Indole derivatives, methods of obtaining them (versions), intermediate compounds used for obtaining them, pharmaceutical composition containing them, and their use in treating conditions, related to glycogen-synthase-kinase-3

FIELD: chemistry.

SUBSTANCE: new compounds with formula Ia are proposed, where: P represents pyridine or pyrimidine; R1 represents hydrogen; R2 is chosen from halogen, nitro, C0-6alkylheteroaryl, (CO)OR4, trifluoromethyl, C0-6alkylcyano, C0-6alkylNR4R5, OC1-6alkylNR4R5, C0-6alkylCONR4R5, C0-6alkyl(SO2)NR4R5 and X1R6 group, where X1 represents a direct link; R6 represents a 5- or 6-member heterocyclic group, containing one or two heteroatoms, independently chosen from N, O, and S, for which the given heterocyclic group can be unsaturated and can be substituted with by one substitute, chosen from W; m equals 0, 1, or 2; R3 is chosen from CO(OR4), C0-6alkylNR4R5, C0.6alkylCONR4R5, OC1-6alkylNR4R5 C1-6alkyl(SO2)NR4R5; n equals 1 or 2; R4 is chosen from hydrogen, C1-6alkyl; R5 is chosen from hydrogen, C1-6 alkyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6alkylheteroaryl and C1-6alkylNR14R15 or R4 and R5 together can form a 4-, 5-, 6- or 7-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O, where the given heterocyclic group can be substituted by group Y; and where any C1-6alkyl, indicated in defining R2-R5, can be substituted with one or more one Z group; R14 and R15 together can form a 5-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O; W and Z are independently chosen from halogen, CN, OR16, C1-6alkyl, trifluoromethyl, trifluoromethoxy, 5-member heterocyclic group, containing one heteroatom, independently chosen from N, for which the given heterocyclic group can be substituted with group Y; Y is chosen from oxo, halogen, C1-6alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where the phenyl and C0-6alkylaryl groups can be substituted with nitro, trifluoromethyl; R16 and R17 are independently chosen from hydrogen and C1-6alkyl, or where R16 and R17 together can form a 5-member heterocyclic group, containing one heteroatom, chosen from N; in form of a free base or pharmaceutical salt. Formula Ia compounds have inhibiting effect to glycogen-synthase-kinase-3 (GSK3). The invention also relates to the method of obtaining the proposed compounds and to new intermediate compounds, used in them, pharmaceutical compositions, containing the given therapeutically active compounds, and use of the given active compounds in therapy for treating conditions, related to GSK3.

EFFECT: new method of obtaining indole derivatives.

33 cl, 1 tbl, 112 ex

 

The text descriptions are given in facsimile form.

1. The compound of formula Ia:

where

R represents a pyridine or pyrimidine;

R1represents hydrogen;

R2selected from halogen, nitro, C0-6alkylglycerol, (CO)OR4, trifloromethyl,0-6alkylene, C0-6NR4R5OS1-6NR4R5With0-6CONR4R5With0-6alkyl(SO2)NR4R5group and X1R6where X1represents a direct bond;

R6represents 5 - or 6-membered heterocyclic group containing one or two heteroatoms, independently selected from N, O and S, and this heterocyclic group can be unsaturated and may be substituted by one Deputy, selected from W;

m is 0, 1 or 2;

R3selected from CO(OR4)0-6NR4R5C0-6CONR4R5OS1-6NR4R5and C0-6alkyl(SO2)NR4R5;

n is 1 or ;

R4selected from hydrogen, C1-6of alkyl;

R5selected from hydrogen, C1-6of alkyl, C0-6alkyls3-6cycloalkyl,0-6alkylaryl,0-6alkylglycerol and C1-6NR14R15or R4and R5together may form a 4-, 5-, 6 - or 7-membered heterocyclic group containing one or more than one heteroatom independently selected from N and O, where this heterocyclic group may be substituted by a group Y; and where any1-6alkyl specified in the definition of R2-R5may be substituted by one or more than one group Z;

R14and R15together may form a 5-membered heterocyclic group containing one or more than one heteroatom independently selected from N and O;

W and Z are independently selected from halogen, CN, OR16With1-6of alkyl, trifloromethyl, triptoreline, 5-membered heterocyclic group containing one heteroatom independently selected from N, and this heterocyclic group may be substituted by a group Y;

Y is selected from oxo, halogen, C1-6of alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where phenyl and C0-6alcylaryl group may be substituted by nitro, trifluoromethyl;

R16and R17n is dependent selected from hydrogen and C 1-6the alkyl, or where R16and R17together may form a 5-membered heterocyclic group containing one heteroatom selected from N;

in the form of a free base or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R is a pyridine.

3. The compound according to any one of claims 1 and 2, where

R5represents a C1-6NR14R15;

R4selected from hydrogen, C1-6the alkyl, or where R4and R5together may form a 5 - or 6-membered heterocyclic group containing one or more than one heteroatom independently selected from N and O, where this heterocyclic group may be substituted by a group Y;

and where R14and R15together may form a 5-membered heterocyclic group containing one or more than one heteroatom independently selected from N and O;

Y is selected from C1-6of alkyl, C0-6alkylaryl, NR16R17, phenyl, where phenyl may be substituted by a nitro-group and trifluoromethyl;

where R16and R17together may form a 5-membered heterocyclic group containing one heteroatom selected from n

4. The compound according to any one of claims 1 and 2, where R is a pyridine; R2represents CN; R3represents a C0-6NR 4R5; where R4and R5together may form a 5 - or 6-membered heterocyclic group containing one or more than one heteroatom independently selected from N and O.

5. The compound according to claim 4, where R4and R5together may form a 6-membered heterocyclic group containing one or more than one heteroatom independently selected from N and O.

6. The compound according to claim 1, which is a

2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indol-5-carbonitrile;

2-Hydroxy-3-[6-(2-morpholine-4-ylethoxy)pyrimidine-4-yl]-1H-indol-5-carbonitrile;

3-(5-{[3-(dimethylamino)pyrrolidin-1-yl]methyl}pyridine-2-yl)-2-hydroxy-1H-indol-5-carbonitrile;

2-Hydroxy-3-{5-[(4-methylpiperidin-1-yl)methyl]pyridine-2-yl}-1H-indol-5-carbonitrile;

3-[5-(Azetidin-1-ylmethyl)pyridine-2-yl]-2-hydroxy-1H-indol-5-carbonitrile;

2-Hydroxy-3-[5-(piperidine-1-ylmethyl)pyridine-2-yl]-1H-indol-5-carbonitrile;

3-[5-(Morpholine-4-ylcarbonyl)pyridine-2-yl]-5-nitro-1H-indole-2-ol;

2-Hydroxy-3-[5-(morpholine-4-ylsulphonyl)pyridine-2-yl]-1H-indol-5-carbonitrile;

in the form of a free base or its pharmaceutically acceptable salt.

