Pparγ receptor modulating novel compounds and use thereof in cosmetic and pharmaceutical compositions

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): , optical isomers of said compounds, as well as salts thereof having peroxisome proliferator-activated receptor subtype y (PPARy) modulating property. Values of R1, R2, X, Ar1 and Ar2 are given in the formula of invention.

EFFECT: preparation of compositions based on said compounds, as well as use of said compounds in cosmetic and pharmaceutical industry.

11 cl, 30 ex

 

The invention relates to new and useful industrial products, to a new class of compounds that are modulators of receptor type activated by proliferation peroxisome receptor subtype γ (PPARγ). The invention relates also to a method for their production and their use in pharmaceutical compositions intended for use in human or veterinary medicine, or alternatively in cosmetic compositions.

The activity of the PPAR receptor type was the target of many studies. Reference may be made, as a guide, a publication entitled "Differential expression of receptor subtypes activated by proliferation peroxisome during differentiation of human keratinocytes", Michel Rivier et al., J. Invest. Dermatol 111, 1998, pp. 1116-1121, which lists a large number of bibliographic references relating to the PPAR receptor type. Reference may also be made, as a guide, in a message entitled ” The PPARs: From orphan receptors to Drug Discovery”, Timothy M. Willson, Peter J. Brown, Daniel D. Sternbach and Brad. R. Henke, J. Med. Chem., 2000, Vol. 43, pp. 527-550.

The PPAR receptors activate transcription by binding to elements in DNA sequences, known as response elements of proliferator peroxisome (PPRE), in the form of heterodimer with the retinoid X receptors (known as RXRs).

Identified and described three potty is and PPAR person: PPARα, PPARγ and PPARδ (or NUC1).

PPARα mainly expressed in the liver, whereas PPARδ is omnipresent.

PPARγ is the most intensively studied of these three subtypes. All references suggest a critical role of PPARγ in the regulation of differentiation of adipocytes, where it largely is expressed. He also plays a key role in systemic lipid homeostasis.

In particular, in patent application WO 96/33724 described that PPARγ-selective compounds such as prostaglandin-J2 or-D2, are potential active agents for the treatment of obesity and diabetes.

In addition, the applicant has already described active for PPARγ compounds and/or their application in the patent document FR 2773075, which describes the use of compounds of PPARγ activators in obtaining pharmaceutical compositions, and the composition is intended for treating skin disorders associated with an anomaly of differentiation of epidermal cells.

One of the purposes of the present invention is to propose a new class of PPARγ-modulating compounds that find a very good specific affinity for PPARγ.

Thus, the present invention relates to compounds corresponding to the below General formula (I):

in which:

- R1 is a radical represented below fo the formula (a) or (b):

and R3 and R4 have the meanings given below,

- R2 represents an alkyl radical containing from 1 to 12 carbon atoms, aryl radical, Aracely radical, heteroaryl radical, a heterocyclic radical, 9-fluorenylmethyl radical or a radical of the formula (CH2)m(NR5)n(C(O,N)pR6;

and R5, R6, m, n and p have the meanings specified below;

- R3 represents a radical selected from the following formulas:

moreover, R7, R8, V, W and Y have the meanings given below;

- R4 represents an alkyl radical containing from 1 to 12 carbon atoms, the radicals OR9 or radical SR9 or NHR9;

- R5 and R7, which may be identical or different, represent a hydrogen atom, an alkyl radical containing from 1 to 12 carbon atoms, aryl radical, Aracely radical, heteroaryl radical or a heterocyclic radical,

when Y represents a nitrogen atom, then the radical of formula (e) is not substituted by a radical R7;

- R6 and R8, which may be identical or different, represent

radical O-(CH2)v-R10,

is a hydroxyl radical, an alkyl radical containing from 1 to 12 carbon atoms, aryl radical, Aracely radical, heteroaryl radical, a heterocyclic radical sludge is

radical

radical NR(CH2)vR10,

moreover, R10, R', R” and v have the meanings given below;

- R9 is an alkyl radical having from 1 to 12 carbon atoms, or a radical selected from the following formula:

(f)

(g)- (Q)p-R11or

(h) α-amino acids, N-protected regular amantadine groups such as 9-fluorenylmethoxycarbonyl (FMOC), tert-BUTYLCARBAMATE (BOC), benzyl, or TRIFLUOROACETYL;

and R11, Q and R have the meanings given below,

- m may be equal to the values 0, 1 or 2;

n and p can be equal to the values 0 or 1;

Q represents an oxygen atom, or sulfur, or NR5;

V represents an oxygen atom, nitrogen or sulfur;

W represents a nitrogen atom or a radical C-R5;

- Y represents a nitrogen atom or a carbon atom;

- Z represents an oxygen atom, nitrogen or sulfur;

- v may be equal to values 1, 2 or 3;

R10 represents an alkyl radical containing from 1 to 12 carbon atoms, aryl, Uralkaliy, heteroaryl or heterocyclic radical, a radical NH-CO-R12, a radical NH-CO-O-R12 or-R12R13 or a radical N R12R13, and R12 and R13 have the meanings specified below;

R' represents a hydrogen atom, an alkyl radical containing from 1 is about 12 carbon atoms, heteroaryl radical or a heterocyclic radical;

R” represents a hydrogen atom, an alkyl radical containing from 1 to 12 carbon atoms, aryl radical, Aracely radical, optionally substituted by one or more halogen atoms, a heteroaryl radical, a heterocyclic radical, the radical (CH2)vR10 or other radical10or NR10R10;

- R11 represents a hydrogen atom, an alkyl radical containing from 1 to 12 carbon atoms, aryl radical, Aracely radical, heteroaryl radical, a heterocyclic radical or a radical (CO)s(Z)tR10 with s and t may equal the values 0, 1 or 2;

- R12 represents a hydrogen atom, an alkyl radical containing from 1 to 12 carbon atoms, aryl radical, Aracely radical, heteroaryl radical or a heterocyclic radical;

- R13 represents a hydrogen atom or an alkyl radical containing from 1 to 12 carbon atoms;

- X represents a bond having the following structure:

-(CH2)z-NR14-C(T)-Dw-

moreover, D, z, w, T and R14 have the meanings given below,

T represents an oxygen atom or sulfur;

D represents an oxygen atom or sulfur, a radical-NR15or the radical CH2;

and R15 have the meanings specified below;

- z may be equal to ve is iciam 0 or 1;

- w may be equal to the values from 0 to 6, and

- R14 and R15 represent a hydrogen atom or an alkyl radical containing from 1 to 12 carbon atoms;

- Ar1 and Ar2 may be the same or different and represent an optionally substituted aromatic radical of the formula:

with And representing the atom is S or O, or a radical N-R13,

it is clear that when Ar1 or Ar2 represents a phenyl radical, Ar1 or Ar2 necessarily represents a heteroaryl radical,

and optical and geometrical isomers of the above compounds of formula (I)and their salts.

When the compounds according to the invention are in the form of salts of carboxylic acids, such salt is preferably a salt of an alkali metal, particularly sodium salt, the salt of the alkaline-earth metal or salt of an organic amine, more specifically, amino acids such as arginine or lysine.

When the compounds according to the invention are in the form of a salt of amine functions, such as pyridine, such a salt is preferably a salt of a halogen atom, such as hydrochloride or hydrobromide, or salt of an organic acid, such as fumarate or maleate, or nitrate.

In accordance with the present invention, the term hydroxyl radical, means the radical-HE.

In accordance with the present invention unique is their alkyl radical, containing from 1 to 12 carbon atoms means a linear or cyclic, saturated or unsaturated, optionally branched, hydrogen-containing or fluorine-containing radical, which contains 1-12 carbon atoms and may be interrupted by a heteroatom and alkyl radicals containing from 1 to 12 carbon atoms, preferably represent methyl, ethyl, ISO-propyl, butylene, tert-butylene, hexylene, heptylene, aktalnye, decile, tsiklogeksilnogo or methylenecyclopropane radicals.

The term simple polyester radical means polyether radical containing from 1 to 6 carbon atoms interrupted by at least one oxygen atom, such as methoxyethoxy, ethoxyethoxy or methoxyethoxymethyl.

The term halogen atom means a fluorine atom, chlorine or bromine.

The term alkoxyalkyl containing from 1 to 7 carbon atoms, means methoxy, ethoxy, isopropoxy-, tert-butoxy, hexyloxy, heptyloxy-, benzyloxy -, or peroxyradical, which can be optionally substituted alkyl radical containing from 1 to 12 carbon atoms.

The term aryl radical means phenyl, biphenylyl, cinnamony or nattily radical, which may be mono - or Disaese a halogen atom, the radical CF3, alkyl radical containing from 1 to 12 atmosukarto, alkoxyalkyl containing from 1 to 7 carbon atoms, the functional nitro-group, a polyether radical, aryl radical, benzoline radical, group Olkiluoto of ester, carboxylic acid, a hydroxyl radical optionally protected with acetyl or benzoline group, or a functional amino group, optionally protected by acetyl or benzoline group or optionally substituted by at least one alkyl containing from 1 to 12 carbon atoms.

The term kalkilya group means benzyl, finitely or 2-naphthylmethyl radical, which may be mono - or Disaese a halogen atom, the radical CF3, alkyl radical containing from 1 to 12 carbon atoms, alkoxyalkyl containing from 1 to 7 carbon atoms, the functional nitro-group, a polyether radical, aryl radical, benzoline radical, group Olkiluoto of ester, carboxylic acid group, a hydroxyl radical optionally protected with acetyl or benzoline group, or a functional amino group, optionally protected by acetyl or benzoline group or optionally substituted by at least one alkyl containing from 1 to 12 carbon atoms.

The term heteroaryl radical means aryl radical, interrupted on the him or more heteroatoms, such as peredelnyj, purely, thienyl, isoxazolyl, oxadiazolyl, oxazolidinyl, isothiazolinones, chinadaily, benzothiadiazoles, benzimidazolinyl, khinoksalinona, indaily or benzofuranyl radical, optionally substituted by at least one halogen atom, alkyl containing from 1 to 12 carbon atoms, alkoxy containing from 1 to 7 carbon atoms, aryl radical, functional nitro-group, a polyether radical, a heteroaryl radical, benzoline radical, group Olkiluoto of ester group of carboxylic acid, hydroxyl, optionally protected by acetyl or benzoline group, or a functional amino group, optionally protected acetyl or benzoline group or optionally substituted by at least one alkyl containing from 1 to 12 carbon atoms.

The term heterocyclic radical, preferably, means morpholino, piperidino, piperazine derivatives, 2-oxo-1-piperidinyl or 2-oxo-1-pyrrolidinyloxy radical, optionally substituted by at least one alkyl containing from 1 to 12 carbon atoms, alkoxy containing from 1 to 7 carbon atoms, aryl radical, functional nitro-group, a polyether radical, a heteroaryl radical, benzoline radical, group Olkiluoto complex is th ether, the group of carboxylic acid, hydroxyl, optionally protected by acetyl or benzoline group, or a functional amino group, optionally protected by acetyl or benzoline group or optionally substituted by at least one alkyl containing from 1 to 12 carbon atoms.

Among the compounds of the above formula (I)are within the context of the present invention, it is possible to specify particularly the following compounds (alone or in mixture):

1. N-{4-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenyl]thiophene-2-ylmethyl}-N-methylbenzamide

2. N-{5-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenyl]thiophene-3-ylmethyl}-N-methylbenzamide

3. N-{5-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenyl]pyrid-3-ylmethyl}-N-methylbenzamide

4. N-{3-[5-(2,4-Dioxothiazolidine-5-ylmethyl)pyrid-2-yl]benzyl}-N-methylacrylamide

5. 2(S)-Ethoxy-3-(4-{5-[(methylacrylamide)methyl]thiophene-3-yl}phenyl)propanoic acid

6. 2(S)-Ethoxy-3-(4-{5-[(methylacrylamide)methyl]thiophene-2-yl}phenyl)propanoic acid

7. 2(S)-Ethoxy-3-{4-[2-(3-heptyl-1-methylurea)thiazol-4 - yl]phenyl}propanoic acid

8. 2(S)-Ethoxy-3-{4-[2-(3-pentyl-1 macilwraith)thiazol-5-yl]phenyl}propanoic acid

9. 2(S)-Ethoxy-3-{4-[6-(3-heptyl-1-methylurea)pyrid-2-yl]phenyl}propanoic acid

10. Chloride 2-[4-(2-carboxy-2(S)-ethoxyethyl)phenyl]-6-(3-heptyl-1-methylurea)pyridinium

11. 2(S)-Ethoxy-3-{4-[5-(3-GE the Teal-1-methylurea)-2-methyl-2H-[1,2,4]triazole-3-yl]phenyl}propanoic acid

12. {3-[5-(2,4-Dioxothiazolidine-5-ylmethyl)thiophene-2-yl]benzyl}metalocherepitsya

13. {3-[5-(2,4-Dioxothiazolidine-5-ylmethyl)thiophene-2-yl]benzyl}methylhexaneamine

14. 2(S)-(2-Benzoylamino)-3-(4-{5-[(methylacrylamide)methyl]thiophene-3-yl}phenyl)propanoic acid

15. 2(S)-(2-Benzoylamino)-3-(4-{5-[(exanimation)methyl]thiophene-3-yl}phenyl)propanoic acid

16. 2(S)-Ethoxy-3-(4-{5-[(exanimation)methyl]thiophene-3-yl}phenyl)propanoic acid

17. 2(S)-Ethoxy-3-(4-{5-[(methylpentylamino)methyl]thiophene-3-yl}phenyl)propanoic acid

18. 3-[4-(5-{[(2-Cyclopentylacetyl)methylamino]methyl}thiophene-3-yl)phenyl]-2(S)-ethoxypropanol acid

19. 3-[4-(5-{[(3-Cyclohexylpropionic)methylamino]methyl}thiophene-3-yl)phenyl]-2(S)-ethoxypropanol acid

20. 2 Ethoxy-3-{6-[3-(3-heptyl-1-methylurea)phenyl]pyrid-3 - yl}propanoic acid

21. 2(S)-(2-Benzoylamino)-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid

22. 2(S)-(2-Benzoylamino)-3-{4-[6-(3-heptyl-1-methylurea)pyrid-2-yl]phenyl}propanoic acid

23. 2(S)-Ethoxy-3-{6-[3-(3-heptyl-1-methylurea)phenyl]pyrid-3-yl}propanoic acid

24. Hydrochloride 2(S)-ethoxy-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid

25. 3-{4-[6-(3-Butyl-1-methylurea)pyrid-2-yl]phenyl}-2(S)-ethoxypropanol acid

26. Hydrochloride 2(S)-ethoxy-3-{4-[6-(1-methyl-3-ventilerede)the feast of the d-2-yl]phenyl}propanoic acid

27. 2(S)-Ethoxy-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid

28. 2(S)-Ethoxy-3-{4-[6-(1-methyl-3-naphthalene-2-yureina)pyrid-2-yl]phenyl}propanoic acid

29. 3-{4-[6-(3-Cyclohexyl-1-methylurea)pyrid-2-yl]phenyl}-2(S)-ethoxypropanol acid

30. 2(S)-Ethoxy-3-{4-[3-(3-heptyl-1-methylurea)phenyl]thiazol-2-yl}propanoic acid

31. 2(S)-Ethoxy-3-{4-[3-(1-methyl-3-pentyurina)phenyl]thiazol-2-yl}propanoic acid

32. 2(S)-Ethoxy-3-{6-[3-(1-methyl-3-pentyurina)phenyl]pyrid-3-yl}propanoic acid

33. 2(S)-Ethoxy-3-[4-(6-{3-[2-(4-forfinal)ethyl]-1-methylurea}of pyrid-2-yl)phenyl]propanoic acid

34. 2(S)-Ethoxy-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid

35. 2(S)-Ethoxy-3-{4-[4-(3-heptyl-1-methylurea)pyrid-2-yl]phenyl}propanoic acid

36. 2(S)-Ethoxy-3-{4-[4-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid

37. 2(S)-Ethoxy-3-{4-[2-(1-methyl-3-pentyurina)pyrid-4-yl]phenyl}propanoic acid

38. 2(S)-Ethoxy-3-{4-[2-(3-heptyl-1-methylurea)pyrid-4-yl]phenyl}propanoic acid

39. 2(S)-Ethoxy-3-{4-[2-(3-heptyl-1-methylurea)pyrimidine-4-yl]phenyl}propanoic acid

40. 2(S)-Ethoxy-3-{4-[2-(1-methyl-3-pentyurina)pyrimidine-4-yl]phenyl}propanoic acid

41. 2(S)-Ethoxy-3-{5-[3-(3-heptyl-1-methylurea)phenyl]furan-2-yl}propanoic acid

42. 2(S)-Ethoxy-3-{5-[3-(3-heptyl-1-methylurea)phenyl]thiophene-2-yl}propanoic acid

43. 2(S)-Ethoxy-3-{2[3-(3-heptyl-1-methylurea)phenyl]pyrimidine-5-yl}propanoic acid

44. 2(S)-Ethoxy-3-{6-[3-(3-heptyl-1-methylurea)phenyl]pyrid-3-yl}propanoic acid

45. 2(S)-Ethoxy-3-{4-[5-(3-heptyl-1-methylurea)thiophene-2-yl]phenyl}propanoic acid

46. 2(S)-Ethoxy-3-[4-(5-{[methyl-(6-propoxylation-2-carbonyl)amino]methyl}furan-2-yl)phenyl]propanoic acid

47. 2(S)-Ethoxy-3-{4-[5-(3-heptyl-1-methylurea)furan-2 - yl]phenyl}propanoic acid

48. 2(S)-Ethoxy-3-[4-(5-{[methyl-(6-propoxylation-2-carbonyl)amino]methyl}thiophene-2-yl)phenyl]propanoic acid

49. 2(S)-Ethoxy-3-[4-(4-{[methyl-(6-propoxylation-2-carbonyl)amino]methyl}thiophene-2-yl)phenyl]propanoic acid

50. 3-(6-{3-[3-(4-Dimethylaminophenyl)-1-methylurea]phenyl}of pyrid-3-yl)-2(S)-ethoxypropanol acid

51. 2(S)-Ethoxy-3-[6-(3-{[methyl-(6-propoxylation-2-carbonyl)amino]methyl}phenyl)pyrid-3-yl]propanoic acid

52. 2(S)-Ethoxy-3-(6-{3-[(leptanillinae)methyl]phenyl}pyridine-3-yl)propanoic acid

53. 2(S)-Ethoxy-3-(6-{3-[(exanimation)methyl]phenyl}of pyrid-3-yl)propanoic acid

54. 2(S)-Ethoxy-3-(4-{5-[(methylacrylamide)methyl]furan-2-yl}phenyl)propanoic acid

55. N-{3-[5-(3-Hydroxy-2(S)-Veniaminovich-3-enyl)pyrid-2-yl]benzyl}-N-metalocherepitsya

56. 2(S)-Ethoxy-3-[6-(3-heptyl-1-methylurea)-[2,2]bipyridyl-5-yl]propanoic acid

57. 1-(3-{2-[2(S)-Ethoxy-3-(4-methylpiperid-1-yl)-3-oxopropyl]thiazol-4-yl}phenyl)-1-methyl-3-pencilmation

58. 1-(3-{5-[2(S)-Ethoxy-2-(5-propyl[1,3,4]about sedesol-2-yl)ethyl]pyrimidine-2-yl}phenyl)-3-heptyl-1-metalmachine

59. 1-{6-[4-(2(S)-Ethoxy-3-oxo-3-piperid-1-ylpropyl)phenyl]pyrid-2-yl}-1-methyl-3-pencilmation

60. 1-(6-{4-[(2(S)-Ethoxy-3-(4-methylpiperid-1-yl)-3 - oxopropyl]phenyl}of pyrid-2-yl)-1-methyl-3-pencilmation

61. 1-{6-[4-(2(S)-Ethoxy-3-morpholine-4-yl-3-oxopropyl]phenyl]pyrid-2-yl}-1-methyl-3-pencilmation

62. 2(S)-Ethoxy-3-(4-{5-[(exanimation)methyl]thiophene-3-yl}phenyl)propanoic acid

63. {4-[4-(2(S)-Ethoxy-3-oxo-3-piperid-1-ylpropyl)phenyl]thiophene-2-ylmethyl}methylhexaneamine

64. (4-{4-[2(S)-Ethoxy-3-(4-methylpiperid-1-yl)-3-oxopropyl]phenyl}thiophene-2-ylmethyl) methylhexaneamine

65. {4-[4-(2(S)-Ethoxy-3-morpholine-4-yl-3-oxopropyl)phenyl]thiophene-2-ylmethyl}methylhexaneamine

66. {4-[4-(2(S)-Ethoxy-3-oxo-3-piperid-1-ylpropyl)phenyl]thiophene-2-ylmethyl}metalocherepitsya

67. (4-{4-[2(S)-Ethoxy-3-(4-methylpiperidin-1-yl)-3-oxopropyl]phenyl}thiophene-2-ylmethyl)metalocherepitsya

68. 1-{3-[5-(2(S)-Ethoxy-3-oxo-3-piperid-1-ylpropyl)pyrid-2-yl]phenyl}-1-methyl-3-pencilmation

69. 1-(3-{5-[2(S)-Ethoxy-3-(4-methylpiperid-1-yl)-3-oxopropyl]pyrid-2-yl}phenyl)-1-methyl-3-pencilmation

70. 1-{3-[5-(2(S)-Ethoxy-3-morpholine-4-yl-3-oxopropyl)pyrid-2-yl]phenyl}-1-methyl-3-pencilmation

71. 1-{3-[2-(2,4-Dioxothiazolidine-5-ylmethyl)pyrimidine-5-yl]phenyl}-3-heptyl-1-metalmachine

72. 1-{3-[2-(2,4-Dioxothiazolidine-5-ylmethyl)pyrimidine-5-yl]phenyl}-1-methyl-3-pencilmation

73. 2(S)-Ethoxy-3-{5-[3-(1-methyl-3-pentyurina)phenyl]pyrimidine-2-yl}propanoic acid

74. 2(S)-Ethoxy-3-{6-[4-fluoro-3-(1-methyl-3-pentyurina)phenyl]pyrid-3-yl}propanoic acid

75. 2(S)-Ethoxy-3-{2-fluoro-4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid

76. 2(S)-Ethoxy-3-{4-[5-(1-methyl-3-pentyurina)thiophene-2-yl]phenyl}propanoic acid

77. 2(S)-Ethoxy-3-{4-[5-(3-heptyl-1-methylurea)thiophene-2-yl]phenyl}propanoic acid

78. 2(S)-Methylamino-3-(4-{5-[(methylacrylamide)methyl]thiophene-3-yl}phenyl)propanoic acid

79. 2(S)-Acylamino-3-(4-{5-[(methylacrylamide)methyl]thiophene-3-yl}phenyl)propanoic acid

80. 2(S)-Acylamino-3-(4-{5-[(exanimation)methyl]thiophene-3-yl}phenyl)propanoic acid

81. 3-(4-{5-[(Exanimation)methyl]thiophene-3-yl}phenyl)-2(S)-methylaminopropane acid

82. 2(S)-Acylamino-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid

83. 2(S)-Acylamino-3-{4-[6-(3-heptyl-1-methylurea)pyrid-2-yl]phenyl}propanoic acid

