Derivatives of indolylpiperidine as antihistaminic anti-allergic agents

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

 

The present invention relates to new compounds of intellipedia and their pharmaceutically acceptable salts, having antihistaminic activity and antiallergic activity and are useful as medicines for the treatment of bronchial asthma, allergic rhinitis, conjunctivitis, dermatitis, urticaria and the like.

The present invention relates to a method for producing compounds of intellipedia, pharmaceutical compositions, useful for the treatment of allergic diseases and asthma, which comprises an effective amount of a compound of intellipedia.

There are several antihistamine and antiallergic agents having the structure intellipedia. Examples of compounds of intellipedia, represented by the following formula:

(where R=H, HE, OR' and n=2-6), described in Arch.Pharm. (1996), 329 (1), 3-10.

Furthermore, as compounds useful for the treatment of allergic diseases, EP 224919 describes, for example, compounds represented by the following formula:

(where R1=optional. Thames. amino; R2=H, lower alkyl or aryl; R3=N, NO2, optional. Thames. amino, HE or lower alkoxy; And=the lowest alkylene; Q=H or halogen).

Most of these compounds are characterized as prot is baallergies means, useful for treatment of allergic asthma, rhinitis, conjunctivitis and urticaria.

Existing antihistamines cannot be considered fully satisfactory in respect of safety, and still be problems associated with adverse reactions such as drowsiness, sedation, hydrodive, mydriasis, tachycardia and arrhythmia, mediated their unwanted penetration into the Central nervous system, antiacetylcholinesterase activity, effects on the cardiovascular system or the like. Therefore, there is a clinical need for the existence of antihistamines and antiallergic agents, largely free from side effects sedative and cardiovascular in nature.

The present invention provides new compounds intellipedia with enhanced antihistaminic and antiallergic activity.

The present invention also provides new compounds of intellipedia that due to the lack of lipophilic properties almost completely unable to penetrate into the brain and for this reason are devoid of sedative side effects. It is also clear that the compounds of the present invention have reduced side effects in the cardiovascular system.

Another objective of the present image is the shadow is to develop a method of producing such compounds.

The next goal is to develop a pharmaceutical composition comprising an effective amount of such compounds.

According to the present invention obtained new compounds intellipedia represented by the formula I:

where a1means alkylenes, alkylene, alkylthio-, alkanoyloxy or hydroxyalkyloxy group;

And2means a simple link, alkylenes or alkenylamine group;

W means a simple link or fenelonov or furniture a group which is not substituted or substituted by one or more halogen atoms, alkoxygroup and/or alkyl groups;

R1means a hydrogen atom or alkyl, alkenylphenol, alkenylphenol, alkoxyalkyl, alkenylacyl, alkyloxyalkyl, alkoxylalkyl, phenylalkyl group, where the phenyl cycle is not substituted or substituted by one or more halogen atoms or alkyl, alkoxy or Allakaket-(preferably funeralcare-) groups, or cycloalkylcarbonyl group, where cycloalkyl group not substituted or substituted by one or more halogen atoms, alkyl groups or alkoxygroup;

R2means a hydrogen atom or halogen, or alkyl or alkoxygroup and

R3means carboxyl group or tetrazolyl is the Rupp; and their pharmaceutically acceptable salts.

In the above formula (I) alkyl, alkylene, alkeline, alkenylamine, alkyline, alkylene, alkylthio-, alcoholnye, hydroxyechinenone and alkoxygroup mentioned in connection with groups And1And2, R1and R2in the compounds according to the invention can be branched or linear and preferably are lower alkyl, alkenylamine or alkenylamine groups, which contain up to 7 and preferably up to 5 carbon atoms.

Cycloalkyl group referred to in the relation R2may be mono - or polycyclic, preferably mono - or bicyclic, and most preferably monocyclic. Cycloalkyl group preferably contains from 3 to 14, more preferably from 3 to 10 and, most preferably, from 3 to 7 carbon atoms.

According to another variant implementation of the present invention, the invention provides a method of obtaining a compound represented by formula I.

One of the embodiments of the present invention, the invention provides a pharmaceutical composition comprising an effective amount of the compounds represented by formula I, together with a pharmaceutically acceptable carrier or coating.

In accordance with another variant of implementation of the present is Britanie provides a method of treating allergic diseases or asthma, including the stage of introducing an effective amount of the compounds represented by formula I. Further features and advantages of the present invention will become apparent from the following description of a preferred variant embodiment, viewed in the light of the attached examples and reference (standard) examples.

In preferred compounds according to the invention And1means the following group: alkylen, alkylene, hydroxyalkyl or alkylthio.

In preferred compounds according to the invention And2means of a simple bond or a C1-4-alkylenes or2-5-alkenylamine group.

In preferred compounds according to the invention W means furniture group or fenelonov a group which is not substituted or substituted by one or more fluorine atoms, chlorine, bromine, methyl groups or methoxypropane. It is clear that the compounds according to the invention, where W is different from simple communication, fenelonov or furninova group may be substituted And1and2or, in the case when A2means a simple link, R3when any combination of superseded provisions of the loop relative to each other, for example 1,2; 1,3 or 1,4. In the compounds according to the invention, where phenylenebis or furninova cycle is optionally substituted, e.g. by halogen atoms, alkyl groups and/the Lee alkoxygroup, additional substituents can then be attached by any of the remaining available positions cycle.

In preferred compounds according to the invention R1means C1-7-alkyl, alkenylphenol or alkenylphenol group2-5-alkoxyalkyl group3-7-altnetseattle group3-7-alkyloxyalkyl group3-7-alkoxylalkyl group, benzyl or phenylethylene a group which is not substituted or substituted by one or more halogen atoms, C1-4-alkyl, methoxy - or benzyloxycarbonyl, or cycloalkylcarbonyl group, where cycloalkyl group means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or declines, which is not substituted or substituted by one or more halogen atoms, C1-4is an alkyl or methoxypropane, and the alkyl part cycloalkylation group means methylene, ethylene, propylene or butylene.

In preferred compounds according to the invention R2means hydrogen, fluorine atom, chlorine or bromine, or a methyl or methoxy group. It is clear that the substituent R2can be attached in position 4, 5, 6 or 7 Intellinova kernel.

More preferred compounds of formula I are those in which And1means the group of: methylene, ethylene, propylene, butylene, pentile, hexylen, ethylenoxy, the PCC is Lenox, hydroxybutyl, ethylthio or butylthio; And2means of a simple bond or a group: methylene, ethylene, propylene, mutilation, butylene or ethenylene; W means the group of: an unsubstituted TuranAlem, unsubstituted phenylene, tortenelem, dibromophenyl, methylphenylene or methoxyphenyl; R1means a hydrogen atom or a group: propyl, butyl, isobutyl, pentyl, hexyl, heptyl, 2-methylpropyl, 3-methylbutyl, allyl, propenyl, PROPYNYL, methoxyethyl, methoxypropyl, ethoxyethyl, propoxy-ethyl, ISO-propoxyethyl, prop-2-insociety, prop-2-enyloxy-ethyl, methoxyethoxymethyl, 4-tormentil, 4-methoxybenzyl, 4-(tert-butyl)benzyl, 4-benzyloxybenzyl, 4-methoxyphenylacetyl, cyclopropylmethyl, cyclopropylethyl or cyclopropylmethyl; R2means a hydrogen atom, fluorine, chlorine or bromine, or methyl, or methoxy group; and R3means carboxyl or tetrazolyl group.

Pharmacologically acceptable salts of the compounds of the present invention, represented by formula I, can be salts of the accession of acids or alkalis. Examples of the acid additive salts include additive salts of inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and additive salts of organic acids, such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, met sulfonate and p-toluensulfonate.

Examples of alkali-additive salts include inorganic salts, such as salts of sodium, potassium, calcium and ammonium, and salts of organic bases, such as, for example, Ethylenediamine, ethanolamine, N,N-dialkylimidazolium, triethanolamine, and salts of basic amino acids.

Compounds of the present invention represented by the above formula (I)may include enantiomers depending on their asymmetry, or diastereoisomer. Individual isomers and mixtures of isomers are included in the scope of the present invention and appended claims.

Although the preferred connection of intellipedia of the present invention include the following compounds, the present invention is not limited to these examples:

1. - 2-(2-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}-ethoxy)benzoic acid

2. - 2-{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]ethoxy} benzoic acid

3. - 4-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl} butyric acid

4. - 3-(3-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}-propoxy)benzoic acid

5. - 4-{3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]propoxy} benzoic acid

6. - 2-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}-piperidine-1-yl)ethoxy]benzoic acid

7. - 3-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}-piperidine-1-yl)ethoxy]benzoic acid

8. - 3-(2-{4-[1-(4-Forbes the l)-1H-indol-3-yl]piperidine-1-yl}-ethoxy)benzoic acid

9. - 3-{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]ethoxy} benzoic acid

10. - 3-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl-ethoxy)benzoic acid

11. - 4-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}-piperidine-1-yl)ethoxy]benzoic acid

12. - 4-{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]ethoxy} benzoic acid

13. - 2-[3-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}-piperidine-1-yl)propoxy]benzoic acid

14. - 2-(3-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}-propoxy)benzoic acid

15. - 2-{3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]propoxy} benzoic acid

16. - 2-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}-propoxy)benzoic acid

17. - 3-[3-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}-piperidine-1-yl)propoxy]benzoic acid

18. - 3-{3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]-propoxy} benzoic acid

19. - 3-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}-propoxy)benzoic acid

20. - 4-[3-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}-piperidine-1-yl)propoxy]benzoic acid

21. - 4-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}-propoxy)benzoic acid

22. - 3-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}-piperidine-1-yl)propionic acid

23. - 3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]propionic acid

24. - 4-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}-piperidine-1-yl)butyric acid

25. - 4-{4-[1-(4-forbe the ZIL)-1H-indol-3-yl]piperidine-1-yl} butyric acid

26. - 4-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]butyric acid

27. - 3-{4-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}-piperidine-1-yl)ethyl]phenyl}propionic acid

28. - 3-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}-propionic acid

29. - 3- [4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethyl)phenyl]propionic acid

30. - 3-{4-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}-piperidine-1-yl)ethyl]phenyl}acrylic acid

31. - 3-(4-{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]ethyl}-phenyl)acrylic acid

32. - 3-[4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethyl)phenyl]acrylic acid

33. - 2-{(4-[1-hydroxy-4-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)butyl]phenyl}-2-methylpropionate acid

34. - 2-(4-{1-hydroxy-4-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]butyl}phenyl)-2-methylpropionate acid

35. - 2-[4-(4-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}-1-hydroxybutyl)phenyl]-2-methylpropionate acid

36. - [2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}-piperidine-1-yl)ethoxy]acetic acid

37. - (2-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}-ethoxy)acetic acid

38. - {2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]-ethoxy} acetic acid

39. - (2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}-ethoxy)acetic acid

40. - 5-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}-piperidine-1-yl-methyl)furan-2-carboxylic acid

41. - 5-[4(1-pentyl-1H-indol-3-yl)piperidine-1-yl-methyl]furan-2-carboxylic acid

42. - 5-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl-methyl}furan-2-carboxylic acid

43. - 5-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-ylmethyl}furan-2-carboxylic acid

44. - 2-[4-(4-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}-1-hydroxybutyl)phenyl]-2-methylpropionate acid

45. - 2-{2-[4-(1-heptyl-1H-indol-3-yl)piperidine-1-yl]-ethoxy} benzoic acid

46. - 2-(2-{4-[1-(4-tert-butylbenzyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

47. - 2-(2-{4-[1-(4-methoxybenzyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

48. - 2-(2-{4-[1-(4-benzyloxybenzyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

49. - 2-{2-[4-(1-ISO-butyl-1H-indol-3-yl)piperidine-1-yl]-ethoxy}benzoic acid

50. - 2-[2-(4-{1-[2-(4-methoxyphenyl)ethyl]-1H-indol-3-yl)-piperidine-1-yl)ethoxy]benzoic acid

51. - 2-(4-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethyl}-phenyl)-2-methylpropionate acid

52. - 2-(4-{4-[4-(1H-indol-3-yl)piperidine-1-yl]-butyryl)phenyl)-2-methylpropionate acid

53. - 2-[4-(1H-indol-3-yl)piperidine-1-ylmethyl]benzoic acid

54. - 3-[4-(1H-indol-3-yl)piperidine-1-ylmethyl]benzoic acid

55. - 4-[4-(1H-indol-3-yl)piperidine-1-ylmethyl]benzoic acid

56. - (3-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy}phenyl) acetic acid

57. - (3-{3-[4-(1H-indol-3-yl)piperidine-1-yl]propoxy}phenyl) acetic acid

58. - (4-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy}phenyl) acetic acid is acid

59. - (4-{3-[4-(1H-indol-3-yl)piperidine-1-yl]propoxy)phenyl) acetic acid

60. - 3-(1-{3-[3-(1H-tetrazol-5-yl)phenoxy]propyl} piperidine-4-yl)-1H-indole

61. - 2-methyl-2-[4-(2-{4-[1-(3-methylbutyl)-1H-indol-3-yl]-piperidine-1-yl}ethyl)phenyl]propionic acid

62. - 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethyl)phenyl]-2-methylpropionate acid

63. - 2-methyl-2-[4-(4-{4-[1-(3-methylbutyl)-1H-indol-3-yl]-piperidine-1-yl}butyryl)phenyl]propionic acid

64. - 2-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-ylmethyl) benzoic acid

65. - 2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-ylmethyl} benzoic acid

66. - 3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-ylmethyl} benzoic acid

67. - 4-{4-[1-(3-methylbutyl)-1H-indol-2-yl]piperidine-1-ylmethyl} benzoic acid

68. - [3-(2-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl}-ethoxy)phenyl]acetic acid

69. - [3-(2-{4-[1-(2-ethoxyethyl)-1H-indol-2-yl]piperidine-1-yl}-ethoxy)phenyl]acetic acid

70. - [3-(3-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl}-propoxy)phenyl]acetic acid

71. - [3-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}-propoxy)phenyl]acetic acid

72. - [4-(2-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl}-ethoxy)phenyl]acetic acid

73. - [4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}-ethoxy)phenyl]acetic acid

74. - [4-(3-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl}-propoxy)phenyl]Sosna acid

75. - [4- (3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl} propoxy)phenyl]acetic acid

76. - 2-{2-[4-(1-prop-2-inyl-1H-indol-3-yl)piperidine-1-yl]-ethoxy}benzoic acid

77. - 2-methyl-2-[4-(4-{4-[1-(3-methylbutyl)-1H-indol-3-yl]-piperidine-1-yl}butyryl)phenyl]propionic acid

78. - 1-(2-ethoxyethyl)-3-(1-{3-[2-(2H-tetrazol-5-yl)phenoxy]-propyl} piperidine-4-yl)-1-indole

79. - 1-(3-methylbutyl)-3-(1-{3-[2-(2H-tetrazol-5-yl)phenoxy]-propyl}piperidine-4-yl)-1H-indole

80. - 1-(3-methylbutyl)-3-(1-{3-[4-(2H-tetrazol-5-yl)phenoxy]-propyl}piperidine-4-yl)-1H-indole

81. - 2-(2-{4-[1-(2-ethoxyethyl)-5-methoxy-1H-indol-3-yl]- piperidine-1-yl)ethoxy)-6-Formentera acid

82. - 2-(2-{4-[1-(2-ethoxyethyl)-5-fluoro-1H-indol-3-yl]piperidine - 1-yl}ethoxy)-6-Formentera acid

83. - 2-(2-{4-[1-(2-ethoxyethyl)-6-fluoro-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-6-Formentera acid

84. - 2-(2-{4-[5-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-6-Formentera acid

85. - 2-(2-{4-[7-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-6-Formentera acid

86. - 2-(2-{4-[5-chloro-1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-6-Formentera acid

87. - 2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}-ethoxy)-6-Formentera acid

88. - 3,5-dibromo-2-(2-{4-[1-(2-ethoxyethyl)-5-methoxy-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

89. - 3,5-dibromo-2-(2-{4-[1-(2-ethoxyethyl)-5-fluoro-1H-indol-3-yl]piperidine-1-ylethoxy)benzoic acid

90. - 3,5-dibromo-2-(2-{4-[1-(2-ethoxyethyl)-6-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

91. - 3,5-dibromo-2-(2-{4-[5-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

92. - 3,5-dibromo-2-(2-{4-[7-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

93. - 3,5-dibromo-2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

94. - 2-(2-{4-[1-(2-ethoxyethyl)-6-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid

95. - 2-(2-{4-[5-chloro-1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-5-methylbenzoic acid

96. - 2-(2-{4-[1-(2-ethoxyethyl)-5-methoxy-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-4-methoxybenzoic acid

97. - 2- (2-{4-[1-(2-ethoxyethyl)-6-fluoro-1H-indol-3-yl] piperidine-1-yl}ethoxy)-4-methoxybenzoic acid

98. - 2-(2-{4-[5-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-4-methoxybenzoic acid

99. - 2-(2-{4-[7-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-4-methoxybenzoic acid

100. - 2-(2-{4-[5-chloro-1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl)ethoxy)-4-methoxybenzoic acid

101. - 2-(2-{4-[1-(2-ethoxyethyl)-5-methoxy-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

102. - 2-(2-{4-[1-(2-ethoxyethyl)-5-fluoro-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

103. - 2-(2-{4-[1-(2-ethoxyethyl)-6-fluoro-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

104. - 2-(2-{4-[6-brough is-1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

105. - 2-(2-{4-[5-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-5-methylbenzoic acid

106. - 2-(2-{4-[5-chloro-1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

107. - 2-{2-[4-(1-propyl-1H-indol-3-yl)piperidine-1-yl]-ethoxy} benzoic acid

108. - 2-(2-{4-[1-(2-ISO-propoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

109. - 2-(2-{4-[1-(3-methoxypropyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

110. - 2-(2-{4-[1-(2-ethoxyethyl)-4-fluoro-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

111. - 2-(2-{4-[1-(2-ethoxyethyl)-4-fluoro-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-5-methylbenzoic acid

112. - 2-(2-{4-[1-(2-ethoxyethyl)-4-fluoro-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-4-methoxybenzoic acid

113. - 2-(2-{4-[4-fluoro-1-(2-methoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

114. - 2-(2-{4-[4-fluoro-1-(2-methoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-5-methylbenzoic acid

115. - 2-(2-{4-[4-fluoro-1-(2-methoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-4-methoxybenzoic acid

116. - 5-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl} pentane acid

117. - 6-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl} hexanoic acid

118. - 7-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl} heptane acid

119. - 3-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl)-propoxy)propionic acid

120. - 2-(2-{4-[1-(2-ethoxyethyl)-7-methyl-1H and the Dol-3-yl]- piperidine-1-yl}ethoxy)-5-methylbenzoic acid

121. - 2-(2-{4-[6-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]- piperidine-1-yl}ethoxy)benzoic acid

122. - 2-(2-{4-[6-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-5-methylbenzoic acid

123. - (2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}-ethylthio)acetic acid

124. - (4-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}-butylthio)acetic acid

125. - (3-{3-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]propoxy}phenyl)acetic acid

126. - (4-{2-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}phenyl)acetic acid

127. - (3-{2-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}phenyl)acetic acid

128. - 3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-ylmethyl] benzoic acid

129. - 5-[4-(6-fluoro-1-pentyl-1H-indol-3-yl)piperidine-1-ylmethyl]furan-2-carboxylic acid

130. - 3-[4-(6-fluoro-1-pentyl-1H-indol-3-yl)piperidine-1-ylmethyl]benzoic acid

131. - 2-(4-{4-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]butyryl}phenyl)-2-methylpropionate acid

132. - 3-{3-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]propoxy}benzoic acid

133. - 2-{2-[4-(1-cyclohexylmethyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

134. - 2-(2-{4-[1-(2-allyloxymethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

135. - 2-(2-{4-[1-(2-prop-2-insociety)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

136. - 2-(2-{4-[1-(2-propoxyethyl)-1 is-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

137. - 4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl} ethoxy)benzoic acid

138. - 2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl} ethoxy)benzoic acid

139. - 2-(2-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl} ethoxy)benzoic acid

140. - 2-(2-{4-[1-(2-methoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

141. - 2-{2-[4-(1-allyl-1H-indol-3-yl)piperidine-1-yl]ethoxy} benzoic acid

142. - 2-(2-{4-[1-(2-ethoxyethyl)-5-methoxy-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-5-methylbenzoic acid

143. - 2-(2-{4-[7-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-5-methylbenzoic acid

144. - 2-(2-{4-[7-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

145. - 2-(2-{4-[1-(2-ethoxyethyl)-5-fluoro-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-5-methylbenzoic acid

146. - 2-(2-{4-[1-(2-ethoxyethyl)-5-fluoro-1H-indol-3-yl]- piperidine-1-yl)ethoxy)-4-methoxybenzoic acid

147. - 2-(2-{4-[1-(2-ethoxyethyl)-7-methyl-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

148. - 2-{2-[4-(1-butyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

149. - 2-{2-[4-(1-hexyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

150. - 2-{2-[4-(1-cyclopropylmethyl-6-fluoro-1H-indol-3-yl)-piperidine-1-yl]ethoxy}benaouda acid

151. - 2-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

153. - 3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl} propionic to the slot

154. - 2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}-ethoxy)-5-methylbenzoic acid

155. - 2-[4-(4-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}butyryl)phenyl]-2-methylpropionate acid

156. - 1-(2-ethoxyethyl)-3-(1-{3-[4-(2H-tetrazol-5-yl)phenoxy]-propyl}piperidine-4-yl)-1H-indole

157. - 2-{2-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

158. - 3-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-ylmethyl]benzoic acid

159. - (4-{3-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]propoxy}phenyl)acetic acid

The new compounds of the present invention, represented by formula I, can be obtained according to scheme 1 from the corresponding piperidine derivative of formula II:

where R2accepts the above value, the reactive intermediate compound of General formula III:

H-a1-W-A2-R4

(III)

where a1And2and W agree to the above value, R4means a nitrile group or a group-COOR5where R5means C1-C4-alkyl group and X denotes a leaving group such as chlorine atom or bromine, or a group of methanesulfonate, p-toluensulfonate or benzosulfimide.

