Azetine compounds as orexin receptor antagonists

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula

wherein R1, R2 and X are those as specified in cl.1 of the patent claim, or its pharmaceutically acceptable salt, as well as using such compound or its pharmaceutically acceptable salt for preparing a drug preparation for prevention and treatment of all types of sleeping, eating or drinking disorders.

EFFECT: preparing the new azetidine compounds showing activity of orexin receptor antagonists.

12 cl, 112 ex, 1 tbl

 

The text descriptions are given in facsimile form.

1. The compound of formula (I)

in which
X represents C(O) or SO2;
R1represents aryl, where aryl is unsubstituted or mono-, di - or tizamidine, the substituents which are independently selected from the group consisting of (C1-4)alkoxy, trifloromethyl, triptoreline and unsubstituted or mono-, di - or trisemester phenyl, the substituents which are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, trifloromethyl;
or R1represents a 5-membered heteroaryl, where the 5-membered heteroaryl is unsubstituted or mono-, di - or tizamidine, the substituents which are independently selected from the group consisting of (C1-4)alkyl, NR3R4and unsubstituted or mono-, di - or trisemester phenyl, the substituents which are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen and trifloromethyl;
R2represents aryl, where aryl is unsubstituted or mono-, di - or tizamidine, the substituents which are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen;
8-10-membered heteroaryl, where 8-10-membered hetero is the Rila is unsubstituted or mono-, di - or tizamidine, the substituents which are independently selected from the group consisting of (C1-4)alkyl, halogen, trifloromethyl; or
R2represents heterocyclyl where heterocyclyl means a phenyl ring, a condensed 5 - or 6-membered saturated or unsaturated non-aromatic ring containing 1 or 2 heteroatoms independently selected from oxygen or nitrogen, where the specified heterocyclyl unsubstituted or monogamist (C1-4)alkyl or oxopropoxy;
R3represents hydrogen; and
R4represents hydrogen;
or pharmaceutically acceptable salt of such compounds.

2. The compound according to claim 1, in which the fragment of azetidine has the S-configuration:

or pharmaceutically acceptable salt of such compounds.

3. The compound according to claim 1 or 2, in which X represents S(O);
or pharmaceutically acceptable salt of such compounds.

4. The compound according to claim 1, in which
R1represents a monosubstituted aryl, Deputy selected from the group consisting of (C1-4)alkoxy, trifloromethyl, triptoreline and nizamedinova or mono - or disubstituted phenyl, the substituents which are independently selected from the group consisting of (C1-4)alkyl, halogen and trifloromethyl; or
R1represents a disubstituted 5-member of the first heteroaryl, substituents which are independently selected from the group consisting of (C1-4)alkyl, -NH2and unsubstituted or mono-, di - or trisemester phenyl, the substituents which are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen and trifloromethyl;
or pharmaceutically acceptable salt of such compounds.

5. The compound according to claim 1, in which
R2is an 8-10-membered heteroaryl, where 8-10-membered heteroaryl represents a group selected from the group consisting of indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophene, indazole, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzotriazole, benzoxadiazole, benzothiadiazole, cinnoline, imidazo[2,1-b]thiazolyl; where specified 8-10-membered heteroaryl is unsubstituted or mono - or disubstituted, the substituents which are independently selected from the group consisting of (C1-4)alkyl and halogen; or R2represents heterocyclyl where heterocyclyl represents a group selected from the group consisting of 3,4-dihydro-2H-benzo[1,4]oxazinyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxole, 2,3-dihydrobenzo[1,4]dioxine, 4H-benzo[1,3]dioxine, Romania and chromene where specified heterocyclyl is unsubstituted or monosubstituted (C1-4)alkyl Il what oxopropoxy; or pharmaceutically acceptable salt of such compounds.

6. The compound according to claim 1 or 4, in which case R1represents a 5-membered heteroaryl, the 5-membered heteroaryl is a thiazol-4-yl, which is disubstituted in positions 2 and 5, where the substituent in position 2 is selected from (C1-4)alkyl and-NH2and the substituent in position 5 is unsubstituted or mono - or disubstituted by phenyl, the substituents which are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen and trifloromethyl;
or pharmaceutically acceptable salt of such compounds.

7. The compound according to claim 1, in which case R2is an 8-10-membered heteroaryl, the 8-10-membered heteroaryl is unsubstituted or mono - or disubstituted, the substituents which are independently selected from halogen and (C1-4)alkyl;
or pharmaceutically acceptable salt of such compounds.