84. 3-{4-[6-(3-Heptyl-1-methylurea)pyrid-2-yl]phenyl}-2(S)-methylaminopropane acid

85. 2(S)-Methylamino-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid

86. 2(S)-Cyclopropylmethoxy-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid

87. 2(S)-Ethoxy-3-[6-(1-methyl-3-pentyurina)-[2,2]piperid - 5-yl]propanoic acid

88. 2(S)-Ethoxy-3-(6-{5-[(methylacrylamide)methyl]t is the dryer-3-yl}pyrid-3-yl)propanoic acid

89. 2(S)-Ethoxy-3-(6-{5-[(exanimation)methyl]thiophene-3-yl}pyrid-3-yl)propanoic acid

90. Fumarate 2-[4-(2-carboxy-2(S)-ethoxyethyl)phenyl]-6-(3-heptyl-1-methylurea)pyridinium

91. Maleate 2-[4-(2-carboxy-2(S)-ethoxyethyl)phenyl]-6-(3-heptyl-1-methylurea)pyridinium

92. 3-{4-[6-(1-Methyl-3-pentyurina)pyrid-2-yl]phenyl}-2(S)-propoxyphenol acid

93. 2(S)-Isopropoxy-3-{4-(6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid

94. 2(S)-Ethoxy-3-[4-(5-{[3-1H-indol-3-ylpropionic)methylamino]methyl}thiophene-3-yl)phenyl]propanoic acid

95. 3-{4-[6-(3-Pentyl-1 macilwraith)pyrid-2-yl]phenyl}-2-methylpropanoate acid

96. 3-{4-[6-(3-Heptyl-1-methylurea)pyrid-2-yl]phenyl}-2-methylpropanoate acid

97. 2-Methyl-3-(4-{5-[(methylacrylamide)methyl]thiophene-2-yl}phenyl)propanoic acid

98. 3-{6-[3-(3-Heptyl-1-methylurea)phenyl]pyrid-3-yl}-2-methylpropanoate acid

99. (2S)-Ethoxy-3-(4-{4-[1-methyl-3-(2-piperidine-1-retil)ureido]pyridine-2-yl}phenyl)propanoic acid

100. (2S)-Ethoxy-3-(4-{4-[1-methyl-3-(3 - phenylpropyl)ureido]pyridine-2-yl}phenyl)propanoic acid

101. (2S)-Ethoxy-3-(4-{4-[1-methyl-3-(4-phenylbutyl)ureido]pyridine-2-yl}phenyl)propanoic acid

102. 3-{4-[4-(3-Benzo[1,2,5]thiadiazole-4-yl-1-methylurea)pyridine-2-yl]phenyl}-2(S)-ethoxypropanol acid

103. 3-(4-{4-[3-(4-Dimethylaminophenyl)-1-methylurea]pyridine-2-yl}phenyl)-2(S)-ethoxypropanol acid

104. (2S)-Ethoxy-3-[4(4-{3-[2-(1H-imidazol-2-yl)ethyl]-1-methylurea}pyridine-2-yl)phenyl]propanoic acid

105. 3-(4-{4-[3-(2-Dimethylaminoethyl)-1-methylurea]pyridine-2-yl}phenyl)-2(S)-ethoxypropanol acid

106. (2S)-Ethoxy-3-{4-[4-(1-methyl-3-naphthalene-2-yureina)pyridine-2-yl]phenyl}propanoic acid

107. 3-{4-[6-(3-Benzo[1,2,5]thiadiazole-4-yl-1-methylurea)pyridine-2-yl]phenyl}-2(S)-ethoxypropanol acid

108. (2S)-Ethoxy-3-(4-{6-[1-methyl-3-(3-phenylpropyl)ureido]pyridine-2-yl}phenyl)propanoic acid

109. (2S)-Ethoxy-3-(4-{6-[1-methyl-3-(2-piperidine-1-retil)ureido]pyridine-2-yl}phenyl)propanoic acid

110. (2S)-Ethoxy-3-(4-{6-[1-methyl-3-(4-phenylbutyl)ureido]pyridine-2-yl}phenyl)propanoic acid

111. 3-(4-{6-[3-(4-Dimethylaminophenyl)-1-methylurea]pyridine-2-yl}phenyl)-2(S)-ethoxypropanol acid

112. 3-(4-{6-[3-(2-Dimethylaminoethyl)-1-methylurea]pyridine-2-yl}phenyl)-2(S)-ethoxypropanol acid

113. 2(S)-Ethoxy-3-[4-(6-{3-[2-(1H-imidazol-2-yl)ethyl]-1-methylurea}pyridine-2-yl)phenyl]propanoic acid

114. 2(S)-Ethoxy-3-{4-[6-(1-methyl-3-petitioned)pyridine-2-yl]phenyl}propanoic acid

115. 2(S)-Ethoxy-3-{4-[6-(1-methyl-3-patitioned)pyridine-2-yl]phenyl}propanoic acid

116. 2(S)-Ethoxy-3-{6-[3-(3-heptyl-1-methyl-touraid)phenyl]pyridine-3-yl}propanoic acid

117. 2(S)-Ethoxy-3-{4-[4-(3-heptyl-1-methyl-touraid)pyridine-2-yl]phenyl}propanoic acid

118. 2(S)-Ethoxy-3-(6-{3-[1-methyl-3-(2-piperidine-1-retil)ureido]phenyl}pyridine-3-yl)propanoic acid

119. 3-(6-{3-[3-(2-Benzo[1,2,5]thiadiazole-4-Ile who yl)-1-methylurea]phenyl}pyridine-3-yl)-2(S)ethoxypropanol acid

120. 2(S)-Ethoxy-3-(6-{3-[1-methyl-3-(3-phenylpropyl)ureido]phenyl}pyridine-3-yl)propanoic acid

121. 3-(6-{3-[3-(4-Dimethylaminophenyl)-1-methylurea]phenyl}pyridine-3-yl)-2(S)-ethoxypropanol acid.

In accordance with the present invention, compounds of formula (I), which are more particularly preferred are compounds which have at least one of the following characteristics:

- R1 is a radical of formula (a) or (b); and when R1 corresponds to the formula (b), R3 is preferably a radical of formula (d), and R8 represents a hydroxyl, R NR'r" or heterocyclic radical and R4 represents, preferably, a radical of the formula OR9, in which R9 represents alkyl with 1-12 carbon atoms, or a group of formula (f), and R11 represents hydrogen or a group R10;

- R2 represents alkyl, aryl or heteroaryl radical;

- X represents the communication structure-CH2N(R14)CO -, or-N(R14)-CO-(D)wwith w=0 or 1;

preferred compounds contain at least one group Ar1 or Ar2 type of pyridine, thiazole, pyrimidine, thiophene or a triazole.

Below is a General description of obtaining compounds of General formula (I) with R1 of formula (b), such as compounds 25-30 12-16 and 1, 2, 3 and 4, attached here.

The scheme of reactions described is a figure 1, a General scheme for obtaining managerialistic or digitalistic derivatives. It is, in particular, is used in the case where Ar2 represents phenyl, because the connection 2 that is commercially available.

Connection 1 with R representing NR14G, can be obtained from the derivatives by monosomic, for example, a protective group G, for example, type b, fmoc or acetyl, followed by alkylation with alkylhalogenide in the presence of a base such as sodium hydride. Connection 1, in which R represents a CH2NR14G, usually obtained by the reaction of reductive amination of aldehyde functional group.

Intermediate compound 3 receive through a combination of Suzuki between arylboronic acid, such as 4-formylbenzeneboronic acid, or heteroarylboronic acid, which is commercially available or obtained in advance from the corresponding halogen derivatives, and halogenated heteroarylboronic, for example (6-bromo-2-pyridyl)methylamine, or (5-bromo-2-thiazolyl)methylamine, optionally protected group G as above.

Compound 4 is obtained by combination of the chiral reagent Evans, for example, (S)-4-benzyloxypyridine-2-it, and carboxylic acids, for example alkoxyalkyl or Uralkaliy what usnei acid in the case Y=O, which, preferably, is commercially available, in the presence of a base, for example, utility.

Chiral intermediate compound 5 get through enantioselective accession connection 4 to the intermediate compound 3 in the presence of a derivative of boron.

Connection 6 getting dehydroxylization connection 5 with the use of reaction Barton: education Topolino communication between a hydroxyl group you want to delete, and familiarisation followed by heating to 110°C in the presence of hydride and anti-free-radical agent, AIBN.

Intermediate compounds 9 and 11 can be obtained after removing the protection from amine (-G) joining the isocyanate or thioisocyanate, if D = NR15or gelegenheid acid, if D = CH2. The hydrolysis benzisoxazole-2-about parts for connection 12 is carried out in conditions that preserve the stereochemistry of C-OR9for example 1.5 equivalent of a 1M aqueous solution of lithium hydroxide in tetrahydrofuran at room temperature.

Heterocyclic compounds 13 and 14 are synthesized by standard methods of synthesis of heterocycles, in the case of compound 14, the condensation of hydrazide butyric acid and cyclization by heating to 105°C in the presence of phosphorus oxychloride.

Esters of 15 is to be obtained, for example, esterification of alcohols(CH2)vR10.

Connection 16 get through the amidation reaction with the amine type HNR'R".

Another reaction route for preparing compounds 12-16 described in figure 2.

Schema modification reaction occurs essentially when the derivatization 5.

In particular, the intermediate compound 5 can also be obtained as described in figure 2, through a combination of Suzuki between Bronevoy acid 18 and derivative 19, which is similar to the connection 34, in which G represents R9. This synthetic path is particularly suitable for obtaining derivatives, in which Ar1 represents phenyl. When Ar1 represents an aromatic heterocycle corresponding to boranova acid may be obtained in advance according to standard methods.

Derived 19 receive in accordance with the scheme described in figure 5: the connection 32 is conducted by a combination of chiral reagent Evans, for example, (S)-4-benzyloxypyridine-2-it, and carboxylic acid, and the functional group Y is optional protected group G or alkylated, which, preferably, is commercially available, in the presence of a base, for example, utility. Condensation derived 32 from halogenated aldehyde 31 allows to obtain a connection 33. The medium of the reaction dihydroxypropane Barton get a connection 34 or 19, when the functional group Y alkylate group, R9.

Derived 34 get dehydroxylization connection 33 with the use of reaction Barton, and chiral intermediate connection 33 get enantioselective attach connection 32 to the halogenated aromatic aldehyde 31 in the presence of a derivative of boron. For compounds with Y representing N, and Ar2 represents phenyl, intermediate connection 36 can be obtained from the methyl ester of 4-brompheniramine (L or D) methyl ester of tyrosine (L or D) joining the acid chloride of acid (n=1) or by alkylation using alkylhalogenide (n=0).

You can apply another synthetic path described in figure 3 and 4.

Intermediate compound 20 receive through a combination of Suzuki between arylboronic acid 18, such as 3-formylbenzeneboronic acid, or heteroarylboronic acid, which is commercially available or obtained in advance from the corresponding halogen derivatives, and derivative 36 (figure 3). The connection 20 can also be obtained via Suzuki reaction between halogenated heteroarylboronic and bronovil derived 51 received in advance. This approach is often used in the case of a group Ar2, such as phenyl (figure 4).

Intermediate compound 36 can be obtained from the soedineniya 34, as shown in figure 5, after removing the protection from amine (-G) by joining gelegenheid acid (n=1) or alkylation with alkylhalogenide (n=0).

Another way of obtaining connection 36 in the case where Ar2 represents phenyl, consists in breaking the cycle of chiral epoxide, such as 2(S)-methylphenidate, monocaprate derivative formed from 1,4-dibromobenzene with, with subsequent enantioselective acylation or alkylation, for example, in the presence of alkylhalogenide and silver oxide. The connection 51 then be obtained by interaction between connection 36 with bis(pinacolato)DIBORANE in the presence of a catalyst based on palladium and potassium acetate in dimethylformamide.

Intermediate compounds 22 and 24 can be obtained after removing the protection from amine (-G) (compounds 21 and 23) joining the isocyanate or thioisocyanate, if D represents NR15or gelegenheid acid, if D represents CH2.

The hydrolysis benzisoxazole-2-or alkyl part of a complex ether to obtain compound 25 is carried out in conditions that preserve the stereochemistry of C-OR9for example, using 1.5 equivalent of aqueous 1 M solution of lithium hydroxide in tetrahydrofuran at room temperature.

The connection 25, thus obtained, make connections 26, 27, 28 and 29 by way of the m, described sequentially to obtain derivatives 13, 14, 15 and 16.

General description of obtaining compounds of General formula (I) with R1 of formula (a) (compound 44 6 and 7, attached here) below.

The scheme of reactions described in Fig.6, is a General scheme for obtaining managerialistic or digitalistic derivatives, for which the variation of the R2 groups are produced at the end of the synthesis.

Condensation of 2,4-thiazolidinedione with aldehyde 3 (obtained as described above) in the presence of the acetate piperidine, for example, gives compound 37.

Intermediate compound 38 receive the functional recovery of the nitro group with tin chloride in the presence of hydrochloric acid. Intermediate compounds 39 and 40 is obtained by removing protection from amine (-G).

Compounds 41 and 42, which can be grouped together as compound 43 (Z=0 or Z=1, respectively), can be obtained by joining the isocyanate or thioisocyanate, if D represents NR15or gelegenheid acid, if D represents CH2.

The connection 44 to receive, for example, by hydrogenation of compound 43 pressure of 3 atmospheres in the presence of palladium on coal in a solvent, for example dioxane.

The scheme of reactions described in Fig.7, is a scheme in which different groups R2 injected at the beginning of the synthesis.

The connection 45 get restore what pressure functional nitro compound 1. Intermediate compounds 46 and 47 is obtained by removing the protection of the functional amino group (-G).

Intermediate compounds 48 and 49 receive accession isocyanate or thioisocyanate, if D represents NR15or gelegenheid acid, if D represents CH2.

Through the Suzuki reaction between compounds 48 or 49 and Bronevoy acid 2 get a connection 50.

Condensations of 2,4-thiazolidinedione with aldehyde 50, i.e. the connection 41, if z is 0, or connection 42, if z=1 (obtained as described above), in the presence of the acetate piperidine receive, for example, the connection 43.

The connection 44 to receive, for example, by hydrogenation of compound 43 pressure of 3 atmospheres in the presence of palladium on charcoal, in a solvent, for example dioxane.

Compounds according to the invention find a modulating effect on the PPAR receptor type. This activity on the receptors PPARα, δ and γ measured in the test transactivation and quantitatively determined by the dissociation constant Kdapp (apparent)as described in example 29.

Preferred compounds of the present invention have a dissociation constant that is less than or equal to 5000 nm, and preferably equal to or less than 1000 nm.

Preferably, the compounds are modulators of receptors specific type PPARγ, i.e. they have the relationship between the Kdapp for the of eception PPARα and PPARδ and Kdapp for receptor PPARγ more than 10 or equal to 10. This attitude PPARγ/PPARα or PPARγ/PPARδ, preferably, greater than or equal to 50 and, more predominantly, greater than or equal to 100.

The object of the present invention are also used as medicinal products the compounds of formula (I)described above.

The object of the present invention is the use of compounds of formula (I) for the manufacture of a composition for regulating and/or restoring the metabolism of skin lipids.

Compounds according to the invention are also particularly applicable in the following areas of treatment:

1) for treating dermatological diseases associated with disorders of keratinization related to differentiation and proliferation, especially for treating common acne, comedones, polymorphs, pink acne, nodular-cystic acne, nodular acne, senile acne and secondary acnes such as solar, drug or occupational acne;

2) for treating other types of disorders of keratinization, in particular ichthyosis, States ichthyosiform, disease Daria, Palmar-plantar keratoderma, leukoplakia and States leukoplakia and skin Stripping or Stripping of the mucosa (mouth);

3) for treating other dermatological diseases with inflammatory immuno-allergic component, with impaired cell proliferation or without him, the in particular, all forms of psoriasis, regardless of whether it is skin, nail psoriasis or psoriasis mucosa, and even psoriatic arthritis, or alternatively cutaneous atopy, such as eczema, or respiratory atopy or gingival hypertrophy;

4) for treating all dermal and epidermal proliferate, regardless of whether they are benign or malignant, regardless of whether they have or not of viral origin, such as warts, flat warts and epidermodysplasia borodalopatoy, papillomatosis oral or red papillomatoses, T-lymphoma and proliferation, which can be caused by ultraviolet light, in particular, in the case of basal cell and speckletone epithelioma, as well as any pre-cancerous skin damage, such as keratoakantoma;

5) for treating other dermatological disorders such as immune dermatitis, such as systemic lupus erythematosus, bullous immune diseases and collagen diseases, such as scleroderma;

6) in the treatment of dermatological or systemic diseases with an immunological component;

7) in the treatment of skin disorders due to the action of UV radiation, as well as for skin regeneration or to prevent aging of the skin, regardless of whether it is the action of the Holy is this or is age ageing, to reduce actinic keratoses and pigmentations, or any pathologies associated with age or actinic aging, such as xerosis;

8) for combating disorders of the sebaceous function, such as Hyperborea acne, simple seborrhoea or seborrhoeic dermatitis;

9) for the prevention or treatment of disturbances of wound healing, or for the prevention or healing of abrasions;

10) in the treatment of pigmentation disorders such as hyperpigmentation, melasma, hypopigmentation or vitiligo;

11) in the treatment of disorders of lipid metabolism, such as obesity, hyperlipidemia, non-insulin-dependent diabetes or syndrome X;

12) in the treatment of inflammatory diseases such as arthritis;

13) in the treatment or prevention of cancerous or precancerous conditions;

14) in the prevention or treatment of alopecia of various origins, in particular alopecia caused by chemotherapy or radiation;

15) in the treatment of immune system disorders, such as asthma, diabetes type I, multiple sclerosis or other selective dysfunctions of the immune system; or

16) in the treatment of diseases of the cardiovascular system such as arteriosclerosis or hypertension.

The object of the present invention is also a pharmaceutical or cosmetic composition comprising in a physiologically acceptable medium,at least one compound of the formula (I)as described above.

The composition according to the invention can be introduced enteral, parenteral, local or ocular route. The pharmaceutical composition is preferably packaged in a form that is appropriate for local use.

For enteral route composition, more specifically, the pharmaceutical composition may be in the form of tablets, gel capsules, covered with sugar tablets, syrups, suspensions, solutions, powders, granules, emulsions or lipid or polymer vesicles or nanospheres or microspheres to provide modified release. For parenteral route, the composition may be in the form of solutions or suspensions for infusion or for injection.

Compounds according to the invention is usually administered at a daily dose of about 0.001 mg/kg to 100 mg/kg of body weight with the introduction of 1-3 doses.

Compounds used systemically at a concentration typically between about 0.001% and 10 wt.% and, preferably, between 0.01% and 1 wt.% relative to the weight of the composition.

When local route of administration of the pharmaceutical composition according to the invention is more particularly intended for treating the skin and mucous membranes and may be in the form of ointments, creams, milk, powders, impregnated soft gaskets, sanditov, solutions, gels, sprays, foams, suspensions, sticks, lotions, shampoos or detergents cos the century It could also be in the form of suspensions of lipid or polymer vesicles or nanospheres or microspheres or polymer impregnated soft pads and hydrogels to provide controlled release. This composition for topical application can be in anhydrous form, in aqueous form or in the form of an emulsion.

Compounds applied topically at a concentration typically between about 0.001% and 10 wt.%, preferably, between 0.01% and 1 wt.% relative to the total weight of the composition.

The compounds of formula (I) according to the invention also find application in the cosmetic field, in particular for hygiene of the body and hair and, more specifically, for regulating and/or restoring the metabolism of skin lipids.

The subject of the invention is thus also a cosmetic use of a composition containing, in a physiologically acceptable medium, at least one of the compounds of formula (I), for the purposes of hygiene or hair.

Cosmetic composition according to the invention, containing a cosmetically acceptable medium, at least one compound of formula (I) or an optical or geometric isomer or its salt, may be generally in the form of a cream, a milk, a lotion, a gel, suspensions of lipid or polymer vesicles or nanospheres or microspheres impregnated soft pads, solutions, sprays, foams, sticks, Soaps, shampoos or mouseholes.

The concentration of the compounds of formula (I) in the cosmetic composition is between 0,0001% and 2 wt.% relative to the total weight of the composition.

Pharmaceutical and cosmetic compositions as described above can also contain inert or even pharmacodynamically supplements to pharmaceutical compositions, or combinations of these additives, and especially:

- wetting agents;

- amplifiers aroma or taste;

- preservative agents, such as esters of para-hydroxybenzoic acid;

- stabilizers;

regulators humidity;

- pH regulators;

the osmotic pressure modifiers;

- emulsifiers;

agents, shielding rays UV-a and UV-b;

- antioxidants, such as α-tocopherol, butylhydroxyanisole or equivalent, superoxide dismutase, original or some metalhalide agents;

- depigmenting agents, such as hydroquinone, azelaic acid, caffeic acid or kojic acid;

- emollients;

- humectants, such as glycerol, PEG 400, thiomorpholine and its derivatives or urea;

agents against seborrhea and acne, such as S-carboxymethylcysteine, S-benzylcyanide, their salts or their derivatives, or benzoyl peroxide;

antibiotics such as erythromycin and its esters, neomycin, clindamycin and its esters and etracycline;

antifungal agents such as ketoconazole or polymethylene-4,5-isothiazoline-3;

agents for stimulating re-growth of hair, such as Minoxidil (3-oxide, 2,4-diamino-6-piperidinylidene) and its derivatives, diazoxide (1,1-dioxide 7-chloro-3-methyl-1,2,4-benzotiadiazina) and phenytoin (5,4-diphenylimidazole-2,4-dione);

- nastroenie anti-inflammatory agents;

- carotenoids, especially β-carotene;

- antipsoriatics agents, such as anthralin and its derivatives;

- eicosa-5,8,11,14-Terranova acid and eicosa-5,8,11-TRINOVA acid and their esters and amides;

- retinoids, i.e., the ligands of the receptor RAR or RXR, which can be natural or synthetic;

- corticosteroids or estrogens;

α-hydroxy acid or α-keto acid or derivatives thereof, such as lactic acid, malic acid, citric acid, glycolic acid, mandelic acid, tartaric acid, glyceric acid or ascorbic acid, and their salts, amides or esters, or β-hydroxy acids or their derivatives such as salicylic acid and its salts, amides or esters;

blockers of ion channels, such as blockers of potassium channels;

or, in the alternative case, which is more typical for the pharmaceutical compositions, in combination with medicinal products, which are known to inhibit the action of the immune system (for example, cyclosporine, FK 506, glucocorticoids, monoclonal antibodies, cytokines or growth factors, and so on).

Excessive is the observation that specialist in this area should pay attention to choose the optional compound(s)that you want to add to these compositions, so that the beneficial properties, essentially associated with the present invention, the addition had no or essentially no adverse effect.

Another object of the invention relates to a cosmetic method give the skin an attractive appearance, characterized in that a composition comprising at least one compound of formula (I)as described above, applied to the skin. Regulation and/or restoring the metabolism of skin lipids makes it possible to use this method to improve the appearance of skin's surface.

Now, by way of illustration, but without limitation of the invention, will be given a few examples of active compounds of the formula (I) according to the invention, as well as the results of biological activity for these compounds and various concrete compositions based on these compounds.