The interaction is preferably carried out in an inert organic solvent such as toluene, dioxane or methylisobutyl laketon, at a temperature of between 80°and 140°and in the presence of an inorganic base such as a carbonate or bicarbonate of an alkali metal. When the interaction is formed corresponding alkylation product of General formula IV:

Compound IV alkylate the nitrogen of the indole reactive intermediate compound of General formula V:

R1-X

(V)

where X denotes a leaving group such as chlorine atom or bromine, or a group of methanesulfonate, p-toluensulfonate or benzosulfimide, and R1accept above values.

The interaction is preferably carried out in an inert organic solvent such as dimethylformamide, tetrahydrofuran or diethyl ether, at temperatures between 0°s and 80°With, in the presence of inorganic bases such as sodium hydride or sodium amide. When the interaction is formed corresponding alkylation product of General formula VI (see scheme 1).

Alternatively, the sequence of alkylation, resulting intermediate compound VI may be reversed, based on the compounds of General formula VII, where R2accept above values.

Compound VII alkylate the nitrogen of the indole reactive intermediate is Obedinenie General formula V:

R1-X

(V)

where X denotes a leaving group such as chlorine atom or bromine, or a group of methanesulfonate, p-toluensulfonate or benzosulfimide, and R1accept above values. This interaction leads to the compound VIII (see scheme 1), where R1and R2agree to the above values.

The interaction is preferably carried out in an inert organic solvent such as dimethylformamide, tetrahydrofuran or diethyl ether, at temperatures between 0°s and 80°With, in the presence of inorganic bases such as sodium hydride or sodium amide.

Subsequent removal of the protecting compound VIII (see scheme 1), the initial boiling of the compounds in the presence of excess sodium hydroxide or potassium hydroxide in an alcohol solvent such as ethanol, isopropanol or n-butanol, at a temperature between 80°and 180°C, followed by neutralization with inorganic acid, such as hydrochloric or sulfuric acid, leads to the General structure IX (see scheme 1), where R1and R2agree to the above values.

Subsequent alkylation of compound IX is carried out using reactive intermediate compounds of General formula (III)

H-a1-W-A2-R4

(III)

where a1And2and W agree to the above values, R4means a nitrile group or a group-COOR5where R5means C1-C4-alkyl group and X denotes a leaving group such as chlorine atom or bromine, or a group of methanesulfonate, p-toluensulfonate or benzosulfimide. The interaction is preferably carried out in an inert organic solvent such as toluene, dioxane or methyl isobutyl ketone, at a temperature between 80°and 140°With, in the presence of an inorganic base such as a carbonate or bicarbonate of an alkali metal. When the interaction is formed corresponding alkylation product of General formula VI (see scheme 1).

Compounds of General formula VI, where R4means complex alkilany ether, is treated with sodium hydroxide or potassium hydroxide and then treated with an inorganic acid, such as hydrochloric or sulfuric acid, obtaining the relevant derived indole of the formula I, where R3means of carboxylic acid. The interaction is preferably carried out in a solvent such as methanol, ethanol, tetrahydrofuran, water or a mixture of one of the above solvents with boiling point of the mixture.

When R4means nitrile group, reaction of obtaining tetrazole preferably in the presence of sodium azide in the solvent content of inorganic fillers, such as N,N-dimethylformamide or N-organic, at temperatures between 60°C and 180°C, 10-20 hours, in the presence of inorganic acids such as hydrochloric acid. Form the corresponding compounds of General formula X:

where A1, A2, R1, R2and W agree to the above values.

On the other hand, the compounds of formula IV alkylate the nitrogen of the indole 2-(2-bromoethoxy)tetrahydropyran, obtaining the compounds of General structure XI, where a1And2, R2and R4take the above value (see scheme 2). This interaction is preferably carried out in an inert solvent, such as dimethylformamide, tetrahydrofuran or diethyl ether, at temperatures between 0°s and 80°With, in the presence of inorganic bases such as sodium hydride or sodium amide. Subsequent removal of the protecting compound XI by boiling the specified connection in the presence of hydrogen chloride in an alcohol solvent such as ethanol, methanol or isopropanol, leads to the compound of General formula XII, where a1And2, R2, R4and W agree to the above values. Further alkylation of compounds XII intermediate compound of General formula R6-X (XIII)where R6means C1-C3-alkyl, alkenylphenol or alkylamino is a group and X denotes a leaving group, such as chlorine atom or bromine, or a group of methanesulfonate, p-toluensulfonate or benzosulfimide, leads to the compound of General structure XIV, where A1, A2, R2, R4R6and W agree to the above values.

This interaction is preferably carried out in an inert solvent, such as dimethylformamide, tetrahydrofuran or diethyl ether, at temperatures between 0°C and 80°C, in the presence of inorganic bases such as sodium hydride or sodium amide.

Compounds of General formula XIV, where R4means complex alkilany ether, is treated with sodium hydroxide or potassium hydroxide and then treated with an inorganic acid, receiving the corresponding derivative of the indole of formula XV, where a1And2, W, R2and R6take the above meanings and R3means carboxylic acid.

This interaction is preferably performed in a solvent such as methanol, ethanol, tetrahydrofuran, water or a mixture of one of the above solvents with boiling point of the mixture.

The products are purified by chromatography or crystallization. Typically get high outputs, between 70% and 90%.

If necessary, use an excess of the reagent to ensure completion of the reaction, and the window to add the polymer, such as Methylisothiazolinone and/or 3-(3-mercaptophenyl)-propanedinitrile to interact with an excess of reagent. Selection of products from reaction mixtures using linked polymer reagent is greatly simplified, requiring only filtration under reduced pressure. The product of the above reaction mixtures can be purified by solid-phase extraction using a suitable adsorbent, such as a Varian SCX or Varian C18.

Derivatives of piperidine of formula (II) can be obtained from 4-piperidone as described in the literature (J. Med. Chem. 1992, 35, 4813-4822). Reactive intermediate compounds of General formula (III) can be obtained as described in the literature.

Also in the scope of the present invention and the attached items are pharmaceutical compositions which comprise, as active ingredient, at least one of the derived intellipedia General formula (I) or its pharmacologically acceptable salt, in combination with a pharmaceutically acceptable carrier or diluent. Preferably the composition is obtained in the form suitable for oral or parenteral administration.

Pharmaceutically acceptable carriers or diluents, which are mixed with the active compound or compounds which, or their salts, to obtain compositions according to the invention are well known "per se" and actually used fillers depend, inter alia, from the intended route of administration of compositions.

The compositions of the present invention is primarily intended for oral administration. In this case, the composition for oral administration may be made in the form of tablets, capsules or effervescent granules, or liquid preparations such as elixirs, syrups or suspensions, all containing one or more compounds of the present invention, these drugs can be obtained well-known from the prior art methods.

Diluents which can be used to produce compositions include those liquid or solid diluents that are mixed with the active ingredient, optionally together with dyes or korrigentami. Suitable are tablets or capsules containing from 0.2 to 500 mg, preferably from 1 to 100 mg, of the active ingredient or the equivalent amount of its pharmacologically acceptable salts. Connections can be included in the pill is covered by a natural or synthetic polymers, which are known from the prior art, are used to impart properties of a slow-release, or combined with polymers in the form of tablets for adelaney the same properties.

Liquid compositions intended for oral use may be in the form of a solution or suspension. The solution can be an aqueous solution of an acid additive salt derived intellipedia in combination with, for example, sucrose or sorbitol to obtain syrup. Suspension may include insoluble or microencapsulating the shape of the active compounds according to the invention in combination with water or other pharmaceutically acceptable liquid medium together with suspenders agent or Corrigendum.

Composition for parenteral injection may be obtained from the soluble salts derived intellipedia, subjected or not subjected to drying by freezing, which can be dissolved in water or an appropriate liquid suitable for parenteral administration.

In the treatment of human dose of the compounds of General formula (I) depend on the desired effect and the duration of treatment, dose for adults typically range from 0.2 mg to 500 mg per day and preferably from 1 mg to 100 mg per day. Typically, the physician selects the regimen of medicines with regard to age and weight in need of treatment of the patient.

Pharmacological action

The following examples exhibit excellent pharmacological action of the compounds according to the present invention. The result is ATA (1) tests for histamine H 1receptor binding, (2) permeability of the blood vessels of the skin of rats induced by histamine, with monitoring anti-allergic activity, (3) H1binding, ex vivo, in mice with monitoring the degree of penetration into the brain, and (4) measurement of blood pressure and heart rate have in mind, is not mechanically fixed rats with high blood pressure, monitoring the effects on the cardiovascular system, obtained as described below.

(1) Test for histamine H1receptor binding.

Binding to the histamine H1receptors carried out on the membranes of cerebellar Guinea pigs as previously described (Chang et al., 1979). Briefly, suspensions of membranes (160 μg/ml) incubated at 30°C with 0.7 nm [3N]-mepyramine and various concentrations of test compounds in a final volume of 250 μl. Binding assays are being removed by filtration after 30 min incubation period and measure the associated radioactivity. Specific binding measured in the presence of 10 μm prometazina. The affinity of each test compound to the receptor is determined using at least two double six different concentrations. The values of the IC50determined by nonlinear regression using SAS on DEC AXP computer.

Table 1
CONNECTIONBinding TO the RECEPTOR

H1(IC50nm)
CETIRIZINE226
FEXOFENADIN214
Example 1310
Example 257
Example 3347
Example 10145
Example 1588
Example 1989
Example 3259
Example 34127
Example 38174
Example 40210
Example 41111
Example 54106
Example 66248

Continuation of Table 1
Example 85152
Example 108275
Example 13486
Example 137150
Example 13886
Example 139205
Example 14083
Example 14197
Example 142386
Example 143 222
Example 145116
Example 148127
Example 149142
Example 150121
Example 153245
Example 157140
Example 158104
Example 15968

The results obtained show that the compounds of the present invention have affinity to H1receptors, very close to the corresponding value for the standard compounds (compounds comparison).

(2) the Permeability of the blood vessels of the skin of rats induced by histamine.

Male Wistar rats (180-210 g) treated orally with the test compound or solvent. Later one, 4, 8 and 24 hours rats easily anastasiou diethyl ether. Skin reaction is caused by two intradermal injections of 50 μl of histamine (100 μg/ml) in the back, followed by an intravenous infusion of 3 ml/kg Evan′s Blue (5 mg/ml), both drugs were dissolved in physiological solution. Sixty minutes of rats hammer, turning the neck, and separate the shot from the back skin. The diameter (in millimeters) of the blister is measured in two directions and calculate the area. The results are given as % inhibition at this dose compared with a group of obrabotan the second solvent.

After 4 hours, the compounds described in the examples 2, 41, 108, 138, 140, 141, 142, 148, 149, 150, 157 and 158, demonstrate inhibition of > 50% of the induced histamine blister at the dose of 3 mg/kg (under the same experimental conditions, cetirizine, Fexofenadine demonstrate inhibition of 36% and 21%, respectively).

(3) the study of H1binding, ex vivo, in mice

The test will, in General, as described by Leysen et al., with the following modification. Starving during the night of male Swiss white mice (21±2 g) treated orally with different doses of the tested compounds (10 ml/kg, r.o. - BP) and after 90 minutes the score. The brain is entirely separated and homogenized in 10 ml of cooled ice 0.05 M Na+/K+phosphate buffer (pH 7.4). Aliquot samples of the homogenate, 1 ml incubated in duplicate three times with 0.1 ml of [3H]-mepyramine (final concentration 2 nm, 27 Kyu/mmol, Amersham) for 40 minutes at 30°C. Binding of [3N] -mepyramine with membranes define snapshot filtering homogenates in a vacuum filters (Whatman GF/B glass fiber subsequent three quick washes with 5 ml of chilled buffer containing 10 μm chilled mepyramine. Bound radioactivity on the filters is determined by liquid scintillation spectrometry. Nonspecific binding is determined, processing animals at 30 mg/kg, P.O., chlorpheniramineodeine. To determine the total binding using mice treated with solvent (methyl cellulose 0.5% tween 0,1%). The results are expressed as % specific binding at a given dose of the test compound.

Compounds of the present invention detects weak or does not penetrate the blood-brain barrier.

(4) Measurement of blood pressure and heart rate have in mind, is not mechanically fixed rats with high blood pressure

Adult male rats with spontaneous hypertension (SHR - SGK) operate with the aim of implanting sensors in blood pressure in the abdominal aorta immediately above the iliac bifurcation. After exit from anesthesia, rats are placed individually in cages, placed in a radio frequency receivers. Administered amoxicillin (15 mg/kg, i.m. - V.M., after surgery to prevent infection. After implantation of the sensor rats given a chance to recover, at least for 2 weeks. Record arterial blood pressure and analyzed by the system Dataquest V (Data Science, St. Paul, MN). Animals are kept at a 12:12 hour cycle of a day-night during the entire registration period. After 18 hours of fasting with water "on demand", the animals give oral drugs, and then food. Registration hemodynamic and carry out every 15 minutes, starting 4 hours before the injection of the medicinal product and continuing for up to 24 hours after injection. Each registration lasts 10 seconds, and hemodynamic values for all cycles within a specified period average. All animals received all the insertion, between the introduction of the same rat, there is a seven-day washout period and installed a full refund to the values of the zero line. The impact of injections on mean arterial blood pressure and heart rate determine the one-way variance analysis (ANOVA). P value<0.05 is considered statistically significant.

Compounds of the present invention have little effect, or no effect on blood pressure and heart rate at doses of 3 to 30 mg/kg

From the above results, the person skilled in the art can readily understand that the compounds of the present invention have excellent antihistaminic and antiallergic activities. Compounds of the present invention have reduced side effects on the cardiovascular and Central nervous system and, therefore, useful for the treatment of various allergic disorders, for example, bronchial asthma, rhinitis, conjunctivitis, dermatitis and urticaria.

The present invention is additionally illustrated by the trail of the relevant examples. The examples are only for illustrative purposes and are not considered limiting.

Example 1

Obtaining 2- (2-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

A. Obtaining 3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole

Indole (30 g, 026 mol) is dissolved in a solution of potassium hydroxide (77,6 g, 1.38 mol) in methanol (692 ml). Hydrochloride 4-piperidineacetate (of 102.3 g, 0.66 mol) is added in one portion and the mixture is heated at boiling temperature under reflux for 5 hours While cooling to room temperature, precipitated potassium chloride, and the salt is filtered off. The liquid phase to concentrate until in round-bottom flask will be only one third of the liquid. The solid formed when the concentration of the liquid phase is filtered and thoroughly washed with ethanol and then diethyl ether. Get to 31.9 g (yield 63%) of the final product.

Melting point=183-185°C.

C. Obtaining 3-piperidine-4-yl-1H-indole

of 19.03 g (0,096 mol) of 3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole hydronaut in a Parr apparatus for 18 h at 40 psi (16,87 kg/cm2) 2.2 g of 10% Pd/C in 600 ml of methanol. After conventional treatment get 16,76 g (yield 87%) of the desired product.

Melting point=210-212°C.

C. Obtain methyl ester of 2-(2-chloroethoxy)benzoic acid

To 25 g (0.16 mol) of methyl salicylate in 50 ml of methyl ethyl ketone added 34 g (0.25 mol) of potassium carbonate. This mixture is heated at the boiling point under reflux for 1 h, add to 27.3 ml (0.35 mol) of 1-bromo-2-chlorethane and again bring to a boil. Four hours later add another 34 g (0.25 mol) of potassium carbonate and 16.3 ml (0.2 mol) 1-bromo-2-chlorethane. This operation is repeated until completion of the reaction. Then the inorganic salts are filtered and the liquid phase was diluted with the same volume of hexane. The organic phase is twice washed with water and treated in the usual way. The output at this stage of the quantitative and the product is sufficiently pure for use in subsequent stages of the synthesis.

D. Obtaining methyl ester 2-{2-[4-(1H-indol-3-yl)-piperidine-1-yl]ethoxy}benzoic acid

to 0.22 g (0.5 mmol) of the methyl ester of 2-(2-chloroethoxy) benzoic acid is added to a mixture of 0.1 g (0.5 mmol) 3-piperidine-4-yl-1H-indole, 0.08 g (0.6 mmol) of potassium carbonate and 0.04 g (0.2 mmol) of potassium iodide in 1.5 ml of isobutylmethylxanthine, in nitrogen atmosphere and the reaction mixture is heated at boiling temperature under reflux for 18 hours. After cooling to room temperature, add 1.5 ml of dichloromethane and 0.08 g (0.1 mmol) politicalmilitary, and the mixture is stirred at the same temperature for 3 hours. After filtration the solution is transferred directly to the column with 500 mg ion-exchange resin Varian SCX. The column was washed with 5 ml of m is of canola and product elute with 5 ml methanol/ammonia 20:1, receiving, after removal of the solvent under reduced pressure, 0,113 g (yield 60%) of methyl ester of 2-{2- [4-(1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid as a yellow oil.

E. Obtaining 2-(2-{4-[1-(4-terbisil)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

0.02 g (0.42 mmol) of a dispersion of 60% NaH in mineral oil is added to a solution of 0.06 g (0.15 mmol) of methyl ester of 2-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid obtained in stage D, in 1 ml of anhydrous DMF under nitrogen atmosphere. After stirring for 30 minutes at room temperature add 0,026 ml (0.21 mmol) of 4-ftorangidridy and the mixture is stirred for 18 hours. After you have added 0.09 g (0.12 mmol) of 3-(3-mercaptophenyl)propanedinitrile in 1 ml of DMF, the mixture is stirred over night at room temperature. To the reaction mixture add 0.1 ml of 2 N. Hcl and the crude product filtered off. The solvent is removed under reduced pressure and the crude mixture was purified using a chromatographic column filled with 500 mg Varian C18, get 0,059 g (yield 84%) of 2-(2-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}ethoxy) benzoic acid.

ESI/MC m/e=473 [(M+1)+C26H32FN2O4]

NMR (300 MHz, CDCl3) δ=2,04-to 2.06 (m, 4H), 2,45 is 2.46 (m, 2H), 2,90-only 2.91 (m, 3H), 3,18-UP 3.22 (D, 2H), 4,20-5,00 (osirm, 1H), 5,23 (s, 2H), 6,94-of 7.23 (m, 10H), 7,42-7,47 (t, 1H), to 7.59-to 7.61 (d, 2H), 7,89-a 7.92 (d, 2H).