8. The compound according to claim 1 or 5, in which case R2is an 8-10-membered heteroaryl, the 8-10-membered heteroaryl represents a group selected from benzofuran-4-yl, 2-methylbenzofuran-4-yl, 2-methylbenzofuran-3-yl, benzoxazol-4-yl, imidazo[2,1-b]thiazole-5-yl, 6-methylimidazo[2,1-b]thiazole-5-yl, 6-chloroimidazo[2,1-b]thiazole-5-yl, 3-methylimidazo[2,1-b]thiazol-2-yl;
or a pharmaceutically acceptable salt of such compounds.

9. The compound according to claim 1 or 5, in which case R2represents heterocyclyl, heterocyclyl represents a group selected from 3,4-dihydro-2H-benzo[1,4]oxazin-5-yl, 3,4-dihydro-2H-benzo[1,4]oxazin-8-yl, 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl, 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl, 4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl, 4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl, 2,3-dihydrobenzofuran-7-yl, chroman-8-yl, chroman-5-yl and 2H-chromen-5-yl;
or pharmaceutically acceptable salt of such compounds.

10. The compound according to claim 1, selected from the group consisting of:
[1-(biphenyl-2-carbonyl)azetidin-2-ylmethyl]the amide benzofuran-4-carboxylic acid;
[1-(biphenyl-2-carbonyl)azetidin-2-ylmethyl]amide(2S)-benzofuran-4-carboxylic acid;
[1-(biphenyl-2-sulfonyl)azetidin-2-ylmethyl]the amide benzofuran-4-carboxylic acid;
[1-(biphenyl-2-sulfonyl)azetidin-2-ylmethyl]amide(2S)-benzofuran-4-carboxylic acid;
[1-(2-trifloromethyl)azetidin-2-ylmethyl]amide(2S)-benzofuran-4-carboxylic acid;
[1-(2-methoxybenzenesulfonyl)azetidin-2-ylmethyl]amide(2S)-benzofuran-4-carboxylic acid;
{1-[5-(4-forfinal)-2-methylthiazole-4-carbonyl]azetidin-2-ylmethyl}amide benzofuran-4-carboxylic acid;
[1-(2-methyl-5-n-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide is 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{1-[5-(4-forfinal)-2-methylthiazole-4-carbonyl]azetidin-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{1-[5-(3-forfinal)-2-methylthiazole-4-carbonyl]azetidin-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{1-[5-(4-triptoreline)-2-methylthiazole-4-carbonyl]azetidin-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{1-[5-(4-ethylphenyl)-2-methylthiazole-4-carbonyl]azetidin-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
[1-(3-trifloromethyl)azetidin-2-ylmethyl]amide(2S)-benzofuran-4-carboxylic acid;
[1-(3',4'-dimethylbiphenyl-2-carbonyl)azetidin-2-ylmethyl]amide(2S)-benzofuran-4-carboxylic acid;
{1-[5-(4-forfinal)-2-methylthiazole-4-carbonyl]azetidin-2-ylmethyl}amide(2S)-benzofuran-4-carboxylic acid;
{1-[5-(3,4-dimetilfenil)-2-methylthiazole-4-carbonyl]azetidin-2-ylmethyl}amide(2S)-6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide(2S)-6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
[1-(3',4'-dimethylbiphenyl-2-carbonyl)azetidin-2-ylmethyl]amide(2S)-6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
[1-(2-amino-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide(2S)-6-methylimidazo[2,1-b]thiazole-5-carboxylic what Islami;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide(2S)-6-chloroimidazo[2,1-b]thiazole-5-carboxylic acid;
[1-(2-amino-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide(2S)-6-chloroimidazo[2,1-b]thiazole-5-carboxylic acid;
[1-(3',4'-dimethylbiphenyl-2-carbonyl)azetidin-2-ylmethyl]the amide benzofuran-4-carboxylic acid;
{1-[5-(3,4-dimetilfenil)-2-methylthiazole-4-carbonyl]azetidin-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{1-[5-(3-methoxyphenyl)-2-methylthiazole-4-carbonyl]azetidin-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{1-[5-(3-chlorophenyl)-2-methylthiazole-4-carbonyl]azetidin-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{1-[2-methyl-5-(3-triptoreline)thiazole-4-carbonyl]azetidin-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{1-[5-(4-methoxyphenyl)-2-methylthiazole-4-carbonyl]azetidin-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{1-[5-(3,5-differenl)-2-methylthiazole-4-carbonyl]azetidin-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{1-[5-(3-bromo-4-forfinal)-2-methylthiazole-4-carbonyl]azetidin-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{1-[5-(4-chlorophenyl)-2-methylthiazole-4-carbonyl]azetidin-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{1-[5-(3,4-dichlorophenyl)-2-methylthiazole-4-carbonyl]azeti