Example 1: N-{4-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenyl]thiophene-2-ylmethyl}-N-methylbenzamide

(a) (4-Bromothiophene-2-ylmethyl)methylamine

18 g (260 mmol) of methylamine hydrochloride and Satem,5 g (100 mmol) of cyanoborohydride sodium successively added to a solution of 10 g (50 mmol) 4-bromo-2-thiophenecarboxaldehyde in 150 ml of methanol. The reaction mixture was stirred at room temperature for 24 hours and then filtered under vacuum. After evaporation of the filtrate to dryness the residue is dissolved in dichloromethane. The organic phase is washed with 1 n hydrochloric acid. Thus obtained aqueous phase is treated with an aqueous 1 n solution of sodium hydroxide and extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated in vacuum. Obtain 4.5 g (44%) (4-bromothiophene-2-ylmethyl)methylamine.

(b) N-(4-Bromothiophene-2-ylmethyl)-N-methylbenzamide

of 2.8 ml (24 mmol) of benzoyl chloride is added dropwise to a solution of 4.5 g (22 mmol) (4-bromothiophene-2-ylmethyl)of methylamine and 6 ml (44 mmol) of triethylamine in 75 ml of tetrahydrofuran. After stirring at room temperature for 1 hour the precipitate is filtered off and the filtrate was concentrated in vacuo. The residue is dissolved in dichloromethane and washed with water.

The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue is purified by chromatography on a column of silica with elution with a mixture 8/2 heptane/ethyl acetate. Obtain 4.8 g (71%) of N-(4-bromothiophene-2-ylmethyl)-N-methylbenzamide in the form of oil.

(C) N-[4-(4-Formylphenyl)thiophene-2-ylmethyl]-N-methylbenzamide

3 g (20 mmol) 4-formylbenzeneboronic acid added to the solution is of 4.75 g (15 mmol) of N-(4-bromothiophene-2-ylmethyl)-N-methylbenzamide in 60 ml of toluene, followed by adding dropwise 5.5 g (40 mmol) of an aqueous solution of potassium carbonate. Reaction medium Tegaserod, then add 530 mg (0.5 mmol) derived tetragonality and the mixture is heated at 80°C for 18 hours. After extraction with ethyl acetate and washing with water, the organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue is purified by chromatography on a column of silica with elution with a mixture of 1/1 heptane/ethyl acetate. Get 4 g (78%) of N-[4-(4-formylphenyl)thiophene-2-ylmethyl]-N-methylbenzamide.

(d) N-{4-[4-(2,4-Dioxothiazolidine-5-ylidenemethyl)phenyl]thiophene-2-ylmethyl}-N-methylbenzamide

A solution of 4 g (9 mmol) of N-[4-(4-formylphenyl)thiophene-2 - ylmethyl]-N-methylbenzamide, 1.1 g (9 mmol) of 2,4-thiazolidinedione and 0.3 g (1.8 mmol) of the acetate piperidine in 40 ml of toluene is refluxed for 2 hours in the system Dean-stark. The reaction mixture is cooled and the precipitate is filtered off under vacuum. Get 3 g (78%) of N-{4-[4-(2,4-dioxothiazolidine-5-ylidenemethyl)phenyl]thiophene-2-ylmethyl}-N-methylbenzamide.

(e) N-{4-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenyl]thiophene-2-ylmethyl}-N-methylbenzamide

2 g (1 mass equivalent) of palladium on coal added to a solution of 2 g (4.6 mmol) of N-{4-[4-(2,4-dioxothiazolidine-5-ylidenemethyl)phenyl]thiophene-2-ylmethyl}-N-methylbenzamide in 20 ml of dioxane, which was previously Tegaserod, and the reaction mixture is placed in an atmosphere of hydrogen at 3 atm. and 50°C for 6 hours. After otdeleniia by filtration through zeolite filtrate was concentrated in vacuo. The resulting residue is purified by chromatography on a column of silica with elution with a mixture of 9.5/0.5 to dichloromethane/methanol. Receive 1.5 g (75%) of N-{4-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenyl]thiophene-2-ylmethyl}-N-methylbenzamide in the form of a solid substance with a melting point of 134°C.

1H NMR (δ, CDCl3): 2,98-3,10 (m, 3H); 3.15 in (DD, J=22 Hz, J=7 Hz, 1H); to 3.52 (DD, J=6,1 Hz, J=22 Hz, 1H); 4.53-in (DD, J=6,1 Hz, J=15 Hz, 1H); 4.63 to-4,89 (m, 2H); 7,15-rate of 7.54 (m, 11H); to 8.94 (s, 1H).

Example 2: N-{5-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenyl]thiophene-3-ylmethyl}-N-methylbenzamide

(a) Ethylthiophene-3-carboxylate

13 ml (200 mmol) of thionyl chloride is added dropwise at 0°C. to a solution of 9 g (70 mmol) of 3-thiophencarboxylic acid and 86 mg (0.7 mmol) 4-dimethylaminopyridine in 100 ml of ethanol. The reaction mixture is stirred at a temperature of from 0°C. to room temperature for 48 hours and then evaporated to dryness. The resulting residue is purified by chromatography on a column of silica with elution with a mixture of 1/1 heptane/dichloromethane. Get 10 g (91%) ethylthiophene-3-carboxylate.

(b) Ethyl-5-bromothiophene-3-carboxylate

20 g (147 mmol) of aluminium chloride are added in portions to a solution of 10 g (67 mmol) ethylthiophene-3-carboxylate in 160 ml of dichloromethane, in advance, cooled to 0°C. the Reaction mixture is heated to room temperature and then add a solution of 4 ml (73 mmol) of bromine in 10 ml of dichloromethane. After the exclusion of the of the reaction for 50 minutes at room temperature, the reaction medium is poured into a mixture of water + ice and extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated in vacuum. The resulting residue is purified by chromatography on a column of silica with elution with a mixture of 9/1 heptane/ethyl acetate. Get 9 g (57%) ethyl-5-bromothiophene-3-carboxylate.

(C) 5-Bromothiophene-3-carboxylic acid

of 7.4 g (185 mmol) of pellets of sodium hydroxide are added to a solution of 8.7 g (37 mmol) of ethyl-5-bromothiophene-3-carboxylate in 100 ml of tetrahydrofuran, 10 ml of methanol and a few drops of water. After stirring at room temperature for 18 hours, the reaction mixture was dissolved in ethyl acetate and washed with water. The resulting aqueous phase is acidified to pH 1 aqueous solution of hydrochloric acid and then extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. Get 7 g (92%) 5-bromothiophene-3-carboxylic acid.

(d) 5-Bromothiophene-N-methyl-3-carboxylamide

4.7 g (35 mmol) of 1-hydroxybenzotriazole, 2.2 g (32 mmol) of methylamine hydrochloride and 4.5 ml (32 mmol) of triethylamine are sequentially added to a solution of 6.7 g (32 mmol) of 5-bromothiophene-3-carboxylic acid in 120 ml of dichloromethane. The reaction mixture was cooled to 0°C and added dropwise a solution of 6.7 g (35 mmol) of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. After keeping at 0°C for 1 hour, the reaction medium is stirred the ri room temperature for 2 days. The dichloromethane phase is washed with water, dried over sodium sulfate, filtered and evaporated in vacuum. The resulting residue triturated with a mixture of heptane/ethyl acetate, filtered and evaporated. Obtain 5.6 g (60%) 5-bromothiophene-N-methyl-3-carboxylamide.

(e) (5-Bromothiophene-3-ylmethyl)methylamine

A solution of 9 ml (18 mmol) of 2 M dimetilsulfoksida in toluene is added dropwise to a suspension of 3.7 g (17 mmol) of 5-bromothiophene-N-methyl-3-carboxylamide in 50 ml of toluene, cooled beforehand to -78°C. After addition the reaction mixture is stirred at a temperature of from -78°C. to room temperature for 16 hours and then refluxed for 5 hours. To the reaction mixture is added aqueous 10% sodium carbonate solution and the mixture extracted with dichloromethane. After washing the acid-base organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. Obtain 2.3 g (66%) (5-bromothiophene-3-ylmethyl)methylamine.

(f) N-(5-Bromothiophene-3-ylmethyl)-N-methylbenzamide

1.6 ml (13 mmol) of benzoyl chloride is added dropwise to a solution of 2.3 g (11 mmol) (5-bromothiophene-3-ylmethyl)of methylamine and 3 ml (22 mmol) of triethylamine in 30 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 hour, filtered, diluted with ethyl acetate and washed with water. The organic phase is dried over self the volume of sodium filtered and evaporated to dryness. The resulting residue is purified by chromatography on a column of silica with elution with a mixture 8/2 heptane/ethyl acetate. Obtain 3.1 g (80%) of N-(5-bromothiophene-3-ylmethyl)-N-methylbenzamide.

(g) N-[5-(4-Formylphenyl)thiophene-3-ylmethyl]-N-methylbenzamide

In a manner analogous to the method of example 1(C), on the basis of 3 g (10 mmol) of N-(5-bromothiophene-3-ylmethyl)-N-methylbenzamide and 1.9 g (13 mmol) of 4-formylbenzeneboronic acid, 2.6 g (80%) of N-[5-(4-formylphenyl)thiophene-3-yl)methyl]-N-methylbenzamide obtained after purification by chromatography on a column of silica with elution with a mixture 7/3 heptane/ethyl acetate.

(h) N-{5-[4-(2,4-Dioxothiazolidine-5-ylidenemethyl)phenyl]thiophene-3-ylmethyl}-N-methylbenzamide

In a manner analogous to the method of example 1(d), on the basis of 2.6 g (8 mmol) of N-[5-(4-formylphenyl)thiophene-3-ylmethyl]-N-methylbenzamide and 1 g (8.5 mmol) of 2,4-thiazolidinedione, obtain 2.2 g (63%) of N-{5-[4-(2,4-dioxothiazolidine-5-ylidenemethyl)phenyl]thiophene-3-ylmethyl}-N-methylbenzamide.

(i) N-{5-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenyl]thiophene-3-ylmethyl}-N-methylbenzamide

In a manner analogous to the method of example 1(e), the hydrogenation of 1.8 g (4.2 mmol) of N-{5-[4-(2,4-dioxothiazolidine-5-ylidenemethyl)phenyl]thiophene-3-ylmethyl}-N-methylbenzamide 800 mg (45%) of N-{5-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenyl]thiophene-3-ylmethyl}-N-methylbenzamide receive in the form of a solid substance with a melting point of 153°C.

1 H NMR (δ, CDCl3): 2,93-3,10 (m, 3H); 3.15 in (DD, J=22 Hz, J=7 Hz, 1H); 3,51 (DD, J=6,1 Hz, J=22 Hz, 1H); of 4.49 (DD, J=6,1 Hz, J=15 Hz, 1H); 4.63 to-4,89 (m, 2H); 7,02-of 7.69 (m, 11H); 9,36 (s, 1H).

Example 3: N-{5-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenyl]pyrid-3-ylmethyl}-N-methylbenzamide

(a) Ethyl-5-bromonicotinate

20 ml (27 mmol) of thionyl chloride is added dropwise at room temperature to a solution of 10 g (49 mmol) of 5-bromonicotinic acid in 250 ml of ethanol. The reaction mixture was stirred at room temperature for 4 days and then evaporated in vacuum. The residue is dissolved in dichloromethane and washed with an aqueous solution of sodium carbonate. The organic phase is dried over sodium sulfate, filtered and evaporated in vacuum. The resulting residue is purified by chromatography on a column of silica with elution with a mixture 7/3 heptane/ethyl acetate. Get 9 g (82%) of ethyl-5-bromonicotinate.

(b) (5-Pampered-3-yl)methanol

A solution of 9 g (40 mmol) of ethyl-5-bromonicotinate in 25 ml of methanol is added dropwise at room temperature to a suspension of 14.8 g (400 mmol) of sodium borohydride in 75 ml of methanol. After the addition, the reaction mixture is refluxed for 2 hours. The reaction mixture is evaporated in vacuo, dissolved in aqueous sodium hydroxide solution to pH 9 and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated in vacuum. Obtain 3.7 g (50%) (-pampered-3-yl)methanol.

(C) 5-Bromopyridin-3-carbaldehyde

4.5 g (21 mmol) Harrogate pyridinium added at room temperature to a solution of 3 g (16 mmol) (5-pampered-3-yl)methanol in 70 ml of dichloromethane. After stirring for 1 hour, add 70 ml of diethyl ether and the reaction mixture is again stirred for 1 hour. The precipitate is filtered over sodium sulphate and the filtrate is evaporated to dryness. The resulting residue is purified by chromatography on a column of silica with elution with a mixture 7/3 heptane/ethyl acetate. Get 1 g (35%) 5-bromopyridin-3-carbaldehyde.

(d) (5-Pampered-3-ylmethyl)methylamine

1.8 g (27 mmol) of methylamine hydrochloride and then 0.4 g (6 mmol) of cyanoborohydride sodium successively added to a solution of 1 g (5.4 mmol) of 5-bromopyridin-3-carbaldehyde in 20 ml of methanol. The reaction mixture was stirred at room temperature for 2 days. The precipitate is filtered off and the filtrate evaporated to dryness. The residue is dissolved in dichloromethane and washed with water. After extraction the organic phase is washed with aqueous hydrochloric acid. Thus obtained aqueous phase is alkalinized to pH 9 with an aqueous solution of sodium hydroxide and then extracted with dichloromethane. Thus obtained organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue is cidaut chromatography on a column of silica with elution with a mixture of 9.5/0.5 to dichloromethane/methanol. Obtain 0.5 g (50%) (5-bromopyridin-3-ylmethyl)methylamine.

(e) N-(5-Pampered-3-ylmethyl)-N-methylbenzamide

In a manner analogous to the method of example 2(f), starting from 0.5 g (3 mmol) (5-pampered-3-ylmethyl)of methylamine and 0.4 ml (3.6 mmol) of benzoyl chloride, to obtain 0.8 g (90%) of N-(5-pampered-3-ylmethyl)-N-methylbenzamide.

(f) N-[5-(4-Formylphenyl)pyrid-3-ylmethyl]-N-methylbenzamide

In a manner analogous to the method of example 1(C), on the basis of 0.8 g (2.6 mmol) of N-[5-(4-formylphenyl)pyrid-3-ylmethyl)-N-methylbenzamide and 0.5 g (3,15 mmol) 4-formylbenzeneboronic acid, 0.8 g (93%) of N-[5-(4-formylphenyl)pyrid-3-ylmethyl]-N-methylbenzamide obtained after purification on a column of silica with elution with a mixture 7/3 heptane/ethyl acetate.

(g) N-{5-[4-(2,4-Dioxothiazolidine-5-ylidenemethyl)phenyl]pyrid-3-ylmethyl}-N-methylbenzamide

In a manner analogous to the method of example 1(d), on the basis of 0.8 g (2.4 mmol) of N-[5-(4-formylphenyl)pyrid-3-ylmethyl]-N - methylbenzamide and 0.35 g (2.9 mmol) of 2,4-thiazolidinedione, obtain 0.6 g (60%) of N-{5-[4-(2,4-dioxothiazolidine-5-ylidenemethyl)phenyl]pyrid-3-ylmethyl}-N-methylbenzamide.

(h) N-{5-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenyl]pyrid-3-ylmethyl}-N-methylbenzamide

In a manner analogous to the method of example 1(e), the hydrogenation of 0.6 g (1.4 mmol) of N-{5-[4-(2,4-dioxothiazolidine-5-ylidenemethyl)phenyl]pyrid-3-ylmethyl}-N-methylbenzamide 0.2 g (33%) of N-{5-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenyl]pyrid-3-ylmethyl}-N-methylbenzamide which are square in form of a solid substance with a melting point of 92°C.

1H NMR (δ, CDCl3): 2,96-3,10 (m, 3H); 3,20 (DD, J=22 Hz, J=7 Hz, 1H); to 3.58 (DD, J=6,1 Hz, J=22 Hz, 1H); 4,55 (DD, J=6,1 Hz, J=15 Hz, 1H); 4,573-4,84 (m, 2H); 7,30 at 8.60 (m, 12H); 8,79 (s, 1H).

Example 4: N-{3-[5-(2,4-Dioxothiazolidine-5-ylmethyl)pyrid-2-yl]benzyl}-N-methylacrylamide

(a) Ethyl-6-(3-formylphenyl)nicotinate

In a manner analogous to the method of example 1(C), based on 26,3 g (95 mmol) of ethyl-6-etniciteit and 18.5 g (123 mmol) 4-formylbenzeneboronic acid, 6 g (27%) of ethyl-6-(3-formylphenyl)nicotinate obtained after chromatography on a column of silica with elution with a mixture 7/3 heptane/ethyl acetate.

(b) Ethyl-6-(3-methylaminomethyl)nicotinate

In a manner analogous to the method of example 3(d), on the basis of 6.2 g (25.5 mmol) of ethyl-6-(3-formylphenyl)nicotinate and 8.6 g (of 127.5 mmol) of methylamine hydrochloride, 2.7 g (40%) of ethyl-6-(3 - methylaminomethyl)nicotinate obtained after purification by chromatography on a column of silica with elution with a mixture of 95/5/0,5 dichloromethane/methanol/Isopropylamine.

(C) Ethyl-6-{3-[(methylacrylamide)methyl]phenyl}nicotinate

In a manner analogous to the method of example 1(b), starting from 2.1 g (7.8 mmol) of ethyl-6-(3-methylaminomethyl)nicotinate and 1.3 g (8 mmol) of octanoylthio, obtain 2.9 g (100%) of ethyl-6-{3-[(methylacrylamide)methyl]phenyl}nicotinate after purification by chromatography on a column of silica with elution with a mixture of 6/4 heptane/ethyl acetate.

(d) N-[3-(5-Hydroxy who eilperin-2-yl)benzyl]-N-methylacrylamide

0.8 g (35 mmol) of lithium borohydride are added slowly to a solution of 3.3 g (9 mmol) of ethyl-6-{3-[(methylacrylamide)methyl]phenyl}nicotinate in 35 ml of tetrahydrofuran, in advance, cooled to 0°C. the Reaction mixture is stirred at a temperature of from 0°C. to room temperature for 24 hours and then poured into a mixture of water + ice and extracted with ethyl acetate.

The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue is purified by chromatography on a column of silica with elution with a mixture 8/2 heptane/ethyl acetate. Get 1,9 g (61%) of N-[3-(5-hydroxymethylene-2-yl)benzyl]-N-methylacrylamide.

(e) N-[3-(5-Formalised-2-yl)benzyl]-N-methylacrylamide

5.5 g (63 mmol) of manganese dioxide are placed in a solution of 2.25 g (6.3 mmol) of N-[3-(5-hydroxymethylene-2-yl)benzyl]-N - methylacrylamide in 50 ml of dichloromethane. After stirring at room temperature for 18 hours, the reaction mixture was filtered through celite, the residue washed thoroughly with dichloromethane and the filtrate concentrated in vacuo. Obtain 1.7 g (78%) of N-[3-(5-formalised-2-yl)benzyl]-N-methylacrylamide.

(f) N-{3-[5-(2,4-Dioxothiazolidine-5-ylidenemethyl)pyrid-2-yl]benzyl}-N-methylacrylamide

In a manner analogous to the method of example 1(d), starting from 1.7 g (4.8 mmol) of N-[3-(5-formalised-2-yl)benzyl]-N-methylacrylamide and 0.6 g (4.8 mmol) 2,thiazolidinedione, 1.4 g (62%) of N-{3-[5-(2,4-dioxothiazolidine-5-ylidenemethyl)pyrid-2-yl]benzyl}-N-methylacrylamide obtained after purification by chromatography on a column of silica with elution with a mixture 4/6 heptane/ethyl acetate.

(g) N-{3-[5-(2,4-Dioxothiazolidine-5-ylmethyl)pyrid-2-yl]benzyl}-N-methylacrylamide

In a manner analogous to the method of example 1(e), the hydrogenation of 400 mg (0.9 mmol) of N-{3-[5-(2,4-dioxothiazolidine-5-ylidenemethyl)pyrid-2-yl]benzyl}-N-methylacrylamide 210 mg (53%) of N-{3-[5-(2,4-dioxothiazolidine-5-ylmethyl)pyrid-2-yl]benzyl}-N-methylacrylamide obtained after purification on a column of silica with elution with a mixture 3/7 heptane/ethyl acetate.

1H NMR (δ, CDCl3): 0,84 (t, J=7 Hz, 3H); to 1.21 and 1.35 (m, 8H); 1.69 in (m, 2H); 2.40 a (t, J=7.7 Hz, 2H); of 2.97 (s, 3H); 3,30 (DD, J=22 Hz, J=7 Hz, 1H); of 3.48 (DD, J=6,1 Hz, J=22 Hz, 1H); of 4.57 (DD, J=6,1 Hz, J=15 Hz, 1H); 4,573-and 4.68 (m, 2H); 7,20-7,86 (m, 7H); to 8.57 (s, 1H).

Example 5: 2(S)-Ethoxy-3-(4-{5-[(methylacrylamide)methyl]thiophene-3-yl}phenyl)propanoic acid

(a) (4-Bromothiophene-2-ylmethyl)methylamine

In a manner analogous to the method of example 3(d), on the basis of 4.7 g (24.6 mmol) of 4-bromothiophene-2-carbaldehyde and 8.3 g (123 mmol) of methylamine hydrochloride, 1.7 g (33%) (4-bromothiophene-2-ylmethyl)methylamine obtained after purification by chromatography on a column of silica with elution with a mixture 8/2 heptane/ethyl acetate.

(b) N-(4-Bromothiophene-2-ylmethyl)-N-methylacrylamide

In a manner analogous to the way CA is RA 1(b), on the basis of 1.7 g (8.25 mmol) (4-bromothiophene-2-ylmethyl)of methylamine and 1.6 ml (9 mmol) of octanoylthio, 2.1 g (80%) of N-(4-bromothiophene-2-ylmethyl)-N-methylacrylamide obtained after purification on a column of silica with elution with a mixture 8/2 heptane/ethyl acetate.

(C) N-[4-(4-Formylphenyl)thiophene-2-ylmethyl]-N-methylacrylamide

In a manner analogous to the method of example 1(C), starting from 2.1 g (6.3 mmol) of N-(4-bromothiophene-2-ylmethyl)-N-methylacrylamide and 1.1 g (7.6 mmol) of 4-formylbenzeneboronic acid, 1.4 g (61%) of N-[4-(4-formylphenyl)thiophene-2-ylmethyl]-N-methylacrylamide obtained after purification by chromatography on a column of silica with elution with a mixture 7/3 heptane/ethyl acetate.

(d) N-(4-{4-[3-(4-Benzyl-2-oxoacridine-3-yl)-2(S)-ethoxy-1(S)-hydroxy-3-oxopropyl]phenyl}thiophene-2-ylmethyl)-N-methylacrylamide

Getting 4(S)-benzyl-3-(2-ethoxyacetic)oxazolidin-2-it

93 mg (232 mmol) of utility added dropwise to a solution of 41 g (232 mmol) of S-(-)-4-benzyloxypyridine-2-it in 600 ml of tetrahydrofuran, in advance, cooled to -78°C. After stirring for 30 minutes, added dropwise 35 g (279 mmol) of ethoxyacetylene. After stirring for 1 hour at -78°C. the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture is evaporated to dryness, dissolved in ethyl acetate and washed with water. The organic phase is dried on the sodium sulfate, filtered and evaporated. The resulting residue is purified by chromatography on a column of silica with elution with a mixture 8/2 heptane/ethyl acetate. Get 54 g (90%) 4(S)-benzyl-3-(2-ethoxyacetic)oxazolidin-2-it.