Example 2

Getting 2-{2-[4-(1-who until-1H-indol-3-yl)piperidine-1-yl]-ethoxy}benzoic acid

Use the methods described in example 1, using 0.1 g (0.5 mmol) 3-piperidine-4-yl-1H-indole and 0.22 g (0.5 mmol) of the methyl ester of 2-(2-chloroethoxy)benzoic acid. 0.06 g (0.15 mmol) of the crude product obtained in stage D, then alkylate of 0.03 ml (0.21 mmol) of pentaiodide getting 0,052 g (yield 83%) of 2-{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid.

Melting point=113°C.

ESI/MC m/e=435 [(M+1)+, 2734N23]

NMR (Dl3) δ=0,86-of 0.90 (t, 3H), 1,25-of 1.36 (m, 6N), 1,74-of 1.84 (m, 2H), 2.05 is with 2.14 (m, 4H), 2,55-2,70 (m, 2H), 2,94-of 3.12 (m, 5H), 3,24 of 3.28 (d, 2H), 3,99-4,06 (t, 2H), of 4.44-4,50 (m, 2H), 4,70-5,20 (users, 1H), 6.89 in-7,31 (m, 5H), 7,38-the 7.43 (t, 1H), 7,55-7,58 (d, 1H), 7,84-7,86 (d, 1H).

Example 3

Getting 4-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}butyric acid

Use the methods described in example 1, using 0.1 g (0.5 mmol) C-piperidine-4-yl-1H-indole and 0.22 g (0.5 mmol) of the ethyl ester of 4-harpalani acid. 0.07 g (0.22 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.31 mmol) Bromeliaceae ether, receiving 0,061 g (yield 77%) of 4-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}butyric acid.

ESI/MC m/e=359 [(M+1)+, 21H3N24]

NMR (CDCl3) δ=1,13-of 1.18 (t, 3H), 1,90-2,00 (m, 2H), 2,08-of 2.20 (m, 4H), 2,45 is 2.55 (m, 4H), 2,84-of 2.86 (d, 2H), 2.95 and 3.00 for (m, 1H), 3,38-of 3.48 (m, 4H), 3,70-3,74 (t, 2H), 4,22-4.26 deaths (t, 2H), 5,00 (users, 1H), 6,97-7,24 (m, 3H), 7,34-7,37 (d, 1H), EUR 7.57-to 7.59 (d, 1H).

Example 4

Obtaining 3- (3-{4-[1-(4-terbisil)-1H-Indo) - Rev.-3-yl]piperidine-1-yl}propoxy)benzoic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.25 g (1.1 mmol) of methyl ester of 3-(2-chloropropoxy)benzoic acid. 0.08 g (0.20 mmol) of the crude product obtained in stage D, then alkylate 0.036 ml (0.30 mmol) of 4-ftorangidridy getting 0,051 g (yield 53%) of 3-(3-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}propoxy)benzoic acid.

ESI/MC m/e=487 [(M+1)+, C3031FN23]

NMR (300 MHz, l3) δ=2,19-2,22 (m, 6N), 2,60-of 2.75 (m, 2H), 3,02-of 3.07 (m, 3H), 3,40-of 3.60 (m, 2H), 4,11-to 4.15 (t, 2H), 5,23 (s, 2H), 6,93-7,25 (m, 8H), 7,51-the 7.65 (m, 5H).

Example 5

Getting 4-{3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]-propoxy}benzoic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.25 g (1.1 mmol) of methyl ester of 4-(2-chloropropoxy)benzoic acid. 0.08 g (0.20 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.30 mmol) of pentaiodide getting 0,023 g (yield 26%) 4-{3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]propoxy}benzoic acid.

ESI/MC m/e=449 [(M+1)+, 2836N23]

NMR (Dl3) δ=0,85-0,95 (m, 3H), 1,26-of 1.39 (m, 4H), 1,64 of-1.83 (m, 2H), 1,99-of 2.16 (m, 5H), 2,16-2,48 (t, 2H), 2,48 is 3.40 (m, 6N), a 4.03-4,08 (t, 2H), 4,11-to 4.15 (t, 2H), 6,82-7,32 (m, 6N), to 7.61-7,63 (d, 1H), 7,84-7,89 (d, 2H).

Example 6

Obtain 2-[2-(4-{1-[2-(2-methoxyethoxy)-ethyl]-1H-indol-3-yl}piperidine-1-yl)ethoxy]benzoic acid

Use the methods described in example 1 using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.17 g (1.1 mmol) of the methyl ester of 2-(2-chloroethoxy)benzoic acid. 0.07 g (0.21 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.31 mmol) of 1-bromo-2-(2-methoxyethoxy)ethane, getting 0,064 g (yield 65%) of 2-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)ethoxy] benzoic acid.

ESI/MC m/e=467 [(M+1)+, 2734N25]

NMR (300 MHz, Dl3) δ=2,00 is 2.46 (m, 4H), 2,50-2,89 (m, 2H), 2,92-3,20 (m, 3H), 3,24-to 3.35 (m, 2H), 3,38 (s, 3H), 3,48-3,51 (m, 2H), 3,54 is 3.57 (m, 2H), 3,78-is 3.82 (t, 2H), 4,24-the 4.29 (t, 2H), of 4.44-4,48 (t, 2H), 4,60-5,20 (user. s, 1H), 6,98-to 7.59 (m, 8H), of 7.90-to 7.93 (DD, 1H).

Example 7

Obtain 3-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)ethoxy]benzoic acid

Use the methods described in example 1, using 0.2 g (1 mmol) of H-piperidine-4-yl-1H-indole and 0.17 g (1.1 mmol) of methyl ester of 3-(2-chloroethoxy)benzoic acid. 0.06 g (0,19 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.31 mmol) of 1-bromo-2-(2-methoxyethoxy)ethane, getting 0,053 g (yield 60%) of 3-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)ethoxy]benzoic acid.

ESI/MC m/e=467 [(M+1)+, 2734N25]

NMR (300 MHz, CDCl3) δ=2,21-2,39 (m, 4H), 2,84-of 3.07 (m, 4H), of 3.32 (s, 3H), 3,35-of 3.53 (m, 5H), 3.75 to with 3.79 (m, 4H), 4,23-4,27 (t, 2H), 4,50-a 4.53 (m, 2H), 6,99-to 7.35 (m, 5H), to 7.59-to 7.68 (m, 4H).

Example 8

Obtaining 3-(2-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.17 g (1.1 mmol) met the gross ester 3-(2-chloroethoxy)benzoic acid. 0.06 g (0,19 mmol) of the crude product obtained in stage D, then alkylate of 0.03 ml (0.28 mmol) of 4-ftorangidridy getting 0,047 g (yield 52%) of 3-(2-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid.

ESI/MC m/e=473 [(M+1)+, 2929FN23]

NMR (300 MHz, CDCl3) δ=2,10 at 2.45 (m, 4H), 2,83-2,89 (m, 2H), 3,26-to 3.36 (m, 3H), 3,53 is 3.57 (m, 2H), to 4.38-to 4.41 (t, 2H), 5,26 (s, 2H), 6,94-7,38 (m, N), to 7.61-of 7.69 (m, 4H).

Example 9

Obtain 3-{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.17 g (1.1 mmol) of methyl ester of 3-(2-chloroethoxy)benzoic acid. 0.06 g (0,19 mmol) of the crude product obtained in stage D, alkylate then a 0.035 ml (0.28 mmol) of pentaiodide getting 0,037 g (yield 45%) of 3-{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid.

ESI/MC m/e=435 [(M+1)+, 2734N23]

NMR (300 MHz, Dl3) δ=0,86-of 0.90 (t, 3H), 1.30 and of 1.41 (m, 4H), 1.60-to of 1.85 (m, 2H), 2.00 in of 2.20 (m, 4H), 2,60 is 2.80 (m, 2H), 2.95 and was 3.05 (m, 1H), 3,19-up 3.22 (t, 2H), 3,44-3,47 (d, 2H), of 4.05-4.09 to (t, 2H), 4,34-4,37 (m, 4H), 6,94-to 7.67 (m, N).

Example 10

Obtaining 3-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl-ethoxy)benzoic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.17 g (1.1 mmol) of methyl ester of 3-(2-chloroethoxy)benzoic acid. 0.06 g (0,19 mmol) of the crude product obtained in stage D, Ala leraut then 0,028 ml (0.28 mmol) Bromeliaceae ether, getting to 0.032 g (yield 38%) of 3-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl-ethoxy)benzoic acid.

ESI/MC m/e=435 [(M+1)+, C2632N24]

NMR (300 MHz, CDCl3) δ=1,02-to 1.14 (t, 3H), 2,10-of 2.30 (m, 4H), of 2,75 2,90 (m, 2H), 2.95 and is 3.15 (m, 1H), 3,20-3,30 (m, 2H), 3,40 is-3.45 (q, 2H), 3,69-to 3.73 (m, 4H), 4,21-4,24 (t, 2H), 4,40-4,55 (m, 2H), 6,99-7,71 (m, N).

Example 11

Getting 4-[2-(4-{1-[2-(2-methoxyethoxy)-ethyl]-1H-indol-3-yl}piperidine-1-yl)ethoxy]benzoic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.18 g (1.1 mmol} ethyl ester 4-(2-chloroethoxy)benzoic acid. 0.06 g (0,19 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.28 mmol) of 1-bromo-2-(2-methoxyethoxy)ethane, getting 0,024 g (yield 28%) of 4-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)ethoxy]benzoic acid.

ESI/MC m/e=467 [(M+1)+, 2734N25]

NMR (300 MHz, CDCl3) δ=1,80-2,00 (m, 2H), 2.05 is-of 2.20 (m, 2H), 2,35 at 2.45 (m, 2H), 2,80-2,99 (m, 3H), 3,19 is 3.23 (m, 2H), 3.43 points (C, ZN), 3,47-of 3.54 (m, 4H), of 3.77-is 3.82 (t, 2H), 4,24-4,30 (m, 4H), 6,94-the 7.65 (m, N), 8,00-8,02 (d, 2H).

Example 12

Getting 4-{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.18 g (1.1 mmol) of the ethyl ester of 4-(2-chloroethoxy)benzoic acid. 0.06 g (0,19 mmol) of the crude product obtained in stage D, then alkylate of 0.03 ml (0.28 mmol) of pentaiodide, the floor is th 0,028 g (yield 34%) of 4-{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid.

ESI/MC m/e=435 [(M+1)+, 2734N23]

NMR (300 MHz, DMSO) δ=0,81-of 0.91 (m, 3H), 1,20-to 1.38 (m, 4H), 1,65-of 1.74 (m, 4H), 1,91-of 1.94 (m, 2H), 2.00 in to 2.15 (m, 1H), 2,18 was 2.25 (m, 2H), 2,74-2,77 (m, 2H), 2,98-of 3.07 (m, 2H), 4,03-4,17 (m, 4H), 6,93-to 7.15 (m, 5H), 7,38-the 7.43 (m, 1H), 7,54-7,56 (d, 1H), 7,83-7,86 (m, 2H).

Example 13

Getting 2-[3-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)propoxy]benzoic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.25 g (1.1 mmol) of methyl ester of 2-(2-chloropropoxy)benzoic acid. 0,082 g (0.21 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.31 mmol) of 1-bromo-2-(2-methoxyethoxy)ethane, getting 0,056 g (yield 56%) of 2-[3-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)-propoxy]benzoic acid.

ESI/MC m/e=481 [(M+1)+, 2836N25]

NMR (300 MHz, CDCl3) δ=2,20-of 2.28 (m, 6N), 2,75 of 2.92 (m, 2H), 3.00 and-3,10 (m, 1H), 3,19-3,24 (t, 2H), 3.33 and (s, 3H), 3.45 points-of 3.54 (m, 4H), 3,62-to 3.67 (m, 2H), 3,74-of 3.78 (t, 2H), 4,19-of 4.25 (m, 4H), 5,20-the ceiling of 5.60 (users, 1H), 6,94-7,38 (m, 7H), 7,54-EUR 7.57 (d, 1H), 7,97-of 8.00 (DD, 1H).

Example 14

Getting 2- (3-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}propoxy)benzoic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.25 g (1.1 mmol) of methyl ester of 2-(2-chloropropoxy)benzoic acid. 0,082 g (0.21 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.31 mmol) of 4-ftorangidridy getting 0,062 g (in the course of 61%) of 2-(3-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}propoxy)benzoic acid.

ESI/MC m/e=487 [(M+1)+, C3031FN23]

NMR (300 MHz, CDCl3) δ=2,20-2,40 (m, 6N), 2,95-3,10 (m, 2H), 3,15-up 3.22 (m, 1H), 3,34-of 3.42 (m, 3H), 3,76-of 3.80 (d, 2H), 4,19-to 4.23 (m, 4H), at 5.27 (s, 2H), 6,93 and 7.36 (m, 10H), to 7.59-to 7.61 (d, 1H), 7,85-7,88 (DD, 1H).

Example 15

Getting 2-{3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]propoxy}benzoic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.25 g (1.1 mmol) of methyl ester of 2- (2-chloropropoxy)benzoic acid. 0,087 g (0.22 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.33 mmol) of pentaiodide getting 0,057 g (yield 57%) of 2-{3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]propoxy}benzoic acid.

ESI/MC m/e=449 [(M+1)+, 2836N23]

NMR (300 MHz, Dl3) δ=0,84-to 0.89 (t, 3H), of 1.27 to 1.34 (m, 4H), 1,71 is 2.10 (m, 8H), 2,80-of 3.32 (m, 7H), 3,80-4,10 (m, 4H), 6,70-to 7.95 (m, N).

Example 16

Getting 2-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}propoxy)benzoic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.25 g (1.1 mmol) of methyl ester of 2-(2-chloropropoxy)benzoic acid. 0,087 g (0.22 mmol) of the crude product obtained in stage D, then alkylate of 0.03 ml (0.33 mmol) of 2-Bromeliaceae ether, receiving 0,078 g (yield 78%) of 2-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}propoxy)benzoic acid.

ESI/MC m/e=451(M+1)+, C2734N24]

NMR (300 MHz, Dl3) δ=1,11-of 1.16 (t, 3H, 2,23-of 2.34 (m, 8H), 2,90 are 2.98 (t, 2H), 3.00 and-3,18 (m, 1H), 3,29-to 3.33 (t, 2H), 3,69-with 3.79 (m, 4H), 4,19-4,27 (m, 4H), 6,94-6,97 (d, 1H), 7,07-7,37 (m, 5H), 7,55-EUR 7.57 (d, 1H), 7,93-of 7.96 (DD, 1H).

Example 17

Obtain 3-[3-(4-{1-[2-(2-methoxyethoxy)-ethyl]-1H-indol-3-yl}piperidine-1-yl)propoxy]benzoic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.25 g (1.1 mmol) of methyl ester of 3-(2-chloropropoxy)benzoic acid. 0,080 g (0.20 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.30 mmol) of 1-bromo-2-(2-methoxyethoxy)ethane, getting 0,065 g (yield 68%) of 3-[3-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)propoxy]benzoic acid.

ESI/MC m/e=451(M+1)+, C2836N25]

NMR (300 MHz, CDCl3) δ=2,10-2,60 (m, 6N), 2,50-to 2.65 (m, 2H), 2,92-3,10 (m, 3H), of 3.33 (s, 3H), 3,38-of 3.53 (m, 6N), of 3.77-of 3.80 (t, 2H), 4,11-to 4.15 (t, 2H), 4.25 in-the 4.29 (t, 2H), 6,99-7,56 (m, 7H), to 7.61-7,63 (d, 1H).

Example 18

Obtain 3-{3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]propoxy}benzoic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.25 g (1.1 mmol) of methyl ester of 3-(2-chloropropoxy)benzoic acid. 0.08 g (0.20 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.30 mmol) of pentaiodide getting 0,042 g (yield 48%) of 3-{3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]propoxy}benzoic acid.

ESI/MC m/e =449(M+1)+, C28H36N23]

NMR (300 MHz, CDCl3) δ=0,85-0,94 (m 3 is), 1,26-of 1.39 (m, 4H), 1,69-of 1.85 (m, 2H), 2,10-of 2.25 (m, 6N), 2,58-of 2.66 (m, 2H), 2,98-3,03 (m, MN), 3,49-of 3.53 (m, 2H), 4,03-4,08 (t, 2H), 4,10-to 4.14 (t, 2H), 6,93-7,56 (m, 8H), 7,60-7,63 (d, 1H).

Example 19

Obtaining 3-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}propoxy)benzoic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.25 g (1.1 mmol) of methyl ester of 3-(2-chloropropoxy)benzoic acid. 0.08 g (0.20 mmol) of the crude product obtained in stage D, then alkylate of 0.03 ml (0.30 mmol) Bromeliaceae ether, getting to 0.055 g (yield 61%) of 3-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}propoxy)benzoic acid.

ESI/MC m/e =451 [(M+1)+, 2734N24]

NMR (300 MHz, Dl3) δ=1,10-1,15 (t, 3H), 2,17-2,22 (m, 6N), 2,60-of 2.75 (m, 2H), 3,03-is 3.08 (m, 3H), 3,41-of 3.46 (t, 2H), 3,53 is 3.57 (m, 2H), 3,71-3,74 (t, 2H), 4,12-of 4.16 (t, 2H), 4,22-4.26 deaths (t, 2H), of 6.96-of 7.55 (m, 8H), to 7.61-7,63 (d, 1H).

Example 20

Getting 4-[3-(4-{1-[2-(2-methoxyethoxy)-ethyl]-1H-indol-3-yl}piperidine-1-yl)propoxy]benzoic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.25 g (1.1 mmol) of methyl ester of 4-(2-chloropropoxy)benzoic acid. 0.08 g (0.20 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.30 mmol) of 1-bromo-2-(2-methoxyethoxy)ethane, getting 0,033 g (yield 36%) of 4-[3-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)propoxy] benzoic acid.

ESI/MC m/e =481 [(M+1)+, 2836N2 is 5]

NMR (300 MHz, CDCl3) δ=2,14-2,19 (m, 6N), 2,40-to 2.55 (m, 2H), 2.95 and-2,99 (m, 3H), 3,29 is 3.57 (m, 6N), to 3.73-of 3.77 (t, 2H), 4,15-4,18 (t, 2H), 4,21-of 4.25 (t, 2H), of 6.71-6,74 (m, 2H), 6,94 (s, 1H), 7,02-7,07 (t, 1H), 7,14-7,20 (t, 1H), 7,26-to 7.64 (m, 4H).

Example 21

Getting 4-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}propoxy)benzoic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.25 g (1.1 mmol) of methyl ester of 4-(2-chloropropoxy)benzoic acid. 0.08 g (0.20 mmol) of the crude product obtained in stage D, then alkylate of 0.03 ml (0.30 mmol) Bromeliaceae ether, receiving 0,029 g (yield 33%) of 4-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}propoxy)benzoic acid.

ESI/MC m/e =451 [(M+1)+, 2734N2O4]

NMR (300 MHz, CDCl3) δ=1,07 by 1.12 (t, 3H), 2,11-2,17 (m, 6N), 2,43-2,96 (m, 5H), 3,35-of 3.42 (q, 2H), 3,50-of 3.54 (m, 2H), 3,66-3,70 (t, 2H), 4,16-4,22 (m, 4H), of 6.71-6,74 (d, 2H), 6,92 (s, 1H), 7,02-7,07 (t, 1H), 7,14-7,20 (t, 1H), 7,27-7,33 (m, 1H), to 7.59 to 7.62 (m, 3H).

Example 22

Obtaining 3-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)propionic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.15 g (1.1 mmol) of ethyl ester of 3-chloropropionic acid. 0.08 g (0.25 mmol) of the crude product obtained in stage D, alkylate then 0.05 ml (0.38 mmol) of 1-bromo-2-(2-methoxyethoxy)ethane, getting 0,078 g (yield 84%) of 3-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)propionate the acid.

ESI/MC m/e =375 [(M+1)+, C213N24]

NMR (300 MHz, Dl3) δ=2,01 is 2.10 (m, 2H), 2,24-of 2.28 (m, 2H), 2,30 at 2.45 (m, 4H), 2.57 m-2,61 (t, 2H), 2.70 height is 2.80 (m, 2H), 3.04 from-is 3.08 (t, 2H), 3,37 (s, 3H), 3,50-3,81 (m, 4H), 3,79-3,81 (t, 2H), 4,28-4,32 (t, 2H), 7,00 (s, 1H), 7,09-7,14 (t, 1H), 7,20-of 7.25 (t, 1H), was 7.36-7,39 (d, 1H), 7,56-to 7.59 (d, 1H).

