Acylaminothiazole derivatives, their preparation and application as inhibitors of b-amiloyd peptides production

FIELD: chemistry, medicine.

SUBSTANCE: in the general formula (I): X is oxygen atom; R1 is C1-10-alkyl , substituted if necessary by phenyl or thienyl group; or R1 is C3-7-cycloalkyl, thienyl, pyridinyl; the thienyl groups can be substituted if necessary by 1-2 C1-3-alkyl groups; phenyl can be substituted if necessary by 1-2 halogen atoms; R2 is C1-6-alkyl; or R2 is C3-7-cycloalkyl, phenyl or pyridinyl; phenyl if necessary can be substituted by one or more halogen atoms or by the CN, C1-3-alkyl, C1-3-alkoxyl, C1-3-fluoroalkyl groups; R3 is C1-6-alkyl; R4 is hydrogen atom or C1-6-alkyl; R5 and R5' are independently of each other the hydrogen atom, hydroxyl; or R5 and R5' form together the oxo-group; n is integer value in the range from 0 to 3; R6 is independently of each other hydrogen atom, halogen atom, C1-3-alkyl, C1-3-alkoxyl.

EFFECT: compounds of present invention can find application as pharmaceutical for pathology treatment where the inhibitor of β-amiloyd peptide β-A4 is useful.

8 cl, 1 tbl, 7 ex

 

The object of the invention are derivatives of allumination, obtaining them and their use in therapy.

The first object of the invention are compounds corresponding to General formula (I):

in which:

X denotes an oxygen atom or sulfur;

R1stands With1-10-alkyl, if necessary substituted C3-7-cycloalkyl, phenyl, tanila; or R1represents C3-7-cycloalkyl, thienyl, pyridinyl, pyrimidinyl;

thienyl group, if necessary, can be substituted With 1-31-3-alkyl groups; phenyl may be, if necessary substituted by 1-5 halogen atoms or C1-3-alkyl groups, C1-3-alkoxy groups, With1-3-alkyl fluoride groups1-3-feralcode groups;

R2represents C1-6-alkyl, if necessary substituted C3-7-cycloalkyl, phenyl, C1-3-alkoxyl, hydroxyl; or R2stands With3-7-cycloalkyl, piperidinyl, phenyl or pyridinyl;

C3-7-cycloalkyl and piperidinyl, if necessary, can be substituted by one or more groups C1-3-alkyl, C1-3-alkoxyl, hydroxyl, C1-3-foralkyl, C1-3-forecoxae;

phenyl and pyridinyl, if necessary, can be substituted by one or more atoms Gal the gene or CN groups, C1-3-alkyl, C1-3-alkoxyl, hydroxyl, Cl-3-foralkyl, C1-3-forecoxae;

R3denotes a hydrogen atom or a C1-6-alkyl which may be substituted With3-7-cycloalkyl;

R4denotes a hydrogen atom or a C1-6-alkyl;

R5and R5'denote, independently of one another, a hydrogen atom, halogen, hydroxyl, C1-3-alkyl; or R5and R5'together form an oxo-group or oximo group, such as:

where R7denotes a hydrogen atom or a C1-3-alkyl;

n denotes an integer from 0 to 3; and

R6denotes, independently of one another, when n=2 or 3, a hydrogen atom, halogen, hydroxyl, C1-3-alkyl, C1-3-alkoxy, C1-3-foralkyl or C1-3-feralcode.

Of the compounds of General formula (I), a preferred subgroup of compounds represented by the compounds in which:

X denotes an oxygen atom or sulfur; and/or

- R1represents C1-5-alkyl, preferably methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, which can be substituted by phenyl, tanila; or R1represents C3-7-cycloalkyl, preferably, cyclohexyl, thienyl, pyridinyl; thienyl group may be substituted by one or two C1-3-alkyl the YMI, preferably, methyl groups; phenyl may be substituted by one or two halogen atoms, preferably chlorine or fluorine; and/or

- R2represents C1-6-alkyl, preferably ethyl, 1-methylethyl; or R2represents C3-7-cycloalkyl, preferably, cyclohexyl, phenyl or pyridinyl; and phenyl may be substituted by 1-3 groups CN, C1-3-alkilani, preferably, stands, ethyl, C1-3-alkoxylate, preferably, methoxy, ethoxy, hydroxyl, perlconsole, preferably, triptoreline, or halogen atoms, preferably chlorine, fluorine; and/or

- R3represents C1-6-alkyl, preferably methyl, ethyl, propyl; and/or

- R4denotes a hydrogen atom or a C1-6-alkyl, preferably methyl or 4-methylpentyl; and/or

- R5and R5'denote, independently of one another, a hydrogen atom, a hydroxyl; or R5and R5'together form an oxo group; and/or

- R6denotes a hydrogen atom, halogen, preferably chlorine or fluorine, C1-3-alkyl, preferably methyl, C1-3-alkoxy, preferably methoxy or ethoxy; and/or

- n=0 or 1.

Compounds in which both X, R1, R2, R3, R4, R5, R5', R6and n have the meanings given above for subgroups preferred connection is on, are particularly preferred, and most preferred among them are compounds in which:

X denotes an oxygen atom; and/or

C1-4-alkylene is methylene; and/or

the carbon atom carrying the group R3has the configuration (S).

As examples of preferred compounds include the following compounds:

1. (2S)-2-{[(2R)-2-cyclohexyl-2-hydroxyacetic]amino}-N-(5-{2-[(cyclohexyloxy)methyl]phenyl}-1,3-thiazol-2-yl)pentanone;

2. (2S)-2-{[(2S)-2-cyclohexyl-2-hydroxyacetic]amino}-N-(5-{2-[(cyclohexyloxy)methyl]phenyl}-1,3-thiazol-2-yl)pentanone;

3. (2S)-N-(5-{2-[(cyclohexyloxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[2-(3-pyridinyl)acetyl]amino}pentanone;

4. N-((1S)-1-{[(5-{2-[(cyclohexyloxy)methyl]phenyl}-1,3-thiazol-2-yl)amino]carbonyl}butyl)-2-hydroxy-4-methylpentanoic;

5. (2S)-N-{5-[2-(isopropoxyphenyl)phenyl]-4-methyl-1,3-thiazol-2-yl}-2-{[2-(3-thienyl)acetyl]amino}pentanone;

6. (2S)-N-{5-[2-(isopropoxyphenyl)phenyl]-1,3-thiazol-2-yl}-2-{[2-(3-thienyl)acetyl]amino}pentanone;

7. (2S)-N-{5-[2-(isopropoxyphenyl)phenyl]-1,3-thiazol-2-yl}-2-{[3-(3-thienyl)propanoic]amino}pentanone;

8. (2S)-N-{5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}-2-{[2-(3-thienyl)acetyl]amino}pentanone;

9. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-{5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone;

10. (2S)-N-{5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}-2-{[2-(2-thienyl)acetyl]the Mino}butanamide;

11. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-{5-[2-(isopropoxyphenyl)phenyl]-1,3-thiazol-2-yl}pentanone;

12. (2S)-N-{5-[2-(isopropoxyphenyl)phenyl]-1,3-thiazol-2-yl}-2-{[2-(2-thienyl)acetyl]amino}pentanone;

13. (2S)-2-[(3,3-dimethylbutanol)amino]-N-{5-[2-(isopropoxyphenyl)phenyl]-1,3-thiazol-2-yl}pentanone;

14. N-{(1S)-1-[({5-[2-(isopropoxyphenyl)phenyl]-1,3-thiazol-2-yl}amino)carbonyl]butyl}-3-methyl-2-oxopentanoic;

15. (2S)-N-{5-[2-(ethoxymethyl)phenyl]-1,3-thiazol-2-yl}-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

16. (2S)-2-{[2-(2,5-dimethyl-3-thienyl)acetyl]amino}-N-{5-[2-(ethoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone;

17. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-[5-(2-{[3-(triptoreline)phenoxy]methyl}phenyl)-1,3-thiazol-2-yl]pentanone;

18. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-{5-[4-methoxy-2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone;

19. (2S)-N-(5-{2-[(2-pertenece)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

20. (2S)-N-(5-{2-[(2-ethylenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

21. (2S)-2-{[3-(2,4-dichlorophenyl)propanoic]amino}-N-{5-[2-{phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone;

22. (2S)-2-{[2-(5-methyl-2-thienyl)acetyl]amino}-N-{5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone;

23. (2S)-N-{5-{2-[(2,3-dimethoxyphenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]AMI is about}pentanone;

24. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-[5-(2-{[2-(triptoreline)phenoxy]methyl}phenyl)-1,3-thiazol-2-yl]pentanone;

25. (2S)-N-(5-{2-[(3,5-dimethoxyphenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

26. (2S)-N-(5-{2-[(2,3-dimethylphenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

27. (2S)-N-(5-{2-[(3,4-dimethylphenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

28. (2S)-N-(5-{2-[(2,6-dimethylphenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

29. (2S)-N-(5-{2-[(3-chlorophenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

30. (2S)-N-(5-{2-[(3,4-dimethoxyphenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

31. (2S)-N-(5-{2-[(2,6-dimethoxyphenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

32. (2S)-N-(5-{2-[(2,4-dimethylphenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

33. (2S)-N-(5-{2-[(2,5-dimethylphenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

34. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-{4-methyl-5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone;

35. (2R)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-{5-[2-(phenoxymethyl)phenyl]-1,3-t the azole-2-yl}pentanone;

36. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-(5-{2-[(2-methylphenoxy)methyl]phenyl}-1,3-thiazol-2-yl}pentanone;

37. (2S)-2-{[(2S)-2-hydroxy-3-methylbutanoyl]amino}-N-{5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone;

38. (2S)-2-[(2-hydroxy-3,3-dimethylbutanol)amino]-N-(5-{2-[(2-methoxyphenoxy)methyl]phenyl}-1,3-thiazol-2-yl)pentanone;

