Pyrazole derivatives as phosphodiesterase 4 inhibitors

FIELD: chemistry.

SUBSTANCE: proposed phosphodiesterase 4 inhibitors are characterised by formulae II, III, V, VI, where X is CH or N; L is a single bond, -(CH2)nCONH-, -(CH2)nCON(CH2CH3)-, (CH2)nSO2, (CH2)nCO2 or alkylene, optionally substituted oxo or hydroxy; n assumes values from 0 to 3; R1 is optionally substituted alkyl; R3 - H, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted phenyl, phenylalkyl, heterocyclyl, heterocyclylalkyl or cycloalkylalkyl; R4 and R5 represent alkyl; R6 - cycloalkyl, R7 is H; R8 is H, carboxy, alkoxycarbonyl, -CO-alkyl, optionally substituted alkyl.

EFFECT: new phosphodiesterase 4 inhibitors have improved properties.

55 cl, 30 ex

 

The text descriptions are given in facsimile form.

1. The compound of formula II, III, V Il is VI


where
X represents CH or N;
L represents a simple bond; -(CH2)nCONH-; -(CH2)nCON(CH2CH3)-; (CH2)nSO2, (CH2)nCO2or C1-C6linear or branched alkylen,
which is unsubstituted or substituted by oxo or hydroxy;
n has a value from 0 to 3;
R1represents a C1-4alkyl, which is unsubstituted or
substituted with halogen;
R3represents H, C1-8alkyl, C3-8cycloalkyl, pyridylmethyl,3-6cycloalkyl1-6alkyl,
phenyl, which is unsubstituted or substituted by one or two substituents selected from halogen, alkyl, alkoxy, halogenated C1-6of alkyl, halogenated C1-6alkoxy, nitro, amino, carboxy, cyano, alkylsulfonyl or morpholinyl,
heterocyclic group which is saturated, partially saturated or fully unsaturated, and which is monocyclic and has 5-6 atoms in the ring, or bicyclic and has 9-10 atoms in the ring, where 1-2 atom in the ring are N, O or S and which is unsubstituted or substituted by one or two substituents selected from halogen, alkyl and alkoxycarbonyl, or
phenylalkyl having 7 to 9 carbon atoms, which is unsubstituted or substituted by one or two substituents selected from halogen, alkyl, alkoxy, halogenated C1-6of alkyl, amino, carboxy, nitro, alkoxycarbonyl, alkylsulfonyl and arylsulfonyl;
heterocyclisation group, which is saturated, partially saturated or fully unsaturated, and which is monocyclic and has 5-6 atoms in the ring, or bicyclic and has 9-10 atoms in the ring, where 1-2 atom in the ring are N, O or S and which is unsubstituted or substituted by one or two substituents in the heterocyclic ring, selected from halogen, phenyl, alkyl, alkoxy, cyano, halogenated alkyl, nitro, oxo, amino, alkylamino, dialkylamino or carboxy, and/or is substituted in the alkyl group, halogen, oxo or cyano,
cycloalkenyl having from 4 to 16 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl, or
alkoxyalkyl having from 3 to 8 carbon atoms;
R4and R5each represents a C1-6alkyl;
R6represents a C3-8cycloalkyl,
R7represents H; and
R8represents H, carboxy, C2-6alkoxycarbonyl, -CO-C1-6alkyl or C1-6Ala is l, which is unsubstituted or substituted with one to three substituents selected from halogen and hydroxyl,
or its pharmaceutically acceptable salt,
where the specified connection may be in the form of mixtures of enantiomers such as the racemate, or mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereoisomer.

2. The compound according to claim 1, where the specified compound selected from compounds of formulas II, III, V and VI:


where
Y represents CH or N;
L represents a simple bond; -(CH2)nCONH-; (CH2)nSO2-, (CH2)nCO2
or C1-C6linear or branched alkylene, which is unsubstituted or substituted by oxo or hydroxy;
n has a value from 0 to 3;
R1represents a C1-4alkyl, which is unsubstituted or
substituted with halogen;
R3represents H, C1-8alkyl, C3-8cycloalkyl, pyridylmethyl,3-6cycloalkyl1-6alkyl,
phenyl, which is unsubstituted or substituted by one or two substituents selected from halogen, alkyl, alkoxy, nitro, amino, carboxy or cyano,
heterocyclic group which is saturated, casticin is saturated or fully unsaturated, and which is monocyclic and has 5-6 atoms in the ring, or bicyclic and has 9-10 atoms in the ring, where 1-2 atom in the ring are N, O or S and which is unsubstituted or substituted by one or two substituents selected from halogen and alkyl,
phenylalkyl having 7 to 9 carbon atoms, which is unsubstituted or substituted by one or two substituents selected from halogen, alkyl, alkoxy, CF3, amino, carboxy, alkoxycarbonyl and alkylsulfonyl;
heterocyclyl-alkyl group, which is saturated, partially saturated or fully unsaturated, and which is monocyclic and has 5-6 atoms in the ring, or bicyclic and has 9-10 atoms in the ring, where 1-2 atom in the ring are N, O or S and which is unsubstituted or substituted by one or two substituents in the heterocyclic ring, selected from halogen, phenyl, alkyl, alkoxy, cyano, halogenated alkyl, nitro, oxo, amino, alkylamino, dialkylamino or carboxy, and/or is substituted in the alkyl group, halogen, oxo or cyano,
cycloalkenyl having from 4 to 16 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl, or
alkoxyalkyl having from 3 to 8 carbon atoms;
R4and R5each is own the th C 1-6alkyl;
R6represents a C3-8cycloalkyl,
R7represents H; and
R8represents H, carboxy, C2-6alkoxycarbonyl, -CO-C1-6alkyl or C1-6alkyl, which is unsubstituted or substituted one to three times by halogen,
or its pharmaceutically acceptable salt,
where the specified connection may be in the form of mixtures of enantiomers such as the racemate, or mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereoisomer.