Obtaining N-(4-{4-[3-(4-benzyl-2-oxoacridine-3-yl)-2(S)-ethoxy-1(S)-hydroxy-3-oxopropyl]phenyl}thiophene-2-ylmethyl)-N-methylacrylamide

5,9 ml (5.9 mmol) dibutylnitrosamine added dropwise to a solution of 1.2 g (4.7 mmol) of 4(S)-benzyl-3-(2-ethoxyacetic)oxazolidin-2-it in 20 ml of dichloromethane, in advance, cooled to 0°C., followed by adding 1 ml (5.9 mmol) of diisopropylethylamine. The reaction mixture was stirred at 0°C for 30 minutes and then cooled to -78°C and added dropwise 1.4 g (3.9 mmol) of N-[4-(4-formylphenyl)thiophene-2-ylmethyl]-N-methylacrylamide in 15 ml of dichloromethane. Stirring is continued at -78°C for 1 hour and then at room temperature for 2 hours and 30 minutes. The reaction mixture was cooled to 0°C and add 11 ml of buffer solution with pH 7 in 11 ml of methanol, followed by addition of 11 ml of 30% aqueous hydrogen peroxide solution in 11 ml of methanol. After stirring at 0°C for 1 hour and 30 minutes, water is added and the reaction mixture is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by chromatography through which Alonso with silicon dioxide in the elution mixture 6/4 heptane/ethyl acetate. Obtain 1.8 g (75%) of N-(4-{4-[3-(4-benzyl-2-oxoacridine-3-yl)-2-ethoxy-1-hydroxy-3-oxopropyl]phenyl}thiophene-2-ylmethyl)-N-methylacrylamide.

(e) (4-{4-[3-(4-Benzyl-2-oxoacridine-3-yl)-2(S)-ethoxy-3-oxopropyl]phenyl}thiophene-2-ylmethyl)methylacrylamide

0.9 ml (1.8 mmol) of bis(trimethylsilyl)amide sodium are added to a solution of 1 g (1.6 mmol) of N-(4-{4-[3-(4-benzyl-2-oxoacridine-3-yl)-2-ethoxy-1-hydroxy-3-oxopropyl]phenyl}thiophene-2-ylmethyl)-N-methylacrylamide in 20 ml of dichloromethane, pre-cooled to -78°C. After stirring at -78°C for 1 hour add 0.25 ml (1.8 mmol) of penishealthinformation and the reaction mixture was stirred at -78°C for 1 hour and then at room temperature for 2 hours. After adding water, the reaction mixture is extracted with dichloromethane. The organic phase is evaporated in vacuum. The resulting residue is placed in 30 ml of toluene and then added 13 mg (0.1 mmol) of 2,2-azobis-(2-methylpropionitrile) and 0.65 ml (2.4 mmol) of tributyltinhydride. The reaction mixture is heated at 110°C for 30 minutes. The reaction mixture is cooled, diluted with ethyl acetate and washed with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by chromatography on a column of silica with elution with a mixture of 6/4 heptane/ethyl acetate. Obtain 0.65 g (65%) of (4-{4-[3-(4-benzyl-2-oxohexanoyl the DIN-3-yl)-2-ethoxy-3-oxopropyl]phenyl}thiophene-2-ylmethyl)methylacrylamide.

(f) 2(S)-Ethoxy-3-(4-{5-[(methylacrylamide)methyl]thiophene-3-yl}phenyl)propanoic acid

1.3 ml (1.6 mmol) of a 0.5 n aqueous solution of lithium hydroxide are added to a solution of 0.6 g (1 mmol) of (4-{4-[3-(4-benzyl-2-oxoacridine-3-yl)-2-ethoxy-3-oxopropyl]phenyl}thiophene-2-ylmethyl)methylacrylamide in 10 ml of tetrahydrofuran, cooled to 0°C. After stirring at 0°C for 30 minutes the reaction mixture was stirred at room temperature for 1 hour and 30 minutes. To the reaction mixture are added water and ethyl acetate and then added an aqueous solution of sodium hydroxide to obtain a pH of 8-9. After extraction and phase separation, repeated twice, the product is an aqueous phase. This aqueous phase is acidified to pH 3-4 aqueous 1 n solution of hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by chromatography on a column of silica with elution with a mixture 98/2 dichloromethane/methanol. Obtain 0.35 g (76%) 2(S)-ethoxy-3-(4-{5-[(methylacrylamide)methyl]thiophene-3-yl}phenyl)propanoic acid.

1H NMR (δ, CDCl3): 0,89 (m, 3H); to 1.19 (t, J=6.8 Hz, 3H); of 1.30 to 1.34 (m, 8H); 1.69 in (m, 2H); 2,36-of 2.50 (m, 2H); 3,03 (s, 3H); to 3.06 (m, 1H); 3.15 in (DD, J=4.0 Hz, J=14,0 Hz, 1H); 3,41 is-3.45 (m, 1H); 4.09 to of 4.12 (m, 1H); 4,10 (DD, J=4.0 Hz, J=7,0 Hz, 1H); 4,69-4,74 (m, 2H); 7,19-7,35 (m, 4H); 7,49 (d, J=7.9 Hz, 2H).

Example 6: 2(S)-Ethoxy-3-(4-{5-[(methylacrylamide)methyl]thiophene-2-yl}phenyl)p is upanova acid

and- (5-Bromothiophene-2-ylmethyl)-N-methylamine

14 g (209 mmol) of methylamine hydrochloride are added to a solution of 5 g (42 mmol) of 5-bromothiophene-2-carboxaldehyde in 80 ml of ethanol and 40 ml of methanol. The reaction mixture was cooled to 0°C and added 5.8 g (is 83.8 mmol) cyanoborohydride sodium. The reaction mixture was stirred at 0°C for 5 hours, hydrolyzing and diluted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The resulting residue is dissolved in a mixture of 70/30 heptane/dichloromethane and then filtered. Obtain 6.7 g of a crude residue.

b- (5-Bromothiophene-2-ylmethyl)-N-methylacrylamide

6.2 ml (35,7 mmol) octanoylthio added dropwise to a solution of 6.7 g (32.5 mmol) of the crude residual (5-bromothiophene-2-ylmethyl)-N-methylamine obtained in 6A, in 120 ml of tetrahydrofuran and 5 ml (35,7 mmol) of triethylamine, cooled beforehand to 0°C. the Reaction mixture is stirred for 30 minutes at 0°C and then for 4 hours at room temperature. After adding water, the reaction mixture was extracted with ethyl acetate. The organic phase is washed with aqueous sodium chloride solution, separated and then evaporated. The resulting residue is purified by chromatography on a column of silica with elution with a mixture 8/2 and then 7/3 heptane/ethyl acetate. Obtain 1.2 g (11%) (5-bromothiophene-2-ylmethyl)-N-methylacrylamide.

The- [5-(4-Formylphenyl)thiophene-2-ylmethyl]-N-methylacrylamide

of 5.4 ml (10,8 mmol) of an aqueous solution of potassium carbonate are added to a solution of 1.2 g (3.6 mmol) (5-bromothiophene-2-ylmethyl)-N-methylacrylamide and 0.65 g (4.3 mmol) of 4-formylbenzeneboronic acid in 20 ml of toluene. The reaction mixture Tegaserod and then add 0.12 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium. The reaction mixture was stirred at 90°C for 5 hours. After adding water, the reaction mixture was extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by chromatography on a column of silica with elution with a mixture 8/2 and then 7/3 heptane/ethyl acetate. Obtain 0.25 g (19%) [5-(4-Formylphenyl)thiophene-2-ylmethyl]-N-methylacrylamide.

d - N-(5-{4-[3-(4(S)-Benzyl-2-oxoacridine-3-yl)-2(S)-ethoxy-1(S)-hydroxy-3-oxopropyl]phenyl}thiophene-2-ylmethyl)-N-methylacrylamide

and 2.26 ml (of 2.26 mmol) solution dibutylnitrosamine added dropwise to a solution of 0.48 g (1.8 mmol) [5-(4-formylphenyl)thiophene-2-ylmethyl]-N-methylacrylamide in 12 ml of dichloromethane, cooled to 0°C, followed by the addition of 0.39 ml (of 2.26 mmol) diisopropylethylamine. The reaction mixture was stirred at 0°C for 30 minutes and then cooled to -78°C. added dropwise a solution of 0.54 g (1.5 mmol) 4(S)-benzyl-3-(2-ethoxyacetic)oxazolidin-2-it (obtained as described in example 5d) in 5 ml of dichloromethane. Reaction the th mixture was stirred at -78°C for 1 hour and then at room temperature for 2 hours and 30 minutes. After cooling to 0°C is added dropwise a mixture of 4 ml of buffer solution with pH 7 and 4 ml of methanol, followed by adding dropwise a mixture of 4 ml of aqueous 30% hydrogen peroxide solution and 4 ml of methanol. The reaction mixture is stirred for 1 hour at room temperature, water is added and the mixture extracted with dichloromethane. The dichloromethane phase is dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by chromatography on a column of silica with elution with a mixture 7/3 and then 6/4 heptane/ethyl acetate. Gain of 0.62 g (66%) of N-(5-{4-[3-(4(S)-benzyl-2-oxoacridine-3-yl)-2(S)-ethoxy-1(S)-hydroxy-3-oxopropyl]phenyl}thiophene-2-ylmethyl)-N-methylacrylamide.

e - O-[3-(4(S)-Benzyl-2-oxoacridine-3-yl)-2(S)-ethoxy-1-(4-{5-[(methylacrylamide)methyl]thiophene-2-yl}phenyl)-3-oxopropyl]-O-phenylthiocarbamyl

0,55 ml (1.1 mmol) of trimethylsilane sodium are added to a solution of 0.62 g (1 mmol) of N-(5-{4-[3-(4(S)-benzyl-2-oxoacridine-3-yl)-2(S)-ethoxy-1(S)-hydroxy-3-oxopropyl]phenyl}thiophene-2-ylmethyl)-N-methylacrylamide in 15 ml of tetrahydrofuran, in advance, cooled to -78°C and the reaction mixture is stirred for 1 hour at -78°C, followed the addition of 0.15 ml (1.1 mmol) of penishealthinformation. The reaction mixture is again stirred at -78°C for 1 hour and then at room temperature for 1 hour. After adding water actionnow the mixture is extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and evaporated. The crude product is used in stage f.

f- (5-{4-[3-(4(S)-Benzyl-2-oxoacridine-3-yl)-2(S)-ethoxy-3-oxopropyl]phenyl}thiophene-2-ylmethyl)-N-methylacrylamide

The crude product obtained in stage e, placed in 15 ml of toluene with 0.01 g (0.05 mol) AiBN and 0.4 ml (1.5 mmol) of tributyltinhydride. After heating at 110°C for 45 minutes the reaction mixture composition has not changed. Type of 0.56 ml (2.1 mmol) of tributyltinhydride and the reaction mixture stirred at 110°C for 2 hours. Water is added and the reaction mixture is extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by chromatography on a column of silica with elution with a mixture 8/2 and then 7/3 heptane/ethyl acetate. Obtain 0.27 g (45%) (5-{4-[3-(4(S)-benzyl-2-oxoacridine-3-yl)-2(S)-ethoxy-3-oxopropyl]phenyl}thiophene-2-ylmethyl)-N-methylacrylamide.

g - 2(S)-Ethoxy-3-(4-{5-[(methylacrylamide)methyl]thiophene-2 - yl}phenyl)propanoic acid

A solution of 0.27 g (0.45 mmol) of (5-{4-[3-(4(S)-benzyl-2-oxoacridine-3-yl)-2(S)-ethoxy-3-oxopropyl]phenyl}thiophene-2-ylmethyl)-N-methylacrylamide in 10 ml of tetrahydrofuran and 1.3 ml (0.67 mmol) of aqueous 0.5 M sodium hydroxide solution is stirred at a temperature of from 0°C. to room tempera is URS for 18 hours. After adding water the first extraction is performed with ethyl acetate. The resulting aqueous phase is acidified to pH 6 with aqueous solution of hydrochloric acid and then extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride, filtered and evaporated. The resulting residue is purified by chromatography on a column of silica with elution with a mixture 5/5 heptane/ethyl acetate. Obtain 0.06 g (30%) 2(S)-ethoxy-3-(4-{5-[(methylacrylamide)methyl]thiophene-2-yl}phenyl)propanoic acid.

1H NMR (δ CDCl3): 0,88 (t, J=6,7 Hz, 3H); of 1.18 (t, J=7.0 Hz, 3H); of 1.28 and 1.35 (m, 8H); 1,67 is 1.70 (m, 2H); 2,34-2,48 (m, 2H); 3,00 (m, 1H); 3,01 (s, 3H); 3,14 (m, 1H); 3,47 (m, 1H); 3,63 (m, 1H); 4,11 (m, 1H); 4,69 (m, 2H,); make 6.90 (DD, J=17 Hz, J=3.6 Hz, 1H); 7,14 (DD, J=3,6 Hz, J=13 Hz, 1H); 7,27 (d, J=8.1 Hz, 2H); 7,50 (d, J=8.1 Hz, 2H).

Example 7: 2(S)-Ethoxy-3-{4-[2-(3-heptyl-1-methylurea)thiazol-5-yl]phenyl}propanoic acid

and - N-(5-Bromothiazole-2-yl)ndimethylacetamide

5,9 ml (42,3 mmol) of acetic anhydride are added to a solution of 10 g (of 38.5 mmol) to the hydrobromide of 2-amino-5-bromothiazole in 100 ml of dichloromethane and 11 ml (77 mmol) of triethylamine, cooled to 0°C. the Reaction mixture is stirred for 30 minutes at 0°C. and then for 18 hours at room temperature. After adding water pH is adjusted to pH 8 aqueous 1 M sodium hydroxide solution and the reaction mixture is extracted with dichloromethane. The dichloromethane phase is dried over magnesium sulfate, filter the Ute and evaporated. The resulting residue is applied to stage b without purification.

b - N-(5-Bromothiazole-2-yl)-N-methylacetamide

1,9 g (14 mmol) of potassium carbonate and of 3.94 ml (63.3 mmol) under the conditions added to a solution of 2.8 g (12.7 mmol) of N-(5-bromothiazole-2-yl)ndimethylacetamide in 50 ml of acetone. The reaction mixture is refluxed for 3 hours. After adding water, the reaction mixture was extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by chromatography on a column of silica with elution with a mixture 7/3 heptane/ethyl acetate. Obtain 1.1 g (36%) of N-(5-bromothiazole-2-yl)-N-methylacetamide.

s - Methyl-3-(4-bromophenyl)-2(S)-hydroxypropanoate

100 ml (170 mmol) of 1.7 M solution of tert-utility in pentane is added dropwise to a solution of 48 g (204 mmol) of 1,4-dibromobenzene with 160 ml of tert-butyldimethylsilyl simple ether, cooled to -30°C, followed by the addition of 7.3 g (82 mmol) of copper cyanide. The reaction mixture is stirred for 15 minutes and then add a solution of 6 ml (68 mmol) of (S)-methylphenidate in 10 ml of tert-butyldimethylsilyl ether. After stirred for 20 minutes at -30°C. the reaction mixture was hydrolized 150 ml of a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase is washed with saturated aqueous Rast is the PR of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by chromatography on a column of silica with elution with heptane and polarity then raise the mixture to 6/4 heptane/ethyl acetate. Get 23,5 g (44%) of methyl-3-(4-bromophenyl)-2(S)-hydroxypropanoate.

d - Methyl-3-(4-bromophenyl)-2(S)-ethoxypropanol

11 ml of ethyliodide added dropwise to a solution of 23.5 g (91 mmol) of methyl-3-(4-bromophenyl)-2(S)-hydroxypropanoate and 35.6 g (155 mmol) of silver oxide(I) in 120 ml of isopropyl simple ether. The reaction mixture is heated at 70°C over night. Add 10 g (45 mmol) of silver oxide and 3.7 ml (45 mmol) of ethyliodide and the reaction mixture is heated for an additional 4 hours and then filtered through celite, the residue washed with ethyl acetate and the filtrate concentrated in vacuo. The resulting residue is purified by chromatography on a column of silica with elution with a mixture of 95/5 then 90/10 heptane/ethyl acetate. Get 20 g (79%) of methyl-3-(4-bromophenyl)-2(S)-ethoxypropionate.

e - Methyl-2(S)-ethoxy-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]propanoate

A solution of 8.3 g (of 28.9 mmol) methyl-3-(4-bromophenyl)-2(S)-ethoxypropionate, 11 g (43,3 mmol) of bipinchandra and 8.5 g (to 86.7 mmol) of potassium acetate in 250 ml of dimethylformamide Tegaserod for 15 minutes and then add 0,94 g (1.2 mmol) of difenilfosforilatsetamidnymi (PdCl2dpf). The reaction mixture is heated at 60°C for 20 hours. After cooling, water is added and the reaction mixture is extracted with ethyl acetate. The ethyl acetate phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and evaporated. The resulting residue is purified by chromatography on a column of silica with elution with a mixture of 95/5 then 90/10 heptane/ethyl acetate. Get 7 g (73%) of methyl 2(S)-ethoxy-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]propanoate.

f - Methyl-3-{4-[2-(acetylecholine)thiazol-5-yl]phenyl}-2(S)-ethoxypropanol

0.2 g (0.3 mmol) of difenilfosforilatsetamidnymi (PdCl2dppf) are added to a solution of 1 g (4.5 mmol) of N-(5-bromothiazole-2-yl)-N-methylacetamide, 1.8 g (6.8 mmol) of methyl 2(S)-ethoxy-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]propanoate and 1 g (6.8 mmol) of cesium fluoride in 50 ml of dimethyl ether of ethylene glycol, previously degassed. The reaction mixture is heated at 80°C for 18 hours. After cooling, water is added and the reaction mixture is extracted with ethyl acetate. The ethyl acetate phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by chromatography on a column of silica with elution with a mixture of 70/30, then 60/40 heptane/ethyl acetate. Obtain 0.6 g (37%) of methyl-3-{4-[2-(acetylecholine)thiazole--yl]phenyl}-2(S)-ethoxypropionate in the form of painted beige solid with a melting point of 123°C.

g - 2(S)-Ethoxy-3-[4-(2-methylaminomethyl-5-yl)phenyl]propanoic acid

0.6 g (1.6 mmol) of methyl-3-{4-[2-(acetylecholine)thiazol-5-yl]phenyl}-2(S)-ethoxypropionate in 25 ml of methanol and 2.4 ml (2.4 mmol) of aqueous 1 M sodium hydroxide solution is heated at 60°C for 18 hours. The reaction mixture is cooled, diluted with water, acidified to pH 4-5 and then extracted with ethyl acetate and n-butanol. The organic phase is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated. The remainder is used in stage h without treatment.

h - Methyl-2(S)-ethoxy-3-[4-(2-methylaminomethyl-5-yl)phenyl]propanoate

0.5 g (1.6 mmol) of 2(S)-ethoxy-3-[4-(2-methylaminomethyl-5-yl)phenyl]propanoic acid in 10 ml of methanol and a few drops of sulfuric acid is heated at 60°C for 2 hours. The reaction mixture is cooled, diluted with water, neutralized to pH 7 aqueous 1 M sodium hydroxide solution and then extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by chromatography on a column of silica with elution with a mixture of 50/50 heptane/ethyl acetate. Obtain 0.34 g (67%) of methyl 2(S)-ethoxy-3-[4-(2-methylaminomethyl-5-yl)phenyl]propanoate in the form of a yellow solid.

i - Methyl-2(S)-ethoxy-3-{4-[2-(3-gate is-1 macilwraith)thiazol-5-yl]phenyl}propanoate

0.17 ml (1 mmol) captilization added to a solution of 0.17 g (0.5 mmol) of methyl 2(S)-ethoxy-3-[4-(2-methylaminomethyl-5-yl)phenyl]propanoate in 10 ml of dichloromethane. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with water and then extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by thin-layer chromatography on silica with elution with a mixture of 50/50 heptane/ethyl acetate. Obtain 0.07 g (30%) of methyl 2(S)-ethoxy-3-{4-[2-(3-heptyl-1-methylurea)thiazol-5-yl]phenyl}of propanoate.

j - 2(S)-Ethoxy-3-{4-[2-(3-heptyl-1-methylurea)thiazol-5-yl]phenyl}propanoic acid

0.07 g (0.15 mmol) of methyl 2(S)-ethoxy-3-{4-[2-(3-heptyl-1-methylurea)thiazol-5-yl]phenyl}of propanoate placed in 3 ml of tetrahydrofuran and 0.2 ml (0.2 mmol) of aqueous 1 M solution of lithium hydroxide. The reaction mixture was stirred at room temperature for 18 hours. Add 0,07 ml of 1 M aqueous solution of lithium hydroxide and the mixture is heated for an additional 5 hours. The reaction mixture is diluted with water, acidified to pH 4-5 and then extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. Get 55 mg (82%) 2(S)-ethoxy-3-{4-[2-(3-heptyl-1-methylurea)thiazol-5-yl]phenyl}propanoic key is lots in the form of a white solid with a melting point of 97°C.

1H NMR (δ CDCl3): of 0.90 (t, J=6,7 Hz, 3H); 1,22 (t, J=7.0 Hz, 3H); 1,28-to 1.38 (m, 8H)and 1.60 (m, 2H); is 3.08 (DD, J=7.5 Hz, J=4,1 Hz, 1H); 3.15 in (DD, J=4,1 Hz, J=14 Hz, 1H); 3,37 (m, 2H); 3,47 (s, 3H); to 3.49 (m, 1H); 3,66 (m, 1H); of 4.12 (m, 1H); 7,29 (d, J=8,2 Hz, 2H); the 7.43 (d, J=8,2 Hz, 2H); 7,52 (s, 1H); 9,24 (s, 1H).

Example 8: 2(S)-Ethoxy-3-{4-[2-(1-methyl-3-pentyurina)thiazol-5-yl]phenyl}propanoic acid

a - Methyl-2(S)-ethoxy-3-{4-[2-(1-methyl-3-pentyurina)thiazol-5-yl]phenyl}propanoate

In a manner analogous to the method of example 7i, on the basis of 0.17 g (of 0.53 mmol) of methyl 2(S)-ethoxy-3-[4-(2-methylaminomethyl-5-yl)phenyl]propionate and 0.14 ml (1.1 mmol) intilization, obtain 0.06 g (26%) of methyl 2(S)-ethoxy-3-{4-[2-(1-methyl-3-pentyurina)thiazol-5-yl]phenyl}of propanoate.

b - 2(S)-Ethoxy-3-{4-[2-(1-methyl-3-pentyurina)thiazol-5-yl]phenyl}propanoic acid

In a manner analogous to the method of example 7j, on the basis of 0.06 g (0.14 mmol) of methyl 2(S)-ethoxy-3-{4-[2-(1-methyl-3-pentyurina)thiazol-5-yl]phenyl}of propanoate and 0.2 ml (0.2 mmol) of aqueous 1 M solution of lithium hydroxide, 0.05 g (86%) 2(S)-ethoxy-3-{4-[2-(1-methyl-3-pentyurina)thiazol-5-yl]phenyl}propanoic acid is obtained in the form of a white solid with a melting point of 114°C.

