Sulfonamide derivatives as glycokinase activators applicable for treating insulin-dependent diabetes

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

 

The text descriptions are given in facsimile form.

1. The compound of the formula

in which Q, together with the carbon atoms and the nitrogen to which it is attached, forms a 5-6-membered monocyclic heteroaromatic ring; or Q together with the carbon atoms and the nitrogen to which it is attached, forms a 9-10-membered bicyclic a heterocycle;
R1and R2independently of one another denote hydrogen, halogen, alkyl, alkyl substituted by one or more halogen, alkoxygroup, alkoxygroup, replaced by alkoxygroup, allylthiourea, sulfonyl, free or esterified carboxypropyl, carbarnoyl, sulfamoyl, morpholinyl or pyridinyl; or
R2no;
R3means (C3-C6)cycloalkyl;
R4denotes hydrogen, halogen, lower alkyl or lower alkyl substituted by one or more halogen;
R5means (C3-C12)cycloalkyl, (C6-C10)aryl, (C3-C10)heterocyclyl or (C1-C6)alkyl, optionally substituted (C1-C6)alkoxygroup, (C3-C7)cycloalkyl, (C6-C10)aryl or (C3-C10)heterocyclyl;
R6represents free or etherified carboxypropyl; and n is an integer equal to 1 to 6;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which
R3denotes cyclopentyl;
R4denotes hydrogen;
R6represents free or etherified carboxypropyl;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

3. The compound according to claim 2 of the formula

in which R9denotes hydrogen, optionally substituted lower alkyl, lower alkenyl, cycloalkyl, aryl or arylalkyl;
Q together with the carbon atoms and the nitrogen to which it is attached, forms a 5-6-membered monocyclic heteroaromatic ring, which is selected from the group including


or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

4. The compound according to claim 3, in which
n is an integer equal to 1-3;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

5. The compound according to claim 4, in which
R9denotes hydrogen;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

6. The compound according to claim 4, in which
R1denotes hydrogen, halogen, trifluoromethyl, alkoxygroup, allylthiourea or carboxypropyl;
R2no;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

7. The connection according to claim 6, in which
Q together with the carbon atoms and the nitrogen to which it is attached, forms a 5-6-membered monocyclic heteroaromatic ring, which is selected from the group including
and
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

8. The connection according to claim 7, in which
R5means (C3-C7)cycloalkyl or (C1-C4)alkyl, substituted (C1-C6)alkoxygroup, (C3-C7)cycloalkyl, (C6-C10)aryl or ( 5-C6)heterocyclyl;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

9. The connection of claim 8, in which
R9denotes hydrogen;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

10. The connection according to claim 9, in which
(C1-C4)alkyl means methyl or ethyl;
(C1-C6)alkoxygroup denotes a methoxy group or ethoxypropan;
(C6-C10)aryl represents optionally substituted phenyl;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

11. The compound according to claim 2 of the formula

in which R9denotes hydrogen, optionally substituted lower alkyl, lower alkenyl, cycloalkyl, aryl or arylalkyl;
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 including

and
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

12. Connection by claim 11, in which
n is an integer equal to 1-3;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

13. Conn is out on 12, in which
R9denotes hydrogen;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

14. The connection section 12, in which
R1denotes hydrogen, halogen, trifluoromethyl, alkoxygroup, allylthiourea or carboxypropyl;
R2no;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

15. The connection 14, 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 including
and
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

16. The connection 15, which
R5means (C3-C7)cycloalkyl or (C1-C4)alkyl, substituted (C1-C6)alkoxygroup, (C3-C7)cycloalkyl, (C6-C10)aryl or (C5-C6)heterocyclyl;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

17. Connection P16, which
R9denotes hydrogen;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

18. The connection 17, which
(C1-C4)alkyl appears the t methyl or ethyl;
(C1-C6)alkoxygroup denotes a methoxy group or ethoxypropan;
(C6-C10)aryl represents optionally substituted phenyl;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

19. The activation of glucokinase in a mammal, which includes an introduction to the needy in the mammal a therapeutically effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt.

20. A method of treating pathological conditions associated with the activity of glucokinase in a mammal, which includes an introduction to the needy in the mammal a therapeutically effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt.

21. The method according to claim 20, which includes the introduction of a therapeutically effective amount of the compounds or its pharmaceutically acceptable salt in combination with a therapeutically effective amount of antidiabetics, lipid-lowering means, means against obesity or antihypertensives.