the Jn-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{1-[5-(3,4-dimetilfenil)-2-methylthiazole-4-carbonyl]azetidin-2-ylmethyl}amide 6-chloroimidazo[2,1-b]thiazole-5-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide of 6-chloroimidazo[2,1-b]thiazole-5-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide 2-methylbenzofuran-4-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide 2H-chromen-5-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]the amide benzooxazol-4-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]the amide benzofuran-3-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide 2-methylbenzofuran-3-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide 3,5-dimethylimidazo[2,1-b]thiazole-6-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide 3,4-dihydro-2H-benzo[1,4]oxazin-5-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide 5-methylimidazo[2,1-b]thiazole-6-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide 4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide of imidazo[2,1-b]thiazole-5-carb is new acid;
[1-(3',4'-dimethylbiphenyl-2-carbonyl)azetidin-2-ylmethyl]amide of imidazo[2,1-b]thiazole-5-carboxylic acid;
[1-(3',4'-dimethylbiphenyl-2-carbonyl)azetidin-2-ylmethyl]amide of 3-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
[1-(3',4'-dimethylbiphenyl-2-carbonyl)azetidin-2-ylmethyl]amide 3,5-dimethylimidazo[2,1-b]thiazole-6-carboxylic acid;
[1-(3',4'-dimethylbiphenyl-2-carbonyl)azetidin-2-ylmethyl]amide of 6-chloroimidazo[2,1-b]thiazole-5-carboxylic acid;
[1-(biphenyl-2-sulfonyl)azetidin-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide of 6-triptoreline[2,1-b]thiazole-5-carboxylic acid;
[1-(2-methyl-5-phenylthiazol-4-carbonyl)azetidin-2-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
[1-(2-amino-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide 3,4-dihydro-2H-benzo[1,4]oxazin-5-carboxylic acid;
[1-(3',4'-dimethylbiphenyl-2-carbonyl)azetidin-2-ylmethyl]amide of 3-methylimidazo[2,1-b]thiazole-2-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide of 3-methylimidazo[2,1-b]thiazole-2-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide chroman-5-carboxylic acid;
[1-(2-methyl-5-<> m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide chroman-8-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide of 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-carboxylic acid;
[1-(3',4'-dimethylbiphenyl-2-carbonyl)azetidin-2-ylmethyl]amide 2-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{1-[5-(2,4-dimetilfenil)-2-methylthiazole-4-carbonyl]azetidin-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide of 3-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
[1-(2-methyl-5-m-tolyltriazole-4-carbonyl)azetidin-2-ylmethyl]amide 2-methylbenzothiazol-4-carboxylic acid;
[1-(3',4'-dimethylbiphenyl-2-carbonyl)azetidin-2-ylmethyl]amide 3,6-dimethylimidazo[2,1-b]thiazole-5-carboxylic acid;
{1-[5-(2-forfinal)-2-methylthiazole-4-carbonyl]azetidin-2-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid; and
[1-(naphthalene-1-sulfonyl)azetidin-2-ylmethyl]amide(2S)-benzofuran-4-carboxylic acid;
or pharmaceutically acceptable salt of such compounds.

11. The compound according to claim 1 or 10, or its pharmaceutically acceptable salt for use as a medicinal product, which has active antagonists of the receptor orexin.

12. The use of compounds according to one of claims 1 to 10 or its pharmaceutically acceptable salt for the manufacture of lcars the governmental funds for the prevention or treatment of all types of sleep disorders, eating disorder or fluid intake.



 

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27 cl

FIELD: chemistry.