39. (2S)-N-(5-{2-[(2-ethoxyphenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-[(2-hydroxy-3,3-dimethylbutanol)amino]pentanone;

40. (2S)-2-[(2-hydroxy-3-phenylpropanol)amino]-N-{5-[2-(phenoxymethyl)-phenyl]-1,3-thiazol-2-yl}pentanone;

41. (2S)-N-(5-{2-[(2,6-dichlorophenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-[(2-hydroxy-3,3-dimethylbutanol)amino]pentanone;

42. (2R)-3-ethyl-2-hydroxy-N-{(1S)-1-[({5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}amino)carbonyl]butyl}pentanone;

43. (2S)-3-ethyl-2-hydroxy-N-{(1S)-1-[({5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}amino)carbonyl]butyl}pentanone;

44. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-{5-[2-(isopropoxyphenyl)-4-methoxyphenyl]-1,3-thiazol-2-yl}pentanone;

45. (2S)-N-(5-{2-[(2-(chloro-6-methylphenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

46. (2S)-N-(5-{2-[(2,6-divergence)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

47. (2S)-N-{5-[4-chloro-2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

48. (2S)-N-{5-[4-fluoro-2-(phenoxymethyl)Fe is Il]-1,3-thiazol-2-yl}-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

49. (2S)-2-{[(2S)-2-hydroxy-3-methylbutanoyl]amino}-N-{5-[4-methoxy-2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone;

50. (2S)-N-(5-{2-[(3,4-dichlorophenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

51. (2S)-N-((1S)-1-{[(5-{2-[(cyclohexyloxy)methyl]phenyl}-1,3-thiazol-2-yl}amino]carbonyl}butyl)-2-hydroxy-4-methylpentanoic;

52. (2S)-N-{5-[4-ethoxy-2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

53. (2S)-N-{5-[4-ethoxy-2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}-2-{[(2S)-2-hydroxy-3-methylbutanoyl]amino}pentanone;

54. (2S)-N-{5-[5-fluoro-2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

55. (2S)-N-{5-[5-chloro-2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

56. (2S)-N-{5-[5-fluoro-2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}-2-{[(2S)-2-hydroxy-3-methylbutanoyl]amino}pentanone;

57. (2S)-N-(5-{2-[(cyclohexyloxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

58. (2S)-2-hydroxy-3,3-dimethyl-N-[(1S)-1-methyl-2-oxo-2-({5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}amino)ethyl]butanamide;

59. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-{5-[4-methyl-2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone;

60. (2S)-2-{[(2S)-2-hydroxy-3-methylbutanoyl]amino}-N-{5-[5-methyl-2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone;

61. (2S)-N-(5-{2-[(3-tzia is openvxi)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

62. (2S)-N-(5-{2-[(3-pertenece)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

63. (2S)-N-(5-{2-[(3-pertenece)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3-methylbutanoyl]amino}pentanone;

64. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-{5-[5-methyl-2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone;

65. (2S)-2-{[(2S)-2-hydroxy-3-methylbutanoyl]amino}-N-{5-[4-methyl-2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone;

66. (2S)-N-((1S)-2-{[(5-{2-[(cyclohexyloxy)methyl]phenyl}-1,3-thiazol-2-yl}-amino]-1-methyl-2-oxoethyl}-2-hydroxy-3,3-dimethylbutyramide;

67. (2S)-N-(5-{2-[(2-chloro-5-methylphenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

68. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-(5-{2-[(3-methylphenoxy)methyl)phenyl}-1,3-thiazol-2-yl)pentanone

69. (2S)-N-(5-{2-[(2-cianfrocca)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

70. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-(5-{2-[(4-pyridyloxy)methyl]phenyl}-1,3-thiazol-2-yl)pentanone;

71. (2S)-N-(5-{2-[(2-chloro-4,5-dimethylphenoxy))methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

72. (2S)-N-(5-{2-[(4-chloro-3-methylphenoxy))methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

73. (2S)-N-(5-{2-[(2,3-dichlorophenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]Amin is}pentanone;

74. (2S)-N-(5-{2-[(2,3-divergence)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone;

75. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-{4-(4-methylpentyl)-5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl)pentanone.

The object of the invention are also, among the compounds of General formula (I), compounds of General formula (I'):

(I')

in which:

X denotes an oxygen atom or sulfur;

R1represents C1-10-alkyl, if necessary substituted C3-7-cycloalkyl, phenyl, tanila; or R1represents C3-7-cycloalkyl, thienyl, pyridinyl, pyrimidinyl;

thienyl group, if necessary, can be substituted With 1-31-3-alkyl groups; phenyl may be, if necessary substituted by 1-5 halogen atoms or C1-3-alkyl groups, C1-3-alkoxy groups, With1-3-alkyl fluoride groups1-3-feralcode groups;

R2represents C1-6-alkyl, if necessary substituted C3-7-cycloalkyl, phenyl, C1-3-alkoxyl, hydroxyl; or R2stands With3-7-cycloalkyl, piperidinyl, phenyl or pyridinyl;

C3-7-cycloalkyl and piperidinyl, if necessary, can be substituted by one or more groups C1-3-alkyl, C1-3-alkoxyl, hydrox the La, C1-3-foralkyl, C1-3-forecoxae;

phenyl and pyridinyl, if necessary, can be substituted by one or more halogen atoms or groups C1-3-alkyl, C1-3-alkoxyl, hydroxyl, C1-3-foralkyl, C1-3-forecoxae;

R3denotes a hydrogen atom or a C1-6-alkyl which may be substituted With3-7-cycloalkyl;

R4denotes a hydrogen atom or a C1-4-alkyl;

R5and R5'denote, independently of one another, a hydrogen atom, halogen, hydroxyl, C1-3-alkyl; or R5and R5'together form an oxo-group or oximo group, such as:

where R7denotes a hydrogen atom or a C1-3-alkyl;

n denotes an integer from 0 to 3; and

R6denotes, independently of one another, when n=2 or 3, a hydrogen atom, halogen, hydroxyl, C1-3-alkyl, C1-3-alkoxy, C1-3-foralkyl or C1-3-feralcode.

Of the compounds of General formula (I') sub-group of preferred compounds represented by the compounds in which:

X denotes an oxygen atom or sulfur; and/or

- R1represents C1-5-alkyl, preferably methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, which can be substituted by phenyl, tanila; and R 1represents C3-7-cycloalkyl, preferably, cyclohexyl, thienyl, pyridinyl; thienyl group may be substituted by one or two C1-3-alkyl, preferably methyl groups; phenyl may be substituted by one or two halogen atoms, preferably chlorine or fluorine; and/or

- R2represents C1-6-alkyl, preferably ethyl, 1-methylethyl; or R2represents C3-7-cycloalkyl, preferably, cyclohexyl, or phenyl;

whereby phenyl may be substituted by one or two C1-3-alkyl, preferably methyl, ethyl, C1-3-alkoxy, preferably methoxy, ethoxy-, hydroxyl, feralcode is, preferably, triptoreline-, groups or one or two halogen atoms, preferably chlorine, fluorine; and/or

- R3represents C1-6-alkyl, preferably ethyl, propyl; and/or

- R4denotes a hydrogen atom or a C1-4-alkyl, preferably methyl; and/or

- R5and R5'denote, independently of one another, a hydrogen atom, a hydroxyl; or R5and R5'together form an oxo group; and/or

- R6denotes a hydrogen atom, halogen, preferably chlorine or fluorine, C1-3-alkoxy, preferably methoxy; and/or

- n=0 or 1.

In the framework of the invention understand:

- Ct-zwhere t and z mo is ut to take values from 1 to 10, the carbon chain which can have from t to z carbon atoms, for example, With1-3-carbon chain which may contain from 1 to 3 carbon atoms, With3-6-carbon chain which may contain from 3 to 6 carbon atoms, ...;

- alkyl, a straight or branched saturated aliphatic group, for example, With1-6-alkyl denotes a straight or branched carbon chain of 1-6 carbon atoms, in particular methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, ..., preferably, methyl, ethyl, propyl or 1-methylethyl;

- alkylenes, divalent alkyl group;

- cycloalkyl, cyclic alkyl group, for example, C3-7-cycloalkyl denotes the carbon cycle of 3-7 carbon atoms, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, preferably, cyclopentyl or cyclohexyl;

- alkoxyl, -O-alkyl group, where alkyl has the above values;

- perakyla, alkyl group in which one or more hydrogen atoms replaced by fluorine atom;

- coralcalcium, alkoxy group in which one or more hydrogen atoms replaced by fluorine atom; and

the halogen atom, fluorine, chlorine, bromine or iodine.

Compounds of General formula (I) may contain one or more asymmetric carbon atoms. Thus the om, they can exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as mixtures thereof, including racemic mixtures, form part of the invention.

The compounds of formula (I) may exist in the form of bases or of salts of joining with acids. Such salts attach form part of the invention.

These salts preferably get with pharmaceutically acceptable acids, but the salts of other acids that are suitable, for example, for the purification or separation of compounds of formula (I), also form part of the invention.

Compounds of General formula (I) can be in the form of a hydrate or of a solvate, namely, in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrate and solvate are also part of the invention.

In further description, separated by group, see group, which can be easily derived from the molecules with the removal of the electron pair, by breaking the heterolytic communication. This group can thus easily be replaced by another group, for example, during the substitution reaction. Such detachable groups are, for example, Halogens or an activated hydroxyl group such as mutilata, toiletry, triflate, acetyl group... etc. Examples of separable groups, as well as the sources, who described the reception, described in Advanced Organic Chemistry, J. March, 3rd Edition, Wiley Interscience, p 310-316.