Example 23

Obtain 3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]propionic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.15 g (1.1 mmol) of ethyl ester of 3-chloropropionic acid. 0.04 g (0.14 mmol) of the crude product obtained in stage D, then alkylate of 0.03 ml (0.21 mmol) of pentaiodide, getting to 0.022 g (yield 47%) of 3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]propionic acid.

ESI/MC m/e=343 [(M+1)+, C21H30N22]

NMR (300 MHz, CDCl3) δ=0,87-of 0.94 (m, 3H), 1,21-of 1.40 (m, 6N), a 1.75-of 1.84 (m, 3H), 1,99-2,04 (m, 2H), 2,19-of 2.24 (m, 2H), 2,64 of 2.68 (m, 2H), 2,99-to 3.02 (d, 2H), 3.43 points-of 3.53 (m, 4H), 4,03-4,08 (t, 2H), 6.89 in (s, 1H), 7,07-7,34 (m, 3H), EUR 7.57-to 7.59 (d, 1H).

Example 24

Getting 4-(4-{1-[2-(2-methoxyethoxy)-ethyl]-1H-indol-3-yl}piperidine-1-yl)butyric acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.17 g (1.1 mmol) of the ethyl ester of 4-harpalani acid. 0.07 g (0.22 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.33 mmol) of 1-bromo-2-(2-methoxyethoxy)ethane, getting 0,068 g (yield 79%) of 4-(4-{1-[2-(2-methoxyethoxy)-ethyl]-1H-indol-3-yl}piperidine-1-yl)butyric acid

ESI/MC m/e =389 [(M+1)+, 2232N24]

NMR (300 MHz, CDCl3) δ=1,90 of 1.99 (m, 2H), 2,10-of 2.23 (m, 4H), 2,60-and 2.79 (m, 6N), 2,89 totaling 3.04 (m, 3H), on 3.36 (s, 3H), 3,48 is 3.57 (m, 4H), 3,78-is 3.82 (t, 2H), 4.26 deaths-4,30 (t, 2H), 7,02 (s, 1H), 7,08-7,10 (t, 1H), 7,19-7,24 (t, 1H), 7,35-7,38 (d, 1H), 7,55-7,58 (d, 1H).

Example 25

Getting 4-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}butyric acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.17 g (1.1 mmol) of the ethyl ester of 4-harpalani acid. 0.07 g (0.22 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.33 mmol) 4-ftorangidridy getting 0,074 g (yield 85%) of 4-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}butyric acid.

ESI/MC m/e =395 [(M+1)+, 2427FN22]

NMR (300 MHz, CDCl3) δ=1,80-of 1.95 (m, 2H), 2.00 in and 2.14 (m, 4H), 2,48-2,60 (m, 4H), 2,74-2,78 (t, 2H), 2,94-3,00 (m, 2H), 3,29-to 3.33 (m, 2H), total of 5.21 (s, 2H), 6.90 to-7,27 (m, N), to 7.59 to 7.62 (m, 2H).

Example 26

Getting 4-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]butyric acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.17 g (1.1 mmol) of the ethyl ester of 4-harpalani acid. 0.06 g (0.20 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.33 mmol) of pentaiodide getting 0,054 g (yield 76%) of 4-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]butyric acid.

ESI/MC m/e =357 [(M+1)+, 2232N22]

NMR (300 MHz, CDCl3) δ=of 0.87 to 0.92 (t, 3H), 1,27-of 1.36 (m, 4H), 1.77 in-1,9 (m, 4H), 2,04-2,17 (m, 4H), 2,55-of 2.66 (m, 4H), 2,81-2,84 (t, 2H), 2.95 and was 3.05 (m, 1H), 3,35-3,39 (m, 2H), 4,03-4,08 (t, 2H), 6,91 (s, 1H), 7,07-to 7.09 (t, 1H), 7,19-7,34 (m, 2H), EUR 7.57-of 7.60 (d, 1H).

Example 27

Obtain 3-{4-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)ethyl]phenyl}propionic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.31 g (1.1 mmol) of ethyl ester of 3-[4-(2-bromacil)phenyl]propionic acid. 0.08 g (0.20 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.33 mmol) of 1-bromo-2-(2-methoxyethoxy)ethane, receiving of 0.066 g (yield 72%) of 3-{4-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)ethyl]phenyl} propionic acid.

ESI/MC m/e =479 [(M+1)+, 2938N24]

NMR (300 MHz, CDCl3) δ=2,00-2,22 (m, 4H), 2,61-to 2.74 (m, 6N), 2,88-3,10 (m, 5H), 3,62 (s, 3H), 3,48 of 3.56 (m, 6N), 3,79-a 3.83 (t, 2H), 4,27-or 4.31 (t, 2H), 6,93-7,40 (m, 8H), 7,58-to 7.61 (d, 1H).

Example 28

Obtain 3-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}propionic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.15 g (1.1 mmol) of ethyl ester of 3-chloropropionic acid. 0.08 g (0.25 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.38 mmol) of 4-ftorangidridy getting 0,067 g (71%yield) of 3-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}propionic acid.

ESI/MC m/e =381 [(M+1)+, 2325FN22]

NMR (300 MHz, CDCl3) δ=2.06 to and 2.14 (m, 2 is), 2,30-of 2.34 (m, 2H), 2,55-2,60 (t, 2H), 2,90 are 2.98 (t, 2H), 3,10-up 3.22 (m, 3H), 3,59-3,63 (m, 2H), 5,26 (s, 2H), of 6.96-7,29 (m, 8H), to 7.59 to 7.62 (DD, 1H).

Example 29

Obtain 3-[4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethyl)phenyl]propionic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.31 g (1.1 mmol) of ethyl ester of 3-[4-(2-bromacil)phenyl]propionic acid. 0.08 g (0.20 mmol) of the crude product obtained in stage D, then alkylate of 0.03 ml (0.33 mmol) Bromeliaceae ether, receiving 0,054 g (yield 64%) of 3-[4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethyl)phenyl]propionic acid.

ESI/MC m/e =449 [(M+1)+, C2836N23]

NMR (300 MHz, CDCl3) δ=1,13-of 1.18 (t, 3H), 2.00 in to 2.15 (m, 4H), of 2.51-2,98 (m, 11N), 3,40-of 3.54 (m, 4H), 3,70-3,74 (t, 2H), 4,22-4.26 deaths (t, 2H), 6.87 in-7,26 (m, 7H), 7,33 and 7.36 (d, 1H), EUR 7.57-of 7.60 (DD, 1H).

Example 30

Obtain 3-{4-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)ethyl]phenyl}acrylic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.2 g (1.1 mmol) of ethyl ester of 3-[4-(2-bromacil)phenyl]acrylic acid. 0.04 g (0.10 mmol) of the crude product obtained in stage D, alkylate then 0.02 ml (0.15 mmol) 1-bromo-2-(2-methoxyethoxy)ethane, getting 0,020 g (yield 41%) of 3-{4-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)-ethyl]phenyl}-acrylic acid.

ESI/MC m/e =477 [(M+1)+, 2936N24]

NMR (300 MHz, CDCl ) δ=2,10-2,22 (m, 4H), 2,60-to 2.65 (m, 2H), 2,98-to 3.09 (m, 5H), to 3.36 (s, 3H), 3,47-3,62 (m, 6N), 3,76-of 3.80 (t, 2H), 4,24-to 4.28 (t, 2H), of 6.31-6,37 (d, 1H), 6,99 to 7.62 (m, 10H).

Example 31

Obtaining 3-(4-{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]ethyl}phenyl)acrylic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.2 g (1.1 mmol) of ethyl ester of 3-[4-(2-bromacil)phenyl]acrylic acid. 0.03 g (0.08 mmol) of the crude product obtained in stage D, alkylate then 0.02 ml (0.15 mmol) of pentaiodide getting 0,013 g (yield 36%) of 3-(4-{2-[4-(1-pentyl-1H-indol-3-yl)-piperidine-1-yl]ethyl}phenyl)acrylic acid.

ESI/MC m/e =445 [(M+1)+, C2938N22]

NMR (300 MHz, CDCl3) δ=0,85-of 0.94 (m, 3H), 1,22-of 2.20 (m, N), 2,38 at 2.45 (m, 2H), 2,96 totaling 3.04 (m, 3H), 3.45 points-to 3.49 (m, 2H), 4,01-4,06 (t, 2H), 6.22 per 6,27 (d, 1H), 6.89 in to 7.62 (m, 10H).

Example 32

Obtain 3-[4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethyl)phenyl]acrylic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.2 g (1.1 mmol) of ethyl ester of 3-[4-(2-bromacil)phenyl]acrylic acid. 0.03 g (0.08 mmol) of the crude product obtained in stage D, alkylate then 0.02 ml (0.15 mmol) Bromeliaceae ether, receiving 0,018 g (51%yield) of 3-[4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethyl)phenyl]acrylic acid.

ESI/MC m/e =447 [(M+1)+, 2834N23]

NMR (300 MHz, CDCl3) δ=1,11-of 1.53 (t, 3H), 2.00 in of 2.20 (m, 4H), 2,40-2,60 (m, 2H), 2,80-3,20 (who, 5H), 3,38-of 3.54 (m, 4H), 3,68-and 3.72 (t, 2H), 4,20-4,24 (t, 2H), 6,26 of 6.31 (d, 1H), of 6.96-7,44 (m, N), 7,50 to 7.62 (d, 1H).

Example 33

Getting 2-{4-[1-hydroxy-4-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)butyl]phenyl}-2-methylpropionic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.31 g (1.1 mmol) of methyl ester of 2-[4-(4-chloro-1-hydroxybutyl)phenyl]-2-methylpropionic acid. 0.04 g (0.1 mmol) of the crude product obtained in stage D, alkylate then 0.02 ml (0.15 mmol) 1-bromo-2-(2-methoxyethoxy)ethane, getting 0,027 g (yield 49%) of 2-{4-[1-hydroxy-4-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)butyl]phenyl}-2-methylpropionic acid.

ESI/MC m/e =537 [(M+1)+, 3244N25]

NMR (300 MHz, CDCl3) δ=1,58 (C, 6N), 1.70 to 1,95 (m, 2H), 2,20-2,61 (m, 8H), 2,70-to 2.85 (m, 2H), 2,90-of 3.07 (m, 2H), on 3.36 (s, 3H), 3,40 of 3.56 (m, 4H), 3,78-is 3.82 (t, 2H), 4,27-4,30 (t, 2H), 4,55-to 4.62 (m, 1H), 7,01-7,41 (m, 8H), to 7.61-7,63 (d, 1H).

Example 34

Obtaining 2-(4-{1-hydroxy-4- [4- (1-pentyl-1H-indol-3-yl)piperidine-1-yl]butyl}phenyl)-2-methylpropionic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.31 g (1.1 mmol) of methyl ester of 2-[4-(4-chloro-1-hydroxybutyl)phenyl]-2-methylpropionic acid. 0.05 g (0.1 mmol) of the crude product obtained in stage D, alkylate then 0.02 ml (0.15 mmol) of pentaiodide, getting to 0.022 g (yield 41%) of 2-(4-{1-hydroxy-4-[4-(1-pentyl-1H-indol-3-yl)Pieper is DIN-1-yl]butyl}phenyl)-2-methylpropionic acid.

ESI/MC m/e =505 [(M+1)+, 3244N23]

NMR (300 MHz, Dl3) δ=0,86 to 0.92 (t, 3H), 1,27-of 1.36 (m, 4H), 1.57 in (C, 6N), 2,05-2,60 (m, N), 2,89-3,10 (m, 7H), 3,55-of 3.80 (m, 2H), 4,00-4,06 (t, 2H), 2,75-to 2.85 (m, 1H), 6,97-to 7.32 (m, 8H), to 7.59-to 7.61 (d, 1H).

Example 35

Getting 2-[4-(4-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}-1-hydroxybutyl)phenyl]-2-methylpropionic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.31 g (1.1 mmol) of methyl ester of 2-[4-(4-chloro-1-hydroxybutyl)phenyl]-2-methylpropionic acid. 0.05 g (0.1 mmol) of the crude product obtained in stage D, alkylate then 0.02 ml (0.15 mmol) Bromeliaceae ether, receiving 0,046 g (yield 91%) of 2-[4-(4-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}-1-hydroxybutyl)phenyl]-2-methylpropionic acid.

ESI/MC m/e =507 [(M+1)+, 3142N24]

NMR (300 MHz, CDCl3) δ=1,12-of 1.17 (t, 3H), 1.57 in (C, 6N), 1,77-to 2.42 (m, 8H), 2,82-to 3.09 (m, 5H), 3,41-3,61 (m, 6N), 3,65-and 3.72 (t, 2H), 4,21-of 4.25 (t, 2H), 4,67-4,71 (m, 1H), 7,00-7,37 (m, 8H), to 7.59 to 7.62 (d, 1H).

Example 36

Obtaining [2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)ethoxy]acetic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.18 g (1.1 mmol) of ethyl ether (2 chloroethoxy)acetic acid. 0.06 g (0.18 mmol) of the crude product obtained in stage D, then alkylate of 0.03 ml (0.27 mmol) of 1-bromo-2-(2-methoxyethoxy)ethane, getting 0,056 g (yield 77%) of [2-(4-{1-[2-(methoxyethoxy)-ethyl]-1H-indol-3-yl}piperidine-1-yl)ethoxy]acetic acid.

ESI/MC m/e =405 [(M+1)+, 2232N25]

NMR (300 MHz, CDCl3) δ=2,05-to 2.40 (m, 4H), 2,89 was 3.05 (m, 5H), to 3.36 (s, 3H), 3,47 is 3.57 (m, 4H), 3,67-3,81 (m, 4H), a 3.87-3,91 (t, 2H), 4,10 (s, 2H), 4,24-to 4.28 (t, 2H), 7,02-7,27 (m, 3H), 7,35-7,37 (d, 1H), 7,56-7,58 (d, 1H).

Example 37

Receive (2-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}ethoxy)acetic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.18 g (1.1 mmol) of ethyl ether (2 chloroethoxy)acetic acid. 0.06 g (0.18 mmol) of the crude product obtained in stage D, then alkylate of 0.03 ml (0.27 mmol) 4-ftorangidridy getting 0,059 g (yield 80%) of (2-{4-[1-(4-terbisil)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)acetic acid.

ESI/MC m/e =411 [(M+1)+, 2427FN23]

NMR (300 MHz, Dl3) δ=2,25-to 2.40 (m, 4H), 2,96-3,10 (m, 5H), to 3.58-3,63 (m, 2H), a 3.87-3,91 (t, 2H), 4,07 (s, 2H), 5,24 (S, 2H), 6,97-7,28 (m, 8H), EUR 7.57-of 7.60 (d, 1H).

Example 38

Obtain {2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]-ethoxy}acetic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.18 g (1.1 mmol) of ethyl ether (2 chloroethoxy)acetic acid. 0.06 g (0.18 mmol) of the crude product obtained in stage D, then alkylate of 0.03 ml (0.27 mmol) of pentaiodide getting 0,047 g (yield 74%) of {2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]-ethoxy}acetic acid.

ESI/MC m/e =373 [(M+1)+, C22 N N2 O3]

NMR (300 MHz, CDCl3) δ=0,87-of 0.91 (t, 3H), 1,281,36 (m, 4H), 1,79-of 1.84 (m, 2H), 2,21 of-2.32 (m, 4H), 2,89-2,96 (m, 2H), 3.04 from-of 3.07 (m, 3H), 3,55-3,59 (d, 2H), 3,88-to 3.92 (t, 2H), was 4.02-4,07 (t, 2H), 4,11 (s, 2H), 4,40-4,80 (users, 1H), 6,97-7,34 (m, 4H), 7,56-7,58 (d, 1H).

Example 39

Receive (2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)acetic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0.18 g (1.1 mmol) of ethyl ether (2 chloroethoxy)acetic acid. 0.06 g (0.18 mmol) of the crude product obtained in stage D, then alkylate of 0.03 ml (0.27 mmol) Bromeliaceae ether, receiving 0,049 g (yield 76%) of (2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)acetic acid.

ESI/MC m/e =375 [(M+1)+, 213N24]

NMR (300 MHz, Dl3) δ=1,13-of 1.18 (t, 3H), 2,20-2,40 (4H), 2,80-is 3.08 (m, 5H), 3.43 points is 3.57 (m, 4H), 3.72 points is 3.76 (t, 2H), a 3.87-3,91 (t, 2H), 4,08 (s, 2H), 4,23-4,27 (t, 2H), 7,06-7,28 (m, 3H), of 7.36-7,39 (d, 1H), 7,55-7,58 (d, 1H).

Example 40

Getting 5-(4-{1-[2-(2-methoxyethoxy)-ethyl]-1H-indol-3-yl}piperidine-1-yl-methyl)furan-2-carboxylic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0,19 g (1.1 mmol) ethyl ester 5-bromomethylphenyl-2-carboxylic acid. 0.08 g (0.22 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.33 mmol) of 1-bromo-2-(2-methoxyethoxy)ethane, getting 0,034 g (yield 36%) of 5-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl-methyl)-furan-2-carboxylic acid.

Temperature plavini is =159° With

ESI/MC m/e =427 [(M+1)+, 24HN25]

NMR (300 MHz, CDCl3) δ=2,05-2,90 (m, N), of 3.32 (s, 3H), 3,39-of 3.48 (m, 4H), 3,67 of 3.75 (m, 2H), 4,00-of 4.25 (m, 4H), 6,35-6,40 (m, 1H), 6,92-7,33 (m, 5H), 7,53-7,56 (d, 1H).

Example 41

Getting 5-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl-methyl]furan-2-carboxylic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0,19 g (1.1 mmol) ethyl ester 5-bromomethylphenyl-2-carboxylic acid. 0.08 g (0.22 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.33 mmol) of pentaiodide getting 0,064 g (yield 70%) of 5-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl-methyl]furan-2-carboxylic acid.

Melting point =163-165°

ESI/MC m/e =395 [(M+1)+, 2430N23]

NMR (300 MHz, CDCl3) δ=0.79, which is 0.84 (t, 3H), 1,20-to 2.29 (m, N), 2,50-2,70 (m, 1H), 2,89-2,96 (m, 2H), 3,36-to 3.49 (m, 2H), 3,80-4,00 (m, 2H), 5,80-6,00 (m, 1H), 6,70-of 7.23 (m, 5H), 7,50-7,53 (d, 1H).

Example 42

Obtain 5-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl-methyl}furan-2-carboxylic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0,19 g (1.1 mmol) ethyl ester 5-bromomethylphenyl-2-carboxylic acid. 0.08 g (0.22 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.33 mmol) Bromeliaceae ether, receiving 0,069 g (75%yield) of 5-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl-methyl}furan-2-carboxylic acid.

ESI/MC /e =397 [(M+1) +, 2328N24]

NMR (300 MHz, CDCl3) δ=1,05-2,00 (t, 3H), 1,80-3,10 (m, N), 3,32-to 3.34 (d, 2H), 3,50-of 3.80 (m, 4H), 4,00-4,20 (m, 2H), 6,00-of 6.20 (m, 1H), for 6.81-7,20 (m, 5H), 7,50-7,53 (d, 1H).

Example 43

Obtain 5-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-ylmethyl}furan-2-carboxylic acid

Use the methods described in example 1, using 0.2 g (1 mmol) 3-piperidine-4-yl-1H-indole and 0,19 g (1.1 mmol) ethyl ester 5-bromomethylphenyl-2-carboxylic acid. 0.08 g (0.22 mmol) of the crude product obtained in stage D, then alkylate of 0.04 ml (0.33 mmol) 4-ftorangidridy getting 0,031 g (yield 32%) of 5-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-ylmethyl}furan-2-carboxylic acid.

ESI/MC m/e =433 [(M+1)+, 2625FN23]

NMR (300 MHz, DMSO) δ=1,65-1,72 (m, 2H), 1,92 is 1.96 (m, 2H), 2,16-of 2.23 (t, 2H), 2,60 is 2.80 (m, 1H), 2,92-2,96 (m, 2H), 3.45 points (s, 2H), 5,33 (s, 2H), of 6.49-of 6.50 (d, 1H), 6,95-7,27 (m, 8H), 7,38-7,41 (d, 1H), 7,55-7,58 (d, 1H).