7. The compound according to claim 1, which is a

Hydrochloride of 2-hydroxy-3-{4-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indol-5-carbonitrile;

Guide klorid 2-hydroxy-3-{5-[(4-methylpiperazin-1-yl)methyl]pyridine-2-yl}-1H-indol-5-carbonitrile;

Hydrochloride of 2-hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridine-2-yl}-1H-indol-5-carbonitrile;

Hydrochloride of 2-hydroxy-3-[5-(pyrrolidin-1-ylmethyl)pyridine-2-yl]-1H-indol-5-carbonitrile;

Hydrochloride of 2-hydroxy-3-{5-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridine-2-yl}-1H-indol-5-carbonitrile;

Hydrochloride of 2-hydroxy-3-{5-[(4-pyrrolidin-1-reparacin-1-yl)methyl]pyridine-2-yl}-1H-indol-5-carbonitrile;

Hydrochloride 3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridine-2-yl}-1H-indole-2-ol;

The hydrochloride of 6-chloro-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridine-2-yl}-1H-indole-2-ol;

The hydrochloride of 6-bromo-3-[5-(morpholine-4-ylmethyl)pyridine-2-yl]-1H-indole-2-ol;

Hydrochloride, 5-bromo-3-[5-(morpholine-4-ylmethyl)pyridine-2-yl]-1H-indole-2-ol;

Hydrochloride 3-fluoro-3-[5-(morpholine-4-ylmethyl)pyridine-2-yl]-2-oxoindole-6-carbonitrile;

Hydrochloride 3-{5-[(4-benzylpiperazine-1-yl)sulfonyl]pyridine-2-yl}-2-hydroxy-1H-indol-5-carbonitrile;

Hydrochloride of 2-hydroxy-3-{5-[(4-isopropylpiperazine-1-yl)sulfonyl]pyridine-2-yl}-1H-indol-5-carbonitrile;

Hydrochloride 3-{5-[(4-ethylpiperazin-1-yl)sulfonyl]pyridine-2-yl}-2-hydroxy-1H-indol-5-carbonitrile;

Hydrochloride 3-[5-(morpholine-4-ylmethyl)pyridine-2-yl]-5-Tien-2-yl-1H-indole-2-ol;

Hydrochloride 5-(2-furyl)-3-[5-(morpholine-4-ylmethyl)pyridine-2-yl]-1H-indole-2-ol;

Hydrochloride 3-{Brom-5-[(4-methylpiperazin-1-yl)sulfonyl]pyridine-2-yl}-5-nitro-1H-indole-2-ol;

Hydrochloride 3-[5-(morpholine-4-ylmethyl)pyridine-2-yl]-5-(trifluoromethyl)-1H-indole-2-ol;

The hydrochloride of 6-(2-hydroxy-5-nitro-1H-indol-3-yl)-N-(2-morpholine-4-retil)nicotinamide;

The hydrochloride of 6-(2-hydroxy-5-nitro-1H-indol-3-yl)-N-methyl-N-(1-methylpiperidin-4-yl)nicotinamide;

Hydrochloride 5-nitro-3-{5-[(4-pyrrolidin-1-reparacin-1-yl)carbonyl]pyridin-2-yl}-1H-indole-2-ol;

Hydrochloride 3-(5-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}pyridine-2-yl)-5-nitro-1H-indole-2-ol;

Fumarate 6-(2-hydroxy-5-nitro-1H-indol-3-yl)-N-(2-pyrrolidin-1-retil)nicotinamide;

Fumarate 6-(5-cyano-2-hydroxy-1H-indol-3-yl)-N-(2-pyrrolidin-1-retil)nicotinamide;

The hydrochloride of 6-(5-cyano-2-hydroxy-1H-indol-3-yl)-N-methyl-N-(2-pyrrolidin-1-retil)pyridine-3-sulfonamida;

Fumarate 2-hydroxy-3-{5-[(4-methyl-1,4-diazepan-1-yl)sulfonyl]pyridine-2-yl}-1H-indol-5-carbonitrile;

Hydrochloride 3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridine-2-yl}-5-(2-methyl-1,3-thiazol-4-yl)-1H-indole-2-ol;

Fumarate 3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridine-2-yl}-5-(1,3-thiazol-4-yl)-1H-indole-2-ol;

Hydrochloride 3-[5-(morpholine-4-ylmethyl)pyridine-2-yl]-5-nitro-1H-indole-2-ol;

or in the form of another pharmaceutically acceptable salt or free base.

8. The compound according to claim 1, which is a

2-Hydroxy-3-{5-[(4-phenylpiperazin-1-yl)methyl]p is ridin-2-yl}-1H-indol-5-carbonitrile in the form of a free base or its pharmaceutically acceptable salt.

9. The compound according to claim 1, which is 2-Hydroxy-3-[5-({4-[2-nitro-4-(trifluoromethyl)phenyl]piperazine-1-yl}methyl)pyridine-2-yl]-1H-indol-5-carbonitrile in the form of a free base or its pharmaceutically acceptable salt.

10. The compound according to claim 1, which is a

2-Hydroxy-3-[5-(morpholine-4-ylmethyl)pyridine-2-yl]-1H-indol-5-carbonitrile in the form of a free base or its pharmaceutically acceptable salt.

11. The compound according to claim 1, which is a

3-[5-(Morpholine-4-ylmethyl)pyridine-2-yl]-5-pyridin-3-yl-1H-indole-2-ol in the form of a free base or its pharmaceutically acceptable salt.

12. The compound according to claim 1, which is a

3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridine-2-yl}-5-(1,3-oxazol-5-yl)-1H-indole-2-ol in the form of a free base or its pharmaceutically acceptable salt.

13. The compound according to claim 1, which is a

The hydrochloride of 6-(5-cyano-2-hydroxy-1H-indol-3-yl)-N-(2-pyrrolidin-1-retil)pyridine-3-sulfonamida;

Hydrochloride of 2-hydroxy-3-[5-(morpholine-4-ylmethyl)pyridine-2-yl]-1H-indol-5-carbonitrile;

Hydrochloride of 2-hydroxy-3-[5-(morpholine-4-ylmethyl)pyridine-2-yl]-1H-indole-6-carbonitrile;

Hydrochloride 5,6-dibromo-3-[5-(morpholine-4-ylmethyl)pyridine-2-yl]-1H-indole-2-ol;

Hydrochloride of 2-hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridine-2-yl}-1H-Indo) - Rev.-6-carbonitrile;

Fumarate 3-{5-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-5-nitro-1H-indole-2-ol;

Fumarate 3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridine-2-yl}-5-(1,3-thiazol-4-yl)-1H-indole-2-ol;

Hydrochloride 3-[5-(morpholine-4-ylmethyl)pyridine-2-yl]-5-nitro-1H-indole-2-ol;

or in the form of another pharmaceutically acceptable salt or free base.

14. The compound according to claim 1, having inhibitory effect compared to the glycogen-synthase-kinase-3.

15. Pharmaceutical composition having inhibitory effect compared to the glycogen-synthase-kinase-3, comprising as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 13, together with pharmaceutically acceptable carriers or diluents.

16. The use of compounds according to any one of claims 1 to 13 in the manufacture of a medicinal product for the prevention and/or treatment of conditions associated with glycogen-synthase-kinase-3.

17. The use of compounds according to any one of claims 1 to 13 in the manufacture of a medicinal product for the prevention and/or treatment of cognitive disorders.

18. The use of compounds according to any one of claims 1 to 13 in the manufacture of a medicinal product for the prevention and/or treatment of dementia, Alzheimer's disease, Parkinson's disease, fronto-temporal dementia Parkinsonism type complex of GUAM island, amyotrophy the definition lateral sclerosis and dementia in Parkinson's disease (Parkinson dementia complex of Guam), AIDS-dementia, diseases associated with the neurofibrillary pathology of nodes, and dementia boxers.

19. Application connection p, where the disease is a disease of Alzheimer's.

20. The use of compounds according to any one of claims 1 to 13 in the manufacture of a medicinal product for the prevention and/or treatment of amyotrophic lateral sclerosis, corticobasal degeneration, down syndrome, Huntington's disease, postentsefaliticheskom parkinsonism, progressive supranuclear paralysis, disease of the Peak, disease, Niemann-pick, stroke, head trauma and other chronic neurodegenerative diseases, bipolar disease, affective disorders, depression, schizophrenia, and hair loss.