1H NMR (δ CDCl3): of 0.93 (t, J=6,7 Hz, 3H); 1,22 (t, J=7.0 Hz, 3H); 1,36-1,40 (m, 4H); and 1.63 (m, 2H); to 3.06 (DD, J=7.5 Hz, J=4,1 Hz, 1H); 3.15 in (DD, J=4,1 Hz, J=14 Hz, 1H); 3,37 (m, 2H); 3,47 (s, 3H); 3,50 (m, 1H); 3,66 (m, 1H); of 4.12 (m, 1H); 7,29 (d, J=8,4 Hz, 2H); the 7.43 (d, J=8,4 Hz, 2H); 7,53 (s, 1H); a 9.25 (s, 1H).

Example 9: 2(S)-Ethoxy-3-{4-[6-(3-heptyl-1-methylurea)pyrid--yl]phenyl}propanoic acid

and tert-Butyl(6-pampered-2-yl)carbamate

62 g (284 mmol) of di-tert-BUTYLCARBAMATE diluted in 200 ml of dichloromethane, is added dropwise to a solution of 49.2 g (284 mmol) of 2-amino-6-bromopyridine that 43.4 ml (312 mmol) of triethylamine and 3.5 g (28.4 mmol) of 4-dimethylaminopyridine in 400 ml of dichloromethane. The reaction mixture was stirred at room temperature for 18 hours. After the addition of water and extraction with dichloromethane the organic phase is dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by thin-layer chromatography on silica with elution with a mixture of 95/5 heptane/ethyl acetate. Get 39 g (50%) of tert-butyl(6-pampered-2-yl)carbamate in the form of a white solid.

b - tert-Butyl-6-pampered-2-yl-N-methylcarbamate

6,9 g (17,2 mmol) of 60% sodium hydride in oil is added in portions to a solution of 39 g (of 14.3 mmol) of tert-butyl(6-pampered-2-yl)carbamate in 400 ml of dimethylformamide. After stirring for 20 minutes at room temperature and added dropwise to 17.8 ml (28.6 mmol) under the conditions. The reaction mixture was stirred at room temperature for 18 hours, dissolved in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated.

C- (6-Pampered-2-yl)-N-methylamine

2,1 g (7.3 mmol) of tert-butyl 6-pampered-2-yl-N-methylcarbamate, 1.6 ml (21.9 mmol) of triperoxonane the th acid and 25 ml of dichloromethane is stirred at room temperature for 20 hours.

After adding water, the reaction mixture is extracted with dichloromethane. The organic phase is washed with an aqueous solution of sodium hydroxide and then washed with water, dried over magnesium sulfate, filtered and evaporated. Obtain 1.4 g (100%) (6-bromopyridin-2-yl)-N-methylamine.

d - 1-(6-Pampered-2-yl)-3-heptyl-1-metalmachine

1 g (5,35 mmol) (6-pampered-2-yl)-N-methylamine, 1 ml of diisopropylethylamine and 1.6 g (8 mmol) of 4-nitrophenylphosphate heated at 130°C for 15 minutes under microwave processing. Add 1.2 ml (8 mmol) of heptylamine and 7 ml of dimethylformamide and the reaction mixture is heated at 130°C for an additional 5 minutes. The resulting residue is purified by thin-layer chromatography on silica gel with elution with a mixture of 70/30 heptane/ethyl acetate. Obtain 1.4 g (80%) of 1-(6-pampered-2-yl)-3-heptyl-1-metalmachine in the form of a yellow solid.

e - Methyl-2(S)-ethoxy-3-{4-[6-(3-heptyl-1-methylurea)pyrid-2-yl]phenyl}propanoate

3.2 g (9.7 mmol) of 1-(6-pampered-2-yl)-3-heptyl-1-metalmachine, 4,2 g (12.6 mmol) of methyl 2(S)-ethoxy-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]propanoate (obtained as in example 7E) and 4.4 g (of 29.1 mmol) of cesium fluoride are placed in 200 ml of dimethoxyacetophenone. The reaction mixture Tegaserod, then add to 0.23 g (0.3 mmol) dichlorodiphenyltrichloroethane and the reaction mixture was stirred at 80°C for 18 hours. The village is E. adding water, the reaction mixture was extracted with ethyl acetate. The organic phase is washed with water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by thin-layer chromatography on silica with elution with a mixture of 80/20 heptane/ethyl acetate. Get 2 g (45%) of methyl 2(S)-ethoxy-3-{4-[6-(3-heptyl-1-methylurea)pyrid-2-yl]phenyl}of propanoate.

f - 2(S)-Ethoxy-3-{4-[6-(3-heptyl-1-methylurea)pyrid-2-yl]phenyl}propanoic acid

1.1 g (2.4 mmol) of methyl 2(S)-ethoxy-3-{4-[6-(3-heptyl-1-methylurea)pyrid-2-yl]phenyl}of propanoate, 20 ml of tetrahydrofuran and 3.6 ml (3.6 mmol) of aqueous 1 M solution of lithium hydroxide was stirred at room temperature for 5 hours. After adding water and ethyl acetate, the reaction mixture is acidified to pH 5.5 aqueous 1 n solution of acetic acid. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. Get 1 g (95%) 2(S)-ethoxy-3-{4-[6-(3-heptyl-1-methylurea)pyrid-2-yl]phenyl}propanoic acid in the form of a viscous syrup.

1H NMR (δ CDCl3): of 0.87 (t, J=6,7 Hz, 3H); to 1.21 (t, J=7.0 Hz, 3H); of 1.26 to 1.37 (m, 8H); to 1.61 (m, 2H); 3,10 (DD, J=7.5 Hz, J=4,1 Hz, 1H); 3,21 (DD, J=4,1 Hz, J=14 Hz, 1H); 3,39 (m, 2H); 3,47 (s, 3H); to 3.49 (m, 1H); 3,66 (m, 1H); 4.16 the (m, 1H); 6,94 (d, J=8,4 Hz, 1H); 7,28-7,40 (m, 3H); 7,75-of 7.82 (m, 3H).

Example 10: Hydrochloride 2(S)-ethoxy-3-{4-[6-(3-heptyl-methylurea)pyrid-2-yl]phenyl}propanoic acid

2.5 ml (2.5 mmol) of 1 M hydrochloric acid in ethanol is dobavlaut dropwise to a solution of 1.1 g (2.5 mmol) of 2(S)-ethoxy-3-{4-[6-(3-heptyl-1-methylurea)pyrid-2-yl]phenyl}propanoic acid in 2 ml of ethanol, cooled to 0°C. the Reaction mixture forms a precipitate. After filtration the precipitate was washed with acetone and ethyl ether and then dried. After recrystallization from hot 9/1 mixture acetone/water 0.6 g (60%) of the hydrochloride of 2(S)-ethoxy-3-{4-[6-(3-heptyl-1-methylurea)pyrid-2-yl]phenyl}propanoic acid is obtained in the form of a white solid with a melting point of 166°C.

1H NMR (δ CDCl3): of 0.77 (t, J=6,7 Hz, 3H); of 1.07 (t, J=7.0 Hz, 3H); 1,10-1,25 (m, 8H); was 1.58 (m, 2H); 3,00 (DD, J=7.5 Hz, J=4,1 Hz, 1H); is 3.08 (DD, J=4,1 Hz, J=14 Hz, 1H); 3,26 (m, 2H); 3.27 to (m, 1H); of 3.60 (s, 3H); 3,61 (m, 1H); of 3.96 (DD, J=4,1 Hz, J=8,4 Hz, 1H); 7,20 (m, 1H); 7,41 (d, J=8.1 Hz, 2H); 7,44 (m, 1H); 7,66 (d, J=8.1 Hz, 2H); 8,03 (m, 1H); 9,00 (m, 2H).

Example 11: 2(S)-Ethoxy-3-{4-[5-(3-heptyl-1-methylurea)-2-methyl-2H-[1,2,4]triazole-3-yl]phenyl}propanoic acid

a - 5-Bromo-1-methyl-3-nitro-1H-[1,2,4]triazole

1.1 g (28.5 mmol) of 60% sodium hydride are added to a solution of 5 g (25,9 mmol) 5-bromo-3-nitro-1H-[1,2,4]triazole in 80 ml of dimethylformamide, in advance, cooled to 0°C. the Reaction mixture is stirred for 20 minutes and then add 8 ml (129,5 mmol) under the conditions. After stirring at room temperature for 18 hours, water is added and the reaction mixture is extracted with ethyl acetate. The organic phase is thoroughly washed with water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by thin-layer chromatography n is the silica with elution with a mixture of 75/25 heptane/ethyl acetate. Obtain 3.2 g (60%) of 5-bromo-1-methyl-3-nitro-1H-[1,2,4]triazole.

b - Methyl-2(S)-ethoxy-3-[4-(2-methyl-5-nitro-2H-[1,2,4]triazole-3-yl)phenyl]propanoate

In a manner analogous to the method of example 9(e), from 0.9 g (4.35 mmol) of 5-bromo-1-methyl-3-nitro-1H-[1,2,4]triazole and 1.9 g (6.5 mmol) of methyl 2(S)-ethoxy-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]propanoate, obtain 0.9 g (62%) of methyl 2(S)-ethoxy-3-[4-(2-methyl-5-nitro-2H-[1,2,4]triazole-3-yl)phenyl]propanoate in the form of a white solid with a melting point of 119°C.

c - Methyl-3-[4-(5-amino-2-methyl-2H-[1,2,4]triazole-3-yl)phenyl]-2(S)-ethoxypropanol

of 0.4 g (0.4 mass equivalent), 10% palladium on coal are added to a solution of 0.9 g (2.7 mmol) of methyl 2(S)-ethoxy-3-[4-(2-methyl-5-nitro-2H-[1,2,4]triazole-3-yl)phenyl]propanoate in 40 ml of ethanol and 10 ml of methanol, degassed beforehand, and the reaction mixture was kept at atmospheric pressure of hydrogen for 3 hours. After filtration through celite and washing with ethyl acetate, the filtrate evaporated in vacuum. Get 0,82 g (100%) methyl-3-[4-(5-amino-2-methyl-2H-[1,2,4]triazole-3-yl)phenyl]-2(S)-ethoxypropionate.

d - Methyl-2(S)-ethoxy-3-[4-(2-methyl-5-methylamino-2H- [1,2,4]triazole-3-yl)phenyl]propanoate

0.2 ml (2.2 mmol) of dimethylsulfate added to a mixture of 0.6 g (2 mmol) of methyl-3-[4-(5-amino-2-methyl-2H-[1,2,4]triazole-3-yl)phenyl]-2(S)-ethoxypropionate, 0.3 ml (2.2 mmol) of triethylamine and 40 ml of ethyl ether. The reaction mixture is heating the Ute at 35°C for 4 hours. The composition of the reaction mixture changed very little, add 20 ml of tetrahydrofuran, 0.3 ml of triethylamine and 0.2 ml (2.2 mmol) of dimethylsulfate and the reaction mixture is heated at 40°C for an additional 24 hours. The reaction mixture is evaporated to dryness. The resulting residue is purified by thin-layer chromatography on silica gel with elution with a mixture of 97/3 and then 95/5 dichloromethane/methanol. Get 0.1 g (16%) of methyl 2(S)-ethoxy-3-[4-(2-methyl-5-methylamino-2H-[1,2,4]triazole-3-yl)phenyl]propanoate and 0.4 g (60%) 2(S)-ethoxy-3-[4-(2-methyl-5-methylamino-2H-[1,2,4]triazole-3-yl)phenyl]propanoic acid.

e - Methyl-2(S)-ethoxy-3-{4-[5-(3-heptyl-1-methylurea)-2-methyl-2H-[1,2,4]triazole-3-yl]phenyl}propanoate

In a manner analogous to the method of example 7(i)proceeding from 80 mg (0.25 mmol) of methyl 2(S)-ethoxy-3-[4-(2-methyl-5-methylamino-2H-[1,2,4]triazole-3-yl)phenyl]propanoate and 60 μl (0.4 mmol) captilization, obtain 37 mg (34%) of methyl 2(S)-ethoxy-3-{4-[5-(3-heptyl-1-methylurea)-2-methyl-2H-[1,2,4]triazole-3-yl]phenyl}of propanoate.

f - 2(S)-Ethoxy-3-{4-[5-(3-heptyl-1-methylurea)-2-methyl-2H-[1,2,4]triazole-3-yl]phenyl}propanoic acid

37 mg (80 μmol) of methyl 2(S)-ethoxy-3-{4-[5-(3-heptyl-1-methylurea)-2-methyl-2H-[1,2,4]triazole-3-yl]phenyl}of propanoate placed in 2 ml of tetrahydrofuran, and 0.1 ml (0.1 mmol) of aqueous 1 M solution of lithium hydroxide was stirred at room temperature over night. The reaction mixture is acidified to pH 4 and ek is tracerout with ethyl acetate. The organic phase is washed with water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. Receive 30 mg (83%) 2(S)-ethoxy-3-{4-[5-(3-heptyl-1-methylurea)-2-methyl-2H-[1,2,4]triazole-3-yl]phenyl}propanoic acid in the form of a white solid.

1H NMR (δ CDCl3): 0,88 (t, J=6,7 Hz, 3H); to 1.24 (t, J=7.0 Hz, 3H); 1.26 in-of 1.39 (m, 8H)and 1.60 (m, 2H); of 3.13 (DD, J=7.5 Hz, J=4,1 Hz, 1H); 3,30 (DD, J=4,1 Hz, J=14 Hz, 1H); to 3.38 (m, 2H); 3,47 (m, 3H); of 3.54 (m, 1H); 3,68 (m, 1H); 3,93 (s, 3H); 4,18 (DD, J=7,3 Hz, J=4,2 Hz, 1H); the 7.43 (d, J=8.1 Hz, 2H); to 7.61 (d, J=8.1 Hz, 2H); and 9.0 (s, 1H).

Case 12: {3-[5-(2,4-Dioxothiazolidine-5-ylmethyl)thiophene-2-yl]benzyl}methyloctanoic

a - tert-Butyl-[3-(5-formylthiophene-2-yl)benzyl]methylcarbamate

In a manner analogous to the method of example 7(f), on the basis of 3 g of 2-bromo-5-formylthiophene and 4 g of tert-butyl methyl[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]carbamate, get 3 g of tert-butyl[3-(5-formylthiophene-2-yl)benzyl]methylcarbamate.

b - tert-Butyl-{3-[5-(2,4-dioxothiazolidine-5-ylidenemethyl)thiophene-2-yl]benzyl}methylcarbamate

A solution of 2.4 g (7.2 mmol) of tert-butyl[3-(5-formylthiophene-2-yl)benzyl]methylcarbamate, of 0.85 g (7.2 mmol) of 2,4-thiazolidinedione and 0.2 g (1.4 mmol) of the acetate piperidine in 50 ml of toluene is refluxed for 4 hours in the office of Dean-stark. After cooling, the product precipitates. The precipitate is filtered and washed with ethyl acetate. Obtain 2.3 g (76%) of tert-butyl{3-[5-(2,4-dioxo isolatin-5-ylidenemethyl)thiophene-2-yl]benzyl}methylcarbamate.

c - tert-Butyl-{3-[5-(2,4-dioxothiazolidine-5-ylmethyl)thiophene-2-yl]benzyl}methylcarbamate

1 g (2.5 mmol) of tert-butyl{3-[5-(2,4-dioxothiazolidine-5-ylidenemethyl)thiophene-2-yl]benzyl}methylcarbamate placed in 20 ml of dioxane and 0.2 ml of acetic acid. The reaction mixture Tegaserod and kept in a hydrogen atmosphere at 3 ATM for 3 days. After filtration through celite obtain 0.2 g (20%) of tert-butyl{3-[5-(2,4-dioxothiazolidine-5-ylmethyl)thiophene-2-yl]benzyl}methylcarbamate.

d - 5-[5-(3-Methylaminomethyl)thiophene-2-ylmethyl]thiazolidine-2,4-dione

0.2 g (0.5 mmol) of tert-butyl{3-[5-(2,4-dioxothiazolidine-5-ylmethyl)thiophene-2-yl]benzyl}methylcarbamate incubated in 10 ml of dichloromethane and 0.2 ml triperoxonane acid for 12 hours. The reaction mixture is evaporated to dryness and receive 200 mg (100%) 5-[5-(3-methylaminomethyl)thiophene-2-ylmethyl]thiazolidine-2,4-dione.

e- {3-[5-(2,4-Dioxothiazolidine-5-ylmethyl)thiophene-2-yl]benzyl}methyloctanoic

In a manner analogous to the method of example 1(b), on the basis of 90 mg (0.3 mmol) of 5-[5-(3-methylaminomethyl)thiophene-2-ylmethyl]thiazolidine-2,4-dione and 32 μl (0.3 mmol) of octanoylthio, obtain 67 mg (92%) of {3-[5-(2,4 - dioxothiazolidine-5-ylmethyl)thiophene-2-yl]benzyl}methylacrylamide.

1H NMR (δ CDCl3): to 0.92 (t, J=6,7 Hz, 3H); of 1.30 to 1.37 (m, 8H); and 1.54 (m, 2H); 2,9 (s, 3H); 3,23 (m, 1H); 3,50 (m, 1H); 3,74 (m, 1H); 4.75 in (m, 1H); 4,79 (m, 2H); 6,93 is 7.50 (m, 6H).

Case 13: {3-[5-(2,4-Dioxothiazolidine-5-ileti is)thiophene-2-yl]benzyl}methylhexanoate

In a manner analogous to the method of example 12(e)on the basis of 90 mg (0.3 mmol) of 5-[5-(3-methylaminomethyl)thiophene-2-ylmethyl]thiazolidine-2,4-dione and 26 μl (0.3 mmol) of hexanolactone, obtain 22 mg (20%) of {3-[5-(2,4-dioxothiazolidine-5-ylmethyl)thiophene-2-yl]benzyl}methylhexaneamine.

1H NMR (δ CDCl3): to 0.92 (t, J=6,7 Hz, 3H); of 1.30 to 1.37 (m, 4H); and 1.54 (m, 2H); 2,9 (s, 3H); 3,23 (m, 2H); 3,50 (m, 1H); 3,74 (m, 1H); 4.75 in (m, 1H); 4,79 (m, 2H); 6,93 is 7.50 (m, 6H).

Example 14: 2(S)-(2-Benzoylamino)-3-(4-{5-[(octanoylthio)methyl]thiophene-3-yl}phenyl)propanoic acid

a - Methyl-2(S)-(2-benzoylamino)-3-(4-hydroxyphenyl)propanoate

A solution of 56 g (0.29 mmol) of the methyl ester of L-tyrosine, 64 g (0.32 mmol) of benzoylecognine and 12 g of 10% palladium on coal in 700 ml of anisole is heated at 158°C for 17 hours. The reaction mixture is cooled at 50°C, filtered through celite and evaporated in vacuum. The obtained crude product is dissolved in a mixture of dichloromethane/pentane and precipitate. After filtration obtain 18 g (20%) of methyl 2(S)-(2-benzoylamino)-3-(4 - hydroxyphenyl)propanoate.

b - Methyl-2(S)-(2-benzoylamino)-3-(4-triftoratsetilatsetonom)propanoate

1.2 g (10 mmol) of 4-dimethylaminopyridine added to a mixture of 24.5 g (65 mmol) of methyl 2(S)-(2-benzoylamino)-3-(4-hydroxyphenyl)propionate and 11 ml (78 mmol) of triethylamine in 20 ml dichloromethane. The reaction mixture was cooled to -78°C and added dropwise to 13.2 ml (78 mmol) tripto methanesulfonamido anhydride. The reaction mixture is stirred at a temperature of from -78°C. to room temperature for 4 hours. After adding a saturated solution of ammonium chloride, the reaction mixture is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated. Get 33 g (100%) of methyl 2(S)-(2-benzoylamino)-3-(4-triftoratsetilatsetonom)propanoate.

c - Methyl-2(S)-(2-benzoylamino)-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]propanoate

In a manner analogous to the method of example 7(e), on the basis of 28 g (55 mol) of methyl 2(S)-(2-benzoylamino)-3-(4-triftoratsetilatsetonom)propanoate receive 24.2 g (90%) of methyl 2(S)-(2-benzoylamino)-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]propanoate.

d - Methyl-2(S)-(2-benzoylamino)-3-(4-{5-[(tert-butoxycarbonylmethylene)methyl]thiophene-3-yl}phenyl)propanoate

In a manner analogous to the method of example 7(f), on the basis of 6 g (17 mmol) of methyl 2-(2-benzoylamino)-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]propanoate and 3.6 g (12 mmol) of tert-butyl(4-bromothiophene-2-ylmethyl)methylcarbamate (obtained as described in 16b), obtain 2.9 g (42%) of methyl 2(S)-(2-benzoylamino)-3-(4-{5-[(tert-butoxycarbonylmethylene)methyl]thiophene-3-yl}phenyl}of propanoate.

e - Methyl-2(S)-(2-benzoylamino)-3-[4-(5-methylaminomethyl-3-yl)phenyl]propanoate

2.9 g (5 mmol) of methyl 2(S)-(2-benzoylphenyl the Mino)-3-(4-{5-[(tert-butoxycarbonylmethylene)methyl]thiophene-3-yl}phenyl}of propanoate incubated in 30 ml of dichloromethane and 2.5 ml (32 mmol) triperoxonane acid. After stirring at room temperature for 18 hours the reaction mixture is evaporated to dryness. Obtain 2.4 g (100%) of methyl 2(S)-(2-benzoylamino)-3-[4-(5-methylaminomethyl-3-yl)phenyl]propanoate.

f - Methyl-2(S)-(2-benzoylamino)-3-(4-{5-[(methylacrylamide)methyl]thiophene-3-yl}phenyl)propanoate

In a manner analogous to the method of example 1(b), on the basis of 0.8 g (of 1.65 mmol) of methyl 2(S)-(2-benzoylamino)-3-[4-(5-methylaminomethyl-3-yl)phenyl]propanoate and 0.3 ml (1.8 mmol) of octanoylthio, obtain 0.8 g (78%) of methyl 2(S)-(2-benzoylamino)-3-(4-{5-[(methylacrylamide)methyl]thiophene-3-yl}phenyl)propanoate.

g - 2(S)-(2-Benzoylamino)-3-(4-{5-[(methylacrylamide)methyl]thiophene-3-yl}phenyl)propanoic acid

In a manner analogous to the method of example 7(j), on the basis of 0.8 g (1 mmol) of methyl 2(S)-(2-benzoylamino)-3-(4-{5-[(methylacrylamide)methyl]thiophene-3-yl}phenyl)propanoate receive 0.5 g (63%) 2(S)-(2-benzoylamino)-3-(4-{5-[(methylacrylamide)methyl]thiophene-3-yl}phenyl)propanoic acid.

1H NMR (δ CDCl3): to 0.89 (t, J=6,7 Hz, 3H); 1,29-of 1.32 (m, 16H); by 1.68 (m, 2H); 2,35-2,48 (m, 2H); 2,99 (s, 3H); 3,23 (m, 1H); 3,37 (m, 1H); 4,48 (m, 1H); of 4.66 (s, 2H); 6,60 (t, J=7,3 Hz, 1H); 6,72 (DD, J=2.5 Hz, J=8,4 Hz, 1H); 7,15-to 7.61 (12H); and 9.0 (s, 1H); 10,5 (m, 1H).