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

p> 23. Pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt, in combination with one or more pharmaceutically acceptable carriers, intended for the treatment of pathological conditions associated with the activity of glucokinase.

24. The pharmaceutical composition according to item 23, intended for the treatment of impaired glucose tolerance; type 2 diabetes and obesity.

25. Pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt, in combination with a therapeutically effective amount of antidiabetics, lipid-lowering means, means against obesity or antihypertensive drugs intended for the treatment of pathological conditions associated with the activity of glucokinase.

26. The pharmaceutical composition according A.25 intended for the treatment of impaired glucose tolerance, type 2 diabetes and obesity.

27. The pharmaceutical composition according to item 23 or 25, intended for use as a medicine.

28. The use of the pharmaceutical composition according to item 23 or 25 for preparing a medicinal product intended for the treatment of pathological conditions associated with the activity of glucokinase.

29. Note the persistence of the compound according to claim 1 or its pharmaceutically acceptable salts for the preparation of pharmaceutical compositions intended for the treatment of pathological conditions associated with the activity of glucokinase.

30. Use p or 29, where the pathological condition associated with the activity of glucokinase, selected from the group including impaired glucose tolerance, type 2 diabetes and obesity.

31. The compound of the formula

in which Q, together with the carbon atoms and the nitrogen to which it is attached, forms a 5-6-membered monocyclic heteroaromatic ring; or Q together with the carbon atoms and the nitrogen to which it is attached, forms a 9-10-membered bicyclic a heterocycle;
R1and R2independently of one another denote hydrogen, halogen, alkyl, alkyl substituted by one or more halogen, alkoxygroup, alkoxygroup, replaced by alkoxygroup, allylthiourea, sulfonyl, free or esterified carboxypropyl, carbarnoyl, sulfamoyl, morpholinyl or pyridinyl;
R3means (C3-C6)cycloalkyl;
R4denotes hydrogen, halogen, lower alkyl or lower alkyl substituted by one or more halogen;
R5denotes hydrogen, (C3-C12)cycloalkyl, (C6-C10)aryl, (C3-C10)heterocyclyl or (C1-C6)alkyl, optionally substituted by carboxypropyl, (C1-C6)alkoxygroup, (C3-C 7)cycloalkyl, (C6-C10)aryl or (C3-C10)heterocyclyl;
R6indicates free or verified carboxypropyl; and
n is an integer equal to 1 to 6;
or its enantiomer, or a mixture of its enantiomers or its pharmaceutically acceptable salt.