Under the protective group see group, which eliminates reaktsionnosposobnykh functional group or provisions during the chemical reaction, which can (it) be affected, and which leads to the original molecule after the removal of well-known specialist methods. Examples of protective groups and methods setting and removing protection, see, among others, Protective groups in Organic Synthesis, Greene et al., 2nd Ed. (John Wiley & Sons, Inc., New York).

The second object of the present invention are methods for producing compounds of formula (I).

Thus, these compounds can be obtained by methods illustrated in the following schemes, operating conditions which are conventional well-known specialist.

Scheme 1

According to scheme 1, the compound of formula (I) can be obtained peptide binding amine of formula (XI) with an acid of formula (XII) under conditions known to the expert, for example, in the presence of hexaflurophosphate benzotriazol-1 yloxy-Tris(dimethylamino) phosphonium (THIEF) and N-ethylmorpholine or N-methylmorpholine in an inert solvent, such as dimethylformamide, acetonitrile or dichloromethane at a temperature in the range from 0°C to room temperature.

Amine of formula (XI) are obtained peptide svyazyvanie the m amine of formula (VIII) with the amino acid of formula (IX), in which Pg denotes a protective group, in the conditions described above, to obtain compounds of formula (X). The amino acid of formula (IX) protect, for example, using N-tert.-butyloxycarbonyl (Boc). Then remove the protection from the compound (X) is known to the expert methods, getting amine of formula (XI). For example, if the protecting group is Boc, it is removed using acid hydrolysis in the presence of anhydrous gaseous hydrochloric acid.

The compound of formula (VIII) can be obtained according to scheme 2.

Scheme 2

According to this scheme, aralkyl formula (II)in which Y denotes a detachable group, preferably a halogen atom such as bromine atom, and Z denotes a halogen atom such as bromine atom, condensed with an alcoholate or tialata alkali metal, for example of formula R2X-Na+where X denotes an oxygen atom or sulfur. The reaction is carried out in an inert solvent, such as dimethylformamide, at temperatures from 0°C to 50°C, obtaining the compound of formula (III). Aryl of formula (III) in turn Bronevoy acid of formula (IV) method, which is an adaptation of the method described Schoevaars, J. Am. Chem. Soc., 1999, 121, 9550-9561. This transformation can, for example, be carried out by pre-formation of the anion of compound (III), for example, by the action of strong bases is of, such as utility, in the ether solvent such as tetrahydrofuran, at temperatures from -50°C to -80°C. This anion then injected into the reaction with borate, such as trimethylboron, obtaining, as a result of hydrolysis, Bronevoy acid of formula (IV).

Linking Bronevoy acid (IV) with 5-bromothiazole formula (VI), in which Pg denotes a protective group, such as aminogroup, for example, diphenylmethane, can be carried out in accordance with the Suzuki reaction, using either the method is an adaptation of the method described by Wolfe, J. Org. Chem., 1997, 62, 4943-4948, obtaining 5-phenylthiazole formula (VII). Linking is carried out, for example, in the ether solvent such as dioxane, in the presence of three-hydrate of tripotassium phosphate and a catalyst such as tetrakis(triphenylphosphine) palladium (0), at a temperature in the range from room temperature to the boiling temperature of the solvent. With the thus obtained 5-phenylthiazole formula (VII) removing the protective group known to the expert methods, receiving 5-phenyl-2-aminothiazol formula (VIII).

5-bromothiazole formula (VI) are obtained by setting the protection of the amino group of the corresponding compounds of formula (V). Preferably, it protects in the form diphenylmethylene known in specialist conditions.

The initial compounds, in particular compounds of formula (II), (V), (IX) and (XII)if the way their receipt is not described, available on the market or known from the literature or can be obtained by the described methods, or a famous person.

For example, 5-bromo-2-amino-thiazole (V) can be obtained by bromirovanii the corresponding 2-amino-thiazole according to the method is an adaptation of the method described Kaye, J. Chem. Soc. Perkins I, 1981, 2335-2339.

For example, the compound of formula (XII) can be obtained by the method is an adaptation of the method described by Middleton et al., J. Org. Chem., 45, 14, 1980, 2883-2887 and Miyamoto et al., J. Amer. Chem. Soc., 114, 15, 1992, 6256-6257.

The values of X, R1, R2, R3, R4, R5, R5', R6and n in the compounds of formulas (II)-(XII) correspond to the values defined for compounds of formula (I).

In the following examples describe some of the compounds according to the invention. These examples are not restrictive and serve only to illustrate the invention. Rooms compounds presented in the examples correspond to the numbers in the following next table. The microanalysis elemental composition and spectra NMR, infrared and mass spectra confirm the structure of the obtained compounds.

Example 1 (compound 9)

(2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-{5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone

1.1. 1-bromo-2-(phenoxymethyl)benzene

For 20.2 g of phenol in solution in 150 ml of dimethylformamide add portions at °C 1.2 g of sodium hydride (50%suspension in oil). Stirred at room temperature and injected at 5°C to 37.2 g of 2-bromobenzylamine in solution in 15 ml of dimethylformamide. After 2 hours at 20°C reaction medium was poured into a mixture of ice water and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated, gaining 36 g of oil.

NMR1H δ in cmln (DMSO d6): 5,22 (s, 2H); 7,09-to 7.67 (multiplet, 9H).

1.2. 2-(phenoxymethyl)phenylboronic acid

To 36 g of 1-bromo-2-(phenoxymethyl)benzene obtained in stage 1.1, in solution in 150 ml of tetrahydrofuran, is added dropwise at -70°C, 90 ml of n-utility (1,6 M) in solution in hexane. After 2 hours at -70°C is added dropwise 16 ml of trimethylborane. Allow the temperature to rise to -30°C. Carry out the hydrolysis with a saturated solution of ammonium chloride, then extracted with ethyl acetate and the organic phase is dried with anhydrous sodium sulfate. After evaporation obtain 33 g of a solid white color.

NMR1H δ in cmln (DMSO d6): the 5.25 (s, 2H); 6,85-to 7.67 (multiplet, 11H).

1.3. 5-bromo-N-(diphenylmethylene)-1,3-thiazol-2-amine

To 34 g of 5-bromo-1,3-thiazole-2-libraryref in suspension in 300 ml of 1,2-dichloroethane added 26 g benzophenone. The mixture is boiled for 18 hours under reflux. Filter the formed precipitate and concentrate the filtrate, getting to 37.2 g of solid ve is esta.

TPL=109°C.

NMR1H δ in cmln (DMSO d6): 7,34 (m, 2H); 7,50-7,76 (multiplet, 9H).

1.4. 5-{2-[(phenoxy)methyl]phenyl}-N-(diphenylmethylene)-1,3-thiazol-2-amine

In 14.8 g of 2-(phenoxymethyl)phenylboronic acid, obtained in stage 1.2, in a solution of 250 ml of 1,4-dioxane consistently give 15 g of dihydrate of tripotassium phosphate, and 10.5 g of 5-bromo-N-(diphenylmethylene)-1,3-thiazol-2-amine, obtained in stage 1.3, 1.5 g of tetrakis(triphenylphosphine) palladium (0) and boiled for 1 hour under reflux. Reaction medium was evaporated to dryness, and placed in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated solvents. The remainder chromatographic on a column of silica gel, using as eluent dichloromethane, and obtain 35 g butter yellow color.

NMR1H δ in cmln: to 4.81 (s, 2H); 7,17-7,83 (multiplet, 20H).

1.5. 5-{2-[(phenoxy)methyl]phenyl}-1,3-thiazol-2-amine

To 35 g of 5-{2-[(phenoxy)methyl]phenyl}-N-(diphenylmethylene)-1,3-thiazol-2-amine, obtained in stage 1.4, in solution in 250 ml of methanol, add 150 ml of an aqueous solution of hydrochloric acid (1 M) and stirred for 18 hours at 20°C. it is Evaporated to dryness, put the residue in diethyl ether and washed with an aqueous solution of sodium hydroxide (0.5 M). The organic phase is dried over anhydrous sodium sulfate and concentrated. The remainder chromatographic on a column of silica gel, and the but using as eluent a mixture of dichloromethane/methanol 98/2 (about./vol.), receiving 15 g of solid beige color.

TPL=154°C.

NMR1H δ in cmln (DMSO d6): 5,07 (s, 2H); 6,98-7,65 (multiplet, 10H).

1.6. tert.-butyl(1S)-1-[({5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}-amino)carbonyl]BUTYLCARBAMATE

To the 3.35 g of (2S)-2-[(tert.-butyloxycarbonyl)amino]pentanol acid in solution in 35 ml of dimethylformamide added at 0°C and 7.1 g of hexaflurophosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium, then, dropwise, to 2.1 ml of N-methylmorpholine. After 15 minutes at 0°C enter 4 g 5-{2-[(phenoxy)methyl]phenyl}-1,3-thiazol-2-amine, obtained in stage 1.5, and stirred for 18 hours at room temperature. Wednesday placed in ethyl acetate and washed 2 times with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The remainder chromatographic on a column of silica gel, using as eluent a mixture of dichloromethane/methanol 98/2 (about./vol.), getting to 5.2 g of a colorless oil.

NMR1H δ in cmln (DMSO d6): to 0.88 (t, 3H); 1,22-1,65 (multiplet, 13H); 4,24 (kV, 1H); 5,09 (s, 2H); 6,94-to 7.67 (multiplet, 10H) 12,23 (s, 1H).

1.7. hydrochloride, (2S)-2-amino-N-(5-{2-[(phenoxy)methyl]phenyl}-1,3-thiazol-2-yl)pentanolide

To 5 g of tert.-butyl(1S)-2-[(5-{2-[(phenoxy)methyl]phenyl}-1,3-thiazol-2-yl)amino]-1-propyl-2-oxoethylidene obtained at the stage of 1.6, in solution in 60 ml of ethyl acetate is added dropwise at 0°C, 25 ml of a solution of gaseous hydrochloric acid (5 M) in ethyl acetate. The medium is stirred for 18 hours at 20°C. the Formed precipitate is filtered off, washed 2 times with diethyl ether and dried, obtaining 3 g of solid white color.

