Novel 4-(azacycloalkyl)benzene-1,3-diol compounds as tyrosinase inhibitors, method for production thereof and use thereof in human treatment and in cosmetics

FIELD: chemistry.

SUBSTANCE: invention relates to 4-(azacycloalkyl)benzene-1,3-diol compounds of general formula (I) given below:

,

where: R1 is: - C1-C5-alkyl radical, - C3-C6-cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, and C1-C5 alkoxy group, a fluorine atom or a trifluoromethyl group, - aralkyl radical, - C1-C5-alkoxy radical, -amine radical, having the structure (a):

,

where R2 is: - hydrogen, - C1-C5-alkyl radical, - C3-C6- cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, and C1-C5 alkoxy group, a fluorine atom and a trifluoromethyl group, - pyridyl radical, - aralkyl radical of the structure (b):

,

where p is equal to 1 or 2, - a radical of the structure (c):

,

where R4 is: - carboxymethyl, -COOCH3, or carboxyethyl, -COOEt, radical, - C1-C3-alkyl radica, - hydrogen, and R5 is: - an unsubstituted aryl radical or an aryl radical substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy group, fluorine atom or a trifluoromethyl group, - C3-C6-cycloalkyl radical, - pyridyl, and R3 is: - hydrogen, - C1-C5-alkyl radical; or R1 can also be a radical of formula (d):

,

where R6 is: - hydrogen, - C1-C5-alkyl radical, - C3-C6-cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy group, a fluorine atom and a trifluoromethyl group, - pyridyl radical, - aralkyl radical, R7 is: - hydrogen, - C1-C5-alkyl radical, and R8 is: - hydrogen, - hydroxyl, - amine radical, - C1-C3-alkoxy radical; Y is hydrogen or fluorine, and m and n are equal to 0, 1 or 2, as well as isomeric and enantiomeric forms of compounds of formula (I). The invention also relates to use of said compounds as a drug for treating pigmentation disorders.

EFFECT: novel compounds, which can be used in pharmacology or cosmetology to treat or prevent pigmentation disorders, are obtained and described.

6 cl, 53 ex

 

The invention relates to new 4-(azacyclonol)benzene-1,3-valovym compounds as industrial and utility products. The invention also relates to a method for their production and to their use as inhibitors of tyrosinase, in pharmaceutical or cosmetic compositions for use for the treatment or prevention of pigmentary disorders.

The pigmentation of the skin, in particular human skin pigmentation is the result of melanin synthesis of dendritic cells, the melanocytes. Melanocytes contain organelles called melanosomes, which carry the melanin in the upper layers of keratinocytes, which are then transported to the skin surface through differentiation of the epidermis (Gilchrest BA, Park HY, Eller MS, Yaar M, Mechanisms of ultraviolet light-induced pigmentation. Photochem. Photobiol. 1996; 63:1-10; Hearing VJ, Tsukamoto K, Enzymatic control of pigmentation in mammals. FASEB j 1991; 5:2902-2909).

Among the enzyme of melanogenesis, the key enzyme is tyrosinase, which catalyzes the first two steps of melanin synthesis. Homozygous mutations of the tyrosinase cause oculocutaneous albinism type 1, characterized by the complete absence of melanin synthesis (Toyofuku K, Wada I, Spritz RA, Hearing VJ, The molecular basis of oculocutaneous albinism type 1 (OCA1): sorting failure and degradation of mutant tyrosinases results in a lack of pigmentation. Biochem. J. 2001; 355:259-269).

For the treatment of pigmentation disorders resulting from increased production of melanin, for the which there is no treatment, which would meet all the expectations of patients and dermatologists, it is important to develop new therapeutic approaches.

Most of the skin lightening compounds which are already known, are phenols and hydrogenosome derivatives. These compounds inhibit tyrosinase, but most of them are cytotoxic to melanocytes due to the formation of quinones. There is a risk that this toxic effect will cause permanent depigmentation of the skin. The formation of compounds that can inhibit melanogenesis, at the same time being very weakly cytotoxic or without the toxicity of melanocytes, is the most desirable.

Among the compounds already described in the literature, in patent application WO 99/15148 as depigmentary tools described the use of 4-cycloalkylation.

In the patent FR2704428 as depigmentary tools described the use of 4-kalogeropoulou.

In patent applications WO 2006/097224 and WO 2006/097223 as depigmentary tools described the use of 4-cycloalkylcarbonyl.

In the patent application WO 2005/085169 as depigmenting tools described the use of alkyl-3-(2,4-dihydroxyphenyl)propionate.

In the patent application WO 2004/017936 described the use of 3-(2,4-dihydroxyphenyl)acrylamide as depigmenting tools.

In the patent application WO 2004/052330 as depigmentary tools described the use of 4-[1,3]dition-2-ylresorcinols.

More specifically, in the patent EP 0341664 as depigmentary tools described the use of 4-alkylresorcinols, among which 4-n-butylstannyl, also known as retinol is part of the composition depigmenting cream sold under the name iklan (Iklen®).

Unexpectedly and surprisingly, the applicants have now found that new compounds with 4-(azacyclonol)benzene-1,3-Volovoi structure have a very good inhibitory activity against the enzyme tyrosinase and very low cytotoxicity. In addition, these compounds possess inhibitory activity against the enzyme tyrosinase, which is greater than the inhibitory activity rucinol, at the same time being less cytotoxic against melanocytes than retinol.

These compounds find application in the treatment of humans, in particular in dermatology and cosmetology.

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

where:

R1 represents:

- C1-C5-alkilany radical

- C3-C6-cycloalkenyl radical

- arrowy radical

- substituted arrowy radical

- Uralkaliy radical

- C1-C5-alkoxy radical,

- amine moiety corresponding to the structure (a):

where R2 represents:

- hydrogen

- C1-C5-alkilany radical

- C3-C6-cycloalkenyl radical

- arrowy radical

- substituted arrowy radical

- pyridyloxy radical

- Uralkaliy radical

radical corresponding to the structure (b):

where the value of p can represent 1 or 2,

radical corresponding to the structure (c)

where R4 represents:

- carboxymethoxy, -COOCH3or carboxitherapy, -COOEt, radical,

- C1-C3-alkilany radical

- hydrogen

and R5 represents:

substituted or unsubstituted arrowy radical

- C3-C6-cycloalkenyl radical

- pyridyl,

and R3 represents:

- hydrogen

- C1-C5-alkilany radical;

R1 can also represent a radical corresponding to the formula (d):

where R6 represents:

- hydrogen

- C1-C5-alkilany radical

- C3-C6-cycloalkenyl radical

- arrowy radical

- substituted arrowy radical

- pyridyloxy radical,

- Uralkaliy radical

R7 represents:

- hydrogen

- C1-C5-alkilany radical

and R8 represents:

- hydrogen

- Oh,

- amine radical,

- C1-C3-alkoxy radical;

Y represents hydrogen or fluorine, and

the value of m and n can represent 0, 1 or 2,

and to salts of compounds of formula (I) and their isomeric and enantiomeric forms.

Among the salts of the compounds of General formula (I) with a pharmaceutically acceptable base preferably you can specify a salt with an organic base or inorganic base.

Suitable inorganic bases are, for example, potassium hydroxide, sodium hydroxide or calcium hydroxide.

Suitable organic bases are, for example, morpholine, piperazine or lysine.

Compounds of General formula (I) can also exist in the form of hydrate or solvate.

Solvents suitable for the formation of the solvate represent, for example, alcohols, such as ethanol or isopropanol.

The term "C1-C5-alkyl" in the present invention means a linear or branched saturated hydrocarbon chain containing from 1 to 5 carbon atoms.

The term "C1-C3-alkyl" in the present invention means a linear or branched saturated with the second hydrocarbon chain, containing from 1 to 3 carbon atoms.

The term "C3-C6-cycloalkyl" in the present invention means a cyclic saturated hydrocarbon chain containing from 3 to 6 carbon atoms.

The term "aryl" in the present invention means phenyl or naphthyl.

The term "substituted aryl" in the present invention means phenyl or naphthyl, substituted by one or more groups of atoms selected from alkyl, alkoxy, fluorine and trifloromethyl.

The term "aralkyl" in the present invention means C1-C5-alkilany radical, as defined above, substituted by substituted or unsubstituted allowin radical.

The term "C1-C5-alkoxy" in the present invention means an oxygen atom, a substituted linear or branched saturated hydrocarbon chain containing from 1 to 5 carbon atoms.