Example 15: 2(S)-(2-Benzoylamino)-3-(4-{5-[(exanimation)methyl]thiophene-3-yl}phenyl)propanoic acid

a - Methyl-2(S)-(2-benzoylamino)-3-(4-{5-[(exanimation)methyl]thiophen-yl}phenyl)propanoate

In a manner analogous to the method of example 1(b), on the basis of 0.8 g (of 1.65 mmol) of methyl 2(S)-(2-benzoylamino)-3-[4-(5-methylaminomethyl-3-yl)phenyl]propionate and 0.25 ml (1.8 mmol) of hexanolactone, obtain 0.8 g (78%) of methyl 2(S)-(2-benzoylamino)-3-(4-{5-[(methylhexaneamine)methyl]thiophene-3-yl}phenyl)propanoate.

b - 2(S)-(2-Benzoylamino)-3-(4-{5-[(exanimation)methyl]thiophene-3-yl}phenyl)propanoic acid

In a manner analogous to the method of example 7(j), on the basis of 0.6 g (1 mmol) of methyl 2(S)-(2-benzoylamino)-3-(4-{5-[(methylhexaneamine)methyl]thiophene-3-yl}phenyl)propanoate get 0,57 g (100%) 2(S)-(2-benzoylamino)-3-(4-{5-[(methylhexaneamine)methyl]thiophene-3-yl}phenyl)propanoic acid.

1H NMR (δ CDCl3): to 0.92 (t, J=6,7 Hz, 3H); 1.30 and of 1.36 (m, 4H); to 1.70 (m, 2H); 2,33-2,47 (m, 2H); 3,00 (s, 3H); 3,23 (DD, J=5.4 Hz, J=a 13.9 Hz, 1H); to 3.38 (DD, J=5.4 Hz, J=8.5 Hz, 1H); of 4.45 (m, 1H); 4,66-4,70 (m, 2H); 6,67 (t, J=7.5 Hz, 1H); of 6.71 (d, J=8,4 Hz, 1H); 7,19 to 7.62 (m, 13H); and 9.0 (s, 1H).

Example 16: 2(S)-Ethoxy-3-(4-{5-[(exanimation)methyl]thiophene-3-yl}phenyl)propanoic acid

a- (4-Bromothiophene-2-ylmethyl)methylamine

of 25.2 g (360 mmol) of cyanoborohydride sodium added to a solution of 35 g (180 mmol) of 4-bromothiophene-2-carbaldehyde, 62 g (640 mmol) of methylamine hydrochloride and 119 ml (846 mmol) of triethylamine. The reaction mixture was stirred at room temperature for 3.5 hours. After adding water and ethyl acetate and washing water 1 M solution is hydroxide sodium organic phase is shaken out. The ethyl acetate phase is dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by thin-layer chromatography on silica with elution with a mixture of from 90/10 to 70/30 heptane/ethyl acetate. Gain of 19.7 g (52%) of (4-bromothiophene-2-ylmethyl)methylamine.

b - tert-Butyl-(4-bromothiophene-2-ylmethyl)methylcarbamate

of 20.8 g (95 mmol) of di-tert-BUTYLCARBAMATE added in portions to a solution of 19.7 g (95 mmol) (4-bromothiophene-2-ylmethyl)of methylamine and 11.9 ml (85 mmol) of triethylamine in 200 ml of dichloromethane. After stirring at room temperature for 16 hours, the reaction mixture was washed with water phase is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated. Get 19 g (44%) of tert-butyl(4-bromothiophene-2-ylmethyl)methylcarbamate.

c - Methyl-3-(4-{5-[(tert - butoxycarbonylmethylene)methyl]thiophene-3-yl}phenyl)-2(S)-ethoxypropanol

In a manner analogous to the method of example 9(e), on the basis of 4 g (13 mmol) of tert-butyl(4-bromothiophene-2-ylmethyl)methylcarbamate and 5.6 g (20 mmol) of methyl 2(S)-ethoxy-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]propanoate get a 5 g (88%) of methyl-3-(4-{5-[(tert-butoxycarbonylmethylene)methyl]thiophene-3-yl}phenyl)-2(S)-ethoxypropionate in the form of a yellow oil.

d - Methyl-2(S)-ethoxy-3-[4-(5-methylaminomethyl-3-yl)phenyl]propanoate

5 g (11.5 mmol) of methyl-3-(4-{5-[(tert-butoxycarbonylmethylene)IU is Il]thiophene-3-yl}phenyl)-2(S)-ethoxypropionate placed in 80 ml dichloromethane and 4.4 ml triperoxonane acid. After stirring at room temperature for 24 hours, water is added and the reaction mixture is extracted with dichloromethane. The dichloromethane phase is washed with aqueous 30% sodium hydroxide solution, dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by thin-layer chromatography on silica with elution with a mixture of 50/50 heptane/ethyl acetate. Obtain 3.2 g (84%) of methyl 2(S)-ethoxy-3-[4-(5-methylaminomethyl-3-yl)phenyl]propanoate.

e - Methyl-2(S)-ethoxy-3-(4-{5-[(exanimation)methyl]thiophene-3-yl}phenyl)propanoate

of 0.18 ml (1.3 mmol) of hexanolactone add to cooled beforehand to 0°C. a solution of 0.4 g (1.2 mmol) of methyl 2(S)-ethoxy-3-[4-(5-methylaminomethyl-3-yl)phenyl]propanoate and 0.18 ml (1.3 mmol) of triethylamine in 20 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours, washed with water and extracted with ethyl acetate. The ethyl acetate phase is dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by thin-layer chromatography on silica with elution with a mixture of 70/30 heptane/ethyl acetate. Obtain 0.4 g (83%) of methyl 2(S)-ethoxy-3-(4-{5-[(exanimation)methyl]thiophene-3-yl}phenyl)propanoate.

f - 2(S)-Ethoxy-3-(4-{5-[(exanimation)methyl]thiophene-3-yl}phenyl)propanoic acid

In a manner analogous to the method of example 11(f), based on the C 0.4 g (1 mmol) of methyl 2(S)-ethoxy-3-(4-{5-[(exanimation)methyl]thiophene-3-yl}phenyl)propanoate, obtain 0.4 g of a crude residue. This residue is recrystallized from hot isopropyl ether. Obtain 0.2 g (50%) 2(S)-ethoxy-3-(4-{5-[(exanimation)methyl]thiophene-3-yl}phenyl)propanoic acid in the form of a white solid with a melting point of 65°C.

1H NMR (δ CDCl3): of 0.90 (t, J=6,7 Hz, 3H); to 1.19 (t, J=7.0 Hz, 3H); of 1.35 to 1.37 (m, 4H); to 1.70 (m, 2H); 2,36-2,48 (m, 2H); to 3.02 (m, 1H); 3,03 (s, 3H); 3.15 in (m, 1H); to 3.45 (m, 1H); the 3.65 (m, 1H); 4,10 (m, 1H); 4,69-4,74 (m, 2H,); 7,19-7,35 (m, 4H); 7,50 (d, J=8,2 Hz, 2H).

Example 17: 3-(4-{5-[(butylmethylamine)methyl]thiophene-3-yl}phenyl-2(S)-ethoxypropanol acid

a - Methyl-3-(4-{5-[(butylmethylamine)methyl]thiophene-3-yl}phenyl-2(S)-ethoxypropanol

In a manner analogous to the method of example 16(e), starting from 0.1 g (0.3 mmol) of methyl 2(S)-ethoxy-3-[4-(5-methylaminomethyl-3-yl)phenyl]propanoate and 40 μl (0.33 mmol) of butanolide, obtain 0.12 g (75%) of methyl-3-(4-{5-[(butylmethylamine)methyl]thiophene-3-yl}phenyl)-2(S)-ethoxypropionate.

b - 3-(4-{5-[(Butylmethylamine)methyl]thiophene-3-yl}phenyl)-2(S)-ethoxypropanol acid

In a manner analogous to the method of example 11(f), on the basis of 90 mg (0.22 mmol) of methyl-3-(4-{5-[(butylmethylamine)methyl]thiophene-3-yl}phenyl)-2(S)-ethoxypropionate get 45 mg (52%) of 3-(4-{5-[(butylmethylamine)methyl]thiophene-3-yl}phenyl)-2(S)-ethoxypropanol acid in the form of a solid substance with a melting point of 56-57°C.

1H NMR (δ CDCl3): and 1.00 (t, J=6,7 Hz, 3H); to 1.19 (t, J=7.0 Hz, 3H); of 1.74 (m, 2H); 2,36-2,48 (m, H); to 3.02 (m, 1H); 3,03 (s, 3H); 3.15 in (m, 1H); of 3.48 (m, 1H); the 3.65 (m, 1H); 4,11 (m, 1H); 4,69-4,74 (m, 2H); 7,19-7,35 (m, 4H); 7,50 (d, J=8,2 Hz, 2H).

Example 18: 3-[4-(5-{[(3-Cyclohexylpropionic)methylamino]methyl}thiophene-3-yl)phenyl]-2(S)-ethoxypropanol acid

a - Methyl-3-[4-(5-{[(2-cyclopentylacetyl)methylamino]methyl}thiophene-3-yl)phenyl]-2(S)-ethoxypropanol

In a manner analogous to the method of example 16(e)on the basis of 0.35 g (1 mmol) of methyl 2(S)-ethoxy-3-[4-(5-methylaminomethyl-3-yl)phenyl]propanoate and 170 μl (1.15 mmol) of 2-cyclopentylacetyl receive 0.39 g (85%) of methyl-3-[4-(5-{[(2-cyclopentylacetyl)methylamino]methyl}thiophene-3-yl)phenyl]-2(S)-ethoxypropionate.

b - 3-[4-(5-{[(2-Cyclopentylacetyl)methylamino]methyl}thiophene-3-yl)phenyl]-2(S)-ethoxypropanol acid

In a manner analogous to the method of example 11(f), on the basis of 0.39 g (0.88 mmol) of methyl-3-[4-(5-{[(2-cyclopentylacetyl)methylamino]methyl}thiophene-3-yl)phenyl]-2(S)-ethoxypropionate, obtain 0.24 g (63%) of 3-[4-(5-{[(2-cyclopentylacetyl)methylamino]methyl}thiophene-3-yl)phenyl]-2(S)-ethoxypropanol acid in the form of a solid substance with melting point 112-113°C.

1H NMR (δ CDCl3): to 1.19 (t, J=7.0 Hz, 3H); 1,60-1,65 (m, 4H); 1,90 (m, 2H); 2,30 (m, 1H); 2,37-2,52 (m, 2H); to 3.02 (m, 1H); 3.04 from (s, 3H); 3,17 (m, 1H); of 3.48 (m, 1H); the 3.65 (m, 1H); of 4.12 (m, 1H); 4,70-of 4.75 (m, 2H); 7,19 was 7.36 (m, 4H); 7,50 (d, J=8,2 Hz, 2H).

Example 19: 3-[4-(5-{[(3-Cyclohexylpropionic)methylamino]methyl}thiophene-3-yl)phenyl]-2(S)-ethoxypropanol acid

a - Methyl-3-[4-(5-{[(3-cyclohexylpropionic)mate the amino]methyl}thiophene-3-yl)phenyl]-2(S)-ethoxypropanol

In a manner analogous to the method of example 16(e)on the basis of 0.35 g (1 mmol) of methyl 2(S)-ethoxy-3-[4-(5-methylaminomethyl-3-yl)phenyl]propanoate and 170 μl (1.15 mmol) of 2-cyclopentylacetyl get 0,41 g (84%) of methyl-3-[4-(5-{[(3-cyclohexylpropionic)methylamino]methyl}thiophene-3-yl)phenyl]-2(S)-ethoxypropionate.

b - 3-[4-(5-{[(3-Cyclohexylpropionic)methylamino]methyl}thiophene-3-yl)phenyl]-2(S)-ethoxypropanol acid

In a manner analogous to the method of example 11(f), based on 0,41 g (0.87 mmol) of methyl-3-[4-(5-{[(3-cyclohexylpropionic)methylamino]methyl}thiophene-3-yl)phenyl]-2(S)-ethoxypropionate get to 0.23 g (57%) of 3-[4-(5-{[(3-cyclohexylpropionic)methylamino]methyl}thiophene-3-yl)phenyl]-2(S)-ethoxypropanol acid in the form of a solid substance with melting point 69-70°C.

1H NMR (δ CDCl3): of 0.95 (m, 2H), 1,19 (t, J=7.0 Hz, 3H); 1,20 of 1.28 (m, 4H); of 1.57 (m, 1H); 1,58-1,72 (m, 6H); 2,37-2,49 (m, 2H); to 3.02 (m, 1H); 3.04 from (s, 3H); 3.15 in (m, 1H); 3,47 (m, 1H); 3,63 (m, 1H); of 4.12 (m, 1H); 4,69-4,74 (m, 2H); 7,19 and 7.36 (m, 4H); 7,50 (d, J=8,2 Hz, 2H).

Example 20: 2-Ethoxy-3-{6-[3-(3-heptyl-1-methylurea)phenyl]pyrid-3-yl}propanoic acid

a- (6-Idered-3-yl)methanol

30 g (108 mmol) of ethyl-6-etniciteit dissolved in 300 ml of ethanol is added dropwise to a solution of 20.5 g (542 mmol) of sodium borohydride in 200 ml of ethanol, in advance, cooled to 0°C. the Reaction mixture was allow to warm to room temperature and then stirred for 1 hour 30 minutes at anatoy temperature. The reaction mixture was hydrolized and extracted with ethyl acetate. Salts of boron are deposited, and the reaction mixture is filtered and then evaporated to dryness. The reaction mixture is dissolved in dichloromethane, the product precipitates, add isopropyl ether and the mixture filtered. The precipitate was washed with isopropyl ether. Get 17 g (67%) (6-idered-3-yl)methanol in the form of a light yellow solid with a melting point of 102°C.

b - 6-Iodopyridine-3-carbaldehyde

63 g (723 mmol) of manganese dioxide are added to a solution of 17 g (72 mmol) (6-idered-3-yl)methanol in 600 ml of dichloromethane. The reaction mixture was stirred at room temperature for 20 hours and then filtered through celite. The precipitate thoroughly washed with water and the filtrate evaporated in vacuum. The resulting residue is dissolved in dichloromethane and the insoluble material was again filtered. After evaporation of the filtrate gain of 13.2 g (78%) 6-iodopyridine-3-carbaldehyde in the form of a light yellow solid with a melting point of 141°C.

c - tert-Butyl-[3-(5-formalised-2-yl)phenyl]methylcarbamate

C.1: tert-Butyl(3-bromophenyl)methylcarbamate

8,4 g (209,4 mmol) of 60% sodium hydride added in portions to a solution of 19 ml (174 mmol) of 3-bromoaniline in 300 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature until gas evolution stops and then added dropwise 38 g (174 mmol) dicret-BUTYLCARBAMATE, dissolved in 40 ml of tetrahydrofuran. The reaction mixture is stirred at the boil under reflux for 8 hours and then at room temperature for 18 hours. Water is added and the reaction mixture is extracted with ethyl acetate. The ethyl acetate phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by thin-layer chromatography on silica with elution with a mixture of 90/10 then 80/20 and 70/30 heptane/ethyl acetate. Get 47 g (92%) of tert-butyl(3-bromophenyl)methylcarbamate.

C.2: tert-Butyl(3-bromophenyl)methylcarbamate

7.6 g (190 mmol) of 60% sodium hydride added in portions to a solution of 47 g (173 mmol) of tert-butyl(3-bromophenyl)methylcarbamate in 500 ml of dimethylformamide. After cessation of gas add 54 ml (865 mmol) under the conditions and the reaction mixture was stirred at room temperature for 5 hours. After adding water, the mixture extracted with ethyl acetate. The ethyl acetate phase is washed thoroughly with water, dried over magnesium sulfate, filtered and evaporated. Get 49 g (100%) of tert-butyl(3-bromophenyl)methylcarbamate.

p.3: tert-Butylmethyl-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]carbamate

In a manner analogous to the method of example 7(e), starting from 5 g (17.5 mmol) of tert-butyl(3-bromophenyl)methylcarbamate, obtain 3.4 g (60%) of tert-BU is ylmethyl-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]carbamate.

p.4: tert-Butyl[3-(5-formalised-2-yl)phenyl]methylcarbamate

In a manner analogous to the method of example 7(f), on the basis of 1.6 g (6.8 mmol) of 6-iodopyridine-3-carbaldehyde and 3.4 g (16.2 mmol) of tert-butylmethyl-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]carbamate, obtain 1.2 g (58%) of tert-butyl[3-(5-formalised-2-yl)phenyl]methylcarbamate.

d - Ethyl-3-{6-[3-(tert-butoxycarbonylmethylene)phenyl]pyrid-3-yl}-2-ethoxyacrylate

d.1: Ethylchloroformiate

A solution of 40 ml (224 mmol) of ethyldiazoacetate, 19 ml (268 mmol) of acetylchloride and 0.1 g (0.45 mmol) of iodine are heated at 50°C for 4 hours. There is only 60% of the desired product. The reaction mixture is cooled to room temperature, add 19 ml (268 mmol) of acetylchloride and the mixture is heated at 50°C for an additional 18 hours. The reaction mixture is evaporated to dryness in a vacuum. Get 36,3 g (100%) of crude ethylchloroformiate.

d.2: Ethyl(diethoxyphosphoryl)ethoxyacetic

of 36.3 g (218 mol) of ethylchloroformiate and 37.4 ml (218 mmol) of triethylphosphite heated at 50°C for 3 hours. The reaction mixture is evaporated to dryness in a vacuum. Get 57 g (100%) of crude ethyl(diethoxyphosphoryl)ethoxyacetic.

D.3: Ethyl-3-{6-[3-(tert-butoxycarbonylmethylene)phenyl]pyrid-3-yl}-2-ethoxyacrylate

0.3 g (8 mmol) of 60% sodium hydride added in portions to a solution of 2.1 g (8 mmol) of ethyl(diethoxyphosphoryl)ethoxyacetic in 8 ml of tet is hydrofuran. After stirring at room temperature for 30 minutes and after the cessation of gas added 1.2 g (4 mmol) of tert-butyl[3-(5-formalised-2-yl)phenyl]methylcarbamate dissolved in 6 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by thin-layer chromatography on silica with elution with a mixture of 90/10 then 80/20 and 70/30 heptane/ethyl acetate. Obtain 0.2 g (12%) ethyl-3-{6-[3-(tert-butoxycarbonylmethylene)phenyl]pyrid-3-yl}-2-ethoxyacrylate.

f - Ethyl-3-{6-[3-(tert-butoxycarbonylmethylene)phenyl]pyrid-3-yl}-2-ethoxypropanol

A solution of 0.2 g (0.5 mmol) of ethyl-3-{6-[3-(tert-butoxycarbonylmethylene)phenyl]pyrid-3-yl}-2-ethoxyacrylate in 10 ml of tetrahydrofuran Tegaserod and add 0.02 g (10 wt.%) 10% Pd/C. After interaction for 5 hours under atmospheric pressure of hydrogen, the reaction mixture is stirred at a pressure of 3 atmospheres of hydrogen for 24 hours. After filtration through celite and evaporation of the filtrate obtain 0.11 g (55%) of ethyl-3-{6-[3-(tert-butoxycarbonylmethylene)phenyl]pyrid-3-yl}-2-ethoxypropionate.

g - Ethyl-2-ethoxy-3-[6-(3-methylaminophenol)pyrid-3-yl]propanoate

0.11 g (0.3 mmol) of ethyl-3-6-[3-(tert-butoxycarbonylmethylene)phenyl]pyrid-3-yl}-2-ethoxypropionate, 5 ml dichloromethane and 0.15 ml (1.9 mmol) triperoxonane acid is stirred at room temperature for 24 hours. After adding water, the reaction mixture is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated. Receive 80 mg (94%) of ethyl-2-ethoxy-3-[6-(3-methylaminophenol)pyrid-3-yl]propanoate.

h - Ethyl-2-ethoxy-3-{6-[3-(3-heptyl-1-methylurea)phenyl]pyrid-3-yl}propanoate

80 μl (0.5 mmol) captilization added to 80 mg (0.24 mmol) of ethyl-2-ethoxy-3-[6-(3-methylaminophenol)pyrid-3-yl]propanoate in 5 ml of dichloromethane. After stirring at room temperature for 24 hours, water is added and the reaction mixture is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by thin-layer chromatography on silica with elution with a mixture of 60/40 heptane/ethyl acetate. Receive 60 mg (54%) of ethyl-2-ethoxy-3-{6-[3-(3-heptyl-1-methylurea)phenyl]pyrid-3-yl}propanoate.

i - 2-Ethoxy-3-{6-[3-(3-heptyl-1-methylurea)phenyl]pyrid-3-yl}propanoic acid

60 mg (0.13 mmol) of ethyl-2-ethoxy-3-{6-[3-(3-heptyl-1-methylurea)phenyl]pyrid-3-yl}propanoate placed in 4 ml of tetrahydrofuran, add 0.2 ml (0.2 mmol) of aqueous 1 M solution of lithium hydroxide and the mixture is stirred at room temperature for 24 hours. After acid hydrolysis to pH 4.5-5 d is clonney the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by thin-layer chromatography on silica with elution with a mixture of 50/50 heptane/ethyl acetate and then a mixture of 90/10 dichloromethane/methanol. Get 40 mg (70%) 2-ethoxy-3-{6-[3-(3-heptyl-1-methylurea)phenyl]pyrid-3 - yl}propanoic acid in the form of a white solid with a melting point of 142-143°C.

1H NMR (δ CDCl3): 0,86 (t, J=6,7 Hz, 3H), 1,19 (t, J=7.0 Hz, 3H); 1.20-1.25 range (m, 8H); to 1.42 (m, 2H); 3.15 in (m, 1H); 3,18 (m, 2H); 3,19 (m, 1H); to 3.34 (s, 3H); of 3.53 (m, 1H); and 3.72 (m, 1H); to 4.41 (m, 1H); 7,30 (m, 1H); 7,50-the 7.85 (m, 5H); at 8.60 (m, 1H).

Example 21: 2(S)-(2-Benzoylamino)-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid

a - Methyl-2(S)-(2-benzoylamino)-3-{4-[6-(tert-butoxycarbonylmethylene)pyrid-2-yl]phenyl}propanoate

In a manner analogous to the method of example 14(d), on the basis of 12.7 g (26 mmol) of methyl 2-(2-benzoylamino)-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]propanoate and 5 g (17 mmol) of tert-butyl(3-bromophenyl)methylcarbamate (obtained as described in (9b), gain of 8.3 g (84%) of methyl 2(S)-(2-benzoylamino)-3-{4-[6-(tert-butoxycarbonylmethylene)pyrid-2-yl]phenyl}of propanoate.

b - Methyl-2(S)-(2-benzoylamino)-3-[4-(6-methylaminomethyl-2-yl)phenyl]propanoate

In a manner analogous to the method of example 14(e)on the basis of 8,3 g (15 mmol) of methyl 2(S)-(2-benzoylamino)-3-{4-[6-(tert-butoxycarbonylmethylene)pyrid-yl]phenyl}of propanoate, get 7,1 g (100%) of methyl 2(S)-(2-benzoylamino)-3-[4-(6-methylaminomethyl-2-yl)phenyl]propanoate.

c - Methyl-2(S)-(2-benzoylamino)-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoate

In a manner analogous to the method of example 7(i)proceeding from 0.9 g (1.9 mmol) of methyl 2(S)-(2-benzoylamino)-3-[4-(6-methylaminomethyl-2-yl)phenyl]propanoate and 0.35 ml (2.1 mmol) intilization, obtain 0.7 g (63%) of methyl 2(S)-(2-benzoylamino)-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}of propanoate.

d - 2(S)-(2-Benzoylamino)-3-{4-[6-(1-methyl-3-pentyurina]pyrid-2-yl]phenyl}propanoic acid

In a manner analogous to the method of example 7(j), according to 0.22 g (0.4 mmol) of methyl 2(S)-(2-benzoylamino)-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}of propanoate, obtain 0.2 g (95%) 2(S)-(2-benzoylamino)-3-{4-[6-(1-methyl-3-pentyurina]pyrid-2-yl]phenyl}propanoic acid.