TPL=148°C.

NMR1H δ in cmln (DMSO d6): of 0.90 (t, 3H); 1.39 in (m, 2H); of 1.85 (m, 2H); 4,18 (kV, 1H); to 5.08 (s, 2H); 6,94-7,68 (multiplet, 10H); 8,65 (s, 3H).

1.8. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-{5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone

To 0.32g (2S)-2-hydroxyl-3,3-dimethylbutanol acid in solution in 25 ml of dimethylformamide at 0°C successively added 1,36 g hexaphosphate benzotriazol-1-electroparadise and 0.7 ml of N-ethylmorpholine. After 20 minutes at 0°C is injected 0.88 g of hydrochloride (2S)-2-amino-N-(5-{2-[(phenoxy)methyl]phenyl}-1,3-thiazol-2-yl)pentanolide obtained at the stage of 1.7, and stirred for 18 hours at room temperature. Reaction medium was placed in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The remainder chromatographic on a column of silica gel, using as eluent a mixture of dichloromethane/methanol 99/1 (about./vol.), getting after crystallization in isopropyl ether 0,83 g solid white color.

TPL=84°C.

NMR1H δ in cmln (DMSO d6): to 0.89 (t, 3H); of 0.93 (s, 9H); of 1.33 (m, 2H); 1,71 (kV, 21H); 3,57 (d, 1H); br4.61 (kV, 1H); 5,09 (s, 2H); 5,61 (d, 1H); 6,97-7,02 (multiplet, 3H); 7,28-to 7.67 (multiplet 7H); 7,81 (d, 1H); to 12.28 (s, 1H).

[α]D20=-81,8 (c=1/CH3OH).

Example 2 (compound 16)

(2S)-2-{[2-(2,5-dimethyl-3-thienyl)acetyl]amino}-N-{5-[2-(ethoxymethyl)-phenyl]-1,3-thiazol-2-yl}pentanone

2.1. 2-(2,5-dimethyl-3-thienyl)-1-(4-morpholinyl)-1-attention

To 5 g of 2,5-dimethyl-3-acetylthiophene add 1.68 g of sulfur, and 6.5 ml of the research and boiled for 10 hours under reflux. Cooled to 20°C and poured into an aqueous solution of hydrochloric acid (1 BC). The medium is extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is purified by chromatography on a column of silica gel, using as eluent a mixture of cyclohexane/ethyl acetate 8/2 (about./vol.), obtaining 6.8 g of orange oil.

NMR1H δ in cmln (DMSO d6): 2,30 (s, 3H); of 2.34 (s, 3H); 3,47 (t, 2H); the 3.65 (m, 4H); 4,07 (s, 2H); 4,20 (t, 2H); 6,56 (s, 1H).

2.2. 2-(2,5-dimethyl-3-thienyl)acetic acid

2-(2,5-dimethyl-3-thienyl)acetic acid is obtained by the method described in Heterocycl. Chem; EN; 25; 1988; 1571-1581.

To 6.7 g of 2-(2,5-dimethyl-3-thienyl)-1-(4-morpholinyl)-1-atention obtained in stage 2.1, in solution in 70 ml of methanol add 21 ml of an aqueous solution of sodium hydroxide (50 wt.%) and boiled for 6 hours under reflux. After evaporation of the methanol, the residue diluted with water and acidified with aqueous hydrochloric acid (6 BC). The formed precipitate is filtered off, then cromatografia on a column of silica gel, using as eluent dichloromethane, and obtain 3.6 g of beige crystals.

TPL=65°C.

NMR1H δ in cmln (DMSO d6): of 2.26 (s, 3H); of 2.34 (s, 3H); 3,39 (s, 2H); 6,56 (s, 1H).

2.3. (2S)-2-{[(2,5-dimethyl-3-thienyl)acetyl]amino}-N-{5-[2-(ethoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone

Are similar stage 1.8 example 1, replacing (2S)-2-hydroxy-3,3-dimethylbutanol acid 2-(2,5-dimethyl-3-thienyl) acetic acid obtained in stage 2.2. Get to 0.67 g of white crystals.

TPL=84°C.

NMR1H δ in cmln (DMSO d6): to 0.89 (t, 3H); to 1.16 (t, 3H); of 1.29 (m, 2H); of 1.65 (m, 2H); of 2.25 (s, 3H); 2,30 (s, 3H); 3.33 and (m, 2H); 3,47 (q, 2H); of 4.44 (s, 2H); 4,49 (kV, 1H); 4,55 (s, 1H); 7,35-7,55 (multiplet, 5H); 8,32 (d, 1H); to 12.28 (s, 1H).

[α]D20=-103 (c=1/CH3OH).

Example 3 (compound 22)

(2S)-2-{[2-(5-methyl-2-thienyl)acetyl]amino}-N-{5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone

3.1. 2-(5-methyl-2-thienyl)-1-(4-morpholinyl)-1-attention

2-(5-methyl-2-thienyl)-1-(4-morpholinyl)-1-atention receive in a manner analogous to the method described in example 2.1.

NMR1H δ in cmln (DMSO d6): is 2.40 (s, 3H); to 3.49 (t, 2H); to 3.64 (t, 2H); 3,81 (t, 2H); 4,19 (t, 2H); however, 4.40 (s, 2H); of 6.49 (d, 1H); 6,77 (d, 1H).

3.2. 2-(5-methyl-2-thienyl)acetic acid

2-(5-methyl-2-thienyl)acetic acid is obtained in a manner analogous to the method described in example 2.2.

TPL=54°C.

NMR1H δ in cmln (DMSO d6): of 2.38 (s, 3H); and 3.72 (s, 3H); 6,1 (d, 1H); 6,69 (d, 1H).

3.3. (2S)-2-{[2-(5-methyl-2-thienyl)acetyl]amino}-N-{5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone

Are similar stage 1.8 example 1, replacing (2S)-2-hydroxy-3,3-dimethylbutanol acid 2-(5-methyl-2-thienyl) acetic acid obtained in stage 3.2. Obtain 0.73 g of beige crystals.

TPL=81°C.

NMR1H δ in cmln (DMSO d6): of 0.87 (t, 3H); 1.32 to (m, 2H); of 1.64 (m, 2H); of 2.36 (s, 3H); 3,62 (q, 2H); 4,48 (kV, 1H); 5,07 (s, 2H); 6,59 (d, 1H); to 6.67 (d, 1H); 6,95-7 (multiplet, 3H); 7,27-7,73 (multiplet, 7H); to 8.41 (d, 1H); 12,30 (s, 1H).

[α]D20=-91,7 (c=1/CH3OH).

Example 4 (compound 7)

(2S)-N-{5-[2-(isopropoxyphenyl)phenyl]-1,3-thiazol-2-yl}-2-{[3-(3-thienyl)propanoic]amino}pentanone

4.1. (E)-3-(3-thienyl)-2-Papanova acid

To 25 g of 3-canaldigital in a solution of 100 ml of pyridine added 46 g of malonic acid, 2 ml of piperidine and heated at 100°C for 4 hours. The reaction medium is cooled down to 30°C and poured into aqueous hydrochloric acid (2 BC). The formed precipitate is filtered and washed with isopropyl ether, receiving after drying 30 g of solid white color.

TPL=152°C.

NMR1H δ in cmln (DMSO d6): 6,36 (d, 1H); 7,51-7,62 (multiplet, 3H); to 7.93 (d, 1H); 12,27 (s, 1H).

4.2. Ethyl-(E)-3-(3-thienyl)-2-propenoate

To 11 g of (E)-3-(3-thienyl)-2-propanolol acid, obtained in stage 4.1, in solution in 50 ml of dimethylformamide doba the amount of 11.5 g of potassium carbonate, 6.8 ml of idtana and stirred for 48 hours at 20°C. the Medium was placed in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated, gaining 12.5 g oil.

NMR1H δ in cmln (DMSO d6): of 1.26 (t, 3H); to 4.17 (q, 2H); 6,47 (d, 1H); EUR 7.57-7,71 (multiplet, 3H); 8,01 (d, 1H).

4.3. Ethyl-3-(3-thienyl)-2-propanoate

12.5 g of ethyl(E)-3-(3-thienyl)-2-propenoate obtained at the stage 4.2, in solution in 100 ml of ethanol, add 4 g of 10%palladium on coal and stirred for 24 hours at 60°C under hydrogen pressure of 5 bar. Filtered off the catalyst and concentrating the filtrate, receiving 11 g of oil.

NMR1H δ in cmln (DMSO d6): of 1.20 (t, 3H); 2,62 (t, 2H); is 2.88 (t, 2H); 4,07 (q, 2H); 7,02 (d, 1H); 7.18 in (m, 1H); 7,45 (m, 1H).

4.4. 3-(3-thienyl)propanoic acid

To 11 g of ethyl-3-(3-thienyl)-2-propanoate obtained at the stage 4.3, in solution in 100 ml ethanol add 75 ml of an aqueous solution of sodium hydroxide (2 BC). Stirred for 18 hours at 20°C. After evaporation of the solvents the residue is acidified. The formed precipitate is filtered off and dried in vacuum, obtaining 6.3 g solid beige color.

TPL=59°C.

NMR1H δ in cmln (DMSO d6): of 2.56 (t, 2H); to 2.85 (t, 2H); 7,02 (t, 1H); 7.18 in (s, 1H); 7,45 (m, 1H); 12,14 (s, 1H).