21. The use of compounds according to claim 20, where the disease is a bipolar disease.

22. The use of compounds according to claim 20, where the disease is a schizophrenic.

23. The use of compounds according to any one of claims 1 to 13 in the manufacture of a medicinal product for the prevention and/or treatment predementia States, mild impairment of cognitive function, age-related weakening of memory, age-related cognitive deterioration, the deterioration of cognitive functions without dementia (cognitive his or her no dementia, mild cognitive decline, mild neurocognitive decline, senile forgetfulness, memory loss and cognitiveneuroscience, vascular dementia, dementia with calves Levi, frontotemporal dementia and androgenetic alopecia.

24. The method of obtaining the compounds of formula Ia according to claim 1, wherein: the compound of formula V, where L1represents a leaving group such as halogen, for example fluorine, chlorine or bromine, and R, R3n are as defined in claim 1, is subjected to the interaction with the compound of the formula where R1, R2and m are as defined in claim 1, with the formation of compounds of formula Ia;

in an appropriate solvent at a temperature between 10 and 150°C.

25. The method of obtaining the compounds of formula Ia according to claim 1, wherein the compound of formula XXV, where halo is a halogen, for example fluorine, chlorine or bromine, and R4, R5are as defined in claim 1, is subjected to the interaction with the compound of the formula where R1, R2and m are as defined in claim 1, with the formation of compounds of formula Ia;

in an appropriate solvent at a temperature between 10 and 150°C.

26. The method of obtaining the compounds of formula Ia according to claim 1, wherein the compound of formula XXVII, where R1, R2and m are as defined in claim 1, is subjected to the interaction with the corresponding amine HNR4R5where R4, R5 are as defined in claim 1, with the formation of compounds of formula Ia;

implemented:

1) by reacting the compounds of formula XXVII with an appropriate amine R4R5NH in a suitable solvent in the presence of a suitable reagent under the reaction temperature between 0°and forming temperature phlegmy, or

2) by reacting the compounds of formula XXVII with an appropriate amine R4R5NH without solvent or in a suitable solvent, with a suitable base or without him at temperatures between -20 and +150°C.

27. The method of obtaining the compounds of formula Ia according to claim 1, wherein the N-oxide of the compound of formula XXVIII, where R1, R2, R4, R5and m are as defined in claim 1, restore with the formation of compounds of formula Ia;

using a suitable reagent in a suitable solvent at a temperature between 0 and +100°C.

28. The compound of formula XXVII

where R1represents hydrogen; R2selected from halogen, nitro, trifloromethyl, OS1-6NR4R5With0-6alkylene,0-6CONR4R5With0-6alkyl(SO2)NR4R5C0-6NR4 R5group and X1R6where X1represents a direct bond,

R4selected from hydrogen, C1-6of alkyl;

R5selected from C1-6NR14R15or R4and R5together may form a 4-, 5-, 6 - or 7-membered heterocyclic group containing one or more than one heteroatom independently selected from N and O, where this heterocyclic group may be substituted by a group Y; and where any1-6alkyl specified in the definition of R2-R5may be substituted by one or more than one group Z;

R6represents 5 - or 6-membered heterocyclic group containing one or two heteroatoms, independently selected from N, O and S, and this heterocyclic group can be unsaturated and may be substituted by one Deputy, selected from W; m is 0, 1 or 2;

R14and R15together may form a 5-membered heterocyclic group containing one or more than one heteroatom independently selected from N and O;

W and Z are independently selected from halogen, CN, OR16With1-6of alkyl, trifloromethyl, triptoreline, 5-membered heterocyclic group containing one heteroatom independently selected from N, and this heterocyclic group may be substituted by a group Y;

Y is selected from oxo, halogen, C1-6of alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where phenyl and C0-6alcylaryl group may be substituted by nitro, trifluoromethyl;

R16and R17independently selected from hydrogen and C1-6the alkyl, or where R16and R17together may form a 5-membered heterocyclic group containing one heteroatom selected from n

29. Connection p, where R1represents hydrogen; R2selected from nitro and cyano; m is 1.

30. Connection p, which is a

Ethyl-6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinate;

Ethyl-6-(2-hydroxy-5-cyano-1H-indol-3-yl)nicotinate,

in free base form or its salt.

31. The compound of formula XXVIII

where R1represents hydrogen;

R2selected from halogen, nitro, trifloromethyl, OC1-6NR4R5With0-6alkylene, C0-6CONR4R5C0-6alkyl(SO2)NR4R5With0-6NR4R5group and X1R6where

X1represents a direct bond,

R4selected from hydrogen, C1-6of alkyl;

R5selected from C1-6NR14R15or R4The R 5together may form a 4-, 5-, 6 - or 7-membered heterocyclic group containing one or more than one heteroatom independently selected from N and O, where this heterocyclic group may be substituted by a group Y;

and where any C1-6alkyl specified in the definition of R2- R5may be substituted by one or more than one group Z;

R6represents 5 - or 6-membered heterocyclic group containing one or two heteroatoms, independently selected from N, O and S, and this heterocyclic group can be unsaturated and may be substituted by one Deputy, selected from W;

m is 0, 1 or 2;

R14and R15together may form a 5-membered heterocyclic group containing one or more than one heteroatom independently selected from N and O;

W and Z are independently selected from halogen, CN, OR16C1-6of alkyl, trifloromethyl, triptoreline, 5-membered heterocyclic group containing one heteroatom independently selected from N, and this heterocyclic group may be substituted by a group Y;

Y is selected from oxo, halogen, C1-6of alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where phenyl and C0-6alcylaryl groups can be possible semestinya, by trifluoromethyl;

R16and R17independently selected from hydrogen and C1-6the alkyl, or where R16and R17together may form a 5-membered heterocyclic group containing one heteroatom selected from n

32. Connection p, where R1represents hydrogen; R2is a group of X1R6where X1represents a direct bond; R6represents 5 - or 6-membered heterocyclic group containing one or two heteroatoms, independently selected from N, O and S; m is 1.

33. Connection p, which represents:

3-[5-(Morpholine-4-ylmethyl)-1-oxidability-2-yl]-5-pyridin-3-yl-1H-indole-2-ol;

3-[5-(Morpholine-4-ylmethyl)-1-oxidability-2-yl]-5-Tien-2-yl-1H-indole-2-ol;

5-(2-Furyl)-3-[5-(morpholine-4-ylmethyl)-1-oxidability-2-yl]-1H-indole-2-ol;

in free base form or its salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula: , where R is -(CH2)n-A, where A: where each of B and C independently represent phenyl or phenyl substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl) and -NO2; or n equals an integer from 0 to 3; n1 equals an integer from 1 to 3; n2 equals an integer from 0 to 4; n3 equals an integer from 0 to 3; n4 equals an integer from 0 to 2; X1 is chosen from a chemical bond -S-, -S(O)2-, -NH-, -NHC(O)- and -C=C-, R1 is chosen from C1-C6alkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, tetrahydropyranyl, CN, -N(C1-C6alkyl)2, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphtyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperizinyl, thiazolydinyl, thiomopholinyl, tetrazolyl, benzoxazolyl, imidazolidine-2-thionyl, 7,7-dimethylbicyclo[2.2.1]heptane-2-onyl, benzo[1.2.5]oxadiazolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl and pyrrolyl, each of which can be optionally substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2N(C1-C3alkyl)2, -COOH, -CH2-COOH, pyridyl, 2-methylazolyl, morpholino, 1-chloro-2-methylpropyl, phenyl, (optionally substituted with one or more halogens), benzyloxy, and , X2 selected from -O-, -CH2-, -S-, -SO-, -SO2-, -NH- and , R2 represents a ring group, chosen from a phenyl or thienyl group. Each ring group is substituted with a group with formula -(CH2)n4-CO2H; and besides that, the ring group can optionally be substituted with 1 or 2 extra substitutes, independently chosen from halogen, - C1-C6alkyl and -C1-C6alkoxy; R3 is chosen from H, halogen and -NO2; R4 is chosen from H, halogen and morpholino; or its salt form, used in pharmaceuticals. The invention also relates to pharmaceutical compositions, to methods of treatment, and to compounds with formula (A).