The term "C1-C3-alkoxy" in the present invention means an oxygen atom, a substituted linear or branched saturated hydrocarbon chain containing from 1 to 3 carbon atoms.

According to the present invention, compounds of General formula (I)which are particularly preferred are compounds where:

- R1 is Uralkaliy radical or an amine radical, corresponding to structure (a):

where R2 to provide the grants:

- C1-C5-alkilany radical

- Uralkaliy radical or

radical corresponding to the structure (d):

where R4 represents:

- carboxymethoxy, -COOCH3or carboxitherapy, -COOEt, radical,

- C1-C3-alkilany radical

and R5 represents:

substituted or unsubstituted arrowy radical

and R3 represents hydrogen,

- Y represents a hydrogen atom or fluorine,

- m=1 and n=1,

as well as salts of these compounds of General formula (I) and their isomeric and enantiomeric forms.

Among the compounds of formula (I)constituting a part of the context of the present invention, specifically, you can specify the following:

1: tert-butyl ether 3-(2,4-dihydroxyphenyl)azetidin-1-carboxylic acid

2: [3-(2,4-dihydroxyphenyl)azetidin-1-yl]phenylmethanone

3: pencilled 3-(2,4-dihydroxyphenyl)azetidin-1-carboxylic acid

4: tert-butyl ether 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid

5: isobutyl ester of 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid

6: cyclohexylamin 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid

7: phenylamide 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid

8: (4-forfinal)amide 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid

9: (4-triptoreline)amide 3-(2,4-dihydroxyphenyl is)pyrrolidin-1-carboxylic acid

10: ethyl ester of 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

11: [4-(2,4-dihydroxyphenyl)piperidine-1-yl]phenylmethanone

12: butylamide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

13: propelled 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

14: 1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]butane-1-he

15: 1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-methylpropan-1-he

16: phenylamide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

17: (4-forfinal)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

18: p-tailed 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

19: ventilated 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

20: (3-forfinal)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

21: ((R)-1-phenylethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

22: methylphenylene 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

23: pyridine-2-alamid 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

24: ((S)-1-phenylethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

25: ((S)-1-phenylpropyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

26: (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-3-phenylpropane-1-he

27: 1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-3-phenylpropane-1-he

28: 2-forbindelse 4-(2,4-dihydroxyphenyl)piperidine--carboxylic acid

29: 3-forbindelse 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

30: 4-forbindelse 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

31: benzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

32: 2-methylbenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

33: 3-methylbenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

34: 4-methylbenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

35: 2-methoxybenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

36: 3-methoxybenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

37: 4-methoxybenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

38: ((S)-1-p-triletal)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

39: [(S)-1-(4-forfinal)ethyl]amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

40: (S)-indan-1-alamid 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

41: ((S)-1-naphthalen-1-retil)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

42: ((S)-1-naphthalen-2-retil)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

43: [(S)-1-(4-methoxyphenyl)ethyl]amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

44: [(S)-1-(3-methoxyphenyl)ethyl]amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

45: (S)-2-amino-1-[4-(2,4-dihydroxyphenyl)Pieper is DIN-1-yl]-3-phenylpropane-1-he

46: ((S)-1-phenylethyl)amide 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

47: (R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylethanone

48: (S)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylethanone

49:(R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-3-phenylpropane-1-he

50: (S)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-3-phenylpropane-1-he

51: (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-(4-forfinal)alanon

52: (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-phenylethanone

53: (S)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-phenylethanone

54: (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-(4-triptoreline)alanon

55: 2-amino-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-phenylbut-1-he

56: (S)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-methoxy-2-phenylethanol

57: ((S)-1-cyclohexylethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

58: (1,2,3,4-tetrahydronaphthalen-1-yl)amide of 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

59: methyl ester of (R)-{[4-(2,4-dihydroxyphenyl)piperidine-1-carbonyl]amino}phenylacetic acid

60: (pyridine-3-ylmethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

61: (pyridin-4-ylmethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

62: benzylamine 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

63: utilidad 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

64: (3-forfinal)amide 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

65: ventilated 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

66: methyl ester of (R)-{[4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carbonyl]amino}phenylacetic acid

67: (S)-indan-1-alamid 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

68: [(S)-1-(4-methoxyphenyl)ethyl]amide 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

69: ((S)-1-cyclohexylethyl)amide 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

70: (R)-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylethanone

71: (S)-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylethanone

72: (R)-2-amino-1-[4-(5-fluoro-2,4-dihydroxyphenyl)-piperidine-1-yl]-2-phenylethanone

73: (S)-2-amino-1-[4-(5-fluoro-2,4-dihydroxyphenyl)-piperidine-1-yl]-2-phenylethanone

74: (R)-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylpropane-1-he

75: (S)-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylpropane-1-he

76: (R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylpropane-1-he

77: (S)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylpropane-1-he

78: methyl ester of (R)-{[4-(2,4-dihydroxyphenyl)piperidine-1-carbonyl]amino}-(4-forfinal)acetic acid

79: methyl ester of (S)-{[4-(2,4-dihydroxyphenyl)piperidine-1-carbonyl]amino}-(4-ftoh the Nile)acetic acid

80: (R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-methyl-3-phenylpropane-1-he

81: (S)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-methyl-3-phenylpropane-1-he

82: (pyridine-3-ylmethyl)amide 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

83: (pyridin-4-ylmethyl)amide 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

84: ((R)-1-phenylethyl)amide (5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

85: (R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylbutane-1-he

86: (S)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylbutane-1-he

87: (S)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-(4-forfinal)-2-hydroxyethane

88: (R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-(4-forfinal)-2-hydroxyethane

89: (S)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-(3-methoxyphenyl)alanon

90: (R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-(3-methoxyphenyl)alanon

91: cyclohexylethylamine 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

92: cyclohexylethylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

93: (2-ethylbutyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

94: (2-ethylbutyl)amide 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

95: cyclopentylmethyl 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

96: cyclopentylmethyl 4-(-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

97: (6-methylpyridin-3-ylmethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

98: (4-methylpyridin-3-ylmethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

99: (5-methylpyridin-3-ylmethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

100: (2-methylpyridin-3-ylmethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

101: (2,6-dimethylpyridin-4-ylmethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

102: (2-pyridin-2-retil)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

103: (2-pyridin-3-retil)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

104: (2-pyridin-4-retil)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

Compounds of General formula (I) are obtained in accordance with the General reaction scheme presented in figure 1.

In the presence of utility carry out the reaction of the compounds 2,4-bis(benzyloxy)brobinson (X=Br; Y=H) or 1,5-bis(benzyloxy)-2-fluoro-4-iadanza (X=I; Y=F) (1), which are commercially available or obtained by conventional methods of synthesis (W.D. Langley, Org. Synth. I, 122 (1932)) (in the case of compounds of fluorine Mottram, L. F.; Boonyarattanakalin, S.; Kovel, R. E.; Peterson, B.R. Organic Letters 2006, 8(4), 581-584), for example, azacycloheptane (2), which are commercially available or obtained by conventional methods of synthesis (W.D. Langley, Org. Synth. I, 122 (1932)), obtaining for the participating benzyl alcohols of the General formula (3), where Y=H or F and Z=ethyl or tert-butyl (Annoura, H.; Nakanishi, K.; occupied some territories, M.; Fukunaga, A.; Imajo, S.; Miyajima, A.; Tamura-Horikawa, Y.; Tamura, S.; Bioorg. Med. Chem. 2002, 10 (2), 371-383).

Compounds of General formula (4) is obtained by hydrogenation of the benzyl alcohols of the General formula (3) in the presence of hydrogen and of a catalyst based on palladium, such as palladium on charcoal, in a solvent such as methanol (Merschaert, A.; Delhaye, L.; Kestemont, J.-P.; Brione, W.; Delbeke, P.; Mancuso, V.; Napora, F.; Diker, K.; Giraud, D.; Vanmarsenille, M.; Tetrahedron Lett. 2003, 44 (24), 4531-4534).

To obtain compounds of General formula (5) compounds of General formula (4) can be benzylarbutin using benzylbromide and bases, such as potassium carbonate, in a solvent such as methyl ethyl ketone (Bolek, D.; Guetschow, M.; J. Heterocycl. Chem. 2005, 42 (7), 1399-1403).