4.5. (2S)-N-{5-[2-isopropoxyphenyl)phenyl]-1,3-thiazol-2-yl}-2-{[3-(3-thienyl)propanoic]amino}pentanone

Act Academy of Sciences of the logical stage 1.8 example 1, substituting (2S)-2-hydroxy-3,3-dimethylbutanol acid 3-(3-thienyl)propanoic acid obtained in stage 4.4. Obtain 0.75 g of beige crystals.

TPL=101°C.

NMR1H δ in cmln (DMSO d6): of 0.87 (t, 3H); of 1.13 (d, 6H); of 1.33 (m, 2H); of 1.62 (m, 2H); 2,48 (t, 2H); 2,82 (t, 2H); to 3.67 (m, 1H); of 4.45 (s, 2H); of 4.54 (q, 1H); 6,98 (d, 1H); for 7.12 (d, 1H); 7,35-EUR 7.57 (multiplet, 6H); 8,21 (d, 1H); of 12.26 (s, 1H).

[α]D20=-71(c=1/CH3OH).

Example 5

(2R)-3-ethyl-2-hydroxy-N-{(1S)-1-[({5-[2-(phenoxymethyl) phenyl]-1,3-thiazol-2-yl}amino)carbonyl]butyl}pentanone (compound No. 42) and

(2S)-3-ethyl-2-hydroxy-N-{(1S)-1-[({5-[2-(phenoxymethyl) phenyl]-1,3-thiazol-2-yl}amino)carbonyl]butyl}pentanone (compound 43)

5.1. 3-ethyl-2-hydroxypentanal acid

To a solution of 1.24 ml of 2-ethylbutyraldehyde in 18 ml of anhydrous dichloromethane carefully add 1.5 ml of trimethylsilylacetamide, then a catalytic amount of zinc iodide. The reaction medium is stirred for 2 hours at room temperature, then for 3.5 hours at 60°C. the Reaction medium is cooled to 0°C and add 3.5 ml of concentrated hydrochloric acid. The reaction medium is stirred for 18 hours at room temperature, then for 1 hour at boiling under reflux. After cooling, the reaction mixture was poured into water and extracted twice with 50 ml of ethyl acetate. The combined organic phases extrag the shape with 100 ml of sodium hydroxide (7,5 N.) at 4°C. After separation the aqueous phase is washed 3 times with 50 ml of ethyl acetate. The aqueous phase is acidified with 70 ml of hydrochloric acid (12 BC) and extracted three times with 50 ml of ethyl acetate. The combined organic phases are dried and the solvent is evaporated.

TPL=84°C.

5.2. (2R)-3-ethyl-2-hydroxy-N-{(1S)-1-[({5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}amino)carbonyl]butyl}pentanone and

(2S)-3-ethyl-2-hydroxy-N-{(1S)-1-[({5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}amino)carbonyl]butyl}pentanone

Are similar stage 1.8 example 1, replacing (2S)-2-hydroxy-3,3-dimethylbutanol acid 3-ethyl-2-hydroxypentanal acid, obtained in stage 5.1. Get 0,78 g solid white color.

Compound 42 (SR):

TPL=67,4°C.

NMR1H δ in cmln (DMSO d6): to 0.74 (t, 3H); 0,84-0,90 (multiplet, 6H); 1.26 in-1,71 (multiplet, 9H); of 3.94 (m, 1H); of 4.57 (q, 1H); 5,07 (s, 2H); of 5.40 (s, 1H); 6,94-6,99 (multiplet, 3H); 7,26-7,93 (multiplet, 7H); to $ 7.91 (d, 1H); 12,27 (s, 1H).

[α]D20=-41,5(c=1/CH3OH).

Compound 43 (SS):

TPL=122,5°C.

NMR1H δ in cmln (DMSO d6): 0,78-0,89 (multiplet, 9H); 1.18 to 1,38 (multiplet, 6H); of 1.55 (m, 1H); 1,68 (q, 2H); to 3.92 (m, 1H); 4,60 (kV, 1H); 5,07 (s, 2H); 5,49 (d, 1H); 6,95-7 (multiplet, 3H); 7,26-7,62 (multiplet, 7H); 7,87 (d, 1H); 12,27 (s, 1H).

[α]D20=-72,6 (c=1/CH3OH).

Example 6 (compound 40)

(2S)-2-[(2-hydroxy-3-phenylpropanol)amino]-N-{5-[2-(proxime who yl)-phenyl]-1,3-thiazol-2-yl}pentanone

6.1. 3-phenyl-2-hydroxypropionate acid

To a suspension of 1.6 g of phenylalanine in 5.3 ml of sulfuric acid (2,5 BC) is added dropwise at 0°C solution 0,829 g of sodium nitrite in 4.2 ml of water. The reaction mixture is stirred for 2 hours at 0°C, then 17 hours at room temperature. The reaction mixture is extracted twice with 100 ml of ethyl acetate. The combined organic phases are washed with 100 ml of saturated solution of sodium chloride in water. After drying obtain 1.2 g of yellow crystals.

TPL=97°C.

6.2. 2-[(2-hydroxy-3-phenylpropanol)amino]-N-{5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanone

Are similar stage 1.8 example 1, replacing (2S)-2-hydroxy-3,3-dimethylbutanol acid 3-phenyl-2-hydroxypropionic acid, obtained in stage 6.1. Obtain 0.8 g of a solid substance of white color.

TPL=86°C.

NMR1H δ in cmln (DMSO d6): of 0.85 (t, 3H); 1,24 (m, 2H); and 1.63 (m, 2H); 2,70 (m, 1H); 2.57 m (m, 1H); to 4.17 (m, 1H); 4,56 (kV, 1H); to 5.08 (s, 2H); 6,94-7,63 (multiplet, 15H); 8,02 (m, 1H); 12,25 (s, 1H).

[α]D20=-28 (c=1/CH3OH).

Example 7 (compound 70)

(2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-(5-{2-[(4-pyridyloxy)methyl]phenyl}-1,3-thiazol-2-yl)pentanone

7.1. 2-(2-amino-1,3-thiazol-5-yl)phenylmethanol

To 29,86 g of 5-[2-(tert.-butoxymethyl)phenyl]-N-diphenylmethylene)-1,3-thiazol-2-amine, obtained in a manner analogous to FPIC is Boo, described in the stages 1.1-1.4 of example 1, in solution in 140 ml of methanol, add 70 ml of water 3M hydrochloric acid and left for 18 hours at room temperature, then refluxed for 4 hours. The methanol is evaporated. The residue is placed in aqueous 6M hydrochloric acid and extracted with diethyl ether. the pH of the aqueous phase is brought to core values while cooling and extracted with ethyl acetate. An ethyl acetate phase is dried over anhydrous sodium sulfate and concentrated. The remainder utverjdayut diisopropyl ether and receive 6 g solid beige color.

TPL=145°C.

7.2. tert.-butyl-5-[2-(hydroxymethyl)phenyl]-1,3-thiazol-2-ylcarbamate

To 6 g of 2-(2-amino-1,3-thiazol-5-yl)phenylmethanol obtained at the stage 7.1, in solution in 80 ml of 1,4-dioxane successively added 1,17 g of magnesium oxide, 29 ml of aqueous 2M sodium hydroxide solution, then at 0°C, portions of 7.6 g of di-tert.-BUTYLCARBAMATE (RE2About). Leave for 48 hours at room temperature, then the medium is concentrated and placed in water and extracted with ethyl acetate. The organic phase is washed with 5%solution of potassium hydrosulfate, dried over anhydrous sodium sulfate and concentrated. The remainder chromatographic on a column of silica gel, using as eluent a mixture of dichloromethane/methanol 99/1 (about./vol.), and ucaut 2.3 g of oil, which utverjdayut diisopropyl ether.

TPL=180,7°C.

7.3. tert.-butyl-5-{2-[(4-pyridyloxy)methyl]phenyl}-1,3-thiazol-2-ylcarbamate

To of 5.24 g of triphenylphosphine in solution in 60 ml of tetrahydrofuran added by portions at 0°C 4.15 g of diisopropylcarbodiimide (DIAD). After 30 minutes at about 10°C add portions to 1.96 g of 4-hydroxypyridine, leave on for 30 minutes at about 10°C and injected to 4.2 g of tert.-butyl-5-[2-(hydroxymethyl)phenyl]-1,3-thiazol-2-ylcarbamate obtained at the stage of 7.2. Leave for 4 days at room temperature. The medium is concentrated and placed in a saturated solution of sodium carbonate and extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate and concentrated. The remainder chromatographic on a column of silica gel, using as eluent a mixture of increasing polarity from dichloromethane/methanol 99/1 (about./about.) to dichloromethane/methanol 90/10 (vol./vol.), and receive 1 g of oil.

NMR1H δ in cmln (DMSO d6): of 1.52 (s, 9H); at 5.27 (s, 2H); 6,10 (q, 2H); 7,05 (m, 1H); 7,41-7,54 (multiplet, 6H); 11,60 (s, 1H).

7.4. 5-{2-[(4-pyridyloxy)methyl]phenyl}-1,3-thiazolidin

To 1 g of tert.-butyl-5-{2-[(4-pyridyloxy)methyl]phenyl}-1,3-thiazol-2-ylcarbamate obtained at the stage 7.3, in 20 ml of dichloromethane are added 20 ml of a 4M solution of gaseous hydrochloric acid in ethyl acetate. Leave for 4 hours at room temperature the E. Reaction medium was concentrated and adjusted to basic pH values using a 5%solution of sodium hydrosulphate. The formed precipitate is filtered off and chromatographic on a column of silica gel, using as eluent a mixture of dichloromethane/methanol 95/5 (about./vol.), and gain of 0.58 g of a beige foam.

NMR1H δ in cmln (DMSO d6): the 5.25 (s, 2H); 6,10 (d, 2H); 6,98-7,55 (multiplet, 9H).