32. Connection p selected from the group including:
3-(benzyl{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}amino)propionic acid;
3-[{4-[2-cyclopentyl-1-([1,3,4]thiadiazole-2-ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-(benzofuran-2-ylmethyl-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}amino)propionic acid;
3-({4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}pyridine-2-ylmethylamino)propionic acid;
3-({4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}oxazol-2-ylmethylamino)propionic acid;
3-[{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(tetrahydrofuran-2-ylmethyl)amino]propionic acid;
3-({4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}thiophene-2-ylmethylamino)propionic acid;
4-[((2-carboxyethyl)-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-yl who carbamoyl)ethyl]benzazolyl}amino)methyl]benzoic acid;
3-(cyclohexylmethyl-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}amino)propionic acid;
3-[{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(5-methylfuran-2-ylmethyl)amino]propionic acid;
3-[{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(2,5-dimethylfuran-3-ylmethyl)amino]propionic acid;
({4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}furan-2-ylmethylamino)acetic acid;
3-({4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}isopropylamino)propionic acid;
3-[{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(1,5-dimethyl-1H-pyrazole-3-ylmethyl)amino]propionic acid;
3-[{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(5-methylisoxazol-3-ylmethyl)amino]propionic acid;
3-[{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(tetrahydropyran-4-ylmethyl)amino]propionic acid;
3-[{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b] pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(4-terbisil)amine is]propionic acid;
3-({4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}cyclopropanemethylamine)propionic acid;
({4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}methylamino)acetic acid;
3-({4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}methylamino)propionic acid;
3-[{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(tetrahydropyran-4-yl)amino]propionic acid;
3-(cyclohexyl{4-[(R)-2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}amino)propionic acid;
3-[{4-[(R)-2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(4-methoxybenzyl)amino]propionic acid;
({4-[(R)-2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}methylamino)acetic acid;
3-[{4-[(R)-2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(2-isopropoxyphenyl)amino]propionic acid;
3-({4-[(R)-2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}thiazol-2-ylmethylamino)propionic acid;
3-[{4-[2-cyclopentyl-1-(5-herperidin-2-ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[(R)-2-cyclopentyl-1-(pyrimidine-2-ylcarbonyl)ethyl]Benz is sulfonyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[(R)-2-cyclopentyl-1-(1-methyl-1H-pyrazole-3-ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[(R)-2-cyclopentyl-1-(pyrimidine-4-ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[(R)-2-cyclopentyl-1-(4,5-dimethylthiazol-2-ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[(R)-2-cyclopentyl-1-(4,5,6,7-tetrahydroindazole-2-ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[(R)-2-cyclopentyl-1-(pyrazin-2-ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[(R)-2-cyclopentyl-1-(6-fermentation-2-ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{3-[(R)-1-(5-chloropyridin-2-ylcarbonyl)-2-cyclopentylmethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[(R)-1-(5-chloropyridin-2-ylcarbonyl)-2-cyclopentylmethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[(R)-1-(5-chlorothiazole-2-ylcarbonyl)-2-cyclopentylmethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[(R)-1-(5-bromothiazole[5,4-b]pyridine-2-ylcarbonyl)-2-cyclopentylmethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[2-cyclopentyl-1-(5-methylsulfonylmethane[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionanilide;
3-[{4-[2-cyclopentyl-1-(5-methysulfonylmethane[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[(R)-1-(5-chlorination-2-ylcarbonyl)-2-cyclopentylmethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[2-cyclopentyl-1-(thiazolo[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[(R)-2-cyclopentyl-1-(5-methylsulfonylmethane[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[(R)-1-(5-chlorothiazole [5,4-b] pyridine-2-ylcarbonyl)-2-cyclopentylmethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[(4-{(R)-2-cyclopentyl-1-[5-(2-methoxyethanol)thiazolo[5,4-b]pyridine-2-ylcarbonyl]ethyl}benzazolyl)-(2-methoxyethyl)amino]propionic acid;
3-[{4-[(R)-2-cyclopentyl-1-(5-morpholine-4-iltiazem[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[(4-{(R)-2-cyclopentyl-1-[5-(2-methoxyethoxy)thiazolo[5,4-b]pyridine-2-ylcarbonyl]ethyl}benzazolyl)-(2-methoxyethyl)amino]propionic acid;
3-[{4-[(R)-2-cyclopentyl-1-(5-utilizalo[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-{{4-[(R)-1-(5-chlorothiazole[5,4-b]pyridine-2-ylcarbonyl)-2-cyclopentylmethyl]benzazolyl}-[(R)-1-(tetrahydrofuran-2-yl)methyl]amino}about the IP acid;
3-(benzyl{4-[(R)-1-(5-chlorothiazole[5,4-b]pyridine-2-ylcarbonyl)-2-cyclopentylmethyl]benzazolyl}amino)propionic acid;
3-[{4-[(R)-2-cyclopentyl-1-(5-portasilo[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[(R)-1-(5-chlorothiazole [5,4-b]pyridine-2-ylcarbonyl)-2-cyclopentylmethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-{{4-[(R)-1-(5-chlorothiazole[5,4-b]pyridine-2-ylcarbonyl)-2-cyclohexylethyl]benzazolyl}-[(R)-1-(tetrahydrofuran-2-yl)methyl]amino}propionic acid;
3-(benzyl{4-[(R)-1-(5-chlorothiazole[5,4-b]pyridine-2-ylcarbonyl)-2-cyclohexylethyl]benzazolyl}amino)propionic acid;
ethyl ester of 2-[(R)-2-(4-{(2-carboxyethyl)-[(R)-1-(tetrahydrofuran-2-yl)methyl]sulfamoyl}phenyl)-3-cyclopentylpropionyl]benzothiazole-6-carboxylic acid;
2-[(R)-2-(4-{(2-carboxyethyl)-[(R)-1-(tetrahydrofuran-2-yl)methyl]sulfamoyl}phenyl)-3-cyclopentylpropionyl]benzothiazole-6-carboxylic acid;
3-[{4-[(R)-1-(5-chlorothiazole[5,4-b]pyridine-2-ylcarbonyl)-2-cyclohexylethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[(R)-2-cyclopentyl-1-(5-pyridin-4-iltiazem[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
tert-butyl ester 3-[{4-[(R)-1-(5-chlorothiazole[5,4-b]pyridine-2-ylcarbonyl)-2-cyclopentylmethyl]benzazolyl}-(2-methoxyethyl)amino]Rodionovo acid;
Bentley ester 3-[{4-[(R)-1-(5-chlorothiazole[5,4-b]pyridine-2-ylcarbonyl)-2-cyclopentylmethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[(4-{(S)-2-cyclopentyl-1-[5-(2-methoxyethanol)thiazolo[5,4-b]pyridine-2-ylcarbonyl]ethyl}benzazolyl)-(2-methoxyethyl)amino]propionic acid;
3-(carboxymethyl-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}amino)propionic acid;
2-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzosulfimide}-2-methylpropionic acid;
mono-[2-({4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}methylamino)ethyl]ester of succinic acid;
(S)-2-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzosulfimide}propionic acid;
3-((2-carboxyethyl)-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}amino)propionic acid;
{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzosulfimide} acetic acid;
4-{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzosulfimide} butyric acid;
(carboxymethyl{4-[2-cyclopentyl-1-(5-methoxythiazole[5,4-b]pyridine-2-ylcarbonyl)ethyl]benzazolyl}amino)acetic acid;
3-[{4-[2-cyclopentyl-1-(5-cryptomaterial[5,4-b]pyridine--ylcarbonyl)ethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{2-chloro-4-[1-(5-chlorothiazole[5,4-b]pyridine-2-ylcarbonyl)-2-cyclopentylmethyl]benzazolyl}-(2-methoxyethyl)amino]propionic acid;
3-[{4-[2-cyclopentyl-1-(5-utilizalo[5,4-b]pyridine-2-ylcarbonyl)ethyl]-2-trifloromethyl}-(2-methoxyethyl)amino]propionic acid;
or its pharmaceutically acceptable salt.