3. The compound according to claim 1, where the specified compound selected from the compounds of formula II.

4. The compound according to claim 1, where the specified compound selected from the compounds of formula III.

5. The compound according to claim 1, where the specified compound selected from compounds of formula V.

6. The compound according to claim 1, where the specified compound selected from the compounds of formula VI.

7. The compound according to claim 1, where the specified compound is a compound of formula II or V, and R1represents CH3or CF2H.

8. The compound according to claim 1, where R3represents phenyl, bromophenyl, nitrophenyl, forfinal, trifloromethyl, methoxyphenyl, carboxyphenyl, dimetilfenil or methylpyridyl.

9. The compound according to claim 1, where R3is a 4-carboxyphenyl, 2,3-differenl, 4-were, 4-tert-butylphenyl, 4-methoxyphenyl is, 3,4-differenl or 4-forfinal.

10. The compound according to claim 1, where R3represents a cyclohexyl or cyclopentyl.

11. The compound according to claim 1, where R3represents ethyl, CH(CH3)2, n-propyl, n-butyl or tert-butyl.

12. The compound according to claim 1, where R3represents thiazolyl or benzothiazolyl.

13. The compound according to claim 1, where R3represents benzyl or phenethyl, which in each case is substituted or unsubstituted.

14. The compound according to claim 1, where R3represents benzyl, methylbenzyl, tert-butylbenzyl, methoxybenzyl, dimethoxybenzyl, carboxybenzoyl, tormentil, diferential, cryptomelane, chlorbenzyl, nitrobenzyl, methoxycarbonylbenzyl or phenethyl.

15. The compound according to claim 1, where the specified compound is a compound of formula II or V, and R4represents CH3.

16. The compound according to claim 1, where the specified compound is a compound of formula III or VI, and R5represents CH3or CH2CH3.

17. The compound according to claim 1, where the specified compound is a compound of formula III or VI, and X represents CH.

18. The compound according to claim 1, where the specified compound is a compound of formula III or VI, and X represents N.

19. The compound according to claim 1, where L is a bond, CH CH2CH2CH2WITH,
CH2CO2or CH2CONH.

20. The compound according to claim 1, where n is 0 or 1.

21. The compound according to claim 1, where R8represents N, CH3C2H5, CF3, hydroxymethyl, 2-(2-hydroxy)propyl, carboxy, etoxycarbonyl or CH3WITH.

22. The compound according to claim 1, where the specified compound has the formula II or V, and R1represents CH3or CF2H.

23. The compound according to claim 1, where the specified compound has the formula II or V, R1represents CH3or CF2H a R3represents optionally substituted phenyl, optionally substituted heterocycle, With1-8alkyl or C3-8cycloalkyl.

24. The compound according to claim 1, where the specified compound has the formula II or V, R1represents CH3or CF2H and R3represents a 2-(6-methyl-pyridyl), 2-cyanophenyl, 2,3-differenl, 2-were, 4-nitrophenyl, 4-AMINOPHENYL, phenyl, pyridyl, cyclohexyl, cyclopentyl, ethyl, tert-butyl, tetrahydroisoquinoline, 7-isoindolyl or 4-methylsulfinylphenyl.

25. The compound according to claim 1, where the specified compound has the formula II or V, R1represents CH3or CF2H and R4represents CH3.

26. The compound according to claim 1, where the specified compound has the formula II or V, R1is Soboh the CH 3or CF2H, R3represents phenyl, benzyl, phenethyl, cyclohexyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-trifloromethyl, 4-bromophenyl, 4-methylbenzyl, 4-tert-butylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 3,5-dimethoxybenzyl, 3-tormentil, 2,6-diferensial, 4-tormentil, 3,4-diferensial or 4-carboxybenzoyl and L is a bond, CH2CH2CH2or CH2CONH.

27. The compound according to claim 1, where the specified compound has the formula II or V, R1represents CH3or CF2H, R3represents phenyl, benzyl, phenethyl, cyclohexyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-trifloromethyl, 4-bromophenyl, 4-methylbenzyl, 4-tert-butylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 3,5-dimethoxybenzyl, 3-tormentil, 2,6-diferensial, 4-tormentil, 3,4-diferensial or 4-carboxybenzoyl, L is a bond, CH2CH2CH2or CH2CONH and R4represents CH3.