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on them, which have inhibiting effect on cytosolic phospholipase A2.

45 cl, 300 ex

Amid derivative // 2336273

FIELD: chemistry.

SUBSTANCE: invention relates to amid derivatives of formula (I), method of disease treatment and pharmaceutical composition based on them. Compounds can be applied in treatment of different herpes virus infections. In general formula (I) , Z: 1,2,4-oxydiazol-3-yl, 4-oxazolyl, 1,2,3-triazol-2-yl or 2-pyridyl, A: phenyl, which can have a substitute (substitutes) selected from group, including lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene -OH, CN, OH, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2 ,NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, O-lower alkylene- NH2, O-lower alkylene-NH-lower alkyl and O-lower alkylene-N(lower alkyl)2; heteroaryl, representing monocyclic 6-member ring, which contains nitrogen atom as heteroatom or bicyclic 9-member ring, containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which can have a substitute (substitutes), selected from lower alkyl; or phenyl group, condensed with saturated 5-member hydrocarbon cycle; or phenyl group, condensed with saturated 5-member heterocyclic cycle, which contains 1-2 heteroatoms, selected from nitrogen and/or oxygen, which can have a substitute (substitutes), selected from group, including lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, on condition, that aryl group, condensed with saturated hydrocarbon cycle or aryl group, condensed with saturated heterocyclic cycle is bound with nitrogen atom through carbon atom in aromatic cycle, X: CO, R3: C3-C6cycloalkyl, which can have a substitute (substitutes), selected from group, which includes oxo, OH, halogen, CN, O-lower alkyl, -C(O)-NH2, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, lower alkylene-OH, lower alkylene-O-lower alkyl; aryl, selected from phenyl, naphtyl, which can have a substitute (substitutes), selected from halogen; pyridyl; 9-member bicyclic heteroaryl, containing 1-3 heteroatoms, selected from S, N, O; or saturated heterocyclic group, representing monocyclic 6-member group, which contains 1-2 heteroatoms selected from S, SO, SO2, N, O, which can have a substitute (substitutes), selected from halogen.

EFFECT: obtaining amid derivatives that can be applied for treating various herpes virus infections.

17 cl, 26 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method for obtaining 5-{2-[5-{2-[1,3,5-ditiazinan-5-il]ethyl}-4-methyl-1,3,5-tiadiazinan-3-il]ethyl} 1,3,5-ditiazinan with formula including interaction of methyltriethyltetaraamin with water solution of formaldehide saturated with hydrogen sulphide. The given compound can find application as selective sorbents and extragents of precious metals and special reagents for inhibition of vital functions of bacteria in various technological media.

EFFECT: efficient method for obtaining 5-{2-[5-{2-[1,3,5-ditiazinan-5-il]ethyl}-4-methyl-1,3,5-tiadiazinan-3-il]ethyl} 1,3,5-ditiazinan.

1 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. The compounds claimed by the invention have inhibition effect on VR1 receptor activation and can be applied in pain prevention or treatment. In the general formula (I) , or , L is a low alkylene, E cycle is benzene or 5-membered heteroaromatic ring containing sulfur atom as a heteroatom, D cycle is a monocyclic or bicyclic hydrocarbon cycle optionally condensed with C5-7 cycloalkyl, 6-membered monocyclic heteroaromatic cycle containing nitrogen atom as heteroatom or 9-11-membered bicyclic heteroaromatic cycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O, G cycle is a 5-7-membered monocyclic saturated or partially saturated heterocycle or 10-membered bicyclic heterocycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O. The invention also concerns pharmaceutical composition based on the said compounds, and application thereof in obtaining pain prevention or treatment medication, and a method of pain prevention or treatment.

EFFECT: obtaining prevention or treatment medium against pain.

24 cl, 470 ex, 41 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the new compounds presented by the following formula (I), or to the pharmaceutically acceptable salts: , where R1 and R2 represent substitutes, adjoining with each other and with two carbonic atoms, to each of which they are adjoined forming the group presented by the following formula: 1) , or

2) , , , , , , , , or

3) or

4) , , or

where hydrogen atom in each cyclic group can be substituted bi 1-4 substitutes selected fro the following group of substitutes B1, R3 represents hydrogen atom or methyl group; and R6 represents substitute selected from the following group of A1 substitutes, the group of A1 substitutes: (1) hydrogen atom, (2) C1-C6 alkoxy group; substitute B1 group: (1) hydrogen atom, (2) hydroxyl group, (3) oxo group, (4) C1-C6 alkanoyl group, (5) C3-C8 cycloalkyl group, (6) C1-C6 alkyl group (where C1-C6 alkyl group can be substituted by C1-C6 alkoxy group), (7) C1-C6 alkoxy group, (8) C1-C6 alkoxyimino group, (9) C5-C6 cycloalkyl group, derived by two C1-C3 alkyl groups joined to the same carbonic atom with hydrogen atom and the carbons. The invention is also relates to the pharmaceutical composition.

EFFECT: production of the new biologically active compounds and pharmaceutical compositions on their basis having inhibitor potency towards to serotonine1A receptor.

34 cl, 73 ex, 12 tbl, 4 dwg

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to compounds with formula (I), their pharmaceutical salts or N-oxide used as an inhibitor to replication and/or proliferation of HCV, to the method of inhibiting replication or proliferation of hepatitis C virion using formula (I) compounds, as well as to pharmaceutical compositions based on them. The compounds can be used for treating or preventing infections, caused by hepatitis C virus. In general formula (I) cycle B is an aromatic or non-aromatic ring, which contains two heteroatoms, where X and Y, each is independently chosen from C, CH, N or O, under the condition that, both X and Y are not O and that, both X and Y are not N; U and T represent C; Z represents -CH-; A represents N or -CR2-; B represents -CR3-; D represents N or -CR4-; E represents N or -CR5-; G represents N or -CR6-; J represents N or -CR14-; K represents -CR8-; L represents N or -CR9-; M represents N or -CR10-; R2 and R6, each is independently chosen from a group, consisting of hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C1-C6alkoxy, C1-C6substituted alkoxy, C1-C6alkoxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, -O-carbamoil, substituted -O-carbamoil, halogen C1-C6alkyl, diC1-C6alkylamino, substituted diC1-C6alkylamino and sylye ethers, where cycloheteroalkyl is a 3-7-member ring, containing 1-2 heteroatoms, chosen from N and O, under the condition that, one of R2 and R6 is not hydrogen; R3 and R5, each is independently chosen from a group, consisting of hydrogen, halogen; R4 represents hydrogen; R7 represents - NR11C(O)R12; R8, R9, R10 and R14, each is independently represents hydrogen; R11 represents hydrogen, C1-C6alkyl; and R12 is chosen from a group, consisting of halogen C1-C6alkyl; where each substituted group is substituted with one or more groups, chosen from -Q, -R40, -OR40, -C(O)R40, -C(O)OR40, where each Q independently represents halogen, R40 and R41 are independently chosen from a group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, under the condition that: (i) at least one of A, D, E, G, J, L or M represents N; (ii) not more than one of A, D, E or G represents N; and (iii) not more than one of J, L or M represents N.