Examples 44-133

The following compounds are synthesized using the General procedure described in example 1 using the appropriate reagents. ESI/MC data and the outputs are shown in table 2:

td align="center" namest="c1" nameend="c3"> 2-(4-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethyl}-phenyl)-2-methylpropionate acid
Table 2
ExampleESI/MC m/e [(M+1)+]Molecular formulaOutput (%)
442-[4-(4-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}-1-hydroxybutyl)phenyl]-2-methylpropionamide
543S N F N2 O346
452-{2-[4-(1-heptyl-1H-indol-3-yl)piperidine-1-yl]- ethoxy}benzoic acid
463S N N2 O352
462-(2-{4-[1-(4-tert-butylbenzyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
511S N N2 O344
472-(2-{4-[1-(4-methoxybenzyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
485SO N N2 O448
482-(2-{4-[1-(4-benzyloxybenzyl)-1H-indole-Z-yl]piperidine-1-yl}ethoxy)benzoic acid
561C36 H36 N2 O461
492-{2-[4-(1-ISO-butyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid
421S N M2 O438
502-[2-(4-{1-[2-(4-methoxyphenyl)ethyl]-1H-indole-Z-yl}piperidine-1-yl)ethoxy]benzoic acid
499A31 N N2 O458
51
391C25 N N2 O270
522-(4-{4-[4-(1H-indol-3-yl)piperidin-1-yl]butyryl}-phenyl)-2-methylpropionate acid
433On 27 N N2 O367

/tr>
Continuation of table 2
532-[4-(1H-indol-3-yl)piperidine-1-ylmethyl]benzoic acid
335C21 n N2 O258
543-[4-(1H-indol-3-yl)piperidine-1-ylmethyl]benzoic acid
335C21 n N2 O285
554-[4-(1H-indol-3-yl)piperidine-1-ylmethyl]benzoic acid
335C21 n N2 O274
56(3-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy}-phenyl)acetic acid
379C23 N N2 O335
57(3-{3-[4-(1H-indol-3-and the)piperidine-1-yl]-propoxy)phenyl)acetic acid
393C24 N N2 O329
58(4-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy}-phenyl)acetic acid
379C23 N N2 O331
59(4-{3-[4-(1H-indol-3-yl)piperidine-1-yl]propoxy}-phenyl)acetic acid
393C24 N N2 O352
603-(1-{3-[3-(1H-tetrazol-5-yl-1H-phenoxy]propyl}-piperidine-4-yl)-1H-indole
403C23 N About N666
612-methyl-2-[4-(2-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl}ethyl)phenyl]propionic acid
461C30 N N2 O214
622-[4-(2-{4-[1-(2-ethoxyethyl)-1H-indole-Z-yl]piperidine-1-yl}ethyl)phenyl]-2-methylpropionate acid
463S N N2 O349
632-methyl-2-[4-(4-{4-[1-(3-methylbutyl)-1H-indole-Z-yl] piperidine-1-yl}butyryl)phenyl]propionic acid
503C32 N N2 O335
Continuation of table 2
642-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-ylmethyl}benzoic acid
405S N N2 O268
652-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-ylmethyl}benzoic acid
407C25 N N2 O322
663-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-ylmethyl}benzoic acid
407C25 N N2 O327
674-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-ylmethyl}benzoic acid
405S N N2 O238
68[3-(2-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl }ethoxy) phenyl] acetic acid
449S H36 N2 O336
69[3-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)phenyl]acetic acid
451On 27 N N2 O441
70[3-(3-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl}propoxy)phenyl]acetic acid
463S N N2 O335
71[3-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}propoxy)phenyl]acetic acid
465S H36 N2 O470
72[4-(2-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)phenyl]acetic acid
449S H36 N2 O325
73[4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)phenyl]acetic acid
451On 27 N N2 O445
74[4-(3-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl}propoxy)phenyl]acetic acid
463S N N2 O319

Continuation of table 2
75 [4-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl }propoxy)phenyl]acetic acid
465S H36 N2 O446
762-{2-[4-(1-prop-2-inyl-1H-indol-3-yl}piperidine-1-yl]ethoxy}benzoic acid
403C25 N N2 O320
772-methyl-2-[4-(4-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl}butyryl)phenyl]propionic acid
503C32 N N2 O352
781-(2-ethoxyethyl)-3-(1-{3-[2-(2H-tetrazol-5-yl)-phenoxy]propyl}piperidine-4-yl)-1H-indole
475On 27 N N6 O238
791-(3-methylbutyl)-3-(1-{3-[2-(2H-tetrazol-5-yl)-phenoxy]propyl}piperidine-4-yl)-1H-indole
473S H36 N6 O40
801-(3-methylbutyl)-3-(1-{3-[4-(2H-tetrazol-5-yl)-phenoxy]propyl}piperidine-4-yl)-1H-indole
473S H36 N6 O21
812-(2-{4-[1-(2-ethoxyethyl)-5-methoxy-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-Formentera acids is
485On 27 H33 F N2 O525
822-(2-{4-[1-(2-ethoxyethyl)-5-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)-6-Formentera acid
473S H30 F2 N2 O433
832- (2-{4- [1-(2-ethoxyethyl) -6-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)-6-Formentera acid
473S H30 F2 N2 O433
842-(2-{4-[5-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-6-Formentera acid
534S H30 Br F N2 O440
852-(2-{4-[7-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-6-Formentera acid
534S H30 Br F N2 O440

Continuation of table 2
862-(2-{4-[5-chloro-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-6-Formentera acid
489S N Cl F N2 O451
872-(2-{4-[1-(2-ataxia the yl}-1H-indol-3-yl]piperidine-1-yl}ethoxy)-6-Formentera acid
455S n F N2 O422
883,5-dibromo-2-(2-{4-[1-(2-ethoxyethyl)-5-methoxy-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
625On 27 N Br2 N2 O425
893,5-dibromo-2-(2-{4-[1-(2-ethoxyethyl)-5-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
613S N Br2 N2 O433
903,5-dibromo-2-(2-{4-[1-(2-ethoxyethyl)-6-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
613S N Br2 F N2 O436
913,5-dibromo-2-(2-{4-[5-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
674S N Br3 N2 O423
923,5-dibromo-2-(2-{4-[7-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
674S N Br3 N2 O425
933,5-dibromo-2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
ÈA; 595S H30 Br2 N2 O425
942-(2-{4-[1-(2-ethoxyethyl)-6-fluoro-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-5-methylbenzoic acid
469On 27 H33 F N2 O433
952-(2-{4-[5-chloro-1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-5-methylbenzoic acid
486On 27 H33 Cl N2 O447



Continuation of table 2
962-(2-{4- [1-(2-ethoxyethyl)-5-methoxy-1H-indol-3-yl]piperidine-1-yl}ethoxy)-4-methoxybenzoic acid
498S H36 N2 O463
972-(2-{4-[1-(2-ethoxyethyl)-6-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)-4-methoxybenzoic acid
485On 27 N F N2 O546
982-(2-{4-[5-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-4-methoxybenzoic acid
546On 27 N Br N2 O524
992-(2-{4-[7-bromo-1-(2-eh is oxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-4-methoxybenzoic acid
546On 27 N Br N2 O571
1002-(2-{4-[5-chloro-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-4-methoxybenzoic acid
502On 27 N C1 N2 O524
1012-(2-{4-[1-(2-ethoxyethyl)-5-methoxy-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
467On 27 N N2 O533
1022-(2-{4-[1-(2-ethoxyethyl)-5-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
455S n F N2 O428
1032- (2-{4- [1- (2-ethoxyethyl)-6-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
455S n F N2 O456
1042-(2-{4-[5-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
516C26 H31 Br N2 O425
1052-(2-{4-[5-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid
530C7 N Br N2 O4 47

Continuation of table 2
1062-(2-{4-[5-chloro-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
 471S n Cl N2 O428
1072-{2-[4-(1-propyl-1H-indol-3-yl)piperidine-1-yl]-ethoxy}benzoic acid
 407C25 N N2 O322
1082-(2-{4-[1-(2-ISO-propoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
 451On 27 N N2 O432
1092-(2-{4-[1-(3-methoxypropyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
 437S N N2 O437
1102-(2-{4-[1-(2-ethoxyethyl)-4-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
 455S n F N2 O424
1112-(2-{4-[1-(2-ethoxyethyl)-4-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid
 469 C27 N F N2 O422
1122-(2-{4-[1-(2-ethoxyethyl)-4-fluoro-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-4-methoxybenzoic acid
 485On 27 N F N2 O520
1132-(2-{4-[4-fluoro-1-(2-methoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
 441C25 N F N2 O425
1142-(2-{4-[4-fluoro-1-(2-methoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid
 455S n F N2 O525
1152-(2-{4-[4-fluoro-1-(2-methoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-4-methoxybenzoic acid
 471S n F N2 O532
1165-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl] piperidine-1-yl}pentane acid
 373C22 N N2 O341

391
Continuation of table 2
1176-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}hexanoic acid
387C23 N N2 O346
1187-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}heptane acid
401C24 H36 N2 O341
1193-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}propoxy)propionic acid
403C23 N N2 O446
1202- (2-{4- [1- (2-ethoxyethyl)-7-methyl-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid
465On 27 N N2 O455
1212-(2-{4-[6-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
516S n Br N2 O434
1222-(2-{4-[6-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid
530On 27 H33 Br N2 O429
123(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethylthio)acetic acid
C21 H30 N2 O3 S72
124(4-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}butylthio)acetic acid
419C23 N N2 O3 S68
125(3-{3-[4-(1-cyclopropylmethyl-1H-indol-3-yl)-piperidine-1-yl]propoxy}phenyl)acetic acid
447S N N2 O349
126(4-{2-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}phenyl)acetic acid
433On 27 N N2 O336
127(3-{2-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}phenyl)acetic acid
433On 27 N N2 O343
1283-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-ylmethyl]benzoic acid
405S N N2 O235
1295-[4-(6-fluoro-1-pentyl-1H-indol-3-yl)piperidine-1-ylmethyl]-furan-2-carboxylic acid
413 C24 N F N2 O341
1303-[4-(6-fluoro-1-pentyl-1H-indol-3-yl)peridin-1-ylmethyl]benzoic acid
423S n F N2 O244
1312-(4-{4-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]butyryl}phenyl)-2-methylpropionate acid
487A31 N N2 O338
1323-{3-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]-propoxy}benzoic acid
433On 27 N N2 O345
1332-{2-[4-(1-cyclohexylmethyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid
461S H36 N2 O343

Example 134

Obtaining 2-(2-{4-[1-(2-allyloxymethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

A. Obtaining methyl ester 2-[2-(4-{1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)ethoxy] benzoic acid

To a suspension of 0.29 g (7 mmol) of a dispersion of 60% NaH in 10 ml of anhydrous DMF in the atmosphere of inert gas added a solution of 1.5 g (4 mmol) of methyl ester of 2-{2-[4-(1H-indol-3-yl)-Piperi the Jn-1-yl]ethoxy}benzoic acid, obtained in example 1 (stage D), in 5 ml of DMF. After 30 minutes at room temperature add a solution of 1.09 g (5.2 mmol) of 2-(2-bromoethoxy)tetrahydro-2H-Piran in 2 ml of DMF. The reaction mixture was stirred at room temperature for 15 hours. The solvent is removed under reduced pressure and the crude mixture is extracted, distributing between water and ethyl acetate. The organic phase is separated, dried and, after filtration, the solvent is removed under reduced pressure. The crude mixture was purified flash chromatography on silica gel, receiving 1.3 g (yield 65%) of the desired product.

MS=507 [(M+1)+, 338N25]

C. Obtaining 2-(2-{4-[1-(2-hydroxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

To a solution of 0.7 g (1.4 mmol) of the methyl ester 2-[2-(4-{1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)ethoxy]benzoic acid in 10 ml of methanol, add 10 ml of methanol saturated with hydrogen chloride. The crude mixture is heated to 70°C for 1 hour and the solvent is removed under reduced pressure. After adding 20 ml of water, the crude mixture is neutralized 2 N. NaOH and the aqueous phase extracted with chloroform. After removal of the solvent under reduced pressure to obtain 0.5 g of the desired product.

MS=423 [(M+1)+, 253N24]

C. Obtaining 2-(2-{4-[1-(2-allyloxymethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

To a suspension 0,012 g (0.04 mmol) of a dispersion of 60% NaH in 0.5 ml DMF) add a solution 0,042 g (0.01 mmol) of 2-(2-{4-[1-(2-hydroxyethyl)-1H-indol-3-yl)piperidine-1-yl}ethoxy)benzoic acid in 0.5 ml of DMF. After stirring at room temperature for 30 minutes, add a solution of 0.014 g (0.12 mmol) of allylbromide in 0.3 ml of DMF. The crude mixture is stirred at room temperature for 15 hours. The solvent is evaporated under reduced pressure and the crude mixture dissolved in 1 ml ethanol. Add 0.2 ml of aqueous 2 n NaOH solution and the mixture is heated to 60°C for 3 hours. The solvent is removed under reduced pressure and after adding 1 ml of water the mixture is neutralized 2 N. Hcl and extracted with chloroform. The crude mixture is purified by chromatography on silica gel, receiving 0.015 g (yield 33%) of the desired product.

MS=449 [(M+1)+, 2732N24]

NMR (CDCl3) δ=2,01-2,05 (m, 4H), 2,35-2,62 (m, 2H), 2,83-2,89 (m, 3H), 3,13-3,19 (d, 2H), 3.72 points-of 3.77 (t, 2H), 3,91-of 3.95 (t, 2H), 4,23-the 4.29 (t, 2H), to 4.41-to 4.46 (t, 2H), 5,12-a 5.25 (m, 2H), 5,74-5,90 (m, 1H), 6,97 was 7.45 (m, 7H), 7,55-7,58 (d, 1H), 7,88-to 7.93 (DD, 1H).

Examples 135 and 136

The compounds described in examples 135 and 136 receive the procedure described in example 134, ESI/MC data and outputs is given in table 3.

Table 3
ExampleESI/MC m/e [(M+1)+]Molecular formulaOutput (%)
1352-(2-{4-[1-(2-prop-2-insociety)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
 447On 27 N N2 O444
1362-(2-{4-[1-(2-propoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid
 451On 27 N N2 O451

Example 137

Getting 4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

A. Obtaining tert-butyl ester 4-(2-chloroethoxy) benzoic acid

A solution of 2 g (13,2 mmol) of methyl ester of 4-hydroxybenzoic acid in 30 ml of anhydrous DMF is added to a suspension of 0.68 g (17 mmol) of 60% NaH in 30 ml of anhydrous DMF at 0°C under nitrogen atmosphere. After stirring for 40 minutes at room temperature add 2.2 ml (17 mmol) of benzylbromide and stirred for further two hours. The reaction mixture was poured into water and extracted with ethyl acetate, the organic layer is dried over MgSO4after filtration and removal of solvent under reduced pressure, the crude mixture is purified by chromatography on a column of silica gel, receiving 3,18 g (yield 99%) of methyl ester 4-benzyloxybenzyl acid.

16 ml of 2 N. aqueous solution Li added to a solution of 3.0 g (12.5 mmol) of methyl ester 4-benzyloxybenzyl key is lots in 50 ml of THF and the mixture is heated at boiling temperature under reflux overnight. The reaction mixture podkalyvayut 6 N. Hcl and extracted with ethyl acetate, getting after filtration and removal of solvent under reduced pressure 2.8 g (yield 93%) of 4-benzyloxybenzyl acid.

To be heated at the boiling point under reflux a solution of 0.96 g (4.2 mmol) of 4-benzyloxybenzyl acid in benzene is added slowly to 3.45 g (17 mmol) of di-tert-butoxydiethylene for 20 minutes and the mixture is heated at boiling temperature under reflux for 40 minutes. After cooling to room temperature the reaction mixture was poured into a saturated aqueous solution Panso3and extracted with ethyl acetate. The organic layer is dried over gS4after filtration and removal of solvent under reduced pressure the crude mixture is purified by chromatography on a column of silica gel, receiving 1.2 g of tert-butyl methyl ether 4-benzyloxybenzyl acid.

0.36 g of 10% palladium on charcoal are added to a solution of 1.2 g (4.3 mmol) of tert-butyl methyl ether 4-benzyloxybenzyl acid in 45 ml of ethanol and the resulting mixture hydronaut at 20 psi (1,406 kg/cm2) for 3 hours. After filtration through celite and removal of solvent under reduced pressure gain of 0.79 g (yield 95%) of tert-butyl methyl ether 4-hydroxybenzoic acid.

Mixture of 0.79 g (4.1 mmol) of tert-butyl methyl ether 4-HYDR what ximenting acid, 1.13 g (8,14 mmol) To a2CO3and 1.6 ml (16.3 mmol) of 1-bromo-2-chlorethane in 10 ml of isobutylmethylxanthine heated at boiling temperature under reflux for 5 hours. After filtration the solvent is removed under reduced pressure, receiving and 0.98 g (yield 94%) of tert-butyl ester 4-(2-chloroethoxy)benzoic acid.

C. Obtain 4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

4-(2-{4 -[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}-ethoxy)benzoic acid is obtained using the General procedure described in example 1 (part D), starting from 0.1 g (0.5 mmol) 3-piperidine-4-yl-1H-indole, 0.26 g (0.5 mmol) of tert-butyl ester 4-(2-chloroethoxy)benzoic acid, 0.08 g (0.6 mmol) of potassium carbonate and 0.04 g (0.2 mmol) of potassium iodide in 1.5 ml of isobutylmethylxanthine in the first stage alkylation obtain 0.09 g (yield 44%) of 4-{2-[4-(1H-indol-3-yl)piperidine-1-yl]-ethoxy}benzoic acid. 0.05 g (0.11 mmol) 4-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid is subjected to N-indole alkylation using 0,028 g (of 0.68 mmol) of 60% NaH and 0.02 ml (0.15 mmol) 2-pomatomidae in 1 ml of anhydrous DMF, receiving 0.06 g (yield 100%) of 4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)beioley acid.

MS=437 [(M+1)+, S N N2 O4]

NMR (CDCl3) δ=1,11-of 1.16 (t, 3H), 2,27 at 2.45 (m, 4H), 2,96-3,10 (m, 4H), 3,41 is-3.45 (m, 2H), 3,71-of 3.80 (m, 6N), 4,10-of 4.25 (m, 2H), 4,40-4,60 (m, 2H), 6,84-a 7.85 (m, N).

Example 138

aluchemie 2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

A. Obtaining methyl - 2-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoate

10 g (0.05 mol) of 4-(3-indolyl)piperidine, 16,1 g (0,075 mol) methyl ester of 2-(2-chloroethoxy)benzoic acid obtained in example 1 (parts a and b), 31.1 g (0,225 mol) of potassium carbonate and of 1.33 g (0,008 mol) of potassium iodide are suspended in 90 ml of isobutyl ketone. The resulting mixture is heated at boiling temperature under reflux for 24 hours Upon completion of the reaction, the inorganic salts are filtered and the liquid phase is evaporated to dryness. The remaining product is again dissolved in dichloromethane and water, and treated in the usual way. The crude mixture was purified flash chromatography on silica gel, receiving 9,58 g (51%yield) of methyl 2-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoate.

Melting point 124-125°C.

C. Obtaining methyl-2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoate

8.0 g (0,021 mol) of methyl 2-{2-[4-(1H-indol-3-yl)-piperidine-1-yl]ethoxy}benzoate was dissolved in 125 ml of DMF and, at room temperature, carefully add 1.12 g (0,028 mol) of 60% sodium hydride. The resulting mixture is stirred for half an hour. Added dropwise to 2.9 ml (0,023 mol) 2-Bromeliaceae ether and stirring is continued for 4 hours the Solvent is evaporated under reduced pressure and the residue is treated in the usual way. The crude mixture was purified flash chromatography on silica gel, receiving 4.12 g (Ihad 54%) of methyl 2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoate.

C. Obtaining 2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

1,05 g (2,33 mmol) of 2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoate are dissolved in 30 ml of ethanol. The solution to 0.19 g (of 4.66 mmol) of sodium hydroxide in 30 ml water is added to the previous solution and the entire mixture is heated to 60°C for 2 h After dilution with water and neutralization 6 N. Hcl aqueous phase is shaken out three times with chloroform. The organic solution was washed with saturated salt solution, dried over sodium sulfate, filtered and evaporated to dryness. 4,06 g of crude substance is recrystallized from acetonitrile, receiving of 2.54 g (yield 64%) of 2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid.