7.5. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}-N-(5-{2-[(4-pyridyloxy)methyl]phenyl}-1,3-thiazol-2-yl)pentanone

Are similar to the stages of 1.6-1.8 example 1, substituting 5-{2-[(phenoxy)methyl]phenyl}-1,3-thiazol-2-amine 5-{2-[(4-pyridyloxy)methyl]phenyl}-1,3-thiazoline obtained at the stage of 7.4. Obtain 0.4 g in the form of crystals.

TPL=112,7°C.

NMR1H δ in cmln (DMSO d6): to 0.89 (t, 3H); to 0.92 (s, 9H); of 1.34 (m, 2H); 1,68 (q, 2H); to 3.58 (d, 1H); br4.61 (kV, 1H); of 5.24 (s, 2H); 5,61 (d, 1H); 6,09 (d, 2H);? 7.04 baby mortality (m, 1H); 7,41-7,53 (multiplet, 6H); 7,80 (d, 1H); 12,36 (s, 1H).

Connection (n) 61 ((2S)-N-(5-{2-[(3-cianfrocca)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone) and # 69 ((2S)-N-(5-{2-[(2-cianfrocca)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanol]amino}pentanone) can be obtained by the method described in example 7, replacing 4-hydroxypyridine respectively 3-cyanophenyl or 2-cyanophenyl.

The table below presents the chemical structures and the physical is waista of some compounds according to the invention.

In this table:

- TPL (°C) denotes the melting point of connection, in degrees Celsius;

- [αD] (c=1, CH3OH) denotes the torque capacity of the connection at a concentration of 1 g/l in methanol;

- (S) or (R) in the columns "R3and R5, R5'" indicate the stereochemistry of the asymmetric carbon atoms bearing, respectively, R3or R5in the formula (I).

To the carbon atom carrying the R5the designation (S) or (R) does not apply to the case when R5and R5'together form an oxo-group or oximo group.

Compounds described in this table were obtained by the methods described above.

Table

Compounds according to the invention were objects of pharmacological studies, that have shown their value as therapeutically active substances.

In particular, they were tested for their inhibitory effect on the production of β-amyloid peptide (β-A4).

β-amyloid peptide (β-A4) is a fragment of a larger protein precursor, called APP (Amyoid Precursor Protein). The latter is produced and is present in various tissues in animals or humans. At the brain level in its cleavage by enzymes type proteases leads to the formation of peptide β-A4, which accumulates in the form of amyloid plaques. Two protease responsible for the production of amyloid peptide, known as beta - and gamma-secretase (Wolfe MS, Secretase targets for Alzheimer's disease : identification and therapeutic potential, J.Med. Chem., 2001 Jun 21; 44 (13), 2039-60).

However, it was shown that the incremental peptide β-A4 neurotoxic and can play an important role in the development of Alzheimer's disease.

Thus, the compounds according to the invention as inhibitors of the production of β-amyloid peptide (β-A4) by inhibiting gamma-proteases, can be used in the treatment of many pathologies such as senile dementia, Alzheimer's disease, down's syndrome, Parkinson's disease, amyloid angiopathy, cerebrovascular disorders, fronto-temporal dementia and the disease Peak, post-traumatic dementia, pathologies associated with neuro-inflammatory processes, Huntington's disease and Korsakov syndrome.

Testing was performed according to the following Protocol.

For β-amyloid cell research used the line CHO-K1, coexpressing CT100 APP PS1 M146L clone 30-12. The purpose of this line is the inhibition of gamma-secretase. Presenile the n associated with gamma-secretase activity (Wolfe MS, Haass C., The Role of presenilins in gamma-secretase activity, J. Biol. Chem., 2001 Feb 23, 276 (8), 5413-6) and its co-expression with amyloid protein or N-terminal fragment leads to increased secretion of peptide A1-42 (β-A4), which creates a pharmacological tool to assess the inhibition of the compounds of formula (I) production of peptide β-A4. Seeding 96-of linkovich cultural tablets was carried out based 1x105cells per well in 150 μl of incubation medium. The presence of a minimum number (end-1.3%) in the serum makes possible the adhesion of cells on plastic after 2-3 hours of incubation at 37°C in the presence of 5% CO2. The tested products (15 µl) was tested at a final concentration of 10 μm DMSO 1% and incubated for 24-25 hours at 37°C in the presence of 5% CO2and at 100% humidity. After 24-25 hours incubation, cell supernatant (100 μl) is transferred onto the tablets ELISA, treated with antibody capture E (6E10, epitope :aa1-17, INTERCHIM/SENETEK 320-10) to determine the number of amyloid peptides, secreted by cells in the presence of compounds according to the invention. Parallel process range control synthetic peptide, " " peptide 1-40", in concentrations of 5 and 10 ng/ml Tablets ELISA incubated over night at 4°C.

The number of fixed peptide determined indirectly in the presence of a competitor, the corresponding truncated p is ptito, the peptide 1-28 associated with Biotin, which is then detected using streptavidin linked to alkaline phosphatase. The substrate, p-Nitrophenyl Phosphate (pNPP FAST p-Nitrophényl Phosphate, Sigma N2770), leads to the soluble reaction product of yellow color appears at 405 nm. The reaction is stopped with a 0,1M solution EDTU. To do this, after fixing amyloid peptide on the tablet ELISA to 100 μl of cell supernatant add 50 ál of biotinylated peptide 1-28 and incubated for 30 minutes at room temperature. Then the tablets ELISA washed 3 times. After drying on absorbent paper add streptavidin-Alkaline Phosphatase (Interchim/Jackson ImmunoResearch Laboratories 016-050-084) in an amount of 100 μl per well and incubated 1 hour at room temperature. Tablets are again washed, then add substrate for alkaline phosphatase (pNPP 1 mg/ml) at the rate of 100 μl per well. After incubation for 30 minutes at room temperature the reaction is stopped by adding 100 μl of 0.1 m EDTU per well and perform reading at 405 nm.

The compounds of formula (I) according to the invention demonstrate CE50 (effective concentration at 50%) below 500 nm. In particular, the compound n 70 according to the table demonstrates CE50 equal to 295 nm. The compounds of formula (I) according to the invention demonstrate CE50, in particular below 100 nm.

The results of biological tests show that these compounds the Oia are inhibitors of the formation of β-amyloid peptide (β-A4).

Thus, these compounds can be used in the treatment of pathologies in which the inhibitor of the formation of β-amyloid peptide (β-A4) brings therapeutic benefit. Such pathologies, in particular, are senile dementia, Alzheimer's disease, down's syndrome, Parkinson's disease, amyloid angiopathy, cerebrovascular disorders, fronto-temporal dementia and the disease Peak, post-traumatic dementia, pathologies associated with neuro-inflammatory processes, Huntington's disease and Korsakov syndrome.

The use of compounds according to the invention in the form of a pharmaceutically acceptable base, salt, hydrate or MES for obtaining a medicinal product intended for the treatment of the above mentioned pathologies, is part of the invention.

The object of the invention are also medicinal product containing a compound of the formula (I) or its salt affiliations with a pharmaceutically acceptable acid, or a hydrate or MES the compounds of formula (I). These drugs are used in therapy, in particular in the treatment of the aforementioned disorders.

According to another aspect, the present invention relates to pharmaceutical compositions containing as an active beginning at least one compound according to the invention. These pharmaceutical compositions containing the effective dose of a compound according to the invention or a pharmaceutically acceptable salt, hydrate or MES specified connection and, if necessary, one or more pharmaceutically acceptable excipients. These excipients chosen, depending on the pharmaceutical form and the desired route of administration, from the usual well-known specialist of the excipients.

In the pharmaceutical compositions according to the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal introduction of the above-mentioned active principle of formula (I) or, if necessary, its salt, MES or hydrate can be entered as a standard dosage forms, mixed with conventional pharmaceutical excipients, to animals or humans for the prophylaxis or treatment of the above disorders or diseases.

Suitable standard dosage forms for administration include forms for oral administration such as tablets, soft or hard gelatin capsules, powders, granules, chewing gum, and solutions or suspensions for oral administration, the forms for sublingual, buccal, intratracheal, intraocular, intranasal, administration by inhalation, forms for subcutaneous, intramuscular or intravenous administration and forms for rect is high or vaginal administration. For topical application, the compounds according to the invention can be used in creams, lipsticks or lotions.

As an example, a standard dosage form for administration of the compounds according to the invention in the form of tablets may contain the following components:

The connection according to the invention50.0 mg
Mannitol223,75 mg
Croscarmellose sodium6.0 mg
Corn starch15,0 mg
The hypromellose2.25 mg
Magnesium stearate3.0 mg

To obtain the desired prophylactic or therapeutic effect, the dose of the beginning of the current can vary from 0.1 mg to 200 mg per kg of body weight per day. Although these doses are examples of the average situation, in special cases may be acceptable higher or lower doses, which are also included in the scope of the invention. According to usual practice, the dosage appropriate for each patient is determined by the physician depending on the method of administration, the weight and the Indus the individual sensitivity of the specified patient.

Each single dose may contain from 0.1 to 1000 mg, preferably from 0.1 to 500 mg of active beginning in combination with one or more pharmaceutical excipients. This dose can be administered 1 to 5 times per day so that the daily dose ranged from 0.5 to 5000 mg, preferably from 0.5 to 2500 mg.

The present invention also relates, according to another aspect, to a method of treatment of the above mentioned pathologies, which includes the introduction of compounds according to the invention, pharmaceutically acceptable salt, MES or hydrate specified connection.