Compounds of General formula (5) is transformed into amines of General formula (6), for example, the influence of triperoxonane acid, if Z=tert-butyl (Kasyan, A.; Wagner, C.; Maier, M. E.; Tetrahedron 1998, 54 (28), 8047-8054), or, for example, exposure to an aqueous solution of potassium hydroxide, if Z=ethyl (Morice, C.; Domostoj, M.; Briner, K.; Mann, A.; Suffert, J.; Wermuth, C. G.; Tetrahedron Lett. 2001, 42 (37), 6499-6502).

Then the compounds of General formula (6) is converted into compounds of General formula (7).

compounds of General formula (7) can:

- or a urea: they are obtained by reaction of compounds of General formula (6), for example, isocyanates (Ranise, A.; Schenone, S.; Bruno, A.; Bondavalli, F.; Filippelli, W.; Falcone, G.; Rivaldi, B.; Farmaco. 2001, 56 (9), 647-657);

or to represent amides: they are produced by reaction of compounds of General formula (6), for example, acylchlorides (Katritzky, A. R.; Singh, S. K.; Cai, C.; Bobrov, S.; J. Org. Chem. 2006, 71 (9), 3364-3374) or Acadamy (De Laszlo, S. E.; Allen, E. E.; Li, B.; Ondeyka, D.; Rivero, R.; Malkowitz, L.; Molineaux, C.; Siciliano, S. J.; Springer, M. S.; Greenlee, W. J.; Mantlo, N.; Bioorg. Med. Chem. Lett. 1997, 7 (2), 213-218);

or to represent carbamates: they are produced by reaction of compounds of General formula (6), for example, chloroformiate (Brackeen, M. F.; Cowan, D. J.; Stafford, J. A.; Schoenen, F. J.; Veal, J. M.; Domanico, P. L.; Rose, D.; Strickland, A. B.; Verghese, M.; Feldman, P. L.; J. Med. Chem. 1995, 38 (24), 4848-4854).

Ultimately, obtain compounds of General formula (I) by hydrogenation of compounds of General formula (7) in the presence of hydrogen and of a catalyst based on palladium, such as palladium on charcoal, in a solvent such as methanol.

Thus, the invention relates to the use of at least one compound of General formula (I)as defined above, as a medicine.

The invention also relates to the use of at least one compound of General formula (I)as defined above, as a drug, where the specified connection has inhibiting tyrosinase activity.

The invention also relates to PR is to change at least one of the compounds of General formula (I), as defined above, to obtain a pharmaceutical or cosmetic compositions, where the specified connection has inhibiting tyrosinase activity.

Mainly the value of the IC50compounds of the present invention (dose inhibiting 50% of the enzymatic activity) in respect of tyrosinase is less than or equal to 10 microns, and more specifically less than or equal to 1 micron.

The invention also relates to the compound of General formula (I) for its use for the treatment and/or prevention of pigmentary disorders.

In fact, compounds of General formula (I) according to the invention is particularly suitable for use associated with the treatment or prevention of pigmentary disorders such as melasma, chloasma, lentigines, senile lentigo, uneven pigmentation associated with aging of the skin from UV rays, venusfort, postinflammatory hyperpigmentation due to scratches, burns, scars, dermatitis, contact Allergy; nevi, genetically determined Hyper-pigmentation, hyperpigmentation associated with metabolic or drug origin, melanoma or other hyperpigmentation.

The object of the present invention is also a pharmaceutical composition for use, in particular, for the treatment of the above conditions, and to era characterized by it contains in a pharmaceutically acceptable medium compatible with the selected for the specified composition by way of introduction, the compound of General formula (I) in the form of one of its isomers or enantiomers or salts thereof with a pharmaceutically acceptable base.

The term "pharmaceutically acceptable carrier" is intended to denote a medium that is compatible with the skin, mucous membranes and derived leather.

The composition according to the invention can be entered locally. Preferably the pharmaceutical composition is packaged in a form suitable for local use.

The local application of the pharmaceutical composition according to the invention is more specifically intended for use in the treatment of skin and mucous membranes and may be in liquid, pasty or solid form, and more particularly in the form of ointments, creams, solutions or gels.

The concentration of the compounds according to the invention in compositions used for local applications, as a rule, is from 0.001% to 10% by weight, preferably from 0.01% to 5% by weight relative to the total weight of the composition.

Compounds of General formula (I) according to the invention also find application in the field of cosmetics, in particular protection from harmful components of sunlight, to prevent caused by the action of light or age ageing of the skin and tissues similar to the skin and/or combating them.

Thus, the object of the invention is also a composition comprising in a cosmetically acceptable medium, at least one of the compounds of General formula (I). The term "cosmetically acceptable medium" is intended to mean a medium compatible with the skin, mucous membranes and tissues, similar to the skin.

The object of the present invention is also the cosmetic use of compositions containing at least one compound of General formula (I), to prevent and/or treat the signs of aging and/or skin.

The object of the present invention is also the cosmetic use of compositions containing at least one compound of General formula (I), for hygiene or hair.

Cosmetic composition according to the invention, containing a cosmetically acceptable medium, a compound of General formula (I), or one of its isomeric and enantiomeric forms or its salt with a cosmetically acceptable base, in particular can be in the form of a cream, a milk, a gel, suspensions of microspheres or nanospheres or lipid or polymeric vesicles, impregnated wipes, solutions, sprays, foams, pencils, soap, detergent bases or shampoos.

The concentration of the compounds of General formula (I) in the cosmetic composition is preferably from 0.001% to 10% by weight relative to the total mass com is osili.

Pharmaceutical and cosmetic compositions as described above can also contain inert additives or even pharmacodynamically relatively active pharmaceutical compositions additives or combinations of these additives, and in particular:

- humidifiers;

- flavor enhancers;

- preservatives such as esters of parahydroxybenzoic acids;

- stabilizers;

regulators humidity;

the pH regulators;

the osmotic pressure modifiers;

- emulsifiers;

- shielding means against UV-A and UV-B;

- antioxidants, such as α-tocopherol, bottled hydroxyanisol or bottled hydroxytoluene, superoxide dismutase, restored coenzyme Q; sodium pyrosulphite;

- softeners;

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

- protivoseborainey or protivougrevoe tools such as S-carboxymethylcysteine, S-benzylester, their salts or their derivatives, or benzoyl peroxide.

It is clear that the experts in this field will be able to follow the choice of the optimal connection(s) to be added to these compositions so that favorable properties, essentially associated with the present invention, are not violated or essentially does not violate consider adding.

Next, through Illus the radio and without any restrictive character will be given several examples of the preparation of compounds of General formula (I) according to the invention, results of the study of biological activity of these compounds, as well as a variety of drugs on the basis of such compounds.

EXAMPLE 1: tert-butyl ether 3-(2,4-dihydroxyphenyl)azetidin-1-carboxylic acid

a) 2,4-bis(benzyloxy)-1-Brabanthal

106,6 g (0,771 mol, 3 EQ.) potassium carbonate (325 mesh) is added to a solution of 50.1 g (0,257 mol, 1 EQ.) 97% 4-bromoresorcinol in 500 ml of acetone. The reaction mixture was cooled to 5-10°C and added dropwise 75 ml (0,630 mol, of 2.45 equiv.) benzylbromide. The reaction mixture was stirred at ambient temperature overnight and then heated at 50°C for 2 hours. The solvent is evaporated and then the residue is treated with a mixture of water/ethyl acetate. The aqueous phase is extracted with ethyl acetate, and the combined organic phases are washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue (114,34 g) is subjected to chromatography on silica gel (600 g), carrying out elution with heptane/dichloromethane 90/10.