EFFECT: obtaining pyridyl-substituted heterocycles for treating and preventing infections, caused by hepatitis C virus.

33 cl, 85 dwg, 101 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the bonds of the formula (I) and their pharmaceutically acceptable salts in the capacity of modulators of receptors CB1 and to the pharmacological composition on their basis. Bonds can be used for treatment and prophylaxis of diseases, which are associated with the modulation of receptor CB1, for example, obesity and diabetes of type II. In the general formula (I) R1 means hydrogen or the lowest alkyl; R2 means hydrogen, the lowest alkyl, the lowest alkenyl, the lowest alkoxy-lowest alkyl, the lowest alkoxycarbonilamino-group or - (CH2)m-R2a; or R1 and R2 form together with atom of nitrogen to which they are attached, a 5-or 6-member saturated heterocyclic ring; R2a means cycloalkyl, which is not necessarily mono- or tetra-substituted independently by hydroxy-group, the lowest alkyl; C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen; 5- or 6-member monovalent heteroaromatic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heteroaromatic ring is not necessarily mono-substituted independently with the lowest alkyl; or phenyl which is not necessarily mono- or di-substituted independently with the lowest of the alkoxy group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy group or nitro-group; R3 means the lowest alkyl, the lowest alkoxy-lowest alkyl, diphenyl-lowest alkyl or - (CH2)n-R3a; R3a means C3-6cycloalkyl which can be not necessarily condensed with the phenol ring; or C3-6cycloalkyl, which can be not necessarily mono-, di- or trisubstituted independently hydroxy-group, the lowest alkyl, C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heterocyclic rings are not necessarily mono-substituted independently by the lowest alkyl, 5- or 6-member monovalent heteroaromatic ring containing one heteroatom, independently selected from oxygen and sulfur, the aforesaid heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, or the phenyl, which can be not necessarily mono-, di- or trisubstituted independently by the hydroxy-group, lowest alkyl, lowest alkoxy-group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; R4 means the lowest alkyl the lowest alkoxycarbonyl; C3-6 cycloalkyl, 5- or 6-member monovalent heteroaromatic ring, which contains one or two heteroatoms, independently selected from nitrogen, the said heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, lowest alkoxy-group; phenoxy-lowest alkyl, in which the phenyl part is not necessarily mono-, di- or trisubstituted independently by the lowest alkoxy-group; or the phenyl, which not necessarily can be mono-, di- or trisubstituted independently, by the lowest alkyl, by the lowest alkoxy-group, by halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; or two adjusted substitutes of the said phenyl remainder indicate together -O-(CH2)p-O- or -(CH2)2-O-; R5 and R6 each indicates a substitute independently selected from hydrogen of lowest alkyl; R7 indicates hydrogen; m indicates 0,1 or 2; n indicates 1.

EFFECT: new bonds possess useful biological properties.

28 cl, 4 dwg, 380 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new bonds in the formula (I-0): or its pharmaceutically acceptable salts, where X represents a carbon atom or nitrogen atom; X1, X2, X3 and X4, each independently, represents a carbon atom or a nitrogen atom; ring A of the formula (II): represents tiazolil, imidazolil, izotiazolil, tiadiazolil, triazolil, oxazolil, oxadiazolil, izoxazolil, pirazinil, piridil, piridazinil, pirazolil or pirimidinil; R¹ represents aryl or represents a 4-10- membered monocyclic or bicyclic heteroring, which has in the ring from 1 to 4 heteroatoms, selected from the group, consisting of a nitrogen atom, sulphur atom and an oxygen atom, and R¹ can be independently substituted with 1-3 R4, and, when the specified heteroring is an aliphatic heteroring, then it can have 1 or 2 double bonds; R² independently represents hydroxy, formyl, -CH3-aFa, -OCH3-aFa, amino, CN, halogen, C1-6 alkyl or -(CH2)1-4OH; R3 represents -C1-6 alkyl, -(CH2)1-6-OH, -C(O)-OC1-6 alkyl, -C(O)-OC1-6 alkyl, -(CH2)1-6-NH2, cyano, -C(O)-C1-6 alkyl, halogen, -C2-6 alkenyl, -OC1-6 alkyl, -COOH, -OH or oxo; R4 independently represents -C1-6 alkyl, and the alkyl can be substituted with identical or different 1-3 hydroxyls, halogens, -OC(O)-C1-6 alkyls, and the alkyl can be substituted with 1-3 halogens or -OC1-6 alkyls, -C3-7 cycloalkyl, -C2-6 alkenyl, -C(O)-N(R51)R52, -S(O)2-N(R51)R52,-O-C1-6 alkyl, and C1-6 alkylcan be substituted with a halogen or N(R51)R52, -S(O)0-2-C1-6 alkyl, -C(O)-C1-6 alkyl, and C1-6 alkyl can be substituted with a halogen, amino, CN, hydroxy, -O-C1-6 alkyl, -CH3-aFa, -OC(O)-C1-6 alkyl, -N(C1-6 alkyl)C(O)O-C1-6 alkyl, -NH-C(O)O-C1-6 alkyl, phenyl, -N(R51)R52, -NH-C(O)-C1-6 alkyl, -N(C1-6 alkyl)-C(O)-C1-6 alkyl or -NH-S(O)0-2-C1-6 alkyl, -C(S)-C3-7 cycloalkyl, -C(S)- C1-6 alkyl, -C(O)-O- C1-6 alkyl, -(CH2)0-4-N(R53)-C(O)-R54, -N(R53)-C(O)-O-R54,-C(O)-aryl, it is optional to substitute the halogen, -C(O)-aromatic heteroring, -C(O)-aliphatic heteroring, heteroring, and the heteroring can be substituted with C1-6 alkyl, optionally substituting the halogen or -O-C1-6 alkyl, phenyl, optionally substituting the halogen, -C1-6 alkyl, -O-C1-6 alkyl, halogen, CN, formyl, COOH, amino, oxo, hydroxy, hydroxyamidine or nitro; R51 and R52, each independently, represents a hydrogen atom, C1-6 alkyl or a nitrogen atom, R51 and R52 together form 4-7-member heteroring; R53 represents a hydrogen atom or C1-6 alkyl, R54 represents -C1-6 alkyl or alkyls for R53 and R54 and -N-C(O)- together form 4-7-member hydrogen containing heteroring, or alkyls for R53 and R54 and -N-C(O)-O- together form 4-7-member hydrogen containing aliphatic heteroring and an aliphatic heteroring can be substituted with oxo, or an aliphatic heteroring can have 1 or 2 double bonds in the ring; X5 represents -O-, -S-, -S(O)-, -S(O)2-, a single bond or -O-C1-6 alkyl; a independently denotes a whole number 1, 2 or 3; q denotes a whole number from 0 till 2; m denotes a whole number from 0 till 2, except in the case when one of the X5 represents -O-, -S-, -S(O)- or -S(O)2-, and the other from X5 represents a single bond, and R1 represents aryl, optionally substituted with 1-3 R4, or a hydrogen containing aromatic heteroring, consisting of from 1 to 4 heteroatoms, selected from the group, comprising of a hydrogen atom, sulphur atom and an oxygen atom, in the case, when X5, both represent single bonds or in cases, when R1, both represent aliphatic heteroring. The invention also relates to the bonding in the formula (I-12), and also to the bonding in the formula (I-0), to the pharmaceutical composition, to the glucokinase activator and to the medication.