Melting point 147,6-148,9°C.

MS=437(M+1)+, C2632N24]

NMR (CDCl3) δ=of 1.05 (t, 3H), and 1.9 (m, 5H), and 2.6 (t, 1H), 2,9 (m, 3H), 3,2 (m, 2H), 3,4 (kV, 2H), and 3.7 (t, 2H), 4,3 (t, 2H), and 5.5 (m, 1H), 4,5 (m, 2H), of 7.0 to 7.7 (m, 8H).

Example 139

Obtaining 2-(2-{4-[1-(3-methylbutyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

The specified connection get the procedure described in example 138 (part b), starting from 3 g (7.9 mmol) of methyl 2-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoate, 0.54 g (13.5 mmol) of 60% NaH in mineral oil and 1.67 g (11,08 mmol) 3-methylbutylamine. The crude mixture was hydrolized by the procedure described in example 138 (part C), and purified by chromatography on silica compound is barely, obtaining 2.7 g (yield 77%) of the desired product.

Melting point =150-151°C.

ESI/MC m/e =435 [(M+1)+, 2734N23]

NMR (300 MHz, DMSO) δ=0,91-0,93 (d, 6N), 1,48-to 1.67 (m, 3H), 1,92-to 1.98 (m, 4H), 2,62-of 2.66 (m, 2H), 2,88-2,99 (m, 3H), 3,21-of 3.25 (d, 2H), 4.09 to to 4.14 (t, 2H), 4,42-of 4.54 (t, 2H), 4,90-5,10 (users, 1H), of 6.96-7,14 (m, 4H), 7,21-7,24 (d, 2H), was 7.36-7,39 (m, 2H), 7,53-7,56 (DD, 1H), 7,63-7,66 (d, 1H).

Example 140

Obtaining 2-(2-{4-[1-(2-methoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

The specified connection get the procedure described in example 138 (part b), starting from 3 g (7.9 mmol) of methyl 2-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoate, 0.54 g (13.5 mmol) of 60% NaH in mineral oil and 1.04 ml (11,08 mmol) pomatoleios ether. The crude mixture was hydrolized by the procedure described in example 138 (part C), and purified by chromatography on silica gel, receiving 1.3 g (yield 39%) of the desired product.

Melting point =139-140°C.

ESI/MC m/e =423 [(M+1)+, 2530N24]

NMR (300 MHz, DMSO) δ=1,91-to 1.98 (m, 4H), 2,61-2,69 (m, 2H), 2.91 in-2,99 (m, 3H), 3,62-the 3.65 (t, 2H), 4.25 in-the 4.29 (t, 2H), 4,42 is 4.45 (t, 2H), 5,20-6,00 (users, 1H), 6,97-7,14 (m, 4H), 7,22-7,24 (d, 1H), was 7.36-7,42 (m, 2H), 7,53-of 7.55 (d, 1H), 7,63-7,66 (d, 1H).

Example 141

Getting 2-{2-[4-(1-allyl-1H-indol-3-yl)piperidine-1-yl]-ethoxy}benzoic acid

The specified connection get the procedure described in example 138 (part b)on the basis of 2.8 g (7.4 mmol) of methyl 2-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoate, 0,38 g (9.6 mmol) of 60% NaH in the o enable increases oil and 0.77 ml (8.9 mmol) of allylbromide. The crude mixture was hydrolized by the procedure described in example 138 (part C), and purified by chromatography on silica gel, receiving of 0.62 g (yield 23%) of the desired product. Melting point =123-125°C. ESI/MC m/e =405 [(M+1)+, C25 N N2 O3]

NMR (300 MHz, Dl3) δ=1,96 of-2.32 (m, 4H), 2,34-to 2.41 (m, 2H), and 2.83-2.91 in (m, 3H), 3,12-and 3.16 (d, 2H), 4,40-of 4.35 (t, 2H), 4,66-and 4.68 (m, 2H), 5.08 to a total of 5.21 (m, 2H), 5,93-6,92 (m, 3H), 7,00 (s, 1H), 7.03 is-7,31 (m, 5H), 7,40-7,46 (t, 1H}, EUR 7.57-of 7.60 (d, 1H), 7,88-to $ 7.91 (DD, 1H).

Example 142

Obtaining 2-(2-{4-[1-(2-ethoxyethyl)-5-methoxy-1H-indol-3-yl]piperidine-1-yl)ethoxy)-5-methylbenzoic acid

A. obtaining the ethyl ester of 2-(2-chloroethoxy)-5-methylbenzoic acid

The specified connection receive according to the method described in example 1 (part C), starting from 5 g (27.8 mmol) of ethyl ester of 2-hydroxy-5-methylbenzoic acid, 7.9 g (of 55.5 mmol) 1-bromo-2-chlorethane and 7.7 g (of 55.5 mmol) of potassium carbonate. After processing and purification obtain 4.5 g (yield 68%) of the desired product.

NMR (300 MHz, CDCl3) δ=1,37-of 1.42 (t, 3H), 2,31 (s, 3H), 3,82-3,86 (t, 2H), 4,24-to 4.28 (t, 2H), 4,32-4,39 (kV, 2H), 6,86-6,89 (d, 1H), 7.23 percent-7,26 (m, 1H), to 7.59-of 7.60 (d, 1H).

C. Obtain 5-methoxy-3-piperidine-4-yl-1H-indole

The specified connection receive according to the method described in example 1 (parts a and b), starting from 5 g (33,9 mmol) 5-methoxyindole and 13.2 g (86,2 mmol) of the hydrochloride of 4-piperidineacetate. After the usual processing gain of 6.5 g (yield 83%) of the desired product.

ESI/MC m/e =231 [(M+1)+ , 1418N2].

C. Obtaining 2-(2-{4-[1-(2-ethoxyethyl)-5-methoxy-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid

The specified connection get the procedure described in example 138 (part b)on the basis of 1.4 g (3.2 mmol) of the ethyl ester of 2-{2-[4-(5-methoxy-1H-indol-3-yl)piperidine-1-yl]-ethoxy}-5-methylbenzoic acid (obtained in example 138, part a), 0.17 g (4.2 mmol) of 60% NaH in mineral oil and 0.43 ml (3.8 mmol) Bromeliaceae ether. The crude mixture was hydrolized by the procedure described in example 138 (part C), and purified by chromatography on silica gel, receiving 0,470 g (yield 35%) of the desired product.

Melting point =144-146°C.

ESI/MC m/e =481 [(M+1)+, 2836N25]

NMR (300 MHz, CDCl3) δ=1,02-of 1.07 (m, 3H), 1,90-2,05 (m, 4H), 2,10-of 2.25 (m, 3H), 2,50-to 2.65 (m, 2H), 2,80 was 3.05 (m, 3H), 3,20 is 3.23 (d, 2H), 3,36-3,39 (m, 2H), 3,50-to 3.64 (m, 2H), 3,80 (s, 3H), 4,10-of 4.25 (m, 2H), 4,30-4,45 (m, 2H), 6.73 x-6,76 (d, 1H), 7,09-to 7.15 (m, 4H), 7,31-7,35 (m, 2H).

Example 143

Obtaining 2-(2-{4-[7-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-5-methylbenzoic acid

A. Obtain 7-bromo-3-piperidine-4-yl-1H-indole

The specified connection receive according to the method described in example 1 (parts a and b)on the basis of 0.95 g (4.8 mmol) of 7-bromoindole and 1.89 g (12.3 mmol) of the hydrochloride of 4-piperidineacetate. After the usual processing gain of 1.1 g (yield 89%) of the desired product.

ESI/MC m/e =280 [{M+1)+, 1315BrN2]

C. Obtaining 2-(2-{4-[7-bromo-1-(2-ataxia who yl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid

The specified connection get the procedure described in example 138 (part b)on the basis of 1.6 g (3.3 mmol) of methyl ester of 2-{2-[4-(7-bromo-1H-indol-3-yl)piperidine-1-yl]-ethoxy}-5-methylbenzoic acid (obtained in example 138, part a), 0.17 g (4.2 mmol) of 60% NaH in mineral oil and 0.45 ml (4 mmol) Bromeliaceae ether. The crude mixture was hydrolized by the procedure described in example 138 (part C), and purified by chromatography on silica gel, receiving 0.26 g (yield 34%) of the desired product.

ESI/MC m/e =530 [(M+1)+, 2733BrN24]

NMR (300 MHz, CDCl3) δ=1,12-of 1.18 (t, 3H), 1,97 is 2.00 (m, 4H), 2,32 (s, 3H), 2,73-to 3.09 (m, 5H), 3,09-3,13 (d, 2H), 3,41-of 3.48 (q, 2H), 3,76-of 3.80 (t, 2H), to 4.38-to 4.41 (t, 2H), 4,66-4,70 (t, 2H), 6,88-6,97 (m, 3H), 7.23 percent-of 7.25 (m, 1H), 7,50-7,52 (d, 1H), 7,73-7,74 (d, 1H).

Example 144

Obtaining 2-(2-{4-[7-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

The specified connection get the procedure described in example 138 (part b)on the basis of 1.4 g (3.1 mmol) of methyl ester of 2-{2-[4-(7-bromo-1H-indol-3-yl)piperidine-1-yl]-ethoxy}benzoic acid (obtained in example 138, part a), 0.16 g (3.7 mmol) of 60% NaH in mineral oil and 0.42 ml (3.7 mmol) Bromeliaceae ether. The crude mixture was hydrolized by the procedure described in example 138 (part C), and purified by chromatography on silica gel, receiving 0.34 g (yield 28%) of the desired product.

ESI/MC m/e =516 [(M+1)+, S n Br N2 O4]

NMR (300 MHz, Dl3) δ=1,13-of 1.52 (t, 3H), 1,9-2,04 (m, 4H), 2,32-of 2.38 (m, 2H), 2,78-is 2.88 (m, 3H), 3,11-3,14 (d, 2H), 3,40-of 3.48 (m, 2H), 3.72 points was 4.42 (m, 2H), 4,42 is 4.45 (t, 2H), 4,66-4,70 (t, 2H), 5,75 of 5.84 (users, 1H), 6,88-6,97 (m, 2H), 7,05-7,13 (m, 2H), 7,32-7,34 (d, 1H), 7,49-7,53 (m, 2H), to $ 7.91-of 7.95 (d, 1H).

Example 145

Obtaining 2-(2-{4-[1-(2-ethoxyethyl)-5-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid

A. Obtain 5-fluoro-3-piperidine-4-yl-1H-indole

The specified connection receive according to the method described in example 1 (parts a and b)on the basis of 0.7 g (5.5 mmol) of 5-farindola and 2.1 g (to 13.6 mmol) of the hydrochloride of 4-piperidineacetate. After the usual processing gain of 0.8 g (yield 67%) of the desired product.

ESI/MC m/e =219 [(M+1)+, 1315FN2]

C. Obtaining 2-(2-{4-[1-(2-ethoxyethyl)-5-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid

The specified connection get the procedure described in example 138 (part b), based on 0,014 g (0,034 mmol) methyl ester 2-{2-[4-(5-fluoro-1H-indol-3-yl)piperidine-1-yl]-ethoxy}-5-methylbenzoic acid (obtained in example 138 (part a), 0.003 g (0.08 mmol) of 60% NaH in mineral oil and 0.046 ml (0,044 mmol) Bromeliaceae ether. The crude mixture was hydrolized by the procedure described in example 138 (part C), and purified by chromatography on silica gel, receiving 0.005 g (yield 33%) of the desired product.

ESI/MC m/e =469 [(M+1)+, 2733FN24]

NMR (300 MHz, CDCl3) δ=1,02 was 1.06 (m, 3H), 1,87-2,05 (m, 4H), 2,15 was 2.25 (m, 3H), 2,60-by 2.73 (m, 2H), 2,87-3,10 (m, 3H), 3,20-3,24 (d, 2H), 3,35-to 3.38 (m, 2H), 3,64-to 3.67 (t,2H), 4,25-the 4.29 (t, 2H), 4,35 was 4.42 (m, 2H), 6,95-7,49 (m, 7H).

Example 146

Obtaining 2-(2-{4-[1-(2-ethoxyethyl)-5-fluoro-1H-indol-3-yl]-piperidine-1-yl}ethoxy)-4-methoxybenzoic acid

A. Obtain methyl ester of 2-(2-chloroethoxy)-4-methoxybenzoic acid

The specified connection receive according to the method described in example 1 (part C), starting from 5 g (a 27.4 mmol) of methyl ester of 2-hydroxy-5-methylbenzoic acid, 9 ml (60,3 mmol) 1-bromo-2-chlorethane and 5.9 g (42.8 mmol) of potassium carbonate. After processing and purification obtain 6.6 g (yield 99%) of the desired product.

NMR (300 MHz, Dl3) δ=3,81-to 3.89 (m, 8H), 4.26 deaths-4,30 (t, 2H), 6.48 in-of 6.49 (d, 1H), 6,54 return of 6.58 (DD, 1H), 7,85-7,88 (d, 1H).

C. Obtaining 2-(2-{4-[1-(2-ethoxyethyl)-5-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)-4-methoxybenzoic acid

The specified connection get the procedure described in example 138 (part b), based on 0,024 g (0,056 mmol) methyl ester 2-{2-[4-(5-fluoro-1H-indol-3-yl)piperidine-1-yl]ethoxy}-4-methoxybenzoic acid (obtained in example 138, part a), 0.005 g (0.12 mmol) of 60% NaH in mineral oil and 0,076 ml (0,072 mmol) Bromeliaceae ether. The crude mixture was hydrolized by the procedure described in example 138 (part C), and purified by chromatography on silica gel, receiving 0,012 g (yield 44%) of the desired product.

ESI/MC m/e =485 [(M+1)+, 2733FN25]

NMR (300 MHz, DMSO) δ=1,01 was 1.06 (t, 3H), 1,81-2,05 (m, 4H), 2,58-2,70 (m, 2H), 2,81 of 2.92 (m, 2H), 2.95 and-is 3.08 (m, 3H), 3,29 at 3.69 (m, 5H), of 3.77 (s, 3 is), 4,25-to 4.28 (t, 2H), of 4.38 was 4.42 (t, 2H), 6,61-of 6.65 (DD, 1H), 6,77-of 6.78 (d, 1H), 7,21 (s, 1H), was 7.36-7,40 (DD, 1H), 7,44-of 7.48 (DD, 1H), 7,63-7,66 (d, 1H).

Example 147

Obtaining 2-(2-{4-[1-(2-ethoxyethyl)-7-methyl-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid

A. Obtain 7-methyl-3-piperidine-4-yl-1H-indole

The specified connection receive according to the method described in example 1 (parts a and b), based on 1 g (7.6 mmol) of 7-methylindole and 2.9 g (19 mmol) of the hydrochloride of 4-piperidineacetate. After the usual processing gain of 0.8 g (yield 50%) of the desired product.

ESI/MC m/e =215 [(M+1)+, C14 n N2]

C. Obtaining 2-(2-{4-[1-(2-ethoxyethyl)-7-methyl-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

The specified connection get the procedure described in example 138 (part b), based on 0,068 g (0,172 mmol) methyl ester 2-{2-[4-(7-methyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid (obtained in example 138, part a), 0,010 g (0.26 mmol) of 60% NaH in mineral oil and is 0.023 ml (0.22 mmol) Bromeliaceae ether. The crude mixture was hydrolized by the procedure described in example 138 (part C), and purified by chromatography on silica gel, receiving 0,074 g (yield 93%) of the desired product.

ESI/MC m/e =451(M+1)+, C27H34N24]

NMR (300 MHz, DMSO) δ=1,02-of 1.07 (t, 3H), 1,92-2,11 (m, 4H), to 2.65 (s, 3H), 2,60-2,78 (m, 2H), 2,81 totaling 3.04 (m, 3H), 3,24 of 3.28 (d, 2H), 3,32 is 3.40 (q, 2H), 3,62-3,66 (t, 2H), 4,43-4,47 (m, 4H), 5,00-5,18 (users, 1H), 6,85-6,91 (m, 2H), 7,00-7,05 (m, 2H), 7,22-7,24 (d, 1H), 7,37-7,47 (m, 2H), 7,54-7,56 (d, 1H).

P the emer 148

Getting 2-{2-[4-(1-butyl-1H-indol-3-yl)piperidine-1-yl]-ethoxy}benzoic acid

The specified connection get the procedure described in example 138 (part b)on the basis of 0,119 g (0.31 mmol) of methyl ester of 2-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid, of 0.022 g (of 0.53 mmol) of 60% NaH in mineral oil and 0.044 ml (0.41 mmol) of butylated. The crude mixture was hydrolized by the procedure described in example 138 (part C), and purified by chromatography on silica gel, receiving 0,054 g (yield 42%) of the desired product.

ESI/MC m/e =421 [(M+1)+, S N N2 O3]

NMR (300 MHz, DMSO) δ=0,86-of 0.91 (t, 3H), 1,21-of 1.29 (m, 2H), 20 1,68 is 1.96 (m, 6N), 2,32 is 2.43 (m, 2H), 2,80-2,84 (m, 3H), 3,12-and 3.16 (d, 2H), 4,08-of 4.12 (t, 2H), 4,22-4.26 deaths (t, 2H), 6,85-7,25 (m, 6N), 7,31-7,33 (d, 1H), 7,39-7,42 (d, 1H), to 7.59-to 7.61 (d, 1H).

Example 149

Getting 2-{2-[4-(1-hexyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

The specified connection get the procedure described in example 138 (part b)on the basis of 0,119 g (0.31 mmol) of methyl ester of 2-{2-[4-(1H-indol-3-yl)piperidine-1-yl]-ethoxy}benzoic acid, of 0.022 g (0.52 mmol) of 60% NaH in mineral oil and 0,058 ml (0.41 mmol) of hexylidene. The crude mixture was hydrolized by the procedure described in example 138 (part C), and purified by chromatography on silica gel, receiving 0,047 g (yield 34%) of the desired product.

ESI/MC m/e =449 [(M+1)+, 2836N203]

NMR (300 MHz, DMSO) δ=0,81-of 0.85 (m, 3H), 1.20-1.25 range (m, 6N), 1,68-of 1.94 (m, 6N), 2,29-of 2.36 (m, 2H), 2,73-2,84 (m, 2H), 3,10-3,14 (d, 2H), 4,06 of 4.1 (t, 2H), 4,15-is 4.21 (m, 2H), 6.87 in for 7.12 (m, 5H), 7,19-7,25 (m, 1H), 7,37-7,41 (m, 2H), 7,58-of 7.60 (d, 1H).

Example 150

Getting 2-{2-[4-(1-cyclopropylmethyl-S-fluoro-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

A. Obtaining methyl ester 2-{2-[4-(6-fluoro-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

The specified connection get the procedure described in example 138 (part a), from 1.2 g (5.5 mmol) of 6-farindola obtained by the method of example 1 (part a and b), and 1.53 g (7.2 mmol) of the methyl ester of 2-(2-chloroethoxy)benzoic acid, to obtain 2.1 g (yield 96%) of the desired product.

ESI/MC m/e=397 [(M+1)+, 2325FN23]

C. Obtain 2-{2-[4-(1-cyclopropylmethyl-6-fluoro-1H-indol-3-yl)piperidine-1-yl] ethoxy}benzoic acid

The specified connection get the procedure described in example 138 (part b), from 2 g (5.1 mmol) of methyl ester of 2-{2-[4-(6-fluoro-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid, 0.51 g (12.8 mmol) of 60% NaH in mineral oil and 0.99 ml (10.2 mmol) of cyclopropanemethylamine. The crude mixture was hydrolized by the procedure described in example 138 (part C), and purified flash chromatography on silica gel, getting 0.32 g (yield 18%) of the desired product.

Melting point =97°C.

ESI/MC m/e =437 [(M+1)+, 2629FN23]

NMR (300 MHz, CDCl3) δ=0,33-0,38 (m, 2H), 0,59-0,66 (m, 2H), 1,21-of 1.27 (m, 1H), 1,95-2,10 (m, 4H), 2,33-to 2.41 (m, 2H), 2,80-to 2.85 (m, 3H), 3,13-3,17 (m, 2H), 3,84-3,86 (m, 2H), to 4.41-of 4.44 (t, 2H), 6,50 (users,1H), to 6.80-6.87 in (t, 1H), of 6.96 for 7.12 (m, 4H), 7,41-7,47 (m, 2H), of 7.90-to 7.93 (t, 1H).