Get 94,4 g of 2,4-bis(benzyloxy)-1-bromine benzol in the form of white crystals. Yield=99%.

b) tert-butyl ether 3-(2,4-bis(benzyloxy)phenyl)-3-hydroxyazetidine-1-carboxylic acid

In a 100-ml three-neck flask in 60 ml of tetrahydrofuran was dissolved 5 g of 2,4-bis(benzyloxy)-1-bromine benzol. The mixture is cooled to -70°C, and then add 11,4 ml of 2.5m n-utility in hexane. Reactionary see the camping stirred at -70°C for 1 hour, and then added dropwise 2.8 g of 1-Boc-azetidin-3-one, dissolved in 4 ml of THF. The reaction mixture was stirred at -70°C for 2 hours and then left overnight at ambient temperature. The reaction mixture is poured into 40 ml of 2 M hydrochloric acid, and then extracted with 100 ml of ethyl acetate. The combined organic phases are washed with 50 ml water, and then dried over magnesium sulfate and evaporated. The residue is subjected to chromatography on silica gel (column AnaLogix SF40-80 g), carrying out elution with heptane/ethyl acetate 80/20. Obtain 2.2 g of tert-butyl methyl ether 3-(2,4-bis(benzyloxy)phenyl)-3-hydroxyazetidine-1-carboxylic acid. Yield: 37%.

c) tert-butyl ether 3-(2,4-dihydroxyphenyl)azetidin-1-carboxylic acid

1 g of tert-butyl methyl ether 3-(2,4-bis(benzyloxy)phenyl)-3-hydroxyazetidine-1-carboxylic acid dissolved in a mixture of 20 ml of ethyl acetate/10 ml of methanol, and then add 0.2 g of 10% palladium on coal. The reaction mixture is stirred for 24 hours in an atmosphere of hydrogen. The reaction mixture is filtered, and then the residue is subjected to chromatography on silica gel (heptane/ethyl acetate 7/3). Obtain 0.16 g of tert-butyl methyl ether 3-(2,4-dihydroxyphenyl)azetidin-1-carboxylic acid. Yield=28%.

1H NMR (DMSO, 400 MHz): to 1.38 (s, 9H); and 3.72 (m, 1H); 3,85 (USM, 2H); 4,07 (USM, 2H); 6,17 (DD, J=8,4 & 2,4 Hz, 1H); 6,27 (d, J=2.4 Hz, 1H); 6,92 (d, J=8,4 Hz, 1H); 9,12 (s, 1H); to 9.32 (s, 1H).

13C NMR (DMO, 100 MHz): 28,1, 55, 102,4, 105,9, 117,9, 127,6, 155,8, 156,0, 157,0.

EXAMPLE 2: [3-(2,4-dihydroxyphenyl)azetidin-1-yl]phenylmethanone

a) tert-butyl ether 3-(2,4-bis(benzyloxy)phenyl)azetidin-1-carboxylic acid

A 25-ml round bottom flask in small portions added to the solution 0,86 g tert-butyl ester 3-(2,4-dihydroxyphenyl)azetidin-1-carboxylic acid (example 1) in 9 ml of methyl ethyl ketone 1.35 g of potassium carbonate.

Added dropwise with 0.93 ml benzylbromide and then the reaction mixture is stirred for 2 hours while boiling under reflux. The reaction mixture is filtered and then the residue is subjected to chromatography on silica gel (heptane/ethyl acetate 70/30).

Obtain 1.1 g of tert-butyl methyl ether 3-(2,4-bis(benzyloxy)phenyl)azetidin-1-carboxylic acid. Yield=76%.

b) triptorelin 3-(2,4-bis(benzyloxy)phenyl)azetidine

A 25-ml round bottom flask, dissolve 1 g of tert-butyl methyl ether 3-(2,4-bis(benzyloxy)phenyl)azetidin-1-carboxylic acid in 10 ml of dichloromethane, and then add 2.5 ml triperoxonane acid. The reaction mixture is stirred for 2 hours. The solvent is evaporated and then the residue is treated simple isopropyl ether. Get to 0.92 g of 3-(2,4-bis(benzyloxy)phenyl)useridentification. Yield=90%.

c) [3-(2,4-bis(benzyloxy)phenyl)azetidin-1-yl]phenylmethanone

A 10-ml round bottom flask dissolve 0.25 g of 3-(2,4-bis(benzyloxy is)phenyl)useridentification in 5 ml of tetrahydrofuran in the presence of 0.1 ml of N,N-diisopropylethylamine. Add 0,07 ml benzoyl chloride and the mixture is then stirred for 24 hours at ambient temperature. The reaction mixture was extracted with ethyl acetate and then the combined organic phases are dried over magnesium sulfate. The residue is subjected to chromatography on silica gel (heptane/ethyl acetate 9/1). Obtain 0.2 g of [3-(2,4-bis(benzyloxy)phenyl)azetidin-1-yl]phenylmethanone. Yield=82%.

d) [3-(2,4-dihydroxyphenyl)azetidin-1-yl]phenylmethanone

A 10-ml round bottom flask was dissolved 0.2 g of [3-(2,4-bis(benzyloxy)phenyl)azetidin-1-yl]phenylmethanone in 6 ml of methanol in the presence of 0.1 g of 10% palladium on coal. The reaction mixture is stirred for 18 hours in a hydrogen atmosphere. The reaction mixture is filtered and then the residue is subjected to chromatography on silica gel (heptane/ethyl acetate 1/1).

Obtain 0.08 g of [3-(2,4-dihydroxyphenyl)azetidin-1-yl]phenylmethanone. Yield=67%.

1H NMR (DMSO, 400 MHz): 3,86 (m, 1H); Android 4.04 (m, 1H); 4,29 (m, 2H); 4,58 (t, J=8.6 Hz, 1H); to 6.19 (DD, J=8,4 & 2,4 Hz, 1H); 6,28 (d, J=2.4 Hz, 1H); 6,98 (d, J=8,4 Hz, 1H); 7,47 (m, 3H); 7,63 (d, J=8 Hz, 2H) with 9.14 (s, 1H); 9,37 (s, 1H).

13C NMR (DMSO, 100 MHz): 29,3, 54,2, 58,7, 102,4, 105,9, 117,8, 127,7, 127,8, 128,3, 130,7, 133,3, 156,0, 157,0, 168,9.

EXAMPLE 3: pencilled 3-(2,4-dihydroxyphenyl)azetidin-1-carboxylic acid

a) pencilled 3-(2,4-bis(benzyloxy)phenyl)azetidin-1-carboxylic acid

A 10-ml round bottom flask was dissolved 0.15 g of 3-(2,4-bis(benzyloxy)phenyl)useridentification in ml of tetrahydrofuran in the presence of 0.1 ml of N,N-diisopropylethylamine. Add 0,04 ml intilization and then the reaction mixture is stirred for 20 minutes at ambient temperature. The reaction mixture was extracted with ethyl acetate and the organic phases are then combined and dried over magnesium sulfate. The residue is subjected to chromatography on silica gel (heptane/ethyl acetate 9/1). Get 0,1 g pencilled 3-(2,4-bis(benzyloxy)phenyl)azetidin-1-carboxylic acid. Yield=67%.

b) pencilled 3-(2,4-dihydroxyphenyl)azetidin-1-carboxylic acid

A 10-ml round bottom flask was dissolved 0.2 g of pentylamine 3-(2,4-bis(benzyloxy)phenyl)azetidin-1-carboxylic acid in 6 ml of methanol in the presence of 0.1 g of 10% palladium on coal. The reaction mixture is stirred for 6 hours in an atmosphere of hydrogen. The reaction mixture is filtered and then the residue is subjected to chromatography on silica gel (dichloromethane/methanol 95/5).

Obtain 0.02 g of pentylamine 3-(2,4-dihydroxyphenyl)azetidin-1-carboxylic acid. Yield=33%.

1H NMR (DMSO, 400 MHz): 0,85 (t, J=1 Hz, 3H); 1,22 (m, 4H); of 1.34 (m, 2H); 2,94 (USM, 2H); 3,59 (USM, 1H); to 3.73 (USM, 2H); was 4.02 (USM, 2H); 6,17 (m, 3H); of 6.26 (d, J=2.4 Hz, 1H); 6,91 (d, J=8,4 Hz, 1H); 9,1 (USS, 1H); 9,27 (s, 1H).

13C NMR (DMSO, 100 MHz): 13,9, 21,9, 27,6, 28,5, 29,6, 55,0, 102,3, 106,0, 118,5, 127,3, 155,8, 156,8, 159,9.

EXAMPLE 4: tert-butyl ether 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid

a) tert-butyl ether 3-oxopyrrolidin-1-carboxylic acid

In a 1-l three-neck number is e dissolve 10 g of N-Boc-3-hydroxypyrrolidine in 350 ml of dimethyl sulfoxide in the presence 52,3 ml of triethylamine. To the above solution dropwise added 28 g of a complex of pyridine-sulfur trioxide dissolved in 350 ml of dimethyl sulfoxide. The reaction mixture is stirred for 4 hours at ambient temperature. The reaction mixture zachisliaut to pH 4.5-5 1 M solution of hydrochloric acid and then the reaction mixture was extracted with ethyl acetate. The combined organic phases are then dried over anhydrous sodium sulfate. The residue is filtered through silica gel (heptane/ethyl acetate 1/1). Obtain 5.7 g of tert-butyl methyl ether 3-oxopyrrolidin-1-carboxylic acid. Yield: 58%.

b) tert-butyl ether 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid

Tert-butyl ether 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid obtained by the method similar to the method of examples 1b and 1c, but using tert-butyl ester 3-oxopyrrolidin-1-carboxylic acid.