EFFECT: getting new bioactive compounds which can be used for treatment and/or prophylaxis of diabetes or obesity.

23 cl, 603 ex

FIELD: chemistry; obtaining of medicinal preparations.

SUBSTANCE: description is given of a compound with general formula where R1 represents a halogen, C1-C6alkyl, CF3, CF2H or cyano, R2 represents C1-C6alkyl, R3 represents 5- or 6 - member hetero-aryl, optionally substituted with one, two or three substitutes, chosen from a group, consisting of a halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylhalogen, C1-C6alkoxy, NR'R", or substituted with a 1-morpholinyl group or substituted with thiomorpholinyl groups, 1-oxothiomorpholinyl or 1,1-dioxothiomorpholinyl; R', R" independently represent hydrogen, C1-C6alkyl, (CH2)0,1-(C3-C6)cycloalkyl, R represents hydrogen as well as its pharmaceutical salts and the method of obtaining them. The invention also relates to use of the given amidazole derivatives for obtaining medicinal preparations and to medicinal preparations containing them, meant for prevention or treatment of damages, through the mGluR5 receptor, such as acute and/or chronic neurologic damages, primarily shock pain, or for treatment of chronic and sharp pain.

EFFECT: obtaining of new compounds, with useful biological properties.

40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzimidazol of the general formula I R1 designates phenyl group which unessentially contains up to three substitutors independently chosen of the group including F, Cl, Br, J, R4; R2 designates monocyclic or bicyclic 5-10-terms heteroaryl group which contains 1-2 heteroatoms, chosen of N, S and O; R3 designates H; R4 designatesC1-6alkyl; A designates C2-6 alkylene group; B designates group COOH, CONH2, CONHR5 or CONR5R5, in each case attached to atom of carbon of group A; R5 and R5 ' independently designate the residue chosen from group includingC1-6 alkyl where one C-atom can be replaced by O, and(C0-3 alkandiil-C3-7 cycloalkyl); and to their pharmaceutically acceptable salts, except for following compounds: 6 [[1-phenyl-2 (pyridine-4-il)-1H-benzimidazol-6-il] oxi] hexanic acid and 6 [[1-phenyl-2 (benzothien-2-il)-1H-benzimidazol-6-il] oxi] hexanic acid. The invention relates also to pharmaceuticals and to application of compounds of general formula I.

EFFECT: new biologically active compounds possess inhibiting effect on activation of microglia.

10 cl, 34 ex

Carbonyl compounds // 2337099

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to novel compounds of general formula(I) , where D represents phenyl, pyridyl or tienyl, each of which is single-substituted or double-substituted with Hal; R1 represents H, =O, COOR3, OH, OA, NH2, alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms, N3, ethinyl, vinyl, allyloxy, -OCOR3, NHCOA or NHSO2A; R2 represents H, =O, OH, OA or alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms; R1 and R2 together alternatively represent spirocyclically linked 3-6-member carbocyclic ring, R3 represents H or A, R4 represents H or A; represents pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4 or 3,5-diyl, thiazolidine-3,4-diyl, 2,5-dihydro-1H-pyrrol-1,5-diyl, 1,3-dioxolane-4,5-diyl; G represents (CH2)n or (CH2)nNH-; X represents CONH; Y represents 1,3- or 1,4-phenylene, which is not substituted or is single-substituted with methyl, trifluoromethyl, ethyl, propyl, Cl or F; T represents morpholine-4-yl, which is single-substituted or double-substituted with carbonyl oxygen; A represents non-branched or branched alkyl, which has 1-10 carbon atoms and in which 1-7 hydrogen atoms can be substituted with F; Hal represents F, CI, Br or I, n represents 0, 1 or 2; and their pharmaceutically acceptable derivatives, solvates, salts or sterioisomers, including their mixtures in all ratios. Invention also relates to method of obtaining formula I compounds, to medication based on formula I compound and application of formula I compounds for preparation of medication, which has inhibiting activity with respect to coagulation factors Xa and VIla.

EFFECT: obtained novel compounds have inhibiting activity with respect to said coagulation factors.

11 cl, 1 tbl, 14 ex

Amid derivative // 2336273

FIELD: chemistry.

SUBSTANCE: invention relates to amid derivatives of formula (I), method of disease treatment and pharmaceutical composition based on them. Compounds can be applied in treatment of different herpes virus infections. In general formula (I) , Z: 1,2,4-oxydiazol-3-yl, 4-oxazolyl, 1,2,3-triazol-2-yl or 2-pyridyl, A: phenyl, which can have a substitute (substitutes) selected from group, including lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene -OH, CN, OH, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2 ,NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, O-lower alkylene- NH2, O-lower alkylene-NH-lower alkyl and O-lower alkylene-N(lower alkyl)2; heteroaryl, representing monocyclic 6-member ring, which contains nitrogen atom as heteroatom or bicyclic 9-member ring, containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which can have a substitute (substitutes), selected from lower alkyl; or phenyl group, condensed with saturated 5-member hydrocarbon cycle; or phenyl group, condensed with saturated 5-member heterocyclic cycle, which contains 1-2 heteroatoms, selected from nitrogen and/or oxygen, which can have a substitute (substitutes), selected from group, including lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, on condition, that aryl group, condensed with saturated hydrocarbon cycle or aryl group, condensed with saturated heterocyclic cycle is bound with nitrogen atom through carbon atom in aromatic cycle, X: CO, R3: C3-C6cycloalkyl, which can have a substitute (substitutes), selected from group, which includes oxo, OH, halogen, CN, O-lower alkyl, -C(O)-NH2, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, lower alkylene-OH, lower alkylene-O-lower alkyl; aryl, selected from phenyl, naphtyl, which can have a substitute (substitutes), selected from halogen; pyridyl; 9-member bicyclic heteroaryl, containing 1-3 heteroatoms, selected from S, N, O; or saturated heterocyclic group, representing monocyclic 6-member group, which contains 1-2 heteroatoms selected from S, SO, SO2, N, O, which can have a substitute (substitutes), selected from halogen.

EFFECT: obtaining amid derivatives that can be applied for treating various herpes virus infections.

17 cl, 26 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: invention refers to benzothiazole derivatives of general formula I and to their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands and based medicinal product. Compounds can be applied for treatment and prevention of diseases mediated by adenosine receptors, e.g., epilepsy, depressions, narcomania, Parkinson's disease. In general formula I R denotes phenyl unsubstituted or substituted with halogen or -SN2N(CH3) (CH2)nOCH3, or denotes benzyl, lower alkyl, lower alkoxy-group, - (CH2)nOCH3, or denotes pyridine-3- or -4-yl unsubstituted or substituted with lower alkyl, halogen, morpholinyl, - (CH2)n-halogen, - (CH2)nOCH3, - (CH2)n-diethylene-imide oxide-4-yl, or (CH2)n-tetrahydropyrrole-1-yl; R1 denotes phenyl unsubstituted or substituted with halogen tetrahydropyran-4-yl, 3,6-2H-2n-pyran-4-yl or morpholine-4-yl; n denotes mutually independent 1 or 2.

EFFECT: production of benzothiazole derivatives which can be applied for treatment and prevention of diseases mediated by adenosine receptors.