1H NMR (δ CDCl3): of 0.77 (t, J=6,7 Hz, 3H); 1,23-1,25 (m, 4H); 1,53 (m, 2H); 3,20-of 3.46 (m, 4H); to 3.41 (s, 3H); 4,47 (m, 1H); 6,59 (t, J=7,4 Hz, 1H); of 6.68 (d, J=8.5 Hz, 1H); 6,86 (d, J=8.5 Hz, 1H); 7,22-7,73 (m, 13H); 9,0 (s, 1H); to 10.5 (s, 1H).

Example 22: 2(S)-(2-Benzoylamino)-3-{4-[6-(1-methyl-3-heptylene)pyrid-2-yl]phenyl}propanoic acid

a - Methyl-2(S)-(2-benzoylamino)-3-{4-[6-(1-methyl-3-heptylene)pyrid-2-yl]phenyl}propanoate

In a manner analogous to the method of example 7(i)proceeding from 0.35 g (0.7 mmol) of methyl 2(S)-(2-benzoylamino)-3-[4-(6-methylaminomethyl-2-yl)phenyl]propanoate and 0.3 ml (2,mmol) captilization, obtain 0.4 g (94%) of methyl 2(S)-(2-benzoylamino)-3-{4-[6-(1-methyl-3-heptylene)pyrid-2-yl]phenyl}of propanoate.

b - 2(S)-(2-Benzoylamino)-3-{4-[6-(1-methyl-3 - heptylene)pyrid-2-yl]phenyl}propanoic acid

In a manner analogous to the method of example 7(j), on the basis of 0.7 g (0.4 mmol) of methyl 2(S)-(2-benzoylamino)-3-{4-[6-(1-methyl-3-heptylene)pyrid-2-yl]phenyl}of propanoate, obtain 0.65 g (90%) 2(S)-(2-benzoylamino)-3-{4-[6-(1-methyl-3-heptylene)pyrid-2-yl]phenyl}propanoic acid.

1H NMR (δ CDCl3): or 0.83 (t, 3H, J=6,7 Hz); 1,15 of 1.28 (m, 4H); 1,51 is 1.58 (m, 2H); 3.27 to (DD, 1H, J=a 13.8 Hz, J=7.9 Hz); and 3.31 (m, 2H); 3.42 points (s, 3H); 3,44 (DD, 1H, J=1.4 Hz, J=13,8 Hz); 4,50 (m, 1H); 6,62 (t, J=7,4 Hz, 1H); 6.73 x (d, J=8.5 Hz, 1H); 6.89 in (d, J=8.5 Hz, 1H); 7,29-to 7.77 (m, 13H); 9,0 (m, 1H); 10,5 (m, 1H).

Example 23: 2(S)-Ethoxy-3-{6-[3-(3-heptyl-1-methylurea)phenyl]pyrid-3-yl}propanoic acid

a - 2(S)-Ethoxy-3-[6-(3-methylaminophenol)pyrid-3-yl]propanoic acid

0.9 g (2.7 mmol) of ethyl-2-ethoxy-3-[6-(3-methylaminophenol)pyrid-3-yl]propanoate, obtained as described in example 20g, placed in 60 ml of buffer solution with pH 7 with 0.75 g of the enzyme proteinase 2A. After keeping the mixture for 10 days at room temperature the reaction has not progressed. The reaction mixture is heated at 37°C for 1 day, the reaction is finished.

Add water, pH is adjusted to 8 by adding 1 M sodium hydroxide solution and the reaction mixture is extracted with ethyl acetate. Phase ethyl acetate industry is with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The aqueous phase is acidified with aqueous 1 n solution of acetic acid to pH 4 and extracted with ethyl acetate. The ethyl acetate phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by thin-layer chromatography on silica with elution with a mixture of 95/5, 90/10 then 80/20 dichloromethane/methanol. Get 0.1 g (24%) 2(S)-ethoxy-3-[6-(3-methylaminophenol)pyrid-3-yl]propanoic acid.

b - Methyl-2(S)-ethoxy-3-[6-(3-methylaminophenol)pyrid-3-yl]propanoate

0.1 g (0.3 mmol) of 2(S)-ethoxy-3-[6-(3-methylaminophenol)pyrid-3-yl]propanoic acid are placed in 5 ml of methanol and add 2 drops of concentrated sulfuric acid. The reaction mixture is heated at 65°C for 18 hours. The methanol is evaporated and the residue dissolved in a mixture of ethyl acetate/water. The value of the pH is adjusted to 7 by adding 1 n sodium hydroxide solution and the reaction mixture is extracted with ethyl acetate. The ethyl acetate phase is dried over sodium sulfate, filtered and evaporated. Receive 70 mg (70%) of methyl 2(S)-ethoxy-3-[6-(3-methylaminophenol)pyrid-3-yl]propanoate.

c - Methyl-2(S)-ethoxy-3-(6-{3-[methyl-(4-nitrophenoxyacetic)amino]phenyl}of pyrid-3-yl)propanoate

70 mg (0.3 mmol) 4-nitrophenylphosphate and then 60 μl (0.3 mmol) of diisopropylethylamine added to a solution of 70 mg (0.25 mmol) of methyl 2(S)-e is hydroxy-3-[6-(3-methylaminophenol)pyrid-3-yl]propanoate in 3 ml of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. After adding water, the reaction mixture is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated. Obtain 110 mg (100%) of methyl 2(S)-ethoxy-3-(6-{3-[methyl-(4-nitrophenoxyacetic)amino]phenyl}of pyrid-3-yl)propanoate.

d - Methyl-2(S)-ethoxy-3-{6-[3-(3-heptyl-1-methylurea)phenyl]pyrid-3-yl}propanoate

70 μl (0.45 mmol) of heptylamine added to a solution of 110 mg (0.25 mmol) of methyl 2(S)-ethoxy-3-(6-{3-[methyl-(4-nitrophenoxyacetic)amino]phenyl}of pyrid-3-yl)propanoate in 3 ml of dimethylformamide. The reaction mixture is heated at 80°C for 3 hours. After adding water, the reaction mixture was extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by thin-layer chromatography on silica with elution with a mixture of 6/4 and then 5/5 heptane/ethyl acetate. Receive 50 mg (50%) of methyl 2(S)-ethoxy-3-{6-[3-(3-heptyl-1-methylurea)phenyl]pyrid-3-yl}propanoate.

e - 2(S)-Ethoxy-3-{6-[3-(3-heptyl-1-methylurea)phenyl]pyrid-3-yl}propanoic acid

In a manner analogous to the method of example 20(i)on the basis of 50 mg (0.1 mmol) of methyl 2(S)-ethoxy-3-{6-[3-(3-heptyl-1-methylurea)phenyl]pyrid-3-yl}propanoate receive 25 mg (50%) 2(S)-ethoxy-3-{6-[3-(3-heptyl-1-methylurea)phenyl]pyrid-3-yl}propanoic acid in the form of white firmly the of substances with a melting point of 140-141°C.

1H NMR (d, CDCl3): of 0.87 (t, J=6,7 Hz, 3H); to 1.24 and 1.33 (m, 11H); 1,40-1,45 (m, 2H); 3,16-is 3.21 (m, 4H); to 3.34 (s, 3H); 3,56 - of 3.60 (m, 1H); 3,69-to 3.73 (m, 1H); 4,17-4,20 (m, 1H); however, 4.40 (t, J=5,2 Hz, 1H); 7,30-7,33 (m, 1H); 7,51-7,55 (m, 1H); to 7.67 to 7.75 (m, 2H); 7,88-of 7.90 (m, 2H); at 8.60 (d, J=1.2 Hz, 1H).

Example 24: Hydrochloride 2(S)-ethoxy-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid

a - Methyl-2(S)-ethoxy-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoate

A.1 - Methyl-2(S)-ethoxy-3-(4-{6-[methyl-(4-nitrophenoxyacetic)amino]pyrid-2-yl}phenyl)propanoate

0.96 g (4.8 mmol) of 4-nitrophenylphosphate and then of 0.85 ml (4.8 mmol) of diisopropylethylamine added to a solution of 1 g (3.2 mmol) of methyl 2(S)-ethoxy-3-[4-(6-methylaminomethyl-2-yl)phenyl]propanoate in 25 ml of dichloromethane. The reaction mixture was stirred at room temperature for 1 hour and 30 minutes. After addition of water the mixture is extracted with dichloromethane, the organic phase is dried over magnesium sulfate, filtered and evaporated. Gain of 1.9 g (100%) of methyl 2(S)-ethoxy-3-(4-{6-[methyl-(4-nitrophenoxyacetic)amino]pyrid-2-yl}phenyl)propanoate.

A.2 - Methyl-2(S)-ethoxy-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoate

0.65 g (1.1 mmol) of methyl 2(S)-ethoxy-3-(4-{6-[methyl-(4-nitrophenoxyacetic)amino]pyrid-2-yl}phenyl)propanoate, 12 ml of dimethylformamide and 1 ml (8,8 ml) pentylamine heated at 80°C for 18 hours. After adding water, the reaction mixture was extracted with ethyl acetate. Phase utilize the ATA dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by thin-layer chromatography on silica with elution with a mixture 7/3 and then 6/4 heptane/ethyl acetate. Obtain 0.35 g (76%) of methyl 2(S)-ethoxy-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}of propanoate.

b - 2(S)-Ethoxy-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid

In a manner analogous to the method of example 20(i)on the basis of 0.35 g (0.8 mmol) of methyl 2(S)-ethoxy-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}of propanoate receive 300 mg (100%) 2(S)-ethoxy-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid.

with - Hydrochloride 2(S)-ethoxy-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid

In a manner analogous to the method of example 10, based on 300 mg of 2(S)-ethoxy-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid, receive 200 mg of the hydrochloride of 2(S)-ethoxy-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid is obtained in the form of a white solid.

1H NMR (d CDCl3): 0,84 (t, J=6.9 Hz, 3H); of 1.12 (t, J=7.0 Hz, 3H); of 1.29 to 1.34 (m, 4H); 1,63-of 1.66 (m, 2H); 3.04 from (DD, J=8,4 Hz, J=14,0 Hz, 1H); 3,14 (DD, J=4.0 Hz, J=14,0 Hz, 1H); 3,31-3,37 (m, 3H); 3,64-3,70 (m, 4H); 4,01 (DD, J=4.0 Hz, J=8,4 Hz, 1H); 7.23 percent (d, J=8,2 Hz, 1H); 7,45-7,47 (m, 3H); 7,70-7,71 (d, J=8,2 Hz, 2H); of 8.06 (t, J=of 7.70 Hz, 1H).

Example 25: 2(S)-Ethoxy-3-{4-[6-(1-methyl-3-butylurea)pyrid-2-yl]phenyl}propanoic acid

a - Methyl-2(S)-ethoxy-3-{4-[6-(1-methyl-3-butylurea)pyrid-2-yl]phenyl}propanoate

<> In a manner analogous to the method of example 24(a), starting from 0.2 g (0.64 mmol) of methyl 2(S)-ethoxy-3-[4-(6-methylaminomethyl-2-yl)phenyl]propanoate, obtain 0.2 g (80%) of methyl 2(S)-ethoxy-3-{4-[6-(1-methyl-3-butylurea)pyrid-2-yl]phenyl}of propanoate.

b - 2(S)-Ethoxy-3-{4-[6-(1-methyl-3-butylurea)pyrid-2-yl]phenyl}propanoic acid

In a manner analogous to the method of example 20(i)on the basis of 0.2 g (0.5 mmol) of methyl 2(S)-ethoxy-3-{4-[6-(1-methyl-3-butylurea)pyrid-2-yl]phenyl}of propanoate, obtain 130 mg (90%) 2(S)-ethoxy-3-{4-[6-(1-methyl-3-butylurea)pyrid-2-yl]phenyl}propanoic acid in the form of white solids.

1H NMR (d CDCl3): to 0.92 (t, J=7,3 Hz, 3H); to 1.21 (t, J=7.0 Hz, 3H); 1,35-1,45 (m, 2H); 1,57-of 1.64 (m, 2H); 3,11 (DD, J=8.0 Hz, J=14.1 Hz, 1H); up 3.22 (DD, J=4.0 Hz, J=14.1 Hz, 1H); to 3.41 (q, J=6.9 Hz, 2H); 3,47 (s, 3H); 3,48-3,50 (m, 1H): 3,67-3,71 (m, 1H); 4,15 (DD, J=4,1 Hz; J=8.0 Hz, 1H); 6,94 (d, J=8,4 Hz, 1H); of 7.36-7,41 (m, 3H); 7,75-of 7.82 (m, 3H); to 10.5 (s, 1H).

Example 26: Hydrochloride 2(S)-ethoxy-3-{4-[6-(1-methyl-3-ventilerede)pyrid-2-yl]phenyl}propanoic acid

a - Methyl-2(S)-ethoxy-3-{4-[6-(1-methyl-3-ventilerede)pyrid-2-yl]phenyl}propanoate

In a manner analogous to the method of example 24(a), based on 0,63 g (1.1 mmol) of methyl 2(S)-ethoxy-3-[4-(6-methylaminomethyl-2 - yl)phenyl]propanoate, obtain 0.4 g (83%) of methyl 2(S)-ethoxy-3-{4-[6-(1-methyl-3-ventilerede)pyrid-2-yl]phenyl}of propanoate.

b - 2(S)-Ethoxy-3-{4-[6-(1-methyl-3-ventilerede)pyrid-2-yl]phenyl}propanoic acid

In a manner analogous to the method of example 20(i), and the walking of 0.4 g (0.8 mmol) of methyl 2(S)-ethoxy-3-{4-[6-(1-methyl-3-ventilerede)pyrid-2-yl]phenyl}of propanoate, receive 300 mg (85%) 2(S)-ethoxy-3-{4-[6-(1-methyl-3-ventilerede)pyrid-2-yl]phenyl}propanoic acid.

c - Hydrochloride 2(S)-ethoxy-3-{4-[6-(1-methyl-3-ventilerede)pyrid-2-yl]phenyl}propanoic acid

In a manner analogous to the method of example 10, based on 300 mg of 2(S)-ethoxy-3-{4-[6-(1-methyl-3-ventilerede)pyrid-2-yl]phenyl}propanoic acid, receive 200 mg of the hydrochloride of 2(S)-ethoxy-3-{4-[6-(1-methyl-3-ventilerede)pyrid-2-yl]phenyl}propanoic acid in the form of a white solid.

1H NMR (δ, CDCl3): 1,10 (t, J=6,7 Hz, 3H); to 2.85 (m, 2H); 2,94 totaling 3.04 (m, 1H); 3,10-3,13 (m, 1H); and 3.31 (m, 1H); of 3.60 (s, 3H); 3,62 (m, 2H); 3,66 (m, 1H); 3,98 (m, 1H); to 7.09 (m, 1H); 7,19 (m, 5H); 7,38 (m, 3H); to 7.59 (m, 2H,); 7,97 (m, 1H).

Example 27: 2(S)-Ethoxy-3-{4-[6-(1-methyl-3-phenylurea)pyrid-2-yl]phenyl}propanoic acid

a. Methyl-2(S)-ethoxy-3-{4-[6-(1-methyl-3-phenylurea)pyrid-2-yl]phenyl}propanoate

In a manner analogous to the method of example 24(a), based on 0,63 g (1.1 mmol) of methyl 2(S)-ethoxy-3-[4-(6-methylaminomethyl-2-yl)phenyl]propanoate, obtain 0.16 g (37%) of methyl 2(S)-ethoxy-3- {4-[6-(1-methyl-3-phenylurea)pyrid-2-yl]phenyl}of propanoate.

b. 2(S)-Ethoxy-3-{4-[6-(1-methyl-3-phenylurea)pyrid-2-yl]phenyl}propanoic acid

In a manner analogous to the method of example 20(i)on the basis of 0.16 g (0.8 mmol) of methyl 2(S)-ethoxy-3-{4-[6-(1-methyl-3-phenylurea)pyrid-2-yl]phenyl}of propanoate receive 120 mg (92%) 2(S)-ethoxy-3-{4-[6-(1-methyl-3-phenylurea)pyrid-2-yl]phenyl}propanoic acid.

1H NMR (δ, CCl 3): 1,08 (t, J=7.0 Hz, 3H); of 2.97 (DD, J=8.6 Hz, J=14 Hz, 1H); to 3.09 (DD, J=4,1 Hz, J=14,0 Hz, 1H); 3,28-of 3.32 (m, 1H); 3,44 (s, 3H); 3,59-to 3.64 (m, 1H); of 3.97 (DD, J=4,6 Hz, J=8.5 Hz, 1H); 6,94 (t, J=7,4 Hz, 1H); 7,00 (d, J=8,4 Hz, 1H); 7.18 in-7,22 (m, 2H); 7,37-7,39 (m, 3H); 7,43 was 7.45 (m, 2H); 7,78-of 7.82 (m, 3H); 13,00 (s, 1H).

Example 28: 2(S)-Ethoxy-3-{4-[6-(1-methyl-3-naphthalene-2-yureina)pyrid-2-yl]phenyl}propanoic acid

a. Methyl-2(S)-ethoxy-3-{4-[6-(1-methyl-3-naphthalene-2-yureina)pyrid-2-yl]phenyl}propanoate

In a manner analogous to the method of example 7(i)on the basis of 0.4 g (0.8 mmol) of methyl 2(S)-ethoxy-3-[4-(6-methylaminomethyl-2-yl)phenyl]propanoate and 2-naphthylisocyanate, obtain 0.2 g (62%) of methyl 2(S)-ethoxy-3-{4-[6-(1-methyl-3-naphthalene-2-yureina)pyrid-2-yl]phenyl}propionate.

b. 2(S)-Ethoxy-3-{4-[6-(1-methyl-3-naphthalene-2-yureina)pyrid-2-yl]phenyl}propanoic acid

In a manner analogous to the method of example 20(i)on the basis of 0.2 g (0.5 mmol) of methyl 2(S)-ethoxy-3-{4-[6-(1-methyl-3-naphthalene - 2-yureina)pyrid-2-yl]phenyl}of propanoate, obtain 0.15 g (95%) 2(S)-ethoxy-3-{4-[6-(1-methyl-3-naphthalene-2-yureina)pyrid-2-yl]phenyl}propanoic acid.

1H NMR (δ, CDCl3): of 1.23 (t, J=7.0 Hz, 3H); and 3.16 (DD, J=7,6 Hz, J=14.1 Hz, 1H); or 3.28 (DD, J=4.3 Hz, J=14.1 Hz, 1H); 3,52 of 3.56 (m, 1H); to 3.58 (s, 3H); 3,68-and 3.72 (m, 1H); is 4.21 (DD, J=4.3 Hz, J=7,6 Hz, 1H);? 7.04 baby mortality (d, J=8,4 Hz, 1H); 7,28 (m, 1H); 7,37-7,51 (m, 5H); 7,75-to 7.84 (m, 4H); a 7.92 (d, J=8,2 Hz, 2H); of 8.25 (d, J=1.7 Hz, 1H); 13,30 (s, 1H).

Example 29: Test transactivation of PPAR with the use of cross-curves

Activation of PPAR agonist (activator) in HeLN leads to the expression of the reporter gene, luciferase, which in the presence of the substrate generates light. Modulation of PPAR measure quantification of the luminescence produced after incubation of the cells in the presence of a reference agonist. Ligands displace the agonist from its website. Measurement of the activity carried out quantitative measurement of the induced light. This measurement makes it possible to define modulatory activity of the compounds according to the invention by a constant, which represents the affinity of the molecule for the receptor PPAR. Since this value may vary depending on the basal activity and expression of the receptor, it is denoted as apparent Kd (KdApp in nm).

To determine this constant cross-curves of the test product versus the reference agonist receive using 96-well plates: 10 concentrations of the test product plus concentration have 0 in line 7 concentrations of agonist plus the concentration of 0 is placed in the column. This definition consists of 88 measurement points for 1 product and 1 receptor. The remaining 8 holes are used to control replication.

In each well, the cells are in contact with the concentration of the test product and the concentration of the reference agonist, 2-(4-{2-[3-(2,4-differenl)-1-heptylene]ethyl}phenylsulfanyl)-2-methylpropionate sour the s for PPARα, {2-methyl-4-[4-methyl-2-(4-triptoreline)thiazole-5-elmersolver]phenoxy}acetic acid for PPARδ and 5-{4-[2-(methylpiperid-2-ylamino)ethoxy]benzyl}thiazolidine-2,4-dione for PPARγ. The measurements were carried out also for controls full agonist of the same products.

Used cell lines HeLH are stable transfectants containing the plasmid ERE-βGlob-Luc-SV-Neo (reporter gene) and PPAR (α, δ, γ) Gal-hPPAR. These cells inoculant in 96-well tablets at the rate of 10,000 cells per well in 100 μl of DMEM medium without phenol red and supplemented with 10% fat-free bovine serum. The tablets are then incubated at 37°C and 7% CO2for 16 hours.

Different dilution of the tested products and the reference ligand added at the rate of 5 μl per well. The tablets are then incubated for 18 hours at 37°C and 7% CO2. The culture medium is removed by the flip of tablets and to each well was added 100 μl of a mixture of 1:1 PBS/luciferin. After 5 minutes, the tablet reads the detector of luminescence.

These cross-curves allow the determination of the values AS (the concentration at which to observe the 50% activation) of the reference ligand at various concentrations of the test product. These values IS used to calculate the regression Shield build a straight line corresponding to the equation of the Plane (quantitation in receptor pharmacology Terry P. Kenakin, Receptors and Channels, 2001, 7,371-385), which allows to obtain values d app (in nm).

The results of development:

ConnectionPPARα
Kd app
(nm)
PPARδ
Kd app
(nm)
PPARγ
Kd app
(nm)
Standard 1: 2-(4-{2-[3-(2,4-differenl)-1-heptylene]ethyl}phenylsulfanyl)-2-methylpropionate acid200N.A.N.A.
Standard 2: {2-methyl-4-[4-methyl-2-(4-triptoreline)thiazole-5-elmersolver]phenoxy}acetic acidN.A.10N.A.
Standard 3: 5-{4-[2-(methylpiperid-2-ylamino)ethoxy]benzyl}thiazolidine-2,4-dioneN.A.N.A.30
Example 1N.A.N.A.4000
Example 2N.A.N.A.4000
Example 3N.A.N.A. 4000
Example 4N.A.N.A.500
Example 54000N.A.0,06
Example 61000N.A.2
Example 72000N.A.60
Example 8N.A.N.A.30
Example 10120N.A.0,5
Example 152000N.A.1000
Example 20N.A.N.A.4
N.A. means is not active

These results show the affinity of compounds for PPAR-γ and, more specifically, the specificity of the affinity of compounds of the invention for PPARγ subtype compared with the affinity of compounds DL the PPARα subtype or a subtype of PPARδ.