1H NMR (DMSO, 400 MHz): of 1.40 (s, 9H); 1,89 (m, 2H); 3.04 from (t, J=9.5 Hz, 1H); 3,23 (m, 1H); to 3.36 (m, 2H); 3,57 (DD, J=7,6 & 10 Hz, 1H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); 6,28 (d, J=2.4 Hz, 1H); PC 6.82 (m, 1H); 9,06 (s, 1H); 9,27 (s, 1H).

13C NMR (DMSO, 100 MHz): 28,1, 29,9 & 30,8, 36,2 & 37,2, 45,2 & 45,4, 50,7 & 51,1, 78,0, 102,5, 106,0, 127,1, 153,5, 155,5, 156,7.

EXAMPLE 5: isobutyl ester of 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid

a) 3-(2,4-bis(benzyloxy)phenyl)pyrrolidinedithiocarbamate

In a 50 ml round bottom flask, dissolve 1 g of tert-butyl methyl ether 3-(2,4-bis(benzo is Loxy)phenyl)pyrrolidin-1-carboxylic acid (example 4) in 16 ml of dichloromethane, and then add 4 ml triperoxonane acid. The reaction mixture is stirred for 1 hour. The solvent is evaporated and then the residue is treated simple isopropyl ether. Obtain 1.26 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidinedithiocarbamate. Yield=76%.

b) isobutyl ester of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidin-1-carboxylic acid

A 10-ml round bottom flask dissolve 0.25 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidinedithiocarbamate in 5 ml of tetrahydrofuran in the presence of 0.25 ml of N,N-diisopropylethylamine. Add to 0.108 g isobutylphthalate and the reaction mixture is stirred for 30 minutes at ambient temperature. The reaction mixture was extracted with ethyl acetate and then the combined organic phases are dried over magnesium sulfate. The residue is subjected to chromatography on silica gel (heptane/ethyl acetate 8/2). Get 0,22 g isobutyl ester 3-(2,4-bis(benzyloxy)phenyl)-pyrrolidin-1-carboxylic acid. Yield=66%.

c) isobutyl ester of 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid

A 25-ml round bottom flask dissolve 0,22 g isobutyl ester 3-(2,4-bis(benzyloxy)phenyl)pyrrolidin-1-carboxylic acid in 6 ml of methanol in the presence of 0.1 g of 10% palladium on coal. The reaction mixture is stirred for 18 hours in a hydrogen atmosphere. The reaction mixture is filtered and then the residue is subjected to chromatography n is silica gel (heptane/ethyl acetate 1/1).

Obtain 0.1 g of isobutyl ester 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid. Yield=75%.

1H NMR (DMSO, 400 MHz): 0,88 (t, J=1 Hz, 6H); 1,80-2,07 (m, 3H); 3,10 (kV, J=9 Hz, 1H); 3,23-of 3.48 (m, 3H); 3,63 (m, 1H); 3.75 to (m, 2H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); 6,28 (d, J=2.4 Hz, 1H); PC 6.82 (m, 1H); 9,07 (s, 1H); 9,29 (s, 1H).

13C NMR (DMSO, 100 MHz): 18,9, 27,6, 30,0 & 30,8, 36,4 & 37,3, 45,0 & 45,5, 50,6 & 51,0, 70,1, 102,5, 106,0, 117,5, 127,0, 154,1, 155,9, 156,7.

EXAMPLE 6: cyclohexylamin 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid

a) cyclohexylamin 3-(2,4-bis(benzyloxy)phenyl)pyrrolidin-1-carboxylic acid

A 10-ml round bottom flask dissolve 0.25 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidinedithiocarbamate in 5 ml of tetrahydrofuran in the presence of 0.25 ml of N,N-diisopropylethylamine. Add 0.1 g cyclohexylsulfamate and the reaction mixture is stirred for 30 minutes at ambient temperature. The reaction mixture was extracted with ethyl acetate and then the combined organic phases are dried over magnesium sulfate. The residue is subjected to chromatography on silica gel (heptane/ethyl acetate 7/3). Get 0,23 g cyclohexylamin 3-(2,4-bis(benzyloxy)phenyl)pyrrolidin-1-carboxylic acid. Yield=66%.

b) cyclohexylamin 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid

A 25-ml round bottom flask dissolve 0,23 g cyclohexylamine 3-(2,4-bis(benzyloxy)phenyl)pyrrolidin-1-carboxylic acid in 4 ml of methanol in the presence of the tvii 3 ml of ethyl acetate and 0.1 g of 10% palladium on coal. The reaction mixture is stirred for 18 hours in a hydrogen atmosphere. The reaction mixture is filtered and then the residue is subjected to chromatography on silica gel (heptane/ethyl acetate 7/3).

Get 0,095 g cyclohexylamin 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid. Output=100%.

1H NMR (DMSO, 400 MHz): 1,17 (m, 4H); of 1.55 (m, 1H)and 1.60 (m, 4H); to 1.86 (m, 1H); 1,99 (m, 1H); 3,03 (t, J=9,2 Hz, 1H); 3,21 (sq, J=9,2 Hz, 1H); to 3.38 (m, 3H); of 3.56 (t, J=8 Hz, 1H); 5,67 (d, J=7.9 Hz, 1H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); 6,28 (d, J=2.4 Hz, 1H); 6,85 (d, J=8,2 Hz, 1H); 9,04 (s, 1H); a 9.25 (s, 1H).

13C NMR (DMSO, 100 MHz): 25,1, 25,3, 30,6, 33,3, 36,9, 45,0, 48,7, 50,7, 102,4, 105,9, 118,0, 127,0, 155,8, 155,9, 156,6.

EXAMPLE 7: phenylamide 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid

Phenylamide 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid obtained by the method similar to the method of example 6, but using phenylisocyanate.

1H NMR (DMSO, 400 MHz): 1,94-of 2.09 (m, 2H); 3,23 (t, J=9.4 Hz, 1H); 3,37 (m, 1H); of 3.48 (m, 1H); of 3.54 (m, 1H); 3,76 (DD, J=7,7 & 9.5 Hz, 1H); 6,17 (DD, J=8,4 & 2,4 Hz, 1H); 6,30 (d, J=2.4 Hz, 1H); 6.89 in (m, 2H,); 7,21 (t, J=7,6 Hz, 2H); 7,51 (d, J=7,6 Hz, 2H), remaining 9.08 (s, 1H); 9,31 (s, 1H).

13C NMR (DMSO, 100 MHz): 30,5, 37,0, 45,4, 51,0, 102,4, 106,0, 117,7, 119,3, 121,4, 127,2, 128,2, 140,6, 153,8, 156,0, 156,7.

EXAMPLE 8: (4-forfinal)amide 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid

(4-forfinal)amide 3-(2,4-dihydroxyphenyl)-pyrrolidin-1-carboxylic acid obtained by the method similar to the method of example 6, but using 4-florfenicol the Nata.

1H NMR (DMSO, 400 MHz): 1,93-of 2.08 (m, 2H); 3.24 in (t, J=9.4 Hz, 1H); 3,37 (m, 1H); 3,44 (m, 1H); of 3.53 (m, 1H); 3,76 (DD, J=7,7 & 9.5 Hz, 1H); 6,17 (DD, J=8,4 & 2,4 Hz, 1H); 6,30 (d, J=2.4 Hz, 1H); 6,91 (d, J=8,3 Hz, 1H); 7,05 (t, J=8,8 Hz, 2H); 7,51 (m, 2H); 8,15 (s, 1H); remaining 9.08 (s, 1H); 9,31 (s, 1H).

13C NMR (DMSO, 100 MHz): 30,5, 37,0, 45,4, 51,0, 102,5, 106,0, 114,7, 117,7, 121,0, 127,1, 137,0, 155,9, 156,7, 158,3.

EXAMPLE 9: (4-triptoreline)amide 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid

3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid (4-triptoreline)amide receive in a manner analogous to the method of example 6, but using 4-triftormetilfullerenov.