1. Compounds corresponding to General formula (I)

in which
X denotes an oxygen atom;
R1represents C1-10-alkyl, if necessary substituted by phenyl, tanila; or R1stands With3-7-cycloalkyl, thienyl, pyridinyl;
thienyl group, if necessary, can be substituted by 1-2 C1-3-alkyl groups; phenyl may be, if necessary substituted by 1-2 halogen atoms;
R2represents C1-6-alkyl; or R2stands With3-7-cycloalkyl, phenyl or pyridinyl;
phenyl, if necessary, may be substituted by one or more halogen atoms or groups CN, C1-3-alkyl, C1-3-alkoxyl,1-3-forecoxae;
R3oboznachaet 1-6-alkyl;
R4denotes a hydrogen atom or a C1-6-alkyl;
R5and R5'denote, independently of one another, a hydrogen atom, a hydroxyl; or R5and R5'together form oxoprop;
n denotes an integer from 0 to 3; and
R6denotes, independently of one another, a hydrogen atom, halogen, C1-3-alkyl, C1-3-alkoxy,
in the form of a base or in the form of pharmaceutically acceptable salts of joining with acid.

2. The compound of formula (I) according to claim 1, characterized in that
X denotes an oxygen atom;
R1represents C1-5-alkyl, if necessary substituted by phenyl, tanila; or R1stands With3-7-cycloalkyl, thienyl, pyridinyl; thienyl group may be substituted by one or two C1-3-alkyl groups; phenyl may be substituted by one or two halogen atoms;
R2represents C1-6-alkyl, C3-7-cycloalkyl, phenyl or pyridinyl;
whereby phenyl may be substituted by 1-2 groups CN, C1-3-alkyl, C1-3-alkoxy,
With1-3-feralcode atoms or halogen;
R3represents C1-6-alkyl;
R4denotes a hydrogen atom or a C1-6-alkyl;
R5and R5'denote, independently of one another, a hydrogen atom, a hydroxyl; or R5and R5'together form oxoprop;
R6the seat is t a hydrogen atom, halogen, C1-3-alkyl, C1-3-alkoxyl; and
n=0 or 1,
in the form of a base or in the form of pharmaceutically acceptable salts of joining with acid.

3. The compound of formula (I) according to claim 1 or 2, characterized in that
X denotes an oxygen atom;
R1denotes methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 1-methylpropyl, 2-methylpropyl or 1-ethylpropyl, which can be substituted by phenyl or Tienam; or R1denotes cyclohexyl, thienyl or pyridinyl; thienyl group may be substituted by one or two methyl groups; phenyl may be substituted by one or two chlorine atoms or fluorine;
R2denotes ethyl, 1-methylethyl, cyclohexyl, phenyl or pyridinyl;
whereby phenyl may be substituted by 1-2 groups CN, methyl, ethyl, methoxy, ethoxy, cryptomaterial or chlorine atoms or fluorine;
R3denotes methyl, ethyl or propyl;
R4denotes a hydrogen atom, methyl or 4-methylpentyl;
R5and R5'denote, independently of one another, a hydrogen atom, a hydroxyl; or R5and R5'together form oxoprop;
R6denotes a hydrogen atom, a chlorine or fluorine, methyl, methoxy or ethoxy;
n=0 or 1; and
C1-4-alkylene represents methylene;
in the form of a base or in the form of pharmaceutically acceptable salts of joining with acid.

4. Methods for the producing compounds of formula (I) according to one of claims 1 to 3 by peptide binding amine of formula (XI)

with the acid of formula (XII)

in which X, R1, R2, R3, R4, R5, R5', R6and n have the meanings defined in formula (I) according to claim 1.

5. Pharmaceutical composition for treatment of diseases, which is a useful inhibitor of the formation of β-amyloid peptide β-A4, containing at least one compound of formula (I) according to one of claims 1 to 3, in the form of a base or in the form of a pharmaceutically acceptable salt accession acid, in an effective dose, and, if necessary, one or more pharmaceutically acceptable excipients.

6. The compound of formula (I) according to one of claims 1 to 3 in the form of a base or in the form of a pharmaceutically acceptable salt, for use as a drug for the treatment of pathologies in which is a useful inhibitor of the formation of β-amyloid peptide β-A4.

7. The use of the compounds of formula (I) according to one of claims 1 to 3 in the form of a base or in the form of pharmaceutically acceptable salts of Association with an acid to produce a medicinal product intended for treating pathologies in which is a useful inhibitor of the formation of β-amyloid peptide β-A4.

8. The use of the compounds of formula (I) according to one of claims 1 to 3 in the form of a base or in the form of a pharmaceutically acceptable salt accession by kislotoi to obtain medicines designed for treatment of senile dementia, Alzheimer's disease, down syndrome, Parkinson's disease, amyloid angiopathy, cerebrovascular disorders, fronto-temporal dementia and disease Peak, post-traumatic dementia, pathologies associated with neuro-inflammatory processes, diseases of Huntington's disease and/or Korsakov syndrome.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) where R1 stands for hydrogen or linear, branched, saturated or unsaturated hydrocarbon radical; D stands for nitrogen atom or C-R2; E stands for nitrogen atom or C-R3; F stands for nitrogen atom or C-R4; G stands for nitrogen atom or C-R5; R2, R3, R4 and R5 are identical or different and individually represent hydrogen, halogen, alkoxy, linear or branched, saturated or unsaturated hydrocarbon radical; W stands for oxygen atom; X stands for radical of formula radical -(CH2)k-C(O)-(CH2)m-, -(CH2)n- or -(CH2)r-O-(CH2)s-, where k, m, r and s are equal to integers 0 to 6, and n is equal to an integer 1 to 6. Said radicals are optionally substituted with one or more substitutes independently chosen from the group consisting of R7; Y stands for radical of formula radical -(CH2)i-NH-C(O)-(CH2)j-, -(CH2)n-, -(CH2)r-O-(CH2)s-, -(CH2)t-NH-(CH2)u-, where i, j, n, r, s, t and u are equal to integers 0 to 6. Said radicals are optionally substituted C1-3alkyl, or C1-3alkyl-C1-3alkylsulphonylamino; radicals R7, B, R8, A, R9 are as it is presented in the patent claim. The invention also describes the pharmaceutical composition possessing inhibitory activity of receptor tyrosine kinase to KDR receptor including described compounds.

EFFECT: compounds possess inhibitory activity of receptor tyrosine kinase to KDR receptor and can be effective in therapy of the diseases associated uncontrolled angiogenesis.

29 cl, 746 ex, 6 tbl

FIELD: pharmacology.

SUBSTANCE: claimed invention relates to novel 2,4-pyridindiamine compounds of formula (1). In structural formula (I) L1 is direct bond; L2 is direct bond; R2 is phenyl group, three times substituted with three groups R8; R4 is X represents N; Y is selected from group consisting of O, NH, S, SO and SO2; Z is selected from group consisting of O, NH; on condition that if Y is selected from group consisting of NH, S, SO and SO2, Z is not the same as Y; R5 is selected from group consisting from R6, halogen; each R6 is independently selected from group consisting of hydrogen, halogen; R8 is selected from group consisting from Ra, Rb, Ra substituted with one or several similar or different groups Ra or Rb, -ORa, -O-CHRaRb; each R35 independently on others is selected from group consisting of hydrogen and R35, or in alternative case, two groups R35, bound to one and the same carbon atom are taken together with formation of oxogroup (=O), and the remaining two groups R35 each independently on each other are selected from group consisting from hydrogen and R8; each Ra is independently selected from group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl; each Rb is suitable group which is independently selected from group consisting of -ORd, halogen, -CF3, -C(O)NRcRc, and -OC(O)ORd; each Rc is independently protective group or Ra; each Rd is independently protective group or Ra; each index m is independently integer number from 1 to 3.

EFFECT: novel compounds can be used for treatment or prevention of autoimmune diseases, for instance such as rheumatoid arthritis and/or related to it symptoms, systemic lupus erythematosus and/or related to it symptoms, as well as and/or related to it symptoms.

41 cl, 14 dwg, 1 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: compounds of formula (I) as inhibitors of phosphotyrosine phosphotase 1B and their pharmaceutically acceptable salts, their application, based pharmaceutical composition and method of production. In general formula (I) , R1 indicates phenyl, naphthyl, thionaphthyl, pyridyl. Phenyl, naphthyl, thionaphthyl and pyridyl can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, CF3, OCF3, N(R9)(R10), piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, NO2, CN, O-(C1-C6)-alkyl, S(O)0-2-(C1-C6)-alkyl, SO2-N(R9)(R10), CO-(C1-C6)-alkyl, -COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkyleny-COO(C1-C6)-alkyl, (C3-C10)-cycloalkyl, phenyl. These piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, and phenyl rings can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, COOH, CN, NO2, O-(C1-C6)-alkyl, -NH-O-(C1-C6)-alkyl, -(CO)-NH-O-(C1-C6)-alkylene-N(R9)(R10), -(CO)-(C1-C6)-alkyl, -(C1-C6)-alkyl, CF3, OCF3, N(R9)(R10); R2 indicates H, (C1-C6)-alkyl, COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkylene-COO(C1-C6)-alkyl; R3 indicates H, (C1-C6)-alkyl, (C1-C6)-alkylenphenyl, -C(O)-phenyl, (C1-C6)-alkylenheterocycle, where heterocycle represents 5-6-merous heterocyclic ring containing 1-2 heteroatoms, chosen of nitrogen and oxygen, CO-(C1-C6)alkyl; R4, R5 indicate H; R6 indicates H, R9 indicates H, (C1-C4)-alkyl; R10 indicates H, (C1-C4)-alkyl.

EFFECT: applications for treating diseases mediated with phosphotyrosine phosphotase 1B activity, such as diabetes type II, lipidosis and carbohydrate metabolic imbalance, insulin resistivity, reduced sugar content in blood.