Example 151

Getting 2{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy} benzoic acid

A solution of 1.33 g (33 mmol) of sodium hydroxide in 120 ml of water is added to a suspension of 6.31 g (of 16.6 mmol) methyl ester 2-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy)benzoic acid (obtained by the method of example 1, part D) in 120 ml of ethanol.

The resulting mixture was heated to 60°C for 3 hours and the solvent is removed under reduced pressure. After adding 50 ml of water, the crude mixture is neutralized 2 N. Hcl and separate the formed solid product. After recrystallization from acetonitrile obtain 2.6 g (yield 43%) of a white solid corresponding to the desired product.

Melting point =230°C.

ESI/MC m/e =365 [{M+1)+, 2224N23]

NMR (300 MHz, Dl3) δ=1,91-2,07 (m, 4H), 2,53-of 2.72 (m, 2H), 2,86 are 2.98 (m, 3H), 3,19 is 3.23 (d, 2H), to 4.38-of 4.44 (m, 2H), 6,93-to 7.09 (m, 4H), 7,21-7,24 (d, 1H), 7,33-7,42 (m, 2H), 7,54-7,56 (d, 1H), 7,62-to 7.64 (d, 1H).

Example 152

Getting 4-{2-[4-(1-(2-ethoxyethyl)-1H-indol-3-yl)-piperidine-1-yl]ethoxy}benzoic acid

(an alternative way of obtaining)

A. obtaining the ethyl ester of 4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid

5 g of 3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole, obtained by the method of example 1 (part a), dissolved in 25 ml of dichloromethane and to the solution add 3,22 g of triethylamine. The well is the first temperature between 20 and 25° With added dropwise 3,14 g ethylchloride. The mixture is stirred for 2 hours and add 20 ml of water. The organic layer is separated and the solvent is removed under reduced pressure, obtaining with 5.22 g of a colorless oil.

C. obtaining the ethyl ester of 4-(1H-indol-3-yl)piperidine-1-carboxylic acid

In a sealed steel vessel dissolve of 5.1 g of ethyl ester of 4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (13.5 ml of methanol. The solution hydronaut at a pressure of 8-10 KP/cm2using 0.8 g of 10% palladium on coal as a catalyst. The mixture was stirred at 20-25°With 12 hours. The catalyst was removed and the solvent is distilled off. Add a mixture of methanol/water 85:15 and collect 4.12 g (yield 80%) of a white solid.

Melting point: 114-116°C.

C. obtaining the ethyl ester of 4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-carboxylic acid

0.75 g of 60% suspension of sodium hydride in mineral oil are suspended in 20 ml of dry DMF and added to the mixture of 4 g of ethyl ester of 4-(1H-indol-3-yl)piperidine-1-carboxylic acid. Added dropwise at room temperature 1,91 g 2-chloroethylamino ether and the mixture is stirred for 16 hours at 20-25°C. Carefully add water and using ethyl acetate as the extraction solvent. The organic layer is separated and washed with water. The solvent is removed under reduced pressure, polucha,58 g of a colorless oil. The product is then crystallized from a mixture of methyl tert-butyl ether/hexane, getting not quite white solid.

Melting point: 56-58°C.

D. Obtaining 4-[1-(2-ethoxyethyl)indol-3-yl]piperidine

4 g of ethyl ester of 4-[1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-carboxylic acid and 3,81 g of 85% potassium hydroxide is added to 14 g of 2-propanol and the mixture is heated to 95-100°C for 16 hours. The solvent is distilled off and water is added. The mixture is extracted with toluene and the organic layer was separated, washed with water and concentrated. The residue is dissolved in a mixture of 10 ml of 96% ethanol and 6 ml of 2-propanol and added 1.4 g of fumaric acid. The mixture is heated at the boiling point under reflux for 30 minutes. After cooling to 0-5°C for 30 minutes resulting solid product is separated by filtration with suction, of 4.05 g of the white solid isolated in the form of a salt product with fumaric acid.

Melting point: 166-168°C.

E. Obtain 4-{2-[4-(1-(2-ethoxyethyl)-1H-indol-3-yl)-piperidine-1-yl]ethoxy}benzoic acid

0.5 g (of 1.84 mmol) 4-[1-(2-ethoxyethyl)indol-3-yl]-piperidine and 0.55 g (2.4 mmol) of ethyl-4-chlorocarbonate dissolved in 6 ml of 4-methyl-2-butanone and add 0,38 g (was 2.76 mmol) of potassium carbonate. The mixture is heated at the boiling point under reflux for 18 hours and after cooling add the ode, the organic layer was separated, washed with water and saturated salt solution. The solvent is distilled off. The resulting crude product is dissolved in 3 ml 965 ethyl alcohol and add 2 ml of 2 N. aqueous sodium hydroxide solution. After stirring at room temperature for 18 hours, the mixture is neutralized with a 10% solution of sulfuric acid. Foamy solid product (0,390 g, yield 65%) is collected, washed with water and dried.

Melting point: 85°C.

Example 153

Obtain 3 -{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}propionic acid

To a solution of 0.5 g (of 1.84 mmol) 4-[1-(2-ethoxyethyl)indol-3-yl)piperidine obtained by the method of example 152 (part D), in 6 ml of ethyl alcohol add 0,240 g (2.4 mmol) acrylate. The mixture is heated at the boiling point under reflux for 18 hours and the solvent is removed under reduced pressure. The residue is extracted by distributing between water and ethyl acetate. The crude product obtained after removal of solvent, dissolved in 3 ml of ethanol and add 2 ml of 2 N. aqueous sodium hydroxide solution. The mixture is stirred at room temperature for 18 hours and then neutralized 6 N. Hcl. After extraction with chloroform and evaporation of the solvent allocate 0,420 g (67%) of a yellow oil.

ESI/MC m/e =345 [(M+1)+, C2028N23]

NMR (300 MHz, DMSO) δ=1,01 was 1.06 (t, 3H), 1,83-2,05 (m, 4H), 2,61 is 2.75 (m, 4H), 2,9-3,15 (m, 3H), 3,29-to 3.41 (m, 4H), 3,63-to 3.67 (m, 2H), 4,21-4,27 (m, 2H), 6,93-7,07 (m, 1H), 7,11-to 7.15 (m, 2H), 7,43 (d, 1H), to 7.59-to 7.61 (d, 1H).

Example 154

Obtaining 2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid

The specified connection get the procedure described in example 152 (parts D and E)on the basis of 0,85 g (3.1 mmol) of 1-(2-ethoxyethyl)-3-piperidine-4-yl-1H-indole, 0.97 g (4.0 mmol) of the methyl ester of 2-(2-chloroethoxy)-5-methylbenzoic acid, 0.65 g (4.7 mmol) of potassium carbonate and 0.38 g (2.3 mmol) of potassium iodide. After saponification and purification on silica gel obtain 0.52 g (36%) of the corresponding carboxylic acid.

Melting point: 109-112°C.

ESI/MC m/e =451 [(M+1)+, 2734N24]

NMR (300 MHz, CDCl3) δ=1,12-to 1.19 (t, 3H), 2,01-2,05 (m, 4H), 2,31 (s, 3H), 2,36-2,39 (m, 2H), 2,80-2,84 (t, 2H), 2,85-2,90 (m, 1H), 3,13-and 3.16 (d, 2H), 3,42-to 3.49 (q, 2H), 3.72 points is 3.76 (t, 2H), 4,22-4,27 (t, 2H), of 4.38 was 4.42 (t, 2H), 6,10-6,20 (users, 1H), 6,94-7,26 (m, 5H), 7,33 and 7.36 (d, 1H), 7,56-to 7.59 (d, 1H), 7,71 (s, 1H).

Example 155

Getting 2-[4-(4-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}butyryl)phenyl]-2-methylpropionic acid

The specified connection get the procedure described in example 152 (parts D and E), starting from 0.1 g (0,37 mmol) 1-(2-ethoxyethyl)-3-piperidine-4-yl-1H-indole, 0,142 g (0.48 mmol) of methyl ester of 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropionic acid, 0.07 g (0.48 mmol) of potassium carbonate and 0.04 g (0.24 mmol) of potassium iodide.

ESI/MC m/e =505 [(M+1)+, 3140N24]

NMR (300 MHz, DMSO) ; =1,02 was 1.06 (t, 3H)and 1.51 (s, 6N), 1,98-of 2.50 (m, 6N), 2,73-2,96 (m, 5H), 3,10-3,14 (t, 2H, 3,31-of 3.42 (m, 4H), 3,64-to 3.67 (t, 2H), 4,24-4,27 (t, 2H), 6,97-7,02 (t, 1H), 7,09-7,14 (m, 2H), 7,43 to 7.62 (m, 3H), 7,62-of 7.64 (d, 1H), 7,94-of 7.96 (m, 2H).

Example 156

Obtain 1-(2-ethoxyethyl)-3-(1-{3-[4-(2H-tetrazol-5-yl)-phenoxy]propyl}piperidine-4-yl)-1H-indole

A. Obtain 4-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-yl}propoxy)benzonitrile.

A solution of 0.32 g (of 1.34 mmol) of 4-(3-bromopropane)-benzonitrile in 1 ml of isobutylmethylxanthine added to a mixture of 0.28 g (1,03 mmol) 1-(2-ethoxyethyl)-3-piperidine-4-yl-1H-indole obtained in example 142 (part D), 0.21 g (1.6 mmol) of potassium carbonate and 0.13 g (0.8 mmol) of potassium iodide (4.5 ml isobutylmethylxanthine. The reaction mixture is heated at the boiling point under reflux for 16 hours and after filtration of the inorganic salts, the solvent is removed under reduced pressure. The crude mixture was purified flash chromatography on silica gel, receiving 0.31 g (yield 70%) of 4-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}propoxy)-benzonitrile.

NMR (300 MHz, CDCl3) δ=1,12-to 1.19 (t, 3H), 1,87-of 2.26 (m, 8H), 2.57 m-of 2.64 (t, 2H), 2,80 of 2.92 (m, 1H), 3,07-3,13 (d, 2H), 3,37-of 3.48 (q, 2H), 3,69-3,74 (t, 2H), 4,07 is 4.13 (t, 2H), 4,21-4,27 (t, 2H), 6,93-to 7.35 (m, 5H), 7,35-7,65 (m, 4H).

C. Obtain 1-(2-ethoxyethyl)-3-(1-{3-[4-(2H-tetrazol-5-yl)phenoxy]propyl}piperidine-4-yl)-1H-indole

The solution to 0.108 g (0.25 mmol) of 4-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}propoxy)benzonitrile 1.5 ml betwo the aqueous DMF add 0,110 g (2 mmol) of ammonium chloride and is 0.135 g (2 mmol) of sodium azide. The crude mixture is heated to 110°C for 18 hours and after cooling to room temperature, add 1 ml of aqueous 2 n sodium hydroxide. The mixture is brought to pH 6 and the aqueous phase extracted with ethyl acetate. After purification with flash chromatography on silica gel get 0.05 g (yield 41%) of the desired product.

ESI/MC m/e =475 [(M+1)+, 2734N62]

NMR (300 MHz, DMSO) δ=1,02-of 1.07 (t, 3H), 1,92-2,11 (m, 2H), 2,14-2,49 (m, 4H), 2,94-to 3.02 (m, 3H), 3,11 -, and 3.16 (t, 2H), 3,47-3,51 (d, 2H), 3,64-3,68 (t, 2H), 4,12-of 4.16 (t, 2H), 4.25 in-the 4.29 (t, 2H), 6,98-to 7.18 (m, 5H), 7,44-7,47 (d, 1H), 7,62-to 7.64 (d, 1H), 7,94-of 7.97 (m, 2H).

Example 157

Getting 2-{2-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

A. obtaining the ethyl ester of 4-(1H-indol-3-yl)piperidine-1-carboxylic acid

17 ml (0.18 mol) of ethylchloride added to a suspension of 30 g (0.15 mol) of 4-(3-indolyl)piperidine and 28 ml (0.18 mol) of triethylamine in 185 ml of dichloromethane, keeping the temperature between 20 and 25°C. the Mixture is stirred at room temperature for 2 hours and add 150 ml of water. The organic layer is separated and the solvent is removed under reduced pressure, obtaining 36 g (yield 88%) of the desired product.

C. obtaining the ethyl ester of 4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-carboxylic acid

To a suspension 0,76 g (19 mmol) of a 60% suspension of sodium hydroxide in mineral oil, 15 ml of anhydrous DMF add a solution of 4 g (15 mmol) of Atila the CSOs ester 4-(1H-indol-3-yl)piperidine-1-carboxylic acid in 5 ml of anhydrous DMF. After 30 minutes at room temperature add a solution 1,71 ml (18 mmol) of cyclopropanemethylamine in 5 ml of DMF. The crude mixture is stirred at room temperature for 14 hours and the solvent is removed under reduced pressure. The crude mixture is extracted, distributing between water and ethyl acetate. The organic layer is dried over magnesium sulfate and after filtration the solvent is removed under reduced pressure, obtaining 4.7 g of the desired product.

ESI/MC m/e =327 [(M+1)+, 2026N22]

C. Obtaining 1-cyclopropylmethyl-3-piperidine-4-yl-1H-indole

A solution of 4.95 g (75 mmol) of potassium hydroxide in 25 ml of ISO-propanol is added to 4.7 g (15 mmol) of the ethyl ester of 4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-carboxylic acid and the mixture is heated to 95-100°C for 16 hours. The solvent is removed under reduced pressure and the crude mixture is extracted, distributing between water and toluene. The organic layer is dried over sodium sulfate and after filtration the solvent is removed under reduced pressure, obtaining 3.2 g (yield 89%) of the desired product.

ESI/MC m/e =255 [(M+1)+, C17H22N2]

D. Obtain 2-{2-[4-(1-cyclopropylmethyl-1H-indol-3-yl)-piperidine-1-yl]ethoxy}benzoic acid

The suspension containing 3.6 g (14 mmol) of 1-cyclopropylmethyl-3-piperidine-4-yl-1H-indole, 3.7 g (18 mmol) of methyl ester of 2-(2-chloroethoxy)benzoic acid (obtained according to example 1, casts), 2.9 g (21 mmol) of potassium carbonate and 1.7 g (11 mmol) of potassium iodide in 70 ml of ISO-butylmethylamine heated to a temperature of 90°C for 16 hours. The solvent is removed under reduced pressure and the crude mixture is extracted, distributing between water and dichloromethane. The organic layer is dried over sodium sulfate and after filtration the solvent is removed under reduced pressure, getting 6.5 g of colorless oil. The resulting crude mixture was dissolved in 350 ml of ethanol and 14 ml of 2 N. aqueous sodium hydroxide solution. The mixture is stirred for 16 hours at room temperature, the solvent is removed under reduced pressure and add 50 ml of water. The crude mixture was neutralized, extracted with chloroform and purified flash chromatography on silica gel, receiving, and 2.27 g (yield 39%) of the desired product.

Melting point=145-147°

ESI/MC m/e =419 [(M+1)+, 2630N23]

NMR (300 MHz, DMSO) δ=of 0.36 to 0.39 (m, 2H), 0,47-of 0.51 (m, 2H), 1,17-1,24 (m, 1H), 1,92 of 1.99 (m, 4H), 2,60-2,69 (m, 2H), 2,90-of 2.97 (m, 3H), 3,20-3,24 (d, 2H), 3,97-3,99 (d, 2H), 4,42 is 4.45 (t, 2H), 6,10 (users, 1H), 6,97? 7.04 baby mortality (m, 2H), 7,09-7,14 (t, 1H), 7,20-7,24 (m, 2H), was 7.36-7,47 (m, 2H), 7,52-rate of 7.54 (d, 1H), of 7.64-7,66 (d, 1H).

Example 158

Obtain 3-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-ylmethyl]benzoic acid

The specified connection receive according to the method described in example 157 (part D), starting from 1.5 g (6 mmol) of 1-cyclopropylmethyl-3-piperidine-4-yl-1H-indole, 1.8 g (7.8 mmol) were labeled the CSOs ester 3-bromomethylphenyl acid, 1.2 g (9 mmol) of potassium carbonate and 0.9 g (4.5 mmol) of potassium iodide in 25 ml of ISO-butylmethylamine. The crude mixture was purified flash chromatography on silica gel, getting to 0.63 g (yield 27%) of the desired product. Melting point=207°

ESI/MC m/e =389 [(M+1)+, 2528N22]

NMR (300 MHz, DMSO) δ=0,33-0,37 (m, 2H), between 0.46 and 0.50 in (m, 2H), 1,17-1,25 (m, 1H), 1.70 to of 1.78 (m, 2H), 1,92-of 1.97 (d, 2H), 2,20-of 2.27 (t, 2H), 2,75-2,82 (m, 1H), 2,94 are 2.98 (d, 2H), 3,66 (s, 2H), 3.95 to 3,98 (d, 2H), 6,95-7,00 (t, 1H), 7,07 for 7.12 (t, 1H), 7,20 (s, 1H), 7,43 to 7.62 (m, 4H), a 7.85-7,88 (d, 1H), of 7.96 (s, 1H).

Example 159

Receive (4-{3-[4-(1-cyclopropylmethyl-1H-indol-3-yl)-piperidine-1-yl]propoxy}phenyl)acetic acid

The specified connection receive according to the method described in example 157 (part D), starting from 1.5 g (6 mmol) of 1-cyclopropylmethyl-3-piperidine-4-yl-1H-indole, 2 g (6.6 mmol) of the ethyl ester [4-(3-chloropropoxy)phenyl]acetic acid, 1.1 g (12 mmol) of potassium carbonate and 1 g (x 6.15 mmol) of potassium iodide in 32 ml of ISO-butylmethylamine. The crude mixture was purified flash chromatography on silica gel, receiving 1.6 g (yield 58%) of the desired product.

Melting point=83-85°

ESI/MC m/e =447 [(M+1)+, 2834N23]

NMR (300 MHz, DMSO) δ=0,35-0,37 (m, 2H), 0,47-0,50 (m, 2H), 1,13-1,20 (m, 1H), from 1.66 to 1.76 (m, 2H), 1,89-of 1.97 (m, 4H), of 2.05 and 2.13 (t, 2H), 2,46-of 2.50 (m, 2H), 2.71 to 2,78 (m, 1H), 2,97-3,00 (d, 2H), 3.45 points (s, 2H), 3,95-4,01 (m, 4H), 6,85-to 6.88 (m, 2H), 6,95-7,00 (t, 1H), 7,07-to 7.18 (m, 4H), 7,42 was 7.45 (d, 1H), 7,54-7,56 (d, 1H).

Example 160

Obtaining pharmaceutical compositions: syrup

1000 is the Lacona (volume 150 ml), each of which contains a solution of 750 mg of 2-(2-{4-[1-(4-terbisil)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid, prepared as follows:

2-(2-{4-[1-(4-terbisil)-1H-indol-3-yl]-piperidine-1-yl}ethoxy)benzoic acid 750 g

glycerin 15000 g

hydrogenated castor oil - ethylene oxide 1500 g

methyl-p-hydroxybenzoate sodium 240 g

propyl-p-hydroxybenzoate sodium 60 g

Nachrichten 300 g

perfume q.s

sodium hydroxide q.s. pH 4

demineralized water q.s. 150 liters

Technique:

To a solution of methyl- (and propyl-) p-hydroxybenzoate sodium and Matricaria in 30 liters of demineralized water is added an aqueous solution of glycerin and hydrogenated castor oil - ethylene oxide. After stirring 2-(2-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid and homogenized to achieve complete dissolution. After that, the odorant admixed to the solution with vigorous stirring and the mixture is brought to final volume with demineralized water.

The resulting solution was poured into 150 ml flask, using an appropriate filling machine.

Example 161

Obtaining a pharmaceutical composition: capsules

50,000 capsules, each containing 50 mg of 2-{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]-ethoxy}benzoic acid, obtained from the next comp is VA:

2-{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]-ethoxy}benzoic acid 2500 g

magnesium stearate 225 g

lactose obtained by spray drying 18350

cross-stitched sodium carboxymethyl cellulose 900 g

sodium lauryl sulfate 450 g

Technique:

2-{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}-benzoic acid, sodium lauryl sulfate, lactose and cross-linked the sodium carboxymethyl cellulose are mixed together and passed through a sieve with an opening of 0.6 mm Add magnesium stearate and the mixture is filled into gelatin capsules of suitable size.