1H NMR (DMSO, 400 MHz): 1,95-of 2.08 (m, 2H); 3,26 (t, J=9.4 Hz, 1H); 3,37 (m, 1H); 3,44 (m, 1H); 3,57 (m, 1H); of 3.77 (DD, J=7,7 & 9.5 Hz, 1H); 6,17 (DD, J=8,4 & 2,4 Hz, 1H); 6,30 (d, J=2.4 Hz, 1H); 6.90 to (l, J=8,3 Hz, 1H); 7,56 (d, J=8.7 Hz, 1H); 7,76 (d, J=8.7 Hz, 2H); charged 8.52 (s, 1H); remaining 9.08 (s, 1H); was 9.33 (s, 1H).

13C NMR (DMSO, 100 MHz): 30,4, 37,0, 45,5, 51,0, 102,5, 106,0, 117,5, 118,6, 121,1 (kV), 124,6 (kV), 125,4, 127,2, 153,38, 156,0, 156,7.

EXAMPLE 10: ethyl ester of 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

a) ethyl ester of 4-(2,4-bis(benzyloxy)phenyl)-4-hydroxypiperidine-1-carboxylic acid

In a 500-ml three-neck flask dissolve 20 g of 2,4-bis(benzyloxy)-1-bromine benzol in 240 ml of tetrahydrofuran. The mixture is cooled to -70°C, and then add 26 ml of 2.5 M n-utility in hexane. The reaction mixture was stirred at -70°C for 1 hour and then added dropwise to 11.1 g of ethyl ester of 4-oxopiperidin-1-to benovoy acid. The reaction mixture was stirred at -70°C for 2 hours and then left overnight at ambient temperature. The reaction mixture was poured into 100 ml of 2 M hydrochloric acid, and then extracted with 400 ml of ethyl acetate. The combined organic phases are washed with 150 ml of water, and then dried over magnesium sulfate and evaporated.

The residue is crystallized from a mixture of dichloromethane/heptane. Obtain 16 g of ethyl ester of 4-(2,4-bis(benzyloxy)phenyl)-4-hydroxypiperidine-1-carboxylic acid. Yield: 62%.

b) ethyl ester of 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

In a mixture of 50 ml of methanol was dissolved 1 g of ethyl ester of 4-(2,4-bis(benzyloxy)phenyl)-4-hydroxy-piperidine-1-carboxylic acid, and then add 0.5 g of 10% palladium on coal. The reaction mixture is stirred for 2 hours in hydrogen atmosphere. The reaction mixture is filtered and then the residue is crystallized from dichloromethane. Obtain 0.5 g of ethyl ester of 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid. Yield=86%.

1H NMR (DMSO, 400 MHz): 1,17 (t, J=1 Hz, 3H); to 1.38 (m, 2H); of 1.64 (m, 2H); 2,84 (m, 3H) 4,01 (m, 4H); 6,12 (DD, J=8,4 & 2,4 Hz, 1H); of 6.25 (d, J=2.4 Hz, 1H); 6,79 (d, J=8,3 Hz, 1H); 8,96 (s, 1H); 9,14 (s, 1H).

13C NMR (DMSO, 100 MHz): 14,6, 31,6, 34,6, 44,2, 60,5, 102,3, 106,0, 122,1, 126,7, 154,6, 155,2, 156,2.

EXAMPLE 11: [4-(2,4-dihydroxyphenyl)piperidine-1-yl]phenylmethanone

a) ethyl ester of 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid

In 00-ml round bottom flask in small portions to a solution of 6.2 g of ethyl ester of 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid (example 10) in 62 ml of methyl ethyl ketone added 9.7 g of potassium carbonate.

Added dropwise to 6.7 ml of benzylbromide and then the reaction mixture is stirred for 2 hours while boiling under reflux. The reaction mixture is filtered and then the residue is subjected to chromatography on silica gel (heptane/ethyl acetate 80/20).

Gain of 9.8 g of ethyl ester of 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid. Yield=92%.

b) 4-(2,4-bis(benzyloxy)phenyl)piperidine

In a 500-ml three-neck flask was dissolved 9 g of ethyl ester of 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid in 180 ml of ethanol, and then add 40 ml of 5 M sodium hydroxide solution. The reaction mixture is brought to boiling point under reflux for 48 hours. The reaction mixture is poured into 400 ml of water. The solid is filtered off, and then spend chromatography on silica gel (dichloromethane/methanol 98/2). Obtain 3.8 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine.

c) [4-(2,4-bis(benzyloxy)phenyl)piperidine-1-yl]phenylmethanone

A 25-ml round bottom flask dissolve 0.5 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine in 10 ml of tetrahydrofuran in the presence of 0.26 ml of N,N-diisopropylethylamine. Add to 0.17 ml of benzoyl chloride and the mixture is then stirred for 24 hours at ambient temperature. The reaction mixture was extracted with ethyl acetate and then the combined organic phases are dried over magnesium sulfate. The remainder of the basement is Laut chromatography on silica gel (heptane/ethyl acetate 8/2). Obtain 0.5 g of [4-(2,4-bis(benzyloxy)phenyl)-piperidine-1-yl]phenylmethanone. Yield=80%.

d) [4-(2,4-dihydroxyphenyl)piperidine-1-yl]phenylmethanone

A 25-ml round bottom flask dissolve 0.5 g of [4-(2,4-bis(benzyloxy)phenyl)piperidine-1-yl]phenylmethanone in 15 ml of methanol in the presence of 0.2 g of 10% palladium on coal. The reaction mixture is stirred for 48 hours in an atmosphere of hydrogen. The reaction mixture is filtered and then the residue is subjected to chromatography on silica gel (heptane/ethyl acetate 1/1).

Obtain 0.3 g of [4-(2,4-dihydroxyphenyl)piperidine-1-yl]phenylmethanone. Yield=96%.

1H NMR (DMSO, 400 MHz): 1,50 (USM, 2H); 1,59 (USM, 1H); 1,75, (USM, 1H); 2,79 (USM, 1H); of 2.97 (m, 1H); 3,11 (USM, 1H); 3,62 (USM, 1H); 4,59 (USM, 1H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); 6,27 (d, J=2.4 Hz, 1H); 6,85 (d, J=8,3 Hz, 1H); 7,41 (m, 5H); 8,98 (s, 1H), 9,17 (s, 1H).

13C NMR (DMSO, 100 MHz): 31,7, 34,6, 47,9, 102,4, 106,0, 122,0, 126,6, 126,9, 128,3, 129,2, 136,6, 139,6, 155,1, 156,1, 168,8, 170,3.

EXAMPLE 12: butylamide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

a) butylamide 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid

A 10-ml round bottom flask dissolve 0.25 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine in 5 ml of tetrahydrofuran in the presence of 0.23 ml of N,N-diisopropylethylamine. Add 0,08 ml utilizationof and then the reaction mixture is stirred for 20 minutes at ambient temperature. The reaction mixture was extracted with ethyl acetate and then the organic phase is s are combined and dried over magnesium sulfate. The residue is subjected to chromatography on silica gel (heptane/ethyl acetate 8/2). Obtain 0.25 g of butylamine 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid. Yield=78%.

b) butylamide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

A 25-ml round bottom flask dissolve 0.25 g of butylamine 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid in 9 ml of methanol in the presence of 0.1 g of 10% palladium on coal. The reaction mixture is stirred for 4 hours in hydrogen atmosphere. The reaction mixture is filtered. Obtain 0.14 g of butylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid. Yield=90%.

1H NMR (DMSO, 400 MHz): 0,86 (t, J=7 Hz, 3 H); of 1.30 (m, 2H); to 1.37 (m, 4H)and 1.60 (m, 2H); 2,62 (m, 2H); 2,80 (m, 1H); 3,00 (m, 2H); is 4.03 (m, 2H); 6,12 (DD, J=8,4 & 2,4 Hz, 1H); of 6.25 (d, J=2.4 Hz, 1H); 6,38 (t, J=5.4 Hz, 1H); 6,77 (d, J=8,2 Hz, 1H); of 8.95 (s, 1H); 9,11 (s, 1H).

13C NMR (DMSO, 100 MHz): 13,8, 19,6, 31,7, 32,0, 34,7, 44,3, 102,3, 106,0, 122,5, 126,7, 155,2, 156,0, 157,3.

EXAMPLE 13: propelled 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

Propelled 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using propositionthe.