28. The compound according to claim 1, where the specified compound has the formula III or VI, and R3represents optionally substituted phenyl, optionally substituted heterocycle, With1-8alkyl or C3-8cycloalkyl.

29. The compound according to claim 1, where the specified compound has the formula III or VI and R5represents alkyl having from 1 to 3 carbon atoms.

30. The compound according to claim 1, where the specified compound has the formula III or VI and R6is cycloalkyl having from 4 to 7 carbon atoms.

31. The compound according to claim 1, where the specified compound has the formula III or VI, R3represents optionally substituted phenyl, optionally substituted heterocycle, With1-8alkyl or C3-8cycloalkyl, R5represents CH2CH3and R6is cyclopentyl.

32. The compound according to claim 1, where the specified compound has the formula III or VI, R3represents optionally substituted phenyl, optionally substituted heterocycle, With1-8alkyl or C3-8cycloalkyl, R5represents CH2CH3, R6is cyclopentyl, X represents CH and L is
a CH2CH2CH2CH2CH2CH2CH2CO, CH2CO2, SO2or CH2CONH.

33. The compound according to claim 1, where the specified connection is selected from the following compounds:
3-(2-acetyl-7-methoxybenzophenone-4-yl)-1H-pyrazole;
3-[(1-cyclopentyl-3-ethylindole)-6-yl]-1H-pyrazole;
3-(2-acetyl-7-methoxybenzophenone-4-yl)-1-(2-methylbenzyl)-1H-pyrazole;
3-[(1-cyclopentyl-3-ethylindole)-6-yl]-1-(2,3-diferensial)-1H-pyrazole;
3-[(1-cyclopentyl-3-ethylindole)-6-yl]-1-(4-carboxyphenyl)-1H-pyrazole;
3-[(1-cyclopentyl-3-this is indazol)-6-yl]-1-(4-methoxyphenyl)-1H-pyrazole;
3-[(1-cyclopentyl-3-ethylindole)-6-yl]-1-(2-methylbenzyl)-1H-pyrazole;
3-[(1-cyclopentyl-3-ethylindole)-6-yl]-1-(4-methylsulfonylbenzoyl)-1H-pyrazole;
3-[(1-cyclopentyl-3-ethylindole)-6-yl])-1-(2-pyridylmethyl)-1H-pyrazole;
5-[(1-cyclopentyl-3-ethylindole)-6-yl])-1-(2-pyridylmethyl)-1H-pyrazole;
and their pharmaceutically acceptable salts, where in each case the compound can be in the form of mixtures of enantiomers such as the racemate, or mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereoisomer.

34. The compound according to claim 1, where the specified connection is selected from the following compounds:
3-(2-acetyl-7-methoxybenzophenone-4-yl)pyrazole;
3-[(1-cyclopentyl-3-ethylindole)-6-yl]pyrazole,
3-(2-acetyl-7-methoxybenzophenone-4-yl)-1-(2,3-diferensial)pyrazole,
3-(2-acetyl-7-methoxybenzophenone-4-yl)-1-(4-methylsulfonylbenzoyl)pyrazole,
3-[(1-cyclopentyl-3-ethylindole)-6-yl]-1-(2,3-differenl)pyrazole,
3-[(1-cyclopentyl-3-ethylindole)-6-yl])-1-(2-methylbenzyl)pyrazole,
3-[(1-cyclopentyl-3-ethylindole)-6-yl])-1-(4-methylsulfonylbenzoyl)pyrazole,
3-[(1-cyclopentyl-3-ethylindole)-6-yl])-1-(2-pyridylmethyl)pyrazole,
and their pharmaceutically acceptable salts, where in each case the compound can be in the form of mixtures of enantiomers such as the racemate, or mixture of diastereomers, or can be in the form of an individual enantiomer or otdelnov is the diastereoisomer.

35. The compound according to claim 1, where the specified connection is selected from the following compounds:
3-(2-acetyl-7-methoxybenzophenone-4-yl)pyrazole,
3-[(1-cyclopentyl-3-ethylindole)-6-yl]pyrazole,
3-(2-acetyl-7-methoxybenzophenone-4-yl)-1-(4-methylsulfonylbenzoyl)pyrazole,
3-[(1-cyclopentyl-3-ethylindole)-6-yl]-1-(2,3-differenl)pyrazole,
3-[(1-cyclopentyl-3-ethylindole)-6-yl])-1-(4-methylsulfonylbenzoyl)pyrazole,
3-[(1-cyclopentyl-3-ethylindole)-6-yl])-1-(2-pyridylmethyl)pyrazole,
and their pharmaceutically acceptable salts, where in each case the compound can be in the form of mixtures of enantiomers such as the racemate, or mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereoisomer.

36. Pharmaceutical composition having inhibitory activity against PDE4 enzyme, comprising the compound according to any one of claims 1 to 35 and a pharmaceutically acceptable carrier.

37. The pharmaceutical composition according p where connection provides a dose of 0.1-50 mg

38. The use of compounds according to any one of claims 1 to 35 for the preparation of medicines intended to improve cognitive abilities and/or treatment of psychosis.

39. The application of § 38, where the specified compound is administered in a unit dosage form suitable for injection of the compounds in an amount of 0.01-100 mg/kg of body weight per day.