Example 162

Obtaining a pharmaceutical composition: tablets

100,000 tablets each containing 25 mg of 2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid is obtained from the following composition:

2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]-

piperidine-1-yl}ethoxy)benzoic acid 2500 g

microcrystalline cellulose 1650

lactose obtained by spray drying 9620

carboximetilkrahmal 570 g

nutritionalvalue 80 g

colloidal silicon dioxide 80 g

Technique:

All the powders are passed through a sieve with openings of 0.6 mm and Then mixed in a suitable mixer for 30 minutes and pressed into tablets 145 mg, using 6 mm discs and flat beveled stamps. The time of disintegration (decay) of the tablets is over is 60 seconds.

1. Derivatives intellipedia formula (I)

where

And1means1-C7alkylenes,1-C7alkylene-From1-C7alkylthio-From1-C7alkanoyloxy or hydroxy - C1-C7-alkylenes group;

And2means simple link1-C7alkylenes or2-C5alkenylamine group;

W means a simple link or fenelonov or furniture group which is not substituted or substituted by one or more halogen atoms, With1-C7alkoxygroup and/or C1-C7alkyl groups;

R1means a hydrogen atom or a C1-C7alkyl, C2-C7alkenylphenol,2-C7alkylamino,2-C5alkoxyalkyl,3-C7alkenylacyl,3-C7alkyloxyalkyl,3-C7alkoxylalkyl, phenylalkyl group, where the alkyl group means With1-C7alkyl group and the phenyl cycle is not substituted or substituted by one or more halogen atoms, or With1-C7alkyl, C1-C7alkoxy - or arilalkilamin, or cycloalkyl-C1-C7is an alkyl group,

where cycloalkyl g is the SCP is 3-C10cycloalkyl group and is not zameshennoj or substituted by one or more halogen atoms, With1-C7alkyl groups or C1-C7alkoxygroup;

R2means a hydrogen atom or halogen, or C1-C7alkyl or C1-C7alkoxygroup,

R3means carboxyl group or tetrazolyl group; and its pharmaceutically acceptable salts.

2. The compound according to claim 1, where a1means1-C7alkylenes,1-C7alkylene-, hydroxy-C1-C7-alkylenes or1-C7alkylation.

3. The compound according to claim 2, where a1means methylene, ethylene, propylene, butylene, Panteleeva, hexylene, ethylenoxy, propionoxy-, hydroxybutylidene group, ethylthio and butylthiourea.

4. The compound according to any one of the preceding paragraphs, where W means furniture group or fenelonov a group which is not substituted or substituted by one or two fluorine atoms, chlorine or bromine, methyl groups or methoxypropane.

5. The compound according to claim 4, where W denotes unsubstituted furniture, unsubstituted fenelonov, ftorhinolonovy, dibromantranilovu, methylphenylene or methoxyphenylazo group.

6. The compound according to any one of the preceding paragraphs, where a 2means simple link1-C4alkylenes or2-C5alkenylamine group.

7. The connection according to claim 6, where a2means of a simple bond or a methylene, ethylene, propylene, methylethanol, butylene or ethenylene group.

8. The compound according to any one of the preceding paragraphs, where R1means a hydrogen atom or a C1-C7alkyl, C2-C7alkenylphenol or2-C7alkylamino group2-C5alkoxyalkyl group3-C7altnetseattle group3-C7alkyloxyalkyl group3-C7alkoxylalkyl group, benzyl or phenylethylene group which is not substituted or substituted by one or more halogen atoms, With1-C4alkyl, methoxy - or benzyloxycarbonyl, or cycloalkylcarbonyl group, where cycloalkyl group means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or declines, which is not substituted or substituted by one or more halogen atoms, With1-C4alkyl or methoxypropane, and the alkyl part cycloalkylation group means methylene, ethylene, propylene or butylene.

9. The connection of claim 8, where R1means a hydrogen atom or through boutelou, isobutylene, pentelow, g is xinnuo, heptylene, 2-methylpropanol, 3-methylbutanol, allyl, propenyloxy, propenyloxy, methoxyaniline, methoxypropanol, amoxicilina, propoxyethanol, isopropoxyaniline, prop-2-unlockitnow, prop-2-relaxiation, methoxyethoxyethoxy, 4-forbindelse, 4-methoxybenzyloxy, 4-(tert-butyl)benzyl, 4-benzyloxybenzyl, 4-methoxyphenylalanine, cyclopropylmethyl, cyclopropylethyl, cyclopropylamino, cyclohexylmethanol, cyclohexylamino or cyclohexylamino group.

10. The compound according to any one of the preceding paragraphs, where R2means a hydrogen atom, fluorine, chlorine or bromine, or a methyl or methoxy group.

11. The compound according to any one of the preceding paragraphs, having antihistaminic and antiallergic activity, with reduced side effects on the cardiovascular and Central nervous system.

12. The compound according to claim 1, which is

2-(2-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}ethoxy) benzoic acid

2-{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]ethoxy} benzoic acid

4-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}butyric acid

3-(3-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}propoxy)benzoic acid

4-{3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]propoxy}

benzoic acid/p>

2-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-

1-yl)ethoxy]benzoic acid

3-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)ethoxy]benzoic acid

3-(2-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}ethoxy) benzoic acid

3-{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]ethoxy) benzoic acid

3-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy) benzoic acid

4-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)ethoxy]benzoic acid

4-{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]ethoxy} benzoic acid

2-[3-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)propoxy]benzoic acid

2-(3-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}propoxy)benzoic acid

2-{3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]propoxy} benzoic acid

2-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl} propoxy)benzoic acid

3-[3-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)propoxy]benzoic acid

3-{3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]-propoxy} benzoic acid

3-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}-propoxy)benzoic acid

4-[3-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)propoxy]benzoic acid 4-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidin-1-yl} propoxy)benzoic acid

3-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)propionic acid

3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]propionic acid

4-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)butyric acid

4-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}butyric acid

4-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]butyric acid

3-{4-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}-piperidine-1-yl)ethyl]phenyl}propionic acid

3-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}propionic acid

3-[4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethyl)phenyl]propionic acid

3-{4-[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)ethyl]phenyl}acrylic acid

3-(4-{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]ethyl}phenyl)acrylic acid

3-[4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethyl)phenyl]acrylic acid

2-{4-[1-hydroxy-4-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)butyl]phenyl}-2-methylpropionate acid

2-(4-{1-hydroxy-4-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]butyl}phenyl)-2-methylpropionate acid

2-[4-(4-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}-1-hydroxybutyl)phenyl]-2-methylpropionate acid

[2-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-yl)ethoxy]acetic acid

(2-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}ethoxy) acetic acid

{2-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-yl]ethoxy} acetic acid

(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl)ethoxy) acetic acid

5-(4-{1-[2-(2-methoxyethoxy)ethyl]-1H-indol-3-yl}piperidine-1-ylmethyl)furan-2-carboxylic acid

5-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-ylmethyl]furan-2-carboxylic acid

5-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-ylmethyl}furan-2-carboxylic acid

5-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-ylmethyl}furan-2-carboxylic acid

2-[4-(4-{4-[1-(4-terbisil)-1H-indol-3-yl]piperidine-1-yl}-1-hydroxybutyl)phenyl]-2-methylpropionate acid

2-{2-[4-(1-heptyl-1H-indol-3-yl)piperidine-1-yl]ethoxy} benzoic acid

2-(2-{4-[1-(4-tert-butylbenzyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-(2-{4-[1-(4-methoxybenzyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-(2-{4-[1-(4-benzyloxybenzyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-{2-[4-(1-ISO-butyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

2-[2-(4-{1-[2-(4-methoxyphenyl)ethyl]-1H-indol-3-yl}piperidine-1-yl)ethoxy]benzoic acid

2-(4-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethyl}phenyl)-2-methylpropionate acid

2-(4-{4-[4-(1H-indol-3-yl)piperidine-1-yl]butyryl}Hairdryer is l)-2-methylpropionate acid

2-[4-(1H-indol-3-yl)piperidine-1-ylmethyl]benzoic acid

3-[4-(1H-indol-3-yl)piperidine-1-ylmethyl]benzoic acid

4-[4-(1H-indol-3-yl)piperidine-1-ylmethyl]benzoic acid

(3-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy}phenyl)acetic acid

(3-{3-[4-(1H-indol-3-yl)piperidine-1-yl]propoxy}phenyl)acetic acid

(4-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy}phenyl)acetic acid

(4-{3-[4-(1H-indol-3-yl)piperidine-1-yl]propoxy}phenyl)acetic acid

3-(1-{3-[3-(1H-tetrazol-5-yl)phenoxy]propyl}piperidine-4-yl)-1H-indole

2-methyl-2-[4-(2-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl}ethyl)phenyl]propionic acid

2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethyl)phenyl]-2-methylpropionate acid

2-methyl-2-[4-(4-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl}butyryl)phenyl]propionic acid

2-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-ylmethyl}benzoic acid

2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-ylmethyl}benzoic acid

3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-ylmethyl}benzoic acid

4-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-ylmethyl}benzoic acid

[3-(2-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)phenyl]acetic acid

[3-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl)ethoxy)phenyl]acetic acid is acid

[3-(3-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl}propoxy)phenyl]acetic acid

[3-(3-{4-[1-(2-ethoxyethyl-1H-indol-3-yl]piperidine-1-yl}propoxy)phenyl]acetic acid

[4-(2-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)phenyl]acetic acid

[4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)phenyl]acetic acid

[4-(3-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl}propoxy)phenyl]acetic acid

[4-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}propoxy)phenyl]acetic acid

2-{2-[4-(1-prop-2-inyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

2-methyl-2-[4-(4-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl}butyryl)phenyl]propionic acid

1-(2-ethoxyethyl)-3-(1-{3-[2-(2H-tetrazol-5-yl)phenoxy]propyl}piperidine-4-yl)-1H-indole

1-(3-methylbutyl)-3-(1-{3-[2-(2H-tetrazol-5-yl)phenoxy]propyl}piperidine-4-yl)-1H-indole

1-(3-methylbutyl)-3-(1-{3-[4-(2H-tetrazol-5-yl)phenoxy]propyl}piperidine-4-yl)-1H-indole

2-(2-{4-[1-(2-ethoxyethyl)-5-methoxy-1H-indol-3-yl]piperidine-1-yl}ethoxy)-6-Formentera acid

2-(2-{4-[1-(2-ethoxyethyl)-5-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)-6-Formentera acid

2-(2-{4-[1-(2-ethoxyethyl)-6-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)-6-Formentera acid

2-(2-{4-[5-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-6-FPO is benzoic acid

2-(2-{4-[7-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-6-Formentera acid

2-(2-{4-[5-chloro-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-6-Formentera acid

2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-6-Formentera acid

3,5-dibromo-2-(2-{4-[1-(2-ethoxyethyl)-5-methoxy-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

3,5-dibromo-2-(2-{4-[1-(2-ethoxyethyl)-5-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

3,5-dibromo-2-(2-{4-[1-(2-ethoxyethyl)-6-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

3,5-dibromo-2-(2-{4-[5-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

3,5-dibromo-2-(2-{4-[7-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

3,5-dibromo-2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-(2-{4-[1-(2-ethoxyethyl)-6-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid

2-(2-{4-[5-chloro-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid

2-(2-{4-[1-(2-ethoxyethyl)-5-methoxy-1H-indol-3-yl]piperidine-1-yl}ethoxy)-4-methoxybenzoic acid

2-(2-{4-[1-(2-ethoxyethyl)-6-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)-4-methoxybenzoic acid

2-(2-{4-[5-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-4-methoxime sauna acid

2-(2-{4-[7-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-4-methoxybenzoic acid

2-(2-{4-[5-chloro-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-4-methoxybenzoic acid

2-(2-{4-[1-(2-ethoxyethyl)-5-methoxy-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-(2-{4-[1-(2-ethoxyethyl)-5-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-(2-{4-[1-(2-ethoxyethyl)-6-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-(2-{4-[5-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-(2-{4-[5-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid

2-(2-{4-[5-chloro-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl)ethoxy)benzoic acid

2-{2-[4-(1-propyl-1H-indol-3-yl)piperidine-1-yl]ethoxy)benzoic acid

2-(2-{4-[1-(2-isopropoxyphenyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-(2-{4-[1-(3-methoxypropyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-(2-{4-[1-(2-ethoxyethyl)-4-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-(2-{4-[1-(2-ethoxyethyl)-4-fluoro-1H-indol-3-yl] piperidine-1-yl}ethoxy)-5-methylbenzoic acid

2-(2-{4-[1-(2-ethoxyethyl)-4-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)-4-methoxybenzoic acid

2-(2-{4-[4-fluoro-1-(2-methoxyethyl)-1H-indol-3-yl]piperidine-1-yl}the toxi)benzoic acid

2-(2-{4-[4-fluoro-1-(2-methoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid

2-(2-{4-[4-fluoro-1-(2-methoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-4-methoxybenzoic acid

5-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}pentane acid

6-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl)hexanoic acid

7-(4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}heptane acid

3-(3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}-propoxy)propionic acid

2-(2-{4-[1-(2-ethoxyethyl)-7-methyl-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid

2-(2-{4-[6-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-(2-{4-[6-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid

(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethylthio)acetic acid

(4-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}butylthio)acetic acid

(3-{3-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]propoxy}phenyl)acetic acid

(4-{2-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}phenyl)acetic acid

(3-{2-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}phenyl)acetic acid

3-[4-(1-pentyl-1H-indol-3-yl)piperidine-1-ylmethyl]benzoic acid

5-[4-(6-fluoro-1-pentyl-1H and the Dol-3-yl)piperidine-1-ylmethyl]furan-2-carboxylic acid

3-[4-(6-fluoro-1-pentyl-1H-indol-3-yl)piperidine-1-ylmethyl]benzoic acid

2-(4-{4-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]butyryl}phenyl)-2-methylpropionate acid

3-{3-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]propoxy}benzoic acid

2-{2-[4-(1-cyclohexylmethyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

2-(2-{4-[1-(2-allyloxymethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-(2-{4-[1-(2-prop-2-insociety)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-(2-{4-[1-(2-propoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

4-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-(2-{4-[1-(3-methylbutyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-(2-{4-[1-(2-methoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-{2-[4-(1-allyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

2-(2-{4-[1-(2-ethoxyethyl)-5-methoxy-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid

2-(2-{4-[7-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid

2-(2-{4-[7-bromo-1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-(2-{4-[1-(2-etox is ethyl)-5-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid

2-(2-{4-[1-(2-ethoxyethyl)-5-fluoro-1H-indol-3-yl]piperidine-1-yl}ethoxy)-4-methoxybenzoic acid

2-(2-{4-[1-(2-ethoxyethyl)-7-methyl-1H-indol-3-yl]piperidine-1-yl}ethoxy)benzoic acid

2-{2-[4-(1-butyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

2-{2-[4-(1-hexyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

2-{2-[4-(1-cyclopropylmethyl-6-fluoro-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

2-{2-[4-(1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl} propionic acid

2-(2-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}ethoxy)-5-methylbenzoic acid

2-[4-(4-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]piperidine-1-yl}butyryl)phenyl]-2-methylpropionate acid

1-(2-ethoxyethyl)-3-(1-{3-[4-(2H-tetrazol-5-yl)phenoxy]propyl}piperidine-4-yl)-1H-indole

2-{2-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]ethoxy}benzoic acid

3-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-ylmethyl] benzoic acid

(4-{3-[4-(1-cyclopropylmethyl-1H-indol-3-yl)piperidine-1-yl]propoxy}phenyl)acetic acid

13. A method of obtaining a compound according to any one of the preceding paragraphs, in which R3is carboxypropyl, which includes a step of hydrolysis of the compounds of formula (VI)

where R1, R2And1And2and W have the meanings given in claim 1 and R4means a group-COOR5where R5means1-C4alkyl group.

14. A method of obtaining a compound according to claim 1, in which R3is tetrazolyl group, including the stage of interaction of the compounds of formula (VI)

where R1, R2And1And2and W have the meanings defined in claim 1, and R4means cyano with azide.

15. Composition for treatment of allergic diseases, including bronchial asthma, rhinitis, conjunctivitis, dermatitis and urticaria, comprising the compound according to any one of items 1 to 12, in a mixture with a pharmaceutically acceptable diluent or carrier.



 

Same patents:

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to organic chemistry and can find application in medicine

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

The invention relates to new derivatives of formula (I)

where a represents a 5 - or 6-membered monocyclic aromatic ring containing in the ring 1 or 2 nitrogen atom and unsubstituted or substituted by 1-3 substituents, A represents N; D represents a 2-indolyl, 2-benzimidazolyl or 2-benzo[b]furanyl and is unsubstituted or substituted by 1-3 halogen atoms, except 1-(5-chlorobenzophenone-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine and its pharmaceutically acceptable salts

The invention relates to new imidazole-cyclic acetals of the formula I, where R1- optionally substituted 4-pyridyl or optionally substituted 4-pyrimidinyl; R2is phenyl, substituted with halogen; R3is hydrogen; R4refers to a group - L3-R14; R5is hydrogen, alkyl or hydroxyalkyl; or R4and R5when attached to the same carbon atom, may form with the specified carbon atom kernel cycloalkyl or the group C=CH2; R6is hydrogen or alkyl and m=1; L3and R14have the meanings specified in the description, and pharmaceutically acceptable salts and solvate (for example, hydrates), which have inhibitory activity against TNF-alpha, as well as to intermediate compounds, pharmaceutical compositions and method of treatment

The invention relates to 4-oxocyclohexyl the urea compounds of General formula (I), where X, Y, R, R1, R2, R3, R4, R5And L, such as defined in the claims

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

10 cl, 2 sch, 4 tbl, 9 ex

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to organic chemistry and can find application in medicine

The invention relates to N-substituted indole-3-glycinamide General formula I, possess Antiasthmatic, antiallergic and immunosuppressive/immunomodulatory action

where R is hydrogen, (C1-C6)alkyl, and the alkyl group optionally contains one phenyl substituent, which, in turn, optionally contains at least one Deputy, selected from the group comprising halogen, methoxy, ethoxy, (C1-C6)alkyl; R1means phenyl cycle containing at least one Deputy, selected from the group comprising (C1-C6)alkoxy, hydroxy, nitro, (C1-C6)alkoxycarbonyl one or fluorine, or R1represents the balance of the pyridine of the formula II

where the carbon atoms 2, 3 and 4 of the remaining pyridine optionally have the same or different substituents R5and R6and R5and R6denote (C1-C6)alkyl or halogen, or R1presents arylamination-2-methylprop-1-ilen group, or R and R1together with the nitrogen atom to which IGN="ABSMIDDLE">

where R7denotes phenyl or pyridinyl; R2means (C1-C6)alkyl, which optionally contains a phenyl residue, which, in turn, optionally substituted with halogen, methoxy group or ethoxypropane, or related to R2(C1-C6)alkyl group optionally substituted 2-, 3 - or 4-pyridinium residue; R3and R4are the same or different substituents and represent hydrogen, hydroxy, (C1-C6)alkoxy, (C1-C3)alkoxycarbonyl or (C1-C3)alkoxycarbonyl(C1-C3)alkyl, or R3is cyclopentanecarbonitrile; Z denotes Oh, and alkyl, alkoxy or alkylamino mean as an unbranched group, such as methyl, ethyl, n-propyl, n-butyl, n-hexyl and branched alkyl groups such as isopropyl or tert-butylene group; halogen means fluorine, chlorine, bromine or iodine and alkoxygroup means methoxy, propoxy, butoxy, isopropoxy, isobutoxy or phenoxypropan, and their pharmaceutically acceptable salts with acids

The invention relates to 1-(6-amino-3,5-differencein-2-yl)-8-bromo-7-(3-acylaminoalkyl-1-yl)-6-fluoro-4-oxo-1,4-dihyd-rhinolin-3-carboxylic acid or its salt, as well as to antimicrobial drug and compositions on the basis of this compound or its salt

The invention relates to organic chemistry, in particular to derive SIM-triazine-2-ethylamino-4-piperidyl-6-[(4’-methylcarbamyl-5’-methyl-1’,2’,3’,-triazole)-1-yl]-1,3,5-triazine structure:

as an antidote from fetotoksicheskoe action of the herbicide 2,4 - dichlorophenoxyacetic acid on the sunflower sprouts

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

10 cl, 2 sch, 4 tbl, 9 ex

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