9 cl, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: there is disclosed compounds of formula II , where each R2 independently stands for H, halogen, cyano, NO2, OR5, NR6R7, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo, arylalkyl, substituted arylalkyl, heterocycloalkyl or substituted heterocycloalkyl; B represents O, S, SO or SO2; each W and X independently represents C or N; n is within 0 to 4 if both W and X represent C, 0 to 3, if either X or W represent N, and 0 to 2 if both X and W represent N; R3, R5, R6, R7 are independently chosen from H, alkyl, substituted alkyl, alkenyl, alkinyl, substituted alkinyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo; R4 represents optionally substituted 5-6-merous heteroaryl containing nitrogen atom provided (a) if R4 stands for pyridyl, R4 is not substituted with both hydroxy and methoxy groups; and (b) R4 stands for pyrimidinyl, it is n-substituted =O; A is chosen from following compounds of formula: , where D stands for S or O; m is within 0 to 6; R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 and R27 are independently chosen from H, halogen, NR30R31, OR32, CO2R33, SO2R36, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkinyl, substituted alkinyl, -CN, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl; R28 and R29 are independently chosen from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl or together they form carbocyclic or heterocyclic ring consisting of 3 to 8 atoms; and R30, R31, R32, R33 and R36 are independently chosen from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkinyl, substituted alkinyl, cycloalkyl, substituted cycloalkyl, alkoxycarbonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo, heterocycloalkyl or substituted heterocycloalkyl as pharmaceutical composition for cancer treatment containing compound of formula II.

EFFECT: production of new compounds and based pharmaceutical composition applied for cancer treatment.

18 cl, 147 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to the method of producing compounds with formula I and to their pharmaceutical salts. In formulae I, II, IV, V: R1 or R2 represent H, -(CH2)t(5-member heterocyclic compound), where t equals 4 and where the heterocyclic compound contains one nitrogen atom as the heteroatom, R3 is -(CH2)t(C6-C10aryl), where t equals 1. The given R3 groups are optionally substituted with 3 R4 groups. Each R4 is independently chosen from halogen. R8 is C1-C10alkyl, R9 is C1-C10alkyl, and n equals 2.

EFFECT: treatment of hyper-proliferative diseases using new intermediate compounds with formulae II, IV, V.

15 cl, 2 dwg, 11 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and pharmaceutically acceptable salts. Claimed compounds have modulation effect on CB cannabinoid receptor. In the general formula (I) , R and R1 are the same or different and are phenyl optionally substituted by 1-3 substitutes Y, where Y is substitute selected out of group including chlorine, iodine, bromine, fluorine, on condition that X is not a sub-group (ii); or one of R and R1 radicals is phenyl group, while the other radical is formed or linear C2-8-alkyl group or benzyl group; X is one of the sub-groups (i) or (ii). Also invention concerns application of the compounds in obtaining pharmaceutical composition, pharmaceutical composition with modulation effect on CB cannabinoid receptor, and compound of the general formula (IV) with radical values as indicated in the claim.

EFFECT: enhanced efficiency of composition and treatment method.

5 cl, 1 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention concerns method of treatment, alleviation and/or prevention of neurological state, particularly neurodegenerative disorders, involving administration of effective quantity of compound with formula I: . Also invention concerns application of compound of the formula I as neurotherapeutical, neuroprotective or antimyloid agent, pharmaceutical or veterinary composition for treatment, alleviation and/or prevention of neurological states, and compounds of the formula I on the following additional terms: (b) if R3, R and R' are H, and R2 is (CH2)2NR9R10, then both R9 and R10 are not ethyl or methyl; (c) if R3, R and R' are H, and R2 is (CH2)2NR9R10, then both R9 and R10 are not hydrogen or ethyl; (d) if R3, R and R' are H, and R2 is NR11R12, then both R11 and R12 are not hydrogen; (e) if R3, R and R' are H, and R2 is COR6, then R6 is not H, OH or CH2Cl; (f) if R3, R and R' are H, and R2 is not CH3 or CH2Cl; (g) if R3, R and R' are H, and R2 is HCNN R9R10, then both R9 and R10 are not H.

EFFECT: efficient treatment, alleviation and prevention of neurological state.

24 cl, 14 tbl, 21 ex, 14 dwg

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to novel compounds N(1,3-tiazol-2-yl)amides of 2-diphenylmethylenehydrazono-5,5-dimethyl-2,4-diooxohexane acid of formula (Ia, b): demonstration anti-inflammatory and analgetic activity. Invention also relates to method of their obtaining.

EFFECT: obtaining novel compounds.

2 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: organic chemistry.

SUBSTANCE: invention describes novel substituted benzoylcyclohexenones of the general formula (I): wherein values Q, Y, Z, R1-R5 and their possible tautomeric forms and their possible salts given in the invention claim. Invention proposes substituted benzoylcyclohexenones of the general formula (I) that possess the herbicide activity.

EFFECT: valuable property of compounds.

2 cl, 10 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to 2-heterocyclyl-1,2-ethanediol carbamates of the formula (I) , their enantiomers, enantiomeric mixtures or pharmaceutically acceptable salts wherein A means a heterocyclic fragment chosen from the following group:

B1 and B2 mean independently hydroxy-group or -OCONR1R2 under condition that B1 and B2 don't mean hydroxy-group simultaneously; R1 and R2 mean hydrogen atom; R3, R4 and R5 mean alkyl, halogen atom, trihalogenmethyl, trialkylmethyl, -NO2, -CN and phenyl. These compounds can be used in treatment of the central nervous system disorders being especially as anticonvulsants and anti-epileptic agents. Also, invention describes a pharmaceutical composition based on compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

12 cl, 1 tbl, 34 ex

FIELD: organic chemistry, biochemistry, medicine, endocrinology.

SUBSTANCE: invention relates to a trans-olefinic activator of glucokinase representing compound taken among the group consisting of olefinic amide of the formula (I): wherein R1 and R2 mean independently of one another hydrogen, halogen atom, nitro-group, perfluoro-(lower)-alkyl, (lower)-alkylsulfonyl or (lower)-alkylsulfonylmethyl; R means -(CH2)m-R3 or lower alkyl comprising from 2 to 4 carbon atoms; R3 means cycloalkyl comprising from 3 to 8 carbon atoms; R4 means the group: or unsubstituted, or monosubstituted five- or six-membered heteroaromatic ring linked by ring carbon atom with indicated amino-group wherein this five- or six-membered heteroaromatic ring comprises from 1 to 2 heteroatoms taken among the group consisting of sulfur or nitrogen atom wherein one heteroatom being as nitrogen atom is arranged near with binding ring carbon atom, and wherein indicated monosubstituted heteroaromatic ring is substituted at ring carbon atom not adjacent with mentioned binding carbon atom with a substitute taken among the group consisting of halogen atom and group of the formula: m = 0 or 1; n = 0, 1, 2, 3 or 4; R7 means hydrogen atom or lower alkyl; Δ means trans-configuration relatively to a double bond; or its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition, method for prophylactic or therapeutic treatment of diabetes mellitus of type II and to methods for preparing compounds of the formula (I). Invention provides preparing activators of glucokinase that enhance insulin secretion in treatment of diabetes mellitus of type II.

EFFECT: valuable medicinal properties of compounds.

25 cl, 29 ex

The invention relates to organic chemistry, in particular to the compounds representing amide of the formula I:

in which * denotes an asymmetric carbon atom; R1and R2independently from each other represent a hydrogen atom or halogen, amino, hydroxyamino-, nitro-, cyano-, sulfamidihappo, (ness.)alkyl, -OR5, -C(O)OR5, PERFLUORO(ness.)alkyl, (ness.)alkylthio, PERFLUORO(ness.)alkylthio, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkylsulfonyl or (ness.)alkylsulfonyl; R3denotes cycloalkyl containing from 3 to 7 carbon atoms, or (ness.)alkyl containing from 2 to 4 carbon atoms; R4means (O)other40or unsubstituted or monosubstituted five - or six-membered heteroaromatic ring bound ring carbon atom of the amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur atoms, oxygen, and nitrogen, with one heteroatom is a nitrogen atom, which is adjacent to the connecting ring carbon atom; this is monosubstituted heteroaromatic ring monogamist on the ring angle is found (ness.)alkyl, halo-, nitro-, cyano, -(CH2)n-OR6, -(CH2)n-C(O)OR7, -(CH2)n-C(O)OTHER6, -C(O)-C(O)OR8and -(CH2)n-OTHER6or its pharmaceutically acceptable salts

The invention relates to new derivatives of formula (I), where R1- R4- hydrogen atoms; X - alkylene with 1 to 6 carbon atoms; Y is lower alkyl; B is - NR5R11where R5is a hydrogen atom, R11selected from 5 - to 6-membered heterocyclic radical, in which one ring member is a carbon and 1 to 4 members of the heteroatoms nitrogen, or sulfur, or their pharmaceutically acceptable salts, are useful as inhibitors of the synthesis of nitric oxide

The invention relates to therapeutically active hydroxamic acids and derivatives of carboxylic acids, processes for their preparation, to pharmaceutical compositions containing these compounds and to the use of such compounds in medicine

FIELD: chemistry; medicine.

SUBSTANCE: compounds of claimed invention possess properties of positive allosteric modulator mGluR5. In general formula I , W represents 6-member heterocycloalkyl ring with 1-2 heteroatoms, selected from N, O; R1 and R2 independently represent hydrogen, C1-C6-alkyl; P and Q each independently is selected from: , R3, R4, R5, R6 and R7 independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-member heteroaryl with 1-2 atoms N as heteroatoms; 6-member heterocycle with 2 heteroatoms representing N, O; phenyl, optionally substituted with halogen; naphtyl; -OR8; where optionally two substituents together with located between them atoms form 9-10-member bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S; R8 represents hydrogen, C1-C6-alkyl; D, E, F, G and H independently represent -C(R3)=, -O-, -N=, -N(R3)- or -S-; A represents ethinyl, -C(=O)NR8- or group of formula . B represents -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6-alkenyl-. Invention also relates to pharmaceutical composition based on invention compounds.

EFFECT: novel compounds possess useful biological proprties.

20 cl, 3 dwg, 75 ex

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