40. Application pop, where the specified compound is administered in a unit dosage form suitable for administration person.

41. The application of § 38, where the specified drug is intended for treatment of deterioration or weakening of cognitive abilities.

42. The application of § 38, where the specified drug is intended for treatment of memory loss.

43. The application of § 42, where the specified drug is intended for treatment of memory loss associated with Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, a disease of the Peak, disease, Jakob-Creutzfeldt, HIV, cardiovascular disease, head trauma or age-related weakening of cognitive abilities.

44. The application of § 42, where the specified drug is intended for treatment of memory loss associated with dementia.

45. The application of § 38, where the specified drug is intended for treatment of psychosis.

46. The application of § 45, where the specified drug is intended for the treatment of schizophrenia, bipolar or manic depression or severe depression.

47. A method of treating a patient suffering from a disease involving decreased camp levels, including the introduction of a specified patient an effective amount of a compound according to any one of claims 1 to 35.

48. The application is connected to the I according to any one of claims 1 to 35 for the preparation of a medicinal product, designed for treatment of a patient suffering from an allergic or inflammatory disease.

49. Use p, where the specified drug is intended for treatment of chronic obstructive pulmonary disease.

50. Use p, where the specified drug is intended to treat asthma.

51. The use of compounds according to any one of claims 1 to 35 for the preparation of medicinal products intended for treatment of a patient suffering from neurodegeneration, caused by disease or injury.

52. The application of § 51, where the illness or injury is a stroke, spinal cord injury, Alzheimer's disease, multiple sclerosis, aminosterols or multiple system atrophy.

53. The application of § 42, where the specified drug is intended for treatment of memory loss associated with Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, a disease of the Peak, disease, Jakob-Creutzfeldt, depression, aging, head trauma, stroke, CNS hypoxia, cerebral dementia, multi-infarct dementia, acute neural disease, HIV or heart disease.

54. The use of compounds according to any one of claims 1 to 35 for the preparation of medicines intended for the treatment of the patient is and, suffering from drug or morphine addiction.

55. A method of inhibiting PDE4 enzyme to improve cognitive abilities and/or treatment of psychosis in a patient, comprising the introduction of a specified patient an effective amount of a compound according to any one of claims 1 to 35.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolidine-3,4-dicarboxamide derivatives of formula (I): , where: X is N or C-R6; R1 is C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluoro-C1-7alkyl, hydroxy-C1-7alkyl, CN-C1-7alkyl, R10C(O), R10OC(O)-, N(R11,R12)C(O)-; R10OC(O)C1-7alkyl, N(R11,R12)C(O)-C1-7alkyl, R10SO2, R10-SO2-C1-7alkyl, N(R11, R12)-SO2, N(R11,R12)-SO2-C1-7alkyl, aryl-C1-7alkyl, 5-member monocyclic heteroaryl containing a nitrogen atom, where the ring carbon atom can be substituted with a carbonyl group, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents an aromatic -member monocyclic ring with 1 S atom or a 6-member monocyclic ring with 1 N atom, C1-7alkoxy-C1-7alkyl, C1-7alkoxycarbonyl-C3-10cycloalkyl-C1-7alkyl or halogen substituted 4-member heterocyclyl-C1-7alkyl with one O atom; R2 is H, C1-7alkyl; R3 is aryl, aryl-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 1 S atom, a 6-member monocyclic ring with 1 or 2 N atoms, 9-, 10-member bicyclic system with 1 or 2 N atoms in one ring; R4 is H, C1-7alkyl, OH; R5, R6, R7, R8 are independently selected from a group consisting of H, halogen, C1-7alkyl, C1-7alkoxy, flouro-C1-7alkyl, fluoro-C1-7alkyloxy; R9 is aryl, heterocyclyl, heteroaryl, heterocyclyl-C(O)-; R10 is H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluro-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 4 N atoms, a 5-member heterocyclyl with 1 N atom; R11, R12 are independently selected from a group consisting of H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7 alkyl; and pharmaceutically acceptable salts thereof; where the term "aryl" represents a phenyl group which can be optionally substituted with 1 to 5 substitutes which are independently selected from a group consisting of the following: halogen, CF3, NH2, C1-7alkylsulphonyl, C1-7alkoxy, fluoro-C1-7alkyl, fluoro-C1-7 alkoxy; the term "heterocyclyl" represents a nonaromatic monocyclic 5-, 6-member heterocyclic group with 1, 2 N atoms, or with 1 N atom and 1 O atom, where the heterocyclyl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heterocyclyl group can be substituted with a carbonyl group; the term "heteraryl" represents an aromatic 5- or 6-member monocyclic ring system which can have 1, 2, 3 N atoms, or 1 N atom and 1 S atom, where the heteroaryl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heteroaryl group can be substituted with a carbonyl group. Formula I compounds have inhibitory activity towards coagulation factor Xa.

EFFECT: possibility of using said compounds in a pharmaceutical composition and for preparing a medicinal agent.

27 cl, 90 ex

FIELD: pharmacology.