SUBSTANCE: invention refers to the compounds of formula (I): where R denotes cycloalkyl, heterocyclil, aryl, alkyl-O-C(O)-, alkanoyl or alkyl where each cycloalkyl, heterocyclil and aryl does not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, cyano group, alkoxy group, alkyl-O-C(O)-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil, and where each alkyl-O-C(O)-, alkyl, alkoxy group and heterocyclil does not necessarily have additional 1 to 3 substitutes chosen from the group including a hydroxy group, alkyl, halogen, carboxy group, alkoxy group, alkyl-O-C(O)-, alkanoyl, alkyl-SO2-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil; R2 denotes alkyl, cycloalkyl, cycloalkylalkyl- or alkoxy group where alkyl does not necessarily contain from 1 to 3 substitutes chosen from the alkoxy group or halogen; R3 denotes R8-O-C(O)-, (R8)(R9)N-C(O)-, R8-C(O)-, where R8 and R9 independently denote alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- or nonaromatic heterocyclil where each alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- and nonaromatic heterocyclil do not necessarily contain from 1 to 3 substitutes chosen from the group including a hydroxy group, carboxy group, alkyl-O-C(O)-, alkyl-C(O)-O- and alkanoyl; R4 and R5 independently denote hydrogen, alkyl, alkynyl, alkoxy group, cycloalkyl, arylalkyl-, cycloalkylalkyl-, heteroarylalkyl-, monoalkylamino-C(O)-, dialkylcmino-C(O)- or dialkylamino-C(O)-alkyl-, where both these alkyl groups do not necessarily form a ring and where each alkyl, alkynyl, cycloalkyl, arylalkyl-, cycloalkylalkyl- heteroarylalkyl-, monoalkylamino-C(O)-, dialkylamino-C(O)- or dialkylamino-C(O)-alkyl- do not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, carboxy group and alkoxy group; R6 and R7 independently denote hydrogen, halogenalkyl, halogen, dialkylamino group, alkoxy group, halogenalkoxy group, heteroaryl or alkyl-S(O)2- where each heteroaryl does not necessarily contain from 1 to 3 substitutes chosen from alkyl; where "heterocyclil" denotes fully saturated or nonsaturated aromatic or nonaromatic cyclic group that is represented by 5- or 6-membered monocyclic ring system containing at least one heteroatom chosen from nitrogen, oxygen and sulphur atoms; "heteroaryl" denotes 5- or 6-membered monocyclic ring system containing from 1 to 4 heteroatoms chosen from N, O and S; or to their pharmaceutically acceptable salts and their optical isomers, or to mixtures of the optical isomers. The invention also refers to the method of inhibition of the specimen's CETP activity, to the way of treatment of the specimen's abnormality or disease mediated by CETP or responsive to CETP inhibition, to the pharmaceutical composition, and to application of the formula (I) compounds.

EFFECT: production of new bioactive compounds that inhibit the CETP.

10 cl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): where R1 and R2 represent hydrogen and a group which is hydrolysed in a physiological environment, optionally substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents oxygen atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a group of pyridine N-oxide according to formula A, B or C which is attached as shown by an unmarked linking: where R4, R5, R6 and R7 independently represent aryl, heterocycle, hydrogen, C1-C6-alkyl, C1-C6-alkylthio, C6-C12-aryloxy or C6-C12-arylthio group, C1-C6-alkylsulphonyl or C6-C12-arylsulphonyl, halogen, C1-C6-haloalkyl, trifluoromethyl, or heteroaryl group; or where two or more residues R4, R5, R6 and R7 taken together represent an aromatic ring, and where P represents a central part, preferentially chosen from regioisomers 1,3,4-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3,5-diyl, 4-methyl-4H-1,2,4-triazol-3,5-diyl, 1,3,5-triazine-2,4-diyl, 1,2,4-triazine-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl, 1-alkyl-3-(alkoxycarbonyl)-1R-pyrrol-2,5-diyl, where alkyl is presented by methyl, thiazol-2,4-diyl, 1H-pyrazol-1,5-diyl, pyrimidine-2,4-diyl, oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl, isoxazol-3,5-diyl, furan-2,4-diyl, benzole-1,3-diyl and (Z)-1-cyanoethene-1,2-diyl, and where the regioisomers of the central part include both regioisomers produced by exchanging the nitrocatechol fragment and the -(X)n-(Y)m-R3 fragment. Also, the invention refers to a method for making a compound of formula I, as well as to a method for treating an individual suffering central and peripheral nervous system disorders, to a pharmaceutical composition based on the compounds of formula I, and also to their application for preparing the drug and as COMT inhibitor.

EFFECT: there are produced and described new compounds which show a potentially effective pharmaceutical properties in treating a number of central and peripheral nervous system disorders.