9 cl, 4 dwg, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new compounds presented by the following formula (I), or to the pharmaceutically acceptable salts: , where R1 and R2 represent substitutes, adjoining with each other and with two carbonic atoms, to each of which they are adjoined forming the group presented by the following formula: 1) , or

2) , , , , , , , , or

3) or

4) , , or

where hydrogen atom in each cyclic group can be substituted bi 1-4 substitutes selected fro the following group of substitutes B1, R3 represents hydrogen atom or methyl group; and R6 represents substitute selected from the following group of A1 substitutes, the group of A1 substitutes: (1) hydrogen atom, (2) C1-C6 alkoxy group; substitute B1 group: (1) hydrogen atom, (2) hydroxyl group, (3) oxo group, (4) C1-C6 alkanoyl group, (5) C3-C8 cycloalkyl group, (6) C1-C6 alkyl group (where C1-C6 alkyl group can be substituted by C1-C6 alkoxy group), (7) C1-C6 alkoxy group, (8) C1-C6 alkoxyimino group, (9) C5-C6 cycloalkyl group, derived by two C1-C3 alkyl groups joined to the same carbonic atom with hydrogen atom and the carbons. The invention is also relates to the pharmaceutical composition.

EFFECT: production of the new biologically active compounds and pharmaceutical compositions on their basis having inhibitor potency towards to serotonine1A receptor.

34 cl, 73 ex, 12 tbl, 4 dwg

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to compounds with formula (I), their pharmaceutical salts or N-oxide used as an inhibitor to replication and/or proliferation of HCV, to the method of inhibiting replication or proliferation of hepatitis C virion using formula (I) compounds, as well as to pharmaceutical compositions based on them. The compounds can be used for treating or preventing infections, caused by hepatitis C virus. In general formula (I) cycle B is an aromatic or non-aromatic ring, which contains two heteroatoms, where X and Y, each is independently chosen from C, CH, N or O, under the condition that, both X and Y are not O and that, both X and Y are not N; U and T represent C; Z represents -CH-; A represents N or -CR2-; B represents -CR3-; D represents N or -CR4-; E represents N or -CR5-; G represents N or -CR6-; J represents N or -CR14-; K represents -CR8-; L represents N or -CR9-; M represents N or -CR10-; R2 and R6, each is independently chosen from a group, consisting of hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C1-C6alkoxy, C1-C6substituted alkoxy, C1-C6alkoxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, -O-carbamoil, substituted -O-carbamoil, halogen C1-C6alkyl, diC1-C6alkylamino, substituted diC1-C6alkylamino and sylye ethers, where cycloheteroalkyl is a 3-7-member ring, containing 1-2 heteroatoms, chosen from N and O, under the condition that, one of R2 and R6 is not hydrogen; R3 and R5, each is independently chosen from a group, consisting of hydrogen, halogen; R4 represents hydrogen; R7 represents - NR11C(O)R12; R8, R9, R10 and R14, each is independently represents hydrogen; R11 represents hydrogen, C1-C6alkyl; and R12 is chosen from a group, consisting of halogen C1-C6alkyl; where each substituted group is substituted with one or more groups, chosen from -Q, -R40, -OR40, -C(O)R40, -C(O)OR40, where each Q independently represents halogen, R40 and R41 are independently chosen from a group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, under the condition that: (i) at least one of A, D, E, G, J, L or M represents N; (ii) not more than one of A, D, E or G represents N; and (iii) not more than one of J, L or M represents N.

EFFECT: obtaining pyridyl-substituted heterocycles for treating and preventing infections, caused by hepatitis C virus.

33 cl, 85 dwg, 101 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the general formula: , where R1 is an inferior alkyl, -(CH2)n-aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluormethyl, or pyridine; R2 is an inferior alkyl, -(CH2)n- aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluoromethyl, nitro-, cyano-, -NR'R", hydroxy-, or heteroaryl group that is a monovalent heterocyclic 5- or 6-membered aromatic radical with N atoms, either R2 is a heteroaryl that is monovalent heterocyclic 5- or 6-membered aromatic radical where heteroatoms are chosen from N, O or S group, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl or halogen; R3 is pyridine or aryl, unsubstituted or substituted by a halogen or inferior alkyl; R4 is hydrogen or hydroxy-. A is -S(O)2- or -C(O)-; X, Y are -CH2- or -O- independently from each other, though both X and Y should not be -O- at the same time; R'R" are hydrogen or inferior alkyl independently from each other; n is 0, 1 or 2. Also the invention concerns pharmaceutically acceptable additive salts and acids of the compounds, and a medicine based on it.

EFFECT: new biologically active compounds show inhibition effect in glycine absorption.

21 cl, 214 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the new derivatives of imide indolylmaleic acid with the formula I , where Ra denotes H; C1-4alkyl or C1-4alkyl, with substituted OH, NH2, NH(C1-4 alkyl) or H(C1-4alkyl)2; Rb denotes H or C1-4alkyl; R denotes a radical of the formula (d) or (e) , where each one from R8 and R11 independently denotes OH; heterocyclic residue; NR16R17, where each from R16 and R17 independently denotes H or C1-4alkyl, or R16 and R17 together with a nitrogen atom; to which they are joined, form a heterocyclic residue; or a radical of the formula -X-RC-Y (α) where X denotes a covalent bond, O, S or NR18, where R18 denotes H or C1-4alkyl; Rc denotes C1-4alkylen or C1-4alkylen, in which one CH2 has been changed with the group CRxRy, whereby one of Rx and Ry denotes H, and the other denotes CH3, each of the Rx and Ry denote CH3 or Rx and Ry together form the group -CH2-CH2-, and Y is joined with the terminal carbon atom and is selected from OH, -NR19R20, where each one of R19 and R20 independently denotes C1-4alkyl; each one of R9, R10, R12, R13 independently denotes H, halogen, C1-4alkyl, OH, NH2, C1-4alkoxy, NH(C1-4alkyl) or N(C1-4alkyl)2 or each E denotes -N= and G denotes -CH= or E denotes -CH= and G denotes -N=, and cycle A is unsubstituted, monosubstituted, where the substitute is selected from a group containing halogen, OH, C1-4alkoxy, C1-4alkyl, NO2, NH2, NH(C1-4alkyl) or N(C1-4alkyl)2 or CN; where the heterocyclic residue is 3-8 member saturated, heterocyclic rings, containing 1-2-heteroatoms, of which one is N, and the other N or O, possibly substituted with one or more carbon atoms in the cycle and/or with a nitrogen atom in the cycle, if it is in the ring; where the substitutes of the carbon atom ring, if they exist, are selected from the group which contains C1-4alkyl, C3-C6cycloalkyl, it is optional to further substitute C1-4alkyl; , where p denotes 1, 2 or 3; and where the substitutes on the nitrogen atom ring if they exist, are selected from a group which contains C1-4alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl C1-4alkyl, phenyl, phenylC1-4alkyl, heterocyclic residue and the residue from the formula β: -R21-Y' (β) R21 - denotes C1-C4alkylen, a Y' denotes OH, NH2, NH(C1-4alkyl) or N(C1-4alkyl)2, where the heterocyclic residue is of importance, as stated above, or its pharmaceutically acceptable salts.

EFFECT: bonds possess an action, which has an inhibitory activity on proteinkinase C and can be used in a pharmaceutical composition for treatment or prophylaxis of acute or chronic rejection of allo or xenotransilants of organs or tissues.

10 cl, 7 tbl, 182 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of phtalazine with general formula (I) , in which R represents a methyl or difluromethyl group; R1 represents phenyl or oxazolyl or thiophenyl, chemically bonded to a phtalazine ring through a carbon-carbon bond. Both phenyl and the above mentioned heterocycle are substituted with a carboxylic group, and optionally with a second functional group, chosen from methoxy-, nitro-, N-acetylamino-, N-metanesulphonylamino- group. The invention also relates to pharmaceutical salts of such derivatives. The given compounds with general formula (I) are inhibitors of phosphodiesterase.