1H NMR (DMSO, 400 MHz): 0,86 (t, J=1 Hz, 3 H); to 1.37 (m, 4H); to 1.59 (m, 2H); to 2.65 (m, 2H); and 2.79 (m, 1H); of 2.97 (m, 2H); is 4.03 (m, 2H); 6,12 (DD, J=8,4 & 2,4 Hz, 1H); of 6.25 (d, J=2.4 Hz, 1H); 6,41 (t, J=5.4 Hz, 1H); 6,77 (d, J=8,2 Hz, 1H); of 8.95 (s, 1H); 9,12 (s, 1H).

13C NMR (DMSO, 100 MHz): 11,3, 23,0, 31,7, 34,7, 41,9, 44,3, 102,3, 106,0, 122,5, 126,7, 1552, 156,0, 157,3.

EXAMPLE 14: 1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]butane-1-he

1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]butane-1-he receives a manner analogous to the method of example 11c, but using butanolide.

1H NMR (DMSO, 400 MHz): 0,86 (t, J=7.5 Hz, 3H); 1,29-of 1.55 (m, 4H); to 1.67 (m, 2H); and 2.27 (t, J=8 Hz, 2H); 2,48 (USM, 1H); 2,90 (t, J=11,6 Hz, 1H); to 3.02 (t, J=12,8 Hz, 1H); 3,91 (USD, J=12,8 Hz, 1H); 4,50 (USD, J=13,2 Hz, 1H); 6,13 (DD, J=8,4 & 2,4 Hz, 1H); 6,24 (d, J=2.4 Hz, 1H); 6,77 (d, J=8,3 Hz, 1H); 8,93 (s, 1H), 9,11 (s, 1H).

13C NMR (DMSO, 100 MHz): 14,3, 18,8, 32,1 & 32,9, 34,8, 35,1, 42,3 & 46,3, 102,8, 106,5, 122,6, 127,2, 155,6, 156,6, 170,5.

EXAMPLE 15: 1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-methylpropan-1-he

1-[4-(2,4-dihydroxyphenyl)-piperidine-1-yl]-2-methylpropan-1-he receives a manner analogous to the method of example 11c, but using 2-methylpropanamide.

1H NMR (DMSO, 400 MHz): to 0.96 (2T, J=7.5 Hz, 6H); 1,28 of 1.46 (m, 2H); by 1.68 (m, 2H); of 2.51 (USM, 1H); 2,87 (m, 2H); 3,05 (t, J=12,8 Hz, 1H); 4,01 (USD, J=12,8 Hz, 1H); 4.53-in (USD, J=13,2 Hz, 1H); 6,13 (DD, J=8,4 & 2,4 Hz, 1H); from 6.25 (d, J=2.4 Hz, 1H); 6,79 (d, J=8,3 Hz, 1H); 8,97 (s, 1H), 9.15, with (s, 1H).

13C NMR (DMSO, 100 MHz): 19,3, 19,6, 28,9, 31,6 & 32,6, 34,7, 42,0 & 45,6, 102,3, 106,0, 122,0, 126,7, 155,2, 156,1, 173,9.

EXAMPLE 16: phenylamide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

Phenylamide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using phenylisocyanate.

1H NMR (DMSO, 400 MHz): of 1.46 (m, 2H); 1,70 (d, J=11,6 Hz, 2H); 2,82 (t, =to 11.4 Hz, 2H); 2,90 (m, 1H); to 4.23 (d, J=13.1 Hz, 2H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); of 6.25 (d, J=2.4 Hz, 1H); PC 6.82 (d, J=8,3 Hz, 1H); 6,91 (t, J=8,2 Hz, 1H); 7,21 (t, J=8 Hz, 2H); was 7.45 (d, J=8 Hz, 2H); of 8.47 (s, 1H); 8,97 (s, 1H); 9,16 (s, 1H).

13C NMR (DMSO, 100 MHz): 31,8, 34,7, 44,7, 102,4, 106,0, 119,5, 121,4, 122,3, 126,8, 128,2, 140,7, 154,9, 155,2, 156,1.

EXAMPLE 17: (4-forfinal)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

(4-forfinal)amide 4-(2,4-dihydroxyphenyl)-piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using 4-perteneciente.

1H NMR (DMSO, 400 MHz): of 1.46 (m, 2H); 1.69 in (d, J=11,6 Hz, 2H); 2,82 (t, J=11,4 Hz, 2H); 2,90 (m, 1H); 4,22 (d, J=13.1 Hz, 2H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); 6,28 (d, J=2.4 Hz, 1H); for 6.81 (d, J=8,3 Hz, 1H); 7,08 (t, J=8,2 Hz, 2H); 7,46 (m, 2H); 8,51 (s, 1H); 9,00 (s, 1H); 9,16 (s, 1H).

13C NMR (DMSO, 100 MHz): 31,8, 34,7, 44,6, 102,4, 106,0, 114,6, 121,2, 122,3, 126,8, 137,0, 154,9, 155,2, 156,0, 156,1, 158,4.

EXAMPLE 18: n-tolerated 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

p-Tailed 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using p-trilinoleate.

1H NMR (DMSO, 400 MHz): of 1.46 (m, 2H); 1.69 in (d, J=11,6 Hz, 2H); 2,22 (s, 3H); and 2.83 (t, J=11,4 Hz, 2H); 2,90 (m, 1H); 4,22 (d, J=13.1 Hz, 2H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); 6,27 (d, J=2.4 Hz, 1H); PC 6.82 (d, J=8,3 Hz, 1H); 7,02 (d, J=8,2 Hz, 2H); 7,34 (d, J=8 Hz, 2H); of 8.37 (s, 1H); 8,97 (s, 1H); to 9.15 (s, 1H).

13C NMR (DMSO, 100 MHz): 20,3, 31,8, 34,7, 44,6, 102,4, 106,0, 119,7, 122,3, 126,8, 128,6, 130,2, 138,1, 154,9, 155,2, 156,1.

EXAMPLE 19: ventilated 4-(2,4-dihydroxy who yl)piperidine-1-carboxylic acid

Ventilated 4-(2,4-dihydroxyphenyl)-piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using geneticization.

1H NMR (DMSO, 400 MHz): of 1.34 (m, 2H)and 1.60 (d, J=11,6 Hz, 2H); 2,64-by 2.73 (m, 4H); and 2.83 (m, 1H); up 3.22 (m, 2H); was 4.02 (d, J=13.1 Hz, 2H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); is 6.54 (m, 1H); 6,78 (d, J=8,3 Hz, 1H); 7.18 in (m, 3H); 7,28 (m, 2H); 8,97 (s, 1H); 9,12 (s, 1H).

13C NMR (DMSO, 100 MHz): 31,7, 34,7, 36,0, 41,9, 44,3, 102,4, 106,0, 122,5, 125,8, 126,7, 128,2, 128,6, 139,9, 155,4,1, 156,0, 157,2.

EXAMPLE 20: (3-forfinal)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

(3-forfinal)amide 4-(2,4-dihydroxyphenyl)-piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using 3-perteneciente.

1H NMR (DMSO, 400 MHz): of 1.46 (m, 2H); 1.69 in (d, J=11,6 Hz, 2H); 2,82 (t, J=11,4 Hz, 2H); 2,90 (m, 1H); 4,22 (d, J=13.1 Hz, 2H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); 6,27 (d, J=2.4 Hz, 1H); 6,70 (m, 1H); for 6.81 (d, J=8,3 Hz, 1H); from 7.24 (m, 2H); 7,47 (d, J=18 Hz, 1H); to 8.70 (s, 1H); 9,00 (s, 1H); 9,17 (s, 1H).

13C NMR (DMSO, 100 MHz): 31,8, 34,7, 44,7, 102,4, 106,0, 107,6, 114,9, 122,2, 126,8, 129,6, 142,7, 154,5, 155,2, 156,1, 162,1.

EXAMPLE 21: ((R)-1-phenylethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

((R)-1-phenyl-ethyl) - amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using ((R)-1-isocyanatomethyl)benzene.

1H NMR (DMSO, 400 MHz): 1,35 (d, J=7,1 Hz, 3H); to 1.38 (m, 2H); of 1.62 (m, 2H); 2,82 (t, J=13 Hz, 2H); and 2.83 (m, 1H); 4,22 (d, J=12,3 Hz, 2H); 4,84 (m, 1H); 6,13 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); 6.73 x (d, J=7.9 Hz, 1H); is 6.78 (d, J=8,3 Hz, 1H); 7.18 in (m, 1H); 7,32 (m, 4H); 8,96 (s, 1H); 9,13 (s, 1H).

