invention relates to N-(2-benzothiazolyl)amide 2-hydroxy-4-oxo-4-(4-chlorophenyl)-2-butenoic acid of formula: , which has antimicrobial and anti-inflammatory activity along with low toxicity.

EFFECT: obtaining a compound which can be used to treat diseases associated with pathogenic microorganisms and inflammation.

1 cl, 2 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is described a compound of formula I: or its pharmaceutically acceptable salt, where R2 represents (CR3R4)n-NR5R6 and m, p, q, Ar, R1, R3, R4, R5 and R6 are those as specified in the patent claim and defined as selective 5-NT6 and/or 5-NT2A antagonists. There is also described a pharmaceutical composition containing this compound, and application thereof in preparing drugs for treating diseased conditions of central nervous system chosen from psychoses, schizophrenia, manic depressions, neural disorders, memory impairment, attention deficient syndrome, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, malnutrition and Huntington's disease.

EFFECT: preparation of the compounds which can find application in treatment of a diseased condition of central nervous system.

27 cl, 1 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula

, where R1 is a

or or or group, R2 is morpholine or OR' or N(R")2; R' is a lower alkyl, a lower alkyl substituted with a halogen, or -(CH2)n-cycloalkyl; R" is a lower alkyl; R is NO2 or SO2R'; R4 is hydrogen, hydroxy, halogen, NO2, lower alkoxy, SO2R' or C(O)OR"; R5/R6/R7 denote hydrogen, halogen, lower alkyl; X'/X1 denote CH or N, provided that X1 /X1' are not CH at the same time; X2 is O or S; n equals 0 or 1, and to their pharmaceutically active acid-addition salts. The invention also relates to a drug.

EFFECT: obtaining novel biologically active compounds which are active as glycine transporter 1 inhibitors.

11 cl, 24 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry; medicine.

SUBSTANCE: invention relates to 3-phenylpropionic acid derivatives of formula (I) as ligand of peroxisome proliferator-activated gamma-receptor (PPARγ), to their pharmaceutically acceptable salts, as well as to their application, treatment method and based on them pharmaceutical composition. Compounds can be applied for treatment and prevention of diseases mediated by peroxisome proliferator-activated gamma-receptor (PPARγ), for instance type 2 diabetes, insulin-resistance, metabolic syndrome, complications resulting from or connected with diabetes, cardio-vascular dysfunctions, atherosclerosis, obesity, cognition disturbances and lipid metabolism derangements. In general formula (I): W represents COOH or -COO-C1 - C4-alkyl group; Y represents NH; Z represents S or O; X represents O; R1 - R8 each independently represents hydrogen atom or halogen atom; A represents mono-, bi- or tri-cyclic 5-13-member heteroaryl with 1 or 2 heteroatoms selected from N, S or O, aryl, selected from phenyl and naphtyl, or -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, where heteroaryl is optionally substituted with 1-3 substituents, independently selected from group, consisting of C1-C4-alkyl, CN, phenyl halogen and phenyl, optionally substituted with 1-3 substituents, independently selected from C1-C4alkoxy, halogen and ethylenedioxy-group; and n represents integer number from 0 to 3 including; and their pharmaceutically acceptable salts.

EFFECT: increased efficiency of composition and treatment method.

20 cl, 14 dwg, 10 ex

FIELD: medicine.

SUBSTANCE: in formula (I) , the ring A represents 6-members aryl or 5-6-members heteroaryl containing 1-2 heteroatoms selected from nitrogen and sulphur; Q means C3-8 cycloalkyl, 5-6-members heterocycle containing 1 heteroatom selected from oxygen, nitrogen or sulphur, C1-6 alkyl or C2-6 alkenyl; the ring T represents 5, 6, 9 or 10-members heteroaryl or 9-members heterocycle optionally additionally substituted by 1-3 heteroatoms independently selected from nitrogen or sulphur. The values of other substitutes are specified in the patent claim. Also, the invention refers to methods for preparing oxime derivatives of general formula (I), to pharmaceutical compositions containing the compound of the invention as an active ingredient and to applications of the compounds of the invention in preparing a drug.

EFFECT: compounds of the invention exhibit properties of a glucokinase activator.

33 cl, 1499 ex

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