SUBSTANCE: invention deals with formula I compounds and their sals pharmaceutically relevant in the capacity of phosphatidylinositol 3-kinase inhibitors, their preparation method as well as their application for production of a pharmaceutical preparation, a pharmaceutical compounds based thereon and a therapy method envisaging their application. In a formula compound R1 is represented by aminocarbonyl, non-obligatorily displaced with nitrile, or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with hydroxi, carboxi, C1-C8-alcoxicarbonyl, nitrile, phenyl, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkyl aminocarbonyl alkylcarbonyl that is non-obligatorily displaced with halogen, hydroxi, C1-C8-alkylanimo, di(C1-C8-alkyl)amino, carboxi, C1-C8-alcoxicarbonyl, nitrile, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, non-obligatorily displaced with C1-C8-cycloalkyl or R1 is represented by C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl, each of them non-obligatorily displaced with C1-C8-alcoxi, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, displaced with phenyl, additionally displaced with hydroxi or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-4 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with C1-C8-alkyl on condition that the 6-membered heterocyclic ring is no 1-piperidyl or R1 is represented by C1-C8-alkylaminocarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring is non-obligatorily displaced with C1-C8-alkyl or R1 is represented by -(C=O)-(NH)a-Het, where a stands to denote 0 or 1 and Het stands to denote a 4-, 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with hydroxi, C1-C8-alkyl, C1-C8-alcoxi or a 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 0 or 1 and T stands to denote C3-C8-cycloalkyl that is non-obligatorily displaced with hydroxi or C1-C8-alkyl displaced with hydroxi or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 1 and T stands to denote phenyl that is non-obligatorily displaced with C1-C8-alkyl or C1-C8-alkyl displaced with hydroxi, R2 is represented by C1-C3-alkyl; one of R3 and R4 is represented by R6 while the other is represented by R7; R5 is represented by hydrogen or a halogen; R6 is represented by hydrogen, hydroxi, amino, -SOR8, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxi, -OR8 or C1-C8-halogenalkyl; R7 is represented by hydrogen, R11, -OR11, halogen, -SO2R8, ciano or C1-C8-halogenalkyl or, when R4 is represented by R7, R7 may equally be represented by -NR12R13; R8 and R11 are independently represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, nitrile, amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino; any R9 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, C1-C8-alcoxi, nitrile, amino, C1-C8-akrylamino, di(C1-C8-alkyl)amino or 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring where the ring is non-obligatorily displaced with C1-C8-alkyl, and R10 is represented by hydrogen or C1-C8-alkyl or R9 and R10 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl; any R12 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino and R13 is represented by halogen or C1-C8-alkyl or R12 and R13 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl.

EFFECT: proposed compounds are to be utilised for treatment of diseases mediated by phosphatidilinozitol 3-kinase such as allergy, psoriasis, diabetes, atherosclerosis, diabetes, cancer.

19 cl, 3 tbl, 181 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: pharmacology.

SUBSTANCE: invention refers to compounds of formula (I) as inhibitor of phosphotyrosinphosphotase 1B, and to application thereof for making a based medical product. In general formula (I) X represents C-R2; Y represents O, R1 represents phenyl, 5-merous heterocycle with one sulphur atom with phenyl residue, and heterocyclic residue being mono-, twice- or trisubstituted with halogen, CN, -OH, -CF3, -(C1-C6)alkyl, -COOH, -(CH2)-COOH, phenyl, -O-phenyl with phenyl ring being substituted with halogen; R2, R3, R4, R5, R6, R7 and R8 represent H.

EFFECT: compounds can find application in treating adipose and carbohydrate metabolic disorders, including for controlling blood glucose.

3 cl, 2 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: there are described derivatives of 1,3,4-oxadiazol-2-one of formula I and their pharmaceutically acceptable salts wherein ARYL represents phenyl which can have one substitute chosen from halogen; W represents chain or (CH2)m where m designates an integer 1 to 4; Z represents -O(CH2)n-, -(CH2)n-Y-(CH2)n- where Y designates O, n independently means an integer 1 to 5; X represents O or S; R1 represents C1-6 alkyl; R2 represents substituted phenyl where substitutes are chosen from the group including C1-6alkyl, C1-4perfluoralkyl. There are also described pharmaceutical composition, and method of treating a disease in mammal wherein said disease can be modulated by PPAR-delta receptor binding activity.

EFFECT: compounds possess agonist or antagonist activity with respect to PPAR-delta receptor.

9 cl, 2 tbl, 34 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: object of present invention is the following compounds: thiazol-2-ylamide 2-(3,4-dichlorophenoxy) hexanoic acid, 2-(4-fluorophenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-K-pyridin-2-ylhexaneamide, 2-(3,4-dichlorophenoxy)-4-methyl-N,3-thiazol-2-ylpentaneamide, 2-(1,1'-biphenyl-4-yloxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-isopropylphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(3-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, and others, named in the formula of invention. Present invention also relates to a pharmaceutical composition, which contains the invented compound as an active ingredient and use of compounds in preparing a medicinal agent which increases activity of glucose. The invention also pertains to a compound of formula (I) where G is -C(O)-; L1 is a direct bond, A is >N-, X is a direct bond, R1 is cyclohexyl, R3 is cyclohexyl, substituted with R34, R4 is hydrogen; R5 is thiazol-5-yl, substituted with R48.