25 cl, 64 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazolidinone derivatives of formula and pharmaceutically acceptable salts thereof, where X denotes N or CH; R1 denotes a lower alkyl, fluoro-lower alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-lower alkyl, phenyl, naphthyl, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of a halide, lower alkyl, fluoro-lower alkyl, lower alkoxy group and fluoro-lower alkoxy group; R2 denotes lower alkyl, halide-lower alkyl, lower alkenyl, C3-C6-cycloalkyl, pheny, phenyl-lower alkyl, tetrahydropyran, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide; R3 denotes phenyl or heteroaryl (pyridinyl, thienopyridinyl, benzoisothiazolyl, benzooxazolyl, tetrahydropyrazinyl, pyrazinyl), where the phenyl or heteroaryl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide, CN, lower alkyl, fluoro-lower alkyl, lower alkoxy group; R4, R5, R6, R7, R8, R9, R10 and R11 independently denote hydrogen or lower alkyl. The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: obtaining novel imidazolidinone derivatives, having LXRalpha or LXRbeta receptor agonist activity.

26 cl, 98 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula I

and/or to all isomer forms of a compound of formula I and/or to mixtures of these forms in any proportions, and/or to physiologically acceptable salts of the compound of formula I, wherein R1 represents 1) -(C6-C14)-aryl-Z, wherein Z represents aminomethylene, 2) Het-Z, wherein Z represents amino group, and wherein Het is unsubstituted or additionally monosubstituted by group T, R2 represents 1) -(C0)-alkylene-(C6-C14)aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T or 2) -(C0)-alkylene-Het, wherein Het is unsubstituted or monosubstituted by group T, R3 represents 1) -(C0)-alkylene-(C6-C14)-aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T, 2) -O-(C6-C14)-alkylene(C6-C14)-aryl, wherein aryl is unsubstituted or monosubstituted by group T, 3) -(C0)-alkylene-Het, wherein Het is unsubstituted or mono-, di- or trisubstituted by group T, 4) -(C0)-alkylene-(C6-C14)-aryl-Q-(C6-C14)-aryl, wherein both aryl radicals are unsubstituted, 5) -(C0)-alkylene-(C6-C14)-aryl-Q)-Het, wherein aryl and Het in each case are independently unsubstituted or disubstituted by group T, 6) -(C0)-alkylene-Het-Q-Het, wherein both radicals Het are unsubstituted, Q represents a covalent bond, -(C1-C4)-alkylene, -N((C1-C4)-alkyl)- or -O-, T represents 1) halogen, 2) -(C1-C6)-alkyl, wherein alkyl is unsubstituted disubstituted by group -(C1-C3)-fluoralkyl or -N-C(O)-(C1-C4)-alkyl, 3) -(C1-C3)-fluoralkyl, 4) -(C3-C8)-cycloalkyl, 5) -O-(C1-C4)-alkyl, 6) -O-(C1-C3)-fluoralkyl, 7) -N(R10)(R11), wherein R(10) and R(11) independently represent hydrogen atom or -(C1-C6)-alkyl, 8) -C(O)-NH-R10, 9) -SO2-(C1-C4)-alkyl, 10) -SO2-(C1-C3)-fluoralkyl, R4 and R5 are identical and represent hydrogen atom, and R6 represent hydrogen atom with said Het being 5-10-member ring system consisting of 1 or 2 coupled ring systems, and wherein one or two identical or different heteroatoms are selected from oxygen, nitrogen and sulphur. Also, the invention refers to the use of the compound of formula I for preparing a drug.

EFFECT: there are prepared new compounds exhibiting antithrombotic activity, which particularly inhibit blood coagulation factor lXa.

6 cl, 2 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat such diseases as hypertension, congestive heart failure, cardiac hypertrophy and others. In formula I R1 denotes a) cyclohexyl or trifluoromethyl; or b) phenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-imidazolyl, 2-thiazolyl, 2-benzothienyl, 4-benzofuryl, 4-benzothienyl, 7-benzofuryl, 2,3-dihydro-7-benzofuryl, 7-benzothienyl, 1,3-benzodioxol-4-yl, 7-indazolyl, or 8-quinolinyl, optionally substituted with 1-3 substitutes, and X and Y each denotes a single bond; R2 denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, 5-pentenyloxy, 3,33-trifluoropropyl, 4,4-difluoropentyl, 3-(cyclopropyl)propyl, 4-(cyclopropyl)butyl, 3-hydroxypropyl, 4-hydroxybutyl, 4-hydroxypentyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 2-hydroxyethoxy etc, given in the claim; R3 denotes H, F, OH, methoxy, ethoxy, 3-hydroxypropoxy, acetylamino, propionylamino, (2-methylpropionyl)amino, or butanoylamino; A denotes 2,4-disubstituted morpholine with R1XCR2R3Y, bonded on the second position and Q bonded on the fourth position, 1,3-disubstituted piperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-dibustituted-3-methylpiperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-disubstituted benzene or 1,3-disubstituted cyclohexane; Q denotes Q1, Q2, Q4, Q5, Q9, or Q10 given in the claim, to which A and N are bonded on cut-off bonds, R4 denotes H or methyl.