Example 30: a Song

This example illustrates various specific compositions based on compounds according to the invention.

A - Oral route of administration

(a) Tablet 0.2 g

The compound of example 2
Starch
The dicalcium phosphate
Silicon dioxide
Lactose
Talc
Magnesium stearate
0.001 g
0,114 g
0,020 g
0,020 g
0,030 g
0,010 g
0.005 g

(b) drinkable suspension in 5 ml ampoules

The compound of example 4
Glycerin
70% sorbitol
The sodium saccharinate
Methylparahydroxybenzoate
Corrigent
Purified water
0.001 g
0,500 g
0,500 g
0,010 g
0,040 g
as needed
as needed up to 5 ml

(C) 0.8 g tablet

0.075 g
Connection example 10,500 g
Presleyterians
starch0,100 g
Microcrystalline
cellulose0,115 g
Lactose
Magnesium stearate0,010 g

(d) drinkable suspension in 10 ml ampoules

The compound of example 10
Glycerin
70% sorbitol
The sodium saccharinate
Methylparahydroxybenzoate
Corrigent
Purified water
0,200 g
1,000 g
1,000 g
0,010 g
0,080 g
as needed
as needed up to 10 ml

B - Local route of administration

(a) Ointment

The compound of example 80,020 g
Isopropylmyristate81,700 g
Liquid petrolatum9,100 g
Silicon dioxide (Aerosil
200, Degussa sold)9,180 g

(b) Ointment

The compound of example 7
White petrolatum
0,300 g
how much you want to 100 g

(C) non-ionic cream type water-in-oil

The compound of example 110,100 g/td>
The mixture of emulsifying
lanolin alcohols, waxes and
oils (Anhydrous Eucerin,
sold BDF)39,900 g
Methyl parahydroxybenzoate0.075 g
Sodium propyl parahydroxybenzoate0.075 g
Sterile demineralized
waterhow much you want to 100 g

(d) Lotion

The compound of example 6
Polyethylene glycol (PEG-400)
95% ethanol
0,100 g
69,900 g
30,000 g

(e) Hydrophobic ointment

The compound of example 150,300 g
Isopropylmyristate36,400 g
Silicone oil
(Rhodorail 47 V sold
Rhone-Poulenc)36,400 g
Pchelenoy wax13,600 g
Silicone oil (Abil
300000 CST sold
Goldschmidt)how much you want to 100 g

(f) non-ionic cream type oil-in-water

The compound of example 91,000 g
Cetyl alcohol4,000 g
Glycerylmonostearate2,500 g
PEG-50 stearate2,500 g
Oil Karite9,200 g
Propylene glycol2,000 g
Methyl parahydroxybenzoate0.075 g
Sodium propyl parahydroxybenzoate0.075 g
Sterile
demineralized waterhow much you want to 100 g

1. is soedineniya, characterized in that they correspond to the following formula (I):

in which
- R1 represents the following radical of formula (a) or (b):

and R3 and R4 have the meanings given below,
- R2 represents an alkyl radical containing from 1 to 8 carbon atoms, aryl radical containing from 6 to 10 carbon atoms, an alkyl radical containing from 1 to 6 carbon atoms, substituted aryl radical containing from 6 to 10 carbon atoms;
- R3 represents a radical of the following formula:

- R4 represents a radical OR9 or NHR9;
- R8 is a
is a hydroxyl radical, an alkyl radical containing from 1 to 8 carbon atoms;
- R9 is an alkyl radical having from 1 to 6 carbon atoms, or a radical selected from the following formula:

and R11 has the meanings given below,
- R11 represents a radical (CO)s(Z)tR10 with s equal to the values 0, 1, and t is 0;
R10 has the meanings given below,
R10 represents an alkyl radical containing from 1 to 7 carbon atoms, phenyl,
- X represents a bond having the following structure:
-(CH2)z-NR14-C(T)-Dw-
moreover, D, w, z, T and R14 who have values, below,
T represents an oxygen atom or sulfur;
- D represents the radical-NR15or the radical CH2;
and R15 have the meanings specified below;
- z may be equal to the values 0 or 1;
- w may be equal to the values from 0 to 6 and
-R14 and R15 represent a hydrogen atom or an alkyl radical containing from 1 to 12 carbon atoms,
Ar1 and AG may be the same or different and represent an aromatic radical of the formula:

a, represents a S atom or a radical N-R13,
- R13 represents a hydrogen atom or an alkyl radical containing from 1 to 6 carbon atoms;
moreover, with the proviso that when Ar1 or A represents a phenyl radical, then AG or Ar1 necessarily represents a heteroaryl radical,
and optical isomers of the above compounds of formula (I)and their salts.

2. Compounds according to claim 1, characterized in that they are in the form of salts of carboxylic acids, salts of organic amine or salt functional amino group.

3. Compounds according to claim 2, characterized in that they are in the form of a salt of an alkali metal or alkaline earth metal salts of amino acids, salts of a halogen atom, or an organic acid is you or nitrate salt.

4. Compounds according to claim 1, characterized in that selected individually or as mixtures from the group consisting of:
(1) N-{4-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenyl]thiophene-2-ylmethyl}-N-methylbenzamide
(2) N-{5-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenyl]thiophene-3-ylmethyl}-N-methylbenzamide
(3) N-{5-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenyl]pyrid-3-ylmethyl}-N-methylbenzamide
(4) N-{3-[5-(2,4-Dioxothiazolidine-5-ylmethyl)pyrid-2-yl]benzyl}-N-methylacrylamide
(5) 2(S)-Ethoxy-3-(4-{5-[(methylacrylamide)methyl]thiophene-3-yl}phenyl)propanoic acid
(6) 2(S)-Ethoxy-3-(4-{5-[(methylacrylamide)methyl]thiophene-2-yl}phenyl)propanoic acid
(7) 2(S)-Ethoxy-3-{4-[2-(3-heptyl-1-methylurea)thiazol-4-yl]phenyl}propanoic acid
(8) 2(S)-Ethoxy-3-{4-[2-(3-pentyl-1 macilwraith)thiazol-5-yl]phenyl}propanoic acid
(9) 2(S)-Ethoxy-3-{4-[6-(3-heptyl-1-methylurea)pyrid-2-yl]phenyl}propanoic acid
(10) Chloride 2-[4-(2-carboxy-2(S)-ethoxyethyl)phenyl]-6-(3-heptyl-1-methylurea)pyridinium
(11) 2(S)-Ethoxy-3-{4-[5-(3-heptyl-1-methylurea)-2-methyl-2H-[1,2,4]triazole-3-yl]phenyl}propanoic acid
(12) {3-[5-(2,4-Dioxothiazolidine-5-ylmethyl)thiophene-2-yl]benzyl}methylacryloylamino
(13) {3-[5-(2,4-Dioxothiazolidine-5-ylmethyl)thiophene-2-yl]benzyl}methylhexaneamine
(14) 2(S)-(2-Benzoylamino)-3-(4-{5-[(methylacrylamide)methyl]thiophene-3-yl}phenyl)propanoic acid
(15) 2(S)-(2-Benzoylamino)-3-(4-{5-[(hexa is ylmethylamino)methyl]thiophene-3-yl}phenyl)propanoic acid
(16) 2(S)-Ethoxy-3-(4-{5-[(exanimation)mertie-3-yl}phenyl)propanoic acid
(17) 2(S)-Ethoxy-3-(4-{5-[(methylpentylamino)methyl]thiophene-3-yl}phenyl)propanoic acid
(18) 3-[4-(5-{[(2-Cyclopentylacetyl)methylamino]methyl}thiophene-3-yl)phenyl]-2(S)-ethoxypropanol acid
(19) 3-[4-(5-{ [(3-Cyclohexylpropionic)methylamino]methyl}thiophene-3-yl)phenyl]-2(S)-ethoxypropanol acid
(20) 2-Ethoxy-3-{6-[3-(3-heptyl-1-methylurea)phenyl]pyrid-3-yl}propanoic acid
(21) 2(S)-(2-Benzoylamino)-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid
(22) 2(S)-(2-Benzoylamino)-3-{4-[6-(3-heptyl-1-methylurea)pyrid-2-yl]phenyl}propanoic acid
(23) 2(S)-Ethoxy-3-{6-[3-(3-heptyl-1-methylurea)phenyl]pyrid-3-yl}propanoic acid
(24) Hydrochloride 2(S)-ethoxy-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid
(25) 3-{4-[6-(3-Butyl-1-methylurea)pyrid-2-yl]phenyl}-2(S)-ethoxypropanol acid
(26) Hydrochloride 2(S)-ethoxy-3-{4-[6-(1-methyl-3-ventilerede)pyrid-2-yl]phenyl}propanoic acid
(27) 2(S)-Ethoxy-3-{4-[6-(1-methyl-3-pentyurina)pyrid-2-yl]phenyl}propanoic acid
(28) 2(S)-Ethoxy-3-{4-[6-(1-methyl-3-naphthalene-2-yureina)pyrid-2-yl]phenyl}propanoic acid
(29) 3-{4-[6-(3-Cyclohexyl-1-methylurea)pyrid-2-yl]phenyl}-2(S)-ethoxypropanol acid.

5. Compounds according to claim 1, characterized in that they have at least one of the following differences:
- R1 depict is to place a radical of formula (a) or (b); in the case when R1 corresponds to the formula (b), R3 is preferably a radical of formula (d), and R8 represents hydroxyl, and R4 represents, preferably, a radical of the formula OR9, in which R9 represents alkyl with 1-6 carbon atoms;
- R2 represents an alkyl or aryl radical;
- X represents the communication structure-CH2N(R14)CO -, or-N(R14)-CO-(D)wwith w = 0 or 1;
D represents a radical-NR15or the radical CH2;
- Ar1 or AG contains at least one group type, pyridine, thiazole, thiophene or a triazole.

6. Cosmetic composition for regulating and/or restoring the metabolism of skin lipids, characterized in that it contains, in a physiologically acceptable medium at least one compound according to any one of claims 1 to 5 in a concentration of from 0.0001 to 2 wt.% relative to the total weight of the composition.

7. Compounds according to claim 1, having the property modulator activated by proliferation peroxisome receptor subtype (PPARγ).

8. The use of compounds according to any one of claims 1 to 5 in the manufacture of a composition for regulating and/or restoring the metabolism of skin lipids.

9. The use of compounds according to any one of claims 1 to 5 in the manufacture of a composition having the property modulator activated by proliferation peroxisome receptor subtype (PPARγ).

10 Pharmaceutical composition, having the property modulator activated by proliferation peroxisome receptor subtype (PPARγ), characterized in that it contains, in a physiologically acceptable medium, at least one of the compounds according to any one of claims 1 to 5 in a concentration of from 0.001 to 10 wt.% relative to the total weight of the composition.

11. The composition according to claim 10, characterized in that the concentration of compounds(I) according to one of claims 1 to 5 is from 0.01 to 1 wt.% relative to the total weight of the composition.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I): wherein dashed lines present single or double bonds, and the values of radicals R1, R2, R3, R4 are described in cl. 1 of the patent claim. Besides the invention refers to application and a based pharmaceutical composition for prevention and treatment of neurodegenerative diseases and other diseases wherein cell dystrophy and/or cell loss (apoptosis) caused by free radicals act the main part.

EFFECT: production of new compounds and the based pharmaceutical composition which can find application in medicine for prevention and treatment of neurodegenerative diseases.

6 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, pharmaceutical compositions based on the said compounds, as well as methods of using said compounds in preparing medicinal agents.

EFFECT: obtaining compounds and a composition which can inhibit phosphatase cdc25, particularly phosphatase cdc25-C and can be particularly used for treating cancer.

12 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I and their pharmaceutically acceptable salts and esters. The disclosed compounds have inhibitory effect on cyclin-dependant kinase. In formula I R1 denotes , R3 is selected from a group consisting of H, CO2R6, C(O)R6, SO2R6 and SO2NR5R6, R5 and R6 are each independently selected from a group which includes H and (lower)alkyl, R2 is phenyl which contains one, two or three substitutes independently selected from a group which includes halogen or -O-(lower)alkyl.

EFFECT: preparation of a pharmaceutical composition which contains an effective amount of a formula I compound as an active ingredient.

6 cl, 1 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention describes a phenothiazine derivative, specifically 2-(1-(2-(2-chloro-10H-phenothiazin-10-yl)-2-oxoethyl)-5-methyl-1H-1,2,4-triazol-3-yl)phenol of formula I: .

EFFECT: obtaining compounds with hypotensive and antiarrhythmic activity during intraperitoneal administration.

3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to methods for producing 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzotiazin-3-carboxamides-1,1-dioxide (meloxicam) of formula of a high degree purity. In one of the ways potassium salt monohydrate of meloxicam of formula is dissolved, which is produced by interaction of meloxicam formula (II) with potassium hydroxide or potassium carbonate dissolved in water or in a mixture of water and organic solvent and, if desired, crystallisation of this monohydrate potassium salt of meloxicam of formula (I) in water or in a mixture of water and organic solvent, insoluble impurities are removed and the resulting solution is processed with organic or inorganic acid and crystallise meloxicam. The invention also refers to potassium salt monohydrate of meloxicam of formula (I) and method of its production, as well as to anti-inflammatory pharmaceutical composition based on it.

EFFECT: improvement of composition efficacy.

18 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: formula (I) compounds, radicals of which are defined in the formula of invention, are described. A pharmaceutical composition containing formula (I) compounds is also described.

EFFECT: obtaining compounds which have inhibitory activity on protein kinase MEK1/2 and are meant for use as a therapeutically active substance which is useful for treating MEK1/2 mediated diseases.

13 cl, 18 ex

FIELD: chemistry.

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

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: claimed compounds show effect on receptor activated by peroxysome proliferate δ (PPARδ). In formula I: [Formula I] , [Formula VII] , [Formula VI] , A is R1 is C1-4alkyl group; R3 groups are different and denote halogen atom or C1-4alkyl group substituted or unsubstituted by halogen; R4 is R5 is hydrogen atom or hydroxyl group; the other radicals are as defined in the invention claim. Also invention refers to methods of compound I obtainment, to intermediary compounds VI, VII and methods of their obtainment, to medicines of diabetes, obesity, atherosclerosis, hyperlipidemia treatment and prevention, containing thiazole derivative of the formula I as active component.

EFFECT: enhanced activity of derivatives.

21 cl, 10 tbl, 102 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I): , where R1 is C1-C8alkyl optionally substituted with one to three substitutes selected out of substitute group A; R2 is C1-C6alkyl or C1-C6alkoxyC1-C6alkyl; R3 is C1-C6alkyl or C1-C6alkoxy; or R2 and R3 together with adjoining carbon atoms form optionally substituted non-aromatic 5-10-member carbon ring; R4 is hydrogen; G is group represented by the formula: or the rest as provided in the invention claim; and to pharmaceutical composition, application of claimed compounds, and method of atopic dermatitis prevention or treatment.

EFFECT: novel compounds useful as atopic dermatitis treatment medication and antipruritic medicines.

24 cl, 75 ex, 290 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or its pharmaceutically acceptable salt or its solvate, where ring A is a monocyclic heterocyclic group optionally substituted with 1-2 substitutes selected from the following group A, where the monocyclic heterocyclic group is selected from 1-pyrrolidinyl group, 2-oxopyrrolidin-1-yl group, piperidine group, 2-oxopiperidin-1-yl group, 1-piperazinyl group, morpholine group, 3-oxomorpholin-4-yl group, thiomorpholine group, 1,1-dioxoisothiazolin-2-yl group, 2-pyridyl group, 2-thiazolyl group and 1,2,4-oxadiazol-3-yl group; group A consists of a halogen atom, C1-4alkyl group, -(CH2)n-ORa1 and -CORa2, where Ra1 and Ra2 are identical or different and each of them is a hydrogen atom or a C1-4alkyl group and n equals 0; R1 is a C1-6alkyl group optionally substituted with 1 substitute selected from the following group B; group B consists of -ORb1, where Rb1 is a C1-4alkyl group; R2 is a hydrogen atom, C1-4alkyl group or -OR11, where R11 is an atom, C1-4alkyl group; R3 and R4 are identical or different and each is a halogen atom; R5 is a halogen atom; m equals 0 or 1; and R6 is a hydrogen atom. The invention also relates to a pharmaceutical composition, anti-HIV agent, HIV integrase inhibitor, anti-HIV compositions which contain an active ingredient in form of a formula I compound; to use of formula I compounds to prepare an anti-HIV agent and HIV integrase inhibitor; to a method of preventing or treating infectious diseases caused by HIV and to a method of inhibiting HIV integrase in mammals, involving administration of formula I compounds.

EFFECT: useful biological properties.

27 cl, 9 tbl, 67 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I , where: R1, R2, R3 and R4 independently from each other mean hydrogen, F, CI, Br, I; R5 designates hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, or cycloalkyl with 3, 4, 5 or 6 C atoms; R6 designates hydrogen; R7 and R8 independently from each other mean hydrogen, W means CrH2r or CsH2S-2; and one or more CH2-groups in C2H2r and CsH2s-2 can be substituted with NR17, oxygen or S; R17 means hydrogen, alkyl with 1, 2, 3 or 4 C atoms; r means 1, 2, 3, 4, 5 or 6; s means 2, 3 or 4; X designates-with C(O)- or -S(O)2-; Z means -C(O)- or a bond; and also to their pharmaceutically acceptable salts and trifluoroacetates. The invention also concerns application of the compounds of formula I, and also to a pharmaceutical composition.

EFFECT: preparation of new biologically active compounds exhibiting NHE3 inhibiting activity.

16 cl, 64 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, and more specifically to novel ethyl 5-R1-7-R2-1'-benzyl-3,3-dimethyl-1,2' -dioxo-5'-phenyl- 1',2,2',3,4,10-hexahydro-1H-spiro[acridine-9,3'-pyrrol]-4'-carboxylates of formula , where R1=H, Me; R2=H, OMe; R3=H, Me, OMe, Br, and to a method for synthesis of the said compounds.

EFFECT: obtaining novel compounds which can be used as primary products for synthesis of novel heterocyclic systems and in pharmacology as compounds with analgesic activity.

5 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1-thio-D-glucitol compounds of formula I or to pharmaceutically acceptable salts thereof or hydrates of the compound or salts: , [where R1, R2, R3 and R4 are identical or different, and each is a hydrogen atom, C1-C6-alkyl group), A is -(CH2)n-, -CONH(CH2)n-, -O- or -(CH2)nCH=CH- (where n is an integer from 0 to 3, Ar1 is an arylene group, heteroarylene group, which is an unsaturated 5-9-member mono- or bicyclic group, containing 1-2 heteroatoms, selected from S and N, Ar2 is an aryl group or heteroaryl group which is an unsaturated 5-9-member mono- or bicyclic group containing 1-2 heteroatoms selected from O, S and N, and R5, R6, R7, R8, R9 and R10 are identical or different, and each is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) C1-8-alkyl group, optionally substituted with hydroxyl group(s), (v) -(CH2)m-Q {where m is an integer from 0 to 4, and Q is -CO2H, -ORc1, -CO2Ra3, -SRe1, -NHRa6 or -NRa7Ra7 (where each of Ra3, Ra6 and Ra7 is a C1-6-alkyl group, Rc1 is a C1-6-alkyl group, and Rc1 is a C1-6-alkyl group)}, (vi) -O-(CH2)m'-Q' {where m' is an integer from 1 to 4, and Q' is a hydroxyl group,-CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12 (where each of Ra8, Ra10 and Ra12 is a C1-6-alkyl group)}, (vii) -ORf {where Rf is C3-7-cycloalkyl group or tetrahydropyranyl group)}, (viii) morpholine group, (ix) phenyl group, (x) pyridyl group]. The invention also relates to 1-thio-D-glucitol compounds of formulae IA, II, III, IV, to a pharmaceutical agent, to methods of obtaining 1-thio-D-glucitol compounds, as well as to compounds of formulae XIII, XIV.

EFFECT: obtaining novel biologically active compounds which are inhibitors of sodium-dependent co-transporter-2-glucose.

25 cl, 140 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 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: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.

EFFECT: compound with antagonistic effect on vasopressin V1A receptor.

73 cl, 133 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.

SUBSTANCE: invention claims compounds of the formula (I) with radicals as described in the claim, and medicine with inhibition effect on glycine absorption, based on compound of the formula (I) .

EFFECT: medicine for diseases treatment where glycine absorption inhibition can be effective.

21 cl, 1 tbl, 173 ex

FIELD: chemistry.

SUBSTANCE: there are disclosed 1-(2-aminobenzol)piperazine derivatives of formula (I) and pharmaceutically acceptable acid-additive salts with radical values specified in patent claim. The compounds are characterised with inhibiting effect on glycine I carrier. There is also disclosed medical product based on the compounds of formula (I).

EFFECT: compound can be used for treatment of the diseases associated with glycine uptake inhibition.

12 cl, 5 tbl, 396 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) , where Z means where R means hydrogen, C4-C6cycloalkyl group attached either through one of ring carbon atoms, or through a lower alkylene group attached to the ring, or a linearly chained or branched lower alkyl group or a lower hydroxyalkyl group, or a lower aminoalkyl group, or a phenyl(lower alkyl) group optionally substituted with 1-2 substitutes chosen from lower alkyl, lower alkoxy, halogen and hydroxy, or heteroaryl(lower alkyl)group where heteroaryl is chosen from the group consisting from thienyl, substituted with lower alkyl group, imidazolyl, and thiazolyl substituted with the lower alkyl group; n means 0 or 1; or Z means a group where R means the lower alkyl group; X1 means methylene or NH group; and X2 means methylene; or X1 means methylene and X2 means methylene or a bond; or X1 means methylene, and X2 means O, S or a bond; Y1 means methylene, and Y2 means methylene, vinylene, ethylene, or a bond; Ar1 means unsubstituted or substituted phenyl; Ar2 means unsubstituted or substituted phenyl, unsubstituted or substituted thienyl, unsubstituted or substituted furyl, unsubstituted or substituted pyridyl; and when Ar1 and Ar2 are substituted, each Ar1 and Ar2 are independently substituted with one or more substituted chosen from lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, halogen, di- and trihaloalkyl, di- and trihaloalkoxy, mono- and dialkylamino, alkilthio, alkyl ester and nitro; provided that Ar1 and Ar2 do not simultaneously mean unsubstituted phenyl; W means oxygen or sulphur; or to their pharmaceutically acceptable salts; provided those specified in cl. 1 of the patent claim. Besides the invention concerns the compounds chosen from the group, to compounds of formula (I), to pharmaceutical compositions, to a method of inhibition of monoamine receptor activity, to a method of inhibition of monoamine receptor activation, to a method of treating a diseased state associated with serotonin receptor, to a method of treating schizophrenia, to a method of treating migraine, and also to a method of treating psychosis.

EFFECT: preparation of the new biologically active compounds capable to inhibit monoamine receptor activity.

65 cl, 140 ex, 5 tbl

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