EFFECT: obtaining compounds which can be used for preparing a medicinal agent which can be used for treating diseases caused by glucokinase deficiency, for preparing a medicinal agent for treating diseases where increased activity of glucokinase is favourable.

6 cl, 143 ex

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds with formula I: , in which: R1 is R6C(O)-, HC(O)-, R6SO2-, R6OC(O)-, (R6)2NC(O)-, R6-, (R6)2NC(O)C(O)-; R2 is a hydrogen atom, -CF3 or R8; R3 is a hydrogen atom or (C1-C4)aliphatic group-; R4 is -COOH; R5 is -CH2F or -CH2O-2,3,5,6- tetrafluorophenyl; R6 is (C1-C12)aliphatic or (C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-; and where R6 is substituted with up to 6 substitutes, independently chosen from R; R is a halogen atom, OR7 and -R7; R7 is (C1-C6)aliphatic group-, (C3-C10)cycloaliphatic group; R8 is (C1-C12)aliphatic- or (C3-C10)cycloaliphatic group; to a pharmaceutical composition with caspase-inhibiting activity, based on compound with formula I, to methods of treatment as well as to methods of inhibiting caspase-mediated functions and to a method of reducing production of IGIF or IFN-β. The invention also relates to a method of preserving cells, as well as to a method of producing compound with formula I.

EFFECT: new compounds are obtained and described, which can be used for treating diseases in the development of which caspase activity takes part.

34 cl, 4 tbl, 43 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinoline derivatives of formula I or pharmaceutically acceptable salts thereof or esters with tyrosine kinase inhibitor properties. In formula I , R1 is selected from hydroxy, C1-C4-alkoxy, hydroxy(C2-C4-alkoxy), C1-C3-alkoxy-(C2-C4-alkoxy) or from a group of formula Q2-X3 - in which X3 is O, and Q2 is azetidin-1-yl-C2-C4-alkyl, pyrrolidin-1-yl- C2-C4-alkyl, piperidino-C2-C4-alkyl, piperazino-C2-C4-alkyl or morpholino-C2-C4-alkyl; b is 1, 2, or 3; each R2, which can be identical or different, is selected from fluorine, chlorine, bromine, C1-C4-alkyl, C2-C4-alkenyl and C2-C4-alkenyl; Q1 is piperidinyl; a is 0; X1 is CO; X2 is a group of formula: -(CR12R13)P-(Q5)m-, where m is 0 or 1, p is 0, 1, 2, 3 or 4; each of R12 and R13, which can be identical or different, is selected from hydrogen, C1-C6-alkyl, amino, C1-C6-alkylamino and di-[C1-C6-alkyl]amino, and Q5 is C3-C7cycloalkylene; Z is selected from hydroxy, amino, C1-C6-alkylamino, di-[C1-C6-alkyl]amino, C1-C6-alkoxy and a group of formula: Q6-X9-, in which X9 is a single bond and Q6 is heterocyclyl or heterocyclyl-C1-C4 alkyl; under the condition that, if m and p are equal to 0, Z is heterocyclyl.

EFFECT: proposed derivatives can be used in treating proliferative diseases, particularly for treating malignant growths.

32 cl, 4 dwg, 2 tbl, 37 ex

FIELD: medicine.

SUBSTANCE: invention is related to compound represented by formula (1) , in formula A represents nitrogen-containing saturated ring; m represents integer number, equal to 0, 1 or 2; n represents integer number, equal to 1, 2, 3 or 4; G1 represents atom of hydrogen, hydroxyl group or alkoxygroup; G2 represents atom of halogen, hydroxyl group, cyanogroup, alkyl group, alkenyl group, alkinyl group, which may be substituted with hydroxyalkyl group, alkoxygroup, alkyl thiogroup, aminogroup or aryl group; G3 represents atom of hydrogen; G4 represents hydroxyl group or -N(R1)(R2) (R1 and R2 may be identical or different, and independently represent atom of hydrogen, alkyl group, aralkyl group, alkenyl group or saturated heterocyclic group); and G5 represents substituent at carbonic atom, which constitutes nitrogen-containing saturated ring, represented with A, and represents atom of hydrogen, to medicinal agent on the basis of this compound for treatment and prophylaxis of glaucoma, to inhibitor of phosphorylation of regulatory light chain of myosin and inhibitor of kinase Rho/Rho path, and also to method of therapeutical and/or prophylactic treatment of glaucoma.

EFFECT: new compounds have been produced and described, which efficiently inhibit phosphorylation of regulatory light chain of myosin.

32 cl, 42 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: invention is related to compounds with common formulae I , III , IV and V , value of radicals such as given in formula of invention. Also suggested invention is related to pharmaceutical composition in the basis of above-mentioned compounds, to their use, and also to method of frequent urination treatment, enuresis and increased activity of urinary bladder.

EFFECT: increased efficiency of diseases treatment, in particular for treatment of frequent urination and enuresis, increased activity of urinary bladder and pain.