 

Same patents:

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: 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: invention relates to organic chemistry and specifically to novel biologically active substances of the class of complex compounds of N-heterylamides of 4-aryl-2,4-dioxobutanoic acids. The invention discloses bis{3-phenyl-1-[2-(5-methyl-1,3,4-thiadiazolyl)]carboxamido-1,3-propanedionato}manganese having anti-inflammatory and analgesic activity and formula: .

EFFECT: high output of compounds with pronounced anti-inflammatory and analgesic activity, as well as low toxicity.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to N-[2-(5-ethyl-1,3,4-thiadiazolyl)]amide of 2-(2-hydroxyphenyl)-2-oxoethane acid, which has anti-inflammatory and analgesic activity, of formula: .

EFFECT: compound has low toxicity.

1 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to bis{3-phenyl-1-[2-(5-ethyl-1,3,4-thiadiazol or carboxamido-1,3-propanedionato}cadmium, possessing hypoglycemic activity, of formula: .

EFFECT: compound has low toxicity.

1 tbl, 1 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2,5-diamino-1,3,4-triazole. Method involves interaction at heating of dithiourea with hydrogen peroxide in its concentration 24-26% and excess for 0.04-0.18 g-mole followed by decomposition of hydrogen peroxide excess with gaseous hydrogen sulfide up to onset of detecting sulfide ions in the solution. Proposed method provides preparing the end product with the yield 79-98% being without formation of colored by-side substances.

EFFECT: improved method of synthesis.

1 tbl

The invention relates to new derivatives of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula I, in which R1means a hydrogen atom, a C1-4alkyl group or phenyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom, hydroxy-group, nitro group, WITH1-4alkoxygroup, (C1-4alkyl) amino and di(C1-4alkyl)amino group; or a group of formula (a) Z means a hydrogen atom or a C1-4alkoxygroup, R0means a group of the formula Alk-NR4R5where Alk is alkalinous group having a straight or branched C1-6chain, one of R2and R3is amino and the other is an amino group or a 5-6-membered saturated heterocyclic group containing one or two atom(s) of nitrogen and/or oxygen and attached via its nitrogen atom, and the specified heterocyclic group may be substituted WITH1-4alkyl group, phenyl group or kalogeropoulou group, or the last of the R2and R3is a group of the formula - SR

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

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