EFFECT: objective of the invention is also the method of obtaining compounds with general formula (I) and pharmaceutical compositions for treating allergies and antiphlogistic diseases based on the given compounds.

9 cl, 9 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new bonds in the formula (I-0): or its pharmaceutically acceptable salts, where X represents a carbon atom or nitrogen atom; X1, X2, X3 and X4, each independently, represents a carbon atom or a nitrogen atom; ring A of the formula (II): represents tiazolil, imidazolil, izotiazolil, tiadiazolil, triazolil, oxazolil, oxadiazolil, izoxazolil, pirazinil, piridil, piridazinil, pirazolil or pirimidinil; R¹ represents aryl or represents a 4-10- membered monocyclic or bicyclic heteroring, which has in the ring from 1 to 4 heteroatoms, selected from the group, consisting of a nitrogen atom, sulphur atom and an oxygen atom, and R¹ can be independently substituted with 1-3 R4, and, when the specified heteroring is an aliphatic heteroring, then it can have 1 or 2 double bonds; R² independently represents hydroxy, formyl, -CH3-aFa, -OCH3-aFa, amino, CN, halogen, C1-6 alkyl or -(CH2)1-4OH; R3 represents -C1-6 alkyl, -(CH2)1-6-OH, -C(O)-OC1-6 alkyl, -C(O)-OC1-6 alkyl, -(CH2)1-6-NH2, cyano, -C(O)-C1-6 alkyl, halogen, -C2-6 alkenyl, -OC1-6 alkyl, -COOH, -OH or oxo; R4 independently represents -C1-6 alkyl, and the alkyl can be substituted with identical or different 1-3 hydroxyls, halogens, -OC(O)-C1-6 alkyls, and the alkyl can be substituted with 1-3 halogens or -OC1-6 alkyls, -C3-7 cycloalkyl, -C2-6 alkenyl, -C(O)-N(R51)R52, -S(O)2-N(R51)R52,-O-C1-6 alkyl, and C1-6 alkylcan be substituted with a halogen or N(R51)R52, -S(O)0-2-C1-6 alkyl, -C(O)-C1-6 alkyl, and C1-6 alkyl can be substituted with a halogen, amino, CN, hydroxy, -O-C1-6 alkyl, -CH3-aFa, -OC(O)-C1-6 alkyl, -N(C1-6 alkyl)C(O)O-C1-6 alkyl, -NH-C(O)O-C1-6 alkyl, phenyl, -N(R51)R52, -NH-C(O)-C1-6 alkyl, -N(C1-6 alkyl)-C(O)-C1-6 alkyl or -NH-S(O)0-2-C1-6 alkyl, -C(S)-C3-7 cycloalkyl, -C(S)- C1-6 alkyl, -C(O)-O- C1-6 alkyl, -(CH2)0-4-N(R53)-C(O)-R54, -N(R53)-C(O)-O-R54,-C(O)-aryl, it is optional to substitute the halogen, -C(O)-aromatic heteroring, -C(O)-aliphatic heteroring, heteroring, and the heteroring can be substituted with C1-6 alkyl, optionally substituting the halogen or -O-C1-6 alkyl, phenyl, optionally substituting the halogen, -C1-6 alkyl, -O-C1-6 alkyl, halogen, CN, formyl, COOH, amino, oxo, hydroxy, hydroxyamidine or nitro; R51 and R52, each independently, represents a hydrogen atom, C1-6 alkyl or a nitrogen atom, R51 and R52 together form 4-7-member heteroring; R53 represents a hydrogen atom or C1-6 alkyl, R54 represents -C1-6 alkyl or alkyls for R53 and R54 and -N-C(O)- together form 4-7-member hydrogen containing heteroring, or alkyls for R53 and R54 and -N-C(O)-O- together form 4-7-member hydrogen containing aliphatic heteroring and an aliphatic heteroring can be substituted with oxo, or an aliphatic heteroring can have 1 or 2 double bonds in the ring; X5 represents -O-, -S-, -S(O)-, -S(O)2-, a single bond or -O-C1-6 alkyl; a independently denotes a whole number 1, 2 or 3; q denotes a whole number from 0 till 2; m denotes a whole number from 0 till 2, except in the case when one of the X5 represents -O-, -S-, -S(O)- or -S(O)2-, and the other from X5 represents a single bond, and R1 represents aryl, optionally substituted with 1-3 R4, or a hydrogen containing aromatic heteroring, consisting of from 1 to 4 heteroatoms, selected from the group, comprising of a hydrogen atom, sulphur atom and an oxygen atom, in the case, when X5, both represent single bonds or in cases, when R1, both represent aliphatic heteroring. The invention also relates to the bonding in the formula (I-12), and also to the bonding in the formula (I-0), to the pharmaceutical composition, to the glucokinase activator and to the medication.

EFFECT: getting new bioactive compounds which can be used for treatment and/or prophylaxis of diabetes or obesity.

23 cl, 603 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to non-peptide antagonists GnRH, with general formula 1 , where each of A1, A2 and A3 are independently chosen from A5 and A6; and A4 represents either a covalent bond, or A5; under the condition that, if A4 is a covalent bond, then one of A1-A3 represent A6, and the other two represent A5, and that, if A4 represents A5, then all of A1-A3 represent A5; A5 is chosen from C-R13 and N; A6 is chosen from N-R14, S and O; R1 is chosen from H, NHY1 and COY2, and R2 represents H; or and R1, and R2 represents methyl or together represent =O; each of R3, R4 and R5 independently represents H or low alkyl; each of R6, R7, R8, R9, R10, R11 and R12 are independently chosen from H, NH2, F, CI, Br, O-alkyl and CH2NMe2; R13 is chosen from H, F, CI, Br, NO2, NH2, OH, Me, Et, OMe and NMe2; R14 is chosen from H, methyl and ethyl; W is chosen from CH and N; X is chosen from CH2, O and NH; Y1 is chosen from CO-low alkyl, CO(CH2)bY3, CO(CH2)bCOY3 and CO(CH2)bNHCOY3; Y2 is chosen from OR15, NRI6R17 and NH(CH2)cCOY3; Y3 is chosen from alkyl, OR15 and NR16R17; R15 represents H; each of R16 and R17 is independently chosen from H, low alkyl and (CH2)aR18, or together represent -(CH2)2-Z-(CH2)2-; R18 is chosen from OH, pyridyl, pyrizinyl and oxadiazolyl; Z represents NH; a represents 0-4; and b and c represent 1-3. The invention also relates to use of formula 1 a compound as a therapeutic agent and pharmaceutical composition, with antagonistic effect to GnRH receptor. Description is also given of the method of obtaining compounds with the given formula.

EFFECT: obtaining new compounds, with useful biological properties.

27 cl, 70 ex

FIELD: medicine; pharmacology.

SUBSTANCE: derivatives possess antiproliferative activity and stimulate an apoptosis in cells where absence of normal regulation of development of a cell and its destruction is observed. The derivatives are applied as a part of pharmaceutical compositions in combination with pharmaceutically acceptable mediums. The pharmaceutical compositions can be applied for treatment of diseases caused by hyperproliferation, including tumour growth, lymphoproliterative diseases and angiogenesis. Invention compounds pertain to the group of replaced pyrazoles and Pyrazolinums characterised by the formula of the invention.

EFFECT: derivatives possess useful biological properties.

56 cl, 115 ex

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