16 cl, 406 ex, 73 tbl

V:

Amide derivatives // 2375352

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I, to its pharmaceutically acceptable salts exhibiting properties of inhibitors of cytokine production, such as TNF (tumour necrosis factor) and various members of interleukins (IL) family, and properties of kinase inhibitors, particularly p38α kinase. The invention also concerns methods for producing; pharmaceutical compositions and application thereof for making the medicines for treating diseases affected by the compound of the invention with specified activity. In formula I , m represents 0, 1 or 2; R1 represents halogeno, hydroxy, (1-6C) alkyl, (1-6C)alkoxy, (2-6C)alkenyl, (2-6C) alkinyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, amino-(2-6C) alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, N-(1-6C)alkylcarbamoyl - (1-6C)alkoxy, di[(1-6C) alkyl]amino-(1-6C)alkyl, hydroxy-(2-6C)alkylamino, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyloxy and heterocyclyl-(1-6C)alkoxy and wherein any heteroaryl or heterocyclyl group in substitute representing R1, can probably have 1 or 2 substitutes chosen from hydroxy, halogeno, (1-6C) alkyl, (2-6C)alkinyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxycarbonyl, (2-6C) alkanoyl, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, carboxy- (1-6C)alkyl and methylsulphonyl and wherein any said substitute representing R1 which contains group CH2 attached to 2 carbon atoms, or group CH3 attached to carbon or nitrogen atom, can probably have with each specified group CH2 or CH3, one or two substitutes chosen from halogeno, hydroxy, amino, triflouromethyl, oxo, carboxy, acetamido, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkyamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, halogen-(1-6C)alkyl, (1-6C)alkoxycarbonyl, carbamoyl, N, N-di-[(1-6)alkyl]carbamoyl, (1-6C)alkylsulphonyl, heteroaryl, heteroaryl-(1-6)alkyl and heterocyclyloxy and wherein any heterocyclyl group in substitute representing R1, can probably have 1 oxo-subsitute; R2 represents trifluoromethyl or (1-6C)alkyl; R3 represents hydrogen or (1-6C)alkyl; and R4 represents (3-6C)cycloalkyl, and R4 can be optionally substituted with one or more substitutes chosen from (1-6C)alkyl; and wherein heteroaryl represents aromatic 5- or 6-merous monocyclic ring containing one or two heteroatoms chosen from oxygen, nitrogen and sulphur; heterocyclyl represents saturated 3-10-merous monocyclic or bicyclic ring, each containing one or two heteroatoms chosen from oxygen, nitrogen and sulphur.

EFFECT: improved efficiency.

24 cl, 16 tbl, 66 ex

FIELD: medicine.

SUBSTANCE: invention relates to derivatives of 5- or 6-substituted benzimidazoles, being inhibitory active as regards replication of respiratory syncytial viruses and having formula (I), wherein Q is R6a, piperidinyl, substituted with R6; G is methylene; R1 is piridyl, substituted with 2 substitutes, chosen from hydroxy, C1-6alkyl; one of R2a and R2b is cyano-C2-6alkenyl, Ar3C1-6alkyl, Het-C1-6alkyl, N(R8aR8b)C1-6alkyl, Ar3C2-6alkenyl, Ar3-amino-C1-6alkyl, Het-amino-C1-6alkyl, Het-C1-6alkyl-amino-C1-6alkyl, Ar3tioC1-6alkyl, Ar3amino-carbonyl, Het-amino-carbonyl, Ar3(CH2)ncarbonyl-amino, Het-(CH2)ncarbonyl-amino; and the other of R2a and R2b represents hydrogen; R3 represents hydrogen or C1-6alkyl; in the case when R2a represents hydrogen, R3 represents hydrogen; in the case when R2b represents hydrogen, R3 represents hydrogen or C1-6alkyl; R5 represents hydrogen; R6 represents C1-6alkyl, optionally substituted with one or two substitutes, each of which is independently chosen from group consisting of NR7aR7b, Ar2, hydroxy, amino-carbonyl, amino-sulphonyl; R6a is C1-6alkyl, substituted with one or two substitutes, each of which is independently chosen from group consisting of Ar2, hydroxy or heterocyclic, chosen from a group consisting of piperidinyl, piperazinyl; R7a represents hydrogen; R7b represents hydrogen; R8a represents Ar3, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy C1-6alkyl, cyanoC1-6alkyl, di(C1-6alkyl)aminoC1-6alkyl, Ar3C1-6alkyl, HetC1-6alkyl, amino-carbonyl C1-6alkyl, carboxylC1-6alkyl; R8b represents Ar3, C1-6alkyl, hydroxyC1-6alkyl, Ar3C1-6alkyl, HetC1-6alkyl; each independently represents 1; Ar1 represents phenyl; Ar2 represents phenyl or phenyl substituted with one C1-6alkyl-oxy; Ar3 represents phenyl, naphtalenyl, 1,2,3,4-tetra-hydro- naphtalenyl or indanyl, wherein said phenyl, naphtyl, 1,2,3,4- tetra-hydro- naphtalenyl or indanyl can be optionally and each individually substituted with one or more, for example, 2 or 3 substitutes chosen from group consisting of halogen, hydroxy-, mercapto- cyano-, C1-6alkyl, C2-6alkinyl, Ar3 , hydroxy-C1-6alkyl, CF3, cyano-C1-6alkyl, amino-carbonyl, C1-6alkyl-oxy, C1-6alkyltio, Ar1-oxy, Ar1-amino, amino-sulphonyl, amino-carbonylC1-6alkyl, C1-4alkyl-carbonyl, C1-4alkyl-carbonyl-amino and C1-4alko-oxy-carbonyl; Het represents heterocycle chosen from phuranyl, imidazolyl, morpholinyl, piridyl, quinolene, iso-quinolene, each of said heterocycles can be optionally substituted with hydroxyl-Sibalkyl, as well as to acid additional salt thereof and stereo-chemical isomeric forms. In addition, the invention relates to pharmaceutical composition on the basis of compound of formula I and to application of compound of formula I and for production of medicinal preparation.