EFFECT: obtaining novel compounds having aspartic protease inhibitor properties, particularly renin inhibitor.

10 cl, 1 tbl, 166 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula I or their pharmaceutically acceptable salts exhibiting the properties of voltage-dependent sodium channel inhibitors, such as NaV1.8. The latter play a central role in generating the action potentials in all excitable cells such as neurons and myocytes, and can be used for treating such diseases as epilepsy, irritable bowel syndrome, chronic pain, etc. In the compounds of formula I: R1 and R2 together with nitrogen atom a substituted ring selected from: (A),(B),(C),(D) or (E), which are specified in the patent claim, where in the ring (A): each of m1 and n1 is independently equal to 0-3, provided m1+n1 is equal to 3-4; z1 is equal to 0-4; Sp1 represents -O-, -S-, -NR'- or C1-C4alkylidene linker in which one methylene ring is optionally or independently substituted by -O-, provided Sp1 is bound with carbonyl group through an atom different from carbon; the ring B1 represents a 5-6-members saturated or aromatic, monocyclic or heterocyclic ring containing 1-4 heteroatoms selected from O or N with the ring B1 is optionally substituted by w1 independent variants -R11 with w1 being equal to 0-1; where in the ring (B): G2 represents CH; each of m2 and n2 is independently equal to 0-3, provided m2+n2 is equal to 2-4; p2 is equal to 0-2; q2 is equal to 0 or 1; z2 is equal to 0-4; Sp2 represents a bond or C1-C6alkylidene linker in which up to two methylene links are optionally or independently substituted by -O-. The other radical values are specified in the patent claim.

EFFECT: making new compounds of formula I or to their pharmaceutically acceptable salts showing the properties of voltage-dependent sodium channel inhibitors.

67 cl, 4 tbl, 503 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described compounds of formula

as well as their pharmaceutically acceptable salts where the substitutes are those as described in the patent claim. The compounds of formula (I) are 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme inhibitors.

EFFECT: making the compounds effective for treating and preventing the diseases, such as insulin-independent diabetes and metabolic syndrome, particularly obesity, eating disorders or dislipidemia.

15 cl, 1 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where X denotes a 5-member heterocylic group bonded through a carbon atom, selected from thiophenyl, furanyl, pyrazolyl and pyrrolyl, which can be substituted with 1-3 Ra groups; T denotes O, S; B is as indicated in the claim; Z1 denotes an unsubstituted cyclopropyl; Z2 denotes a hydrogen atom, C1-C8alkyl; or C1-C8alkoxycarbonyl; Z3 independently denotes a hydrogen atom. The invention also relates to a fungicidal composition containing a compound of formula (I) as an active ingredient, and a plant pathogenic fungus control method in agricultural plants.

EFFECT: obtaining compounds of formula (I), having fungicidal activity.

9 cl, 3 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel C-phenyl glycitol compound which serves as a preventive or therapeutic agent for sugar diabetes by inhibiting SGLT1 activity, as well as SGLT2 activity; demonstrating inhibiting effect on glucose absorption, and also acts on release of glucose with urine. The C-phenyl glycitol compound has formula (I) given below, or pharmaceutically acceptable salt or hydrate thereof, where R1 and R2 are identical or different and denote a hydrogen atom, a hydroxyl group, a C1-6 alkyl group, a C1-6 alkoxy group or a halogen atom, R3 is a hydrogen atom, a C1-6 alkyl group or a C1-6 alkoxy group, Y is a C1-6 alkylene group, -O-(CH2)n- (n is a whole number which assumes values from 1 to 4), provided that when Z denotes -NHC(= NH)NH2 or -NHCON(RB)Rc, n not equal to 1, Z is -CONHRA, -NHC(=NH)NH2 or -NHCON(RB)Rc, or The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: high efficiency of the compounds.

19 cl, 8 tbl

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