EFFECT: new derivatives of benzimidazole having useful biological properties.

22 cl, 6 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new a compound of formula I or formula II, or to its pharmaceutically acceptable salts, I II, where X is S; R1 is H or C1-C6alkyl; R2 is NR5R6; R3 is aryl, substituted with a halogen; R4 is H; R5 is H; R6 is H; R7 is CH2NR8R9 where R8 is H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl), heterocycle(C2-C6alkenyl), hydroxyl(C1-C6alkyl), hydroxyl(C2-C6alkyl), C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbamoyl(C1-C6alkyl); where the above mentioned aryl is an aromatic ring and is not substituted or substituted with one to three substituting groups, each of which, independently from the others, is chosen from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, trifluoromethoxy, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy), R9 is H, C1-C10alkyl, heterocycle(C1-C6alkyl) or heterocycle(C2-C6alkenyl); where the above mentioned heterocycle represents a 5-member saturated monocyclic ring system, consisting of carbon atoms, as well as heteroatoms, chosen from a group comprising N, O, and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes NO2, aryl(C1-C6alkyl), arylsulphonyl; or R8 and R9 together with nitrogen, to which they are bonded, form a heterocycle, which represents a 5 - 7-member saturated monocyclic ring system, consisting of carbon atoms, as well as one to three heteroatoms, chosen from a group comprising N, O and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes C1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6-alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidin-2-yl; and m equals 0. The invention also relates to a pharmaceutical composition, as well as to use of formula I or formula II compounds.

EFFECT: obtaining new biologically active compounds, with inhibitory properties towards casein kinase 1ε.

32 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to N-substituted aniline and diphenylamine analogues, chosen from 3,4-bisdifluoromethoxy-(3-carboxyphenyl)-N-(5-(2-chloropyridinylmethyl))-aniline, 3,4-bisdifluoromethoxy - N-(3-carboxyphenyl) - N-(3-(2-chloropyridylmethyl))-aniline, 3,4 - bisdifluoromethoxy - N-(3-carboxyphenyl) - N-(4-(3,5-dimethylisoxazolylmethyl)) aniline, 3 - cyclopentyloxy - 4-methoxy - N-(3-aminocarbonylphenyl) - N-(3-pyridylmethyl) aniline and other compounds given in paragraph 1 of the formula of invention and to their pharmaceutically acceptable salts as inhibitors of PDE4 enzyme.

EFFECT: compounds can be used for treating and preventing diseases caused by activity of the PDE4 enzyme.

15 cl, 8 dwg, 58 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the new compounds of general formula (II) , whereat values R1, R2, X, R11, R12, R18, R19, m, n are displayed in claim 1 of the formula.

EFFECT: compounds display agonistic and antagonistic activity which allows to propose their usage in pharmaceutical compositions for treatment of diseases and distresses connected with histamine H3 receptor.

38 cl, 80 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the triheterocylic compounds of formula (Ia) and their pharmaceutically acceptable salts used as growth inhibitors of the cancer or tumor cells, to the preparation method and pharmaceutical compositions thereof, to the treatment method used aforesaid compounds as well as to the intermediates of formula (II) the to the method of its preparation. In general formulas (Ia) and

, Q1 is -N(R1)-; Q2 is -C(R3)-; Q3 is -C(R5)-; Q4 is -C(R9)-; R1 is -Ym(Ra), where -Ra is -H, -OH, -C(O)R14, -O-C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OS(O)2ONa-; R2 is -H; R3, R4 and R5 independently are -Ym(Rb), where Rb is -H, halogen, -C1-C8 alkyl, -O-(C1-C8 alkyl) or -OR14, -at condition that if value m of radical Ym(Rb) is equal 0, then R5 is not H; R6 is -H; R7 is -Ym-(RC), where -RC is -O-(C1-C8 alkyl) or -NH(phenyl), R8 is -Ym(Rd), where - Rd is -H, -OH, R9, R10, R11, R12 and R13 independently are -Ym(Re), where Re is -H, halogen, 5-6-membered heterocycle containing 2 heteroatoms selected from N or O, -OR14, or -O-C(O)OR14; every R14 independently is -H, -C1-C8 alkyl, -phenyl, 5-6-membered heterocycle containing one heteroatom being S; every Y independently is -C1-C8 alkylene-; every m independently is equal 0 or 1.

EFFECT: claimed compounds can find application for treatment of different cancer species.

41 cl, 4 tbl, 4 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

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