13C NMR (DMSO, 100 MHz): 22,8, 31,7, 31,8, 44,4, 49,3, 102,4, 106,0, 122,5, 125,9, 126,1, 126,7, 127,9, 146,3, 155,2, 156,0, 156,6.

EXAMPLE 22: methylphenylene 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

1H NMR (DMSO, 400 MHz): 1,28 (m, 2H); to 1.48 (d, J=12 Hz, 2H); 2,62 (t, J=12,6 Hz, 2H); 2,77 (m, 1H); to 3.09 (s, 3H); of 3.80 (d, J=13 Hz, 2H); 6,13 (DD, J=8,4 & 2,4 Hz, 1H); from 6.22 (d, J=2.4 Hz, 1H); 6,70 (d, J=7.9 Hz, 1H); 7,11 (m, 3H); 7,35 (m, 2H); 8,96 (s, 1H); which is 9.09 (s, 1H).

13C NMR (DMSO, 100 MHz): 31,2, 34,4, 38,8, 46,0, 102,3, 106,0, 122,2, 122,6, 123,6, 126,6, 129,2, 146,7, 155,1, 156,0, 160,0.

EXAMPLE 23: pyridine-2-alamid 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

a) 4-nitrophenyloctyl ether pyridine-2-ylcarbamate acid

Dissolve 0.5 g of 2-aminopyridine in 10 ml of dichloromethane, and then added 1.18 g of 4-nitrophenylphosphate, and of 1.85 ml of N,N-diisopropylethylamine. The reaction mixture is stirred for one hour at ambient temperature. The reaction mixture was added 50 ml of water, and the mixture is then extracted with 50 ml dichloromethane. The solvent is evaporated and then the solid substance used in the next step without additional purification.

b) pyridine-2-alamid 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid

0.5 g of 4-(2,4-bis(benzyloxy)phenyl)piperidylamine suspended in 5 ml of dimethylformamide, and then add of 0.43 ml of N,N-disop is operationin, and of 0.38 g of 4-nitrophenylamino ether pyridine-2-ylcarbamate acid solution of 2 ml of dimethylformamide. The reaction mixture is stirred for 24 hours at 80°C., It is heated at 80°C for 24 hours. Add 50 ml of water, and then the reaction mixture is extracted with 50 ml ethyl acetate. The solvents are evaporated and then the residue is subjected to chromatography on silica gel (heptane/ethyl acetate 70/30). Receive 20 mg of pyridine-2-ylamide 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid.

c) pyridine-2-alamid 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

20 mg of pyridine-2-ylamide 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid was dissolved in 20 ml of ethyl acetate, and then add 1 ml of methanol. Add 10 mg of 10% palladium on charcoal, and then the reaction mixture is stirred for 18 hours in a hydrogen atmosphere. The mixture is filtered and then the residue is crystallized from a mixture of ethyl acetate/heptane. Receive 5 mg of pyridine-2-ylamide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid. Yield: 39%

1H NMR (DMSO, 400 MHz): 1,458 (m, 2H); by 1.68 (m, 2H); 2,85 (m, 3H); 4.26 deaths (d, J=13,6 Hz, 2H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); of 6.25 (d, J=2.4 Hz, 1H); for 6.81 (d, J=7.9 Hz, 1H); to 6.95 (m, 1H); 7,66 (m, 1H); for 7.78 (d, J=7.9 Hz, 1H); 8,21 (m, 1H); 8,97 (s, 1H); which is 9.09 (s, 1H), 9.15, with (s, 1H).

EXAMPLE 24: ((S)-1-phenylethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

((S)-1-phenyl-ethyl) - amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid is you get way similar to the method of example 12a, but using ((S)-1-isocyanatomethyl)benzene.

1H NMR (DMSO, 400 MHz): 1,35 (d, J=7,1 Hz, 3H); to 1.38 (m, 2H); of 1.62 (m, 2H); 2,82 (t, J=13 Hz, 2H); and 2.83 (m, 1H); 4,22 (d, J=12.3 Hz, 2H); 4,84 (m, 1H); 6,13 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); of 6.73 (d, J=7.9 Hz, 1H); is 6.78 (d, J=8,3 Hz, 1H); 7.18 in (m, 1H); 7,32 (m, 4H); 8,96 (s, 1H); 9,13 (s, 1H).

13C NMR (DMSO, 100 MHz): 22,8, 31,7, 31,8, 44,4, 49,3, 102,4, 106,0, 122,5, 125,9, 126,1, 126,7, 127,9, 146,3, 155,2, 156,0, 156,6.

EXAMPLE 25: ((S)-1-phenylpropyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

((S)-1-phenylpropyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using ((S)-1-isocyanatopropyl)benzene.

1H NMR (DMSO, 400 MHz): 0,82 (t, J=7,1 Hz, 3H); to 1.37 (m, 2H); to 1.67 (m, 4H); to 2.67 (m, 2H); and 2.83 (m, 1H); 4,12 (d, J=12.3 Hz, 2H); 4,56 (m, 1H); 6,13 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); of 6.65 (d, J=7.9 Hz, 1H); 6,77 (d, J=8,3 Hz, 1H); 7.18 in (m, 1H); 7,29 (m, 4H); 8,96 (s, 1H); 9,11 (s, 1H).

13C NMR (DMSO, 100 MHz): 11,4, 29,3, 31,7, 34,7, 44,5, 55,8, 102,4, 106,0, 122,5, 126,1, 126,4, 126,7, 127,9, 145,4, 155,1, 156,0, 156,9.

EXAMPLE 26: (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)-piperidine-1-yl]-3-phenylpropane-1-he

a) benzyl ester {(R)-1-benzyl-2-[4-(2,4-bis(benzyloxy)phenyl)piperidine-1-yl]-2-oxoethyl}carbamino acid

In a 50 ml round bottom flask dissolve of 0.615 g of Z-L-phenylalanine in 10 ml of dimethylformamide, and type of 0.43 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), as well as 0,305 g of 1-hydroxybenzotriazole (HOBT), and then the reaction is ionic mixture is stirred for 5 minutes at ambient temperature.

Add 1 g of 4-(2,4-bis(benzyloxy)phenyl)piperidinedione and 0,36 ml Diisopropylamine. The reaction mixture is stirred for 1 hour at ambient temperature. The reaction mixture is washed with 20 ml of 5% citric acid, and then extracted with 20 ml of ethyl acetate, the organic phase is washed with 20 ml of 1 M sodium hydroxide solution, and the organic phase is dried over magnesium sulfate. After evaporation of the solvents, the crude product is subjected to chromatography on silica gel. Get 1,23 g benzyl ester {(R)-1-benzyl-2-[4-(2,4-bis(benzyloxy)phenyl)piperidine-1-yl]-2-oxoethyl}carbamino acid.

b) (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-3-phenylpropane-1-he

A 25-ml round bottom flask dissolve 1,23 g benzyl ester {(R)-1-benzyl-2-[4-(2,4-bis(benzyloxy)phenyl)piperidine-1-yl]-2-oxoethyl}carbamino acid in 15 ml methanol and 15 ml of ethyl acetate in the presence of 0.25 g of 10% palladium on coal. The reaction mixture is stirred for 18 hours in a hydrogen atmosphere. The reaction mixture is filtered. The residue is subjected to chromatography on silica gel (dichloromethane/methanol 95/5). Receive 0.625 g (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-3-phenylpropane-1-it. Yield=64%.

1H NMR (DMSO, 400 MHz): 0,6 (m, 1H); 1,09 (m, 1H); 1.30 and a 1.75 (m, 5H); 2,56-of 2.97 (m, 4 H); of 3.94 (m, 2H); 4,51 (d, J=12,8 Hz, 1H); 6,11 (m, 1H); 6,24 (m, 1H); 6,57 & 6,77 (d, J=8,3 Hz, 1H); 7.18 in-7,40 (m, 5H); 8,97 (s, 1H); 9,11 & 9,1 (s, 1H).

13C NMR (DMSO, 100 MHz): (shortness of rotation) 31,6, 32,3, 31,1, 34,6, 42,0, 42,2, 42,7, 45,3, 45,6, 51,3, 51,6, 102,3, 105,9, 121,9, 126,0, 126,7, 127,9, 128,1, 129,4, 138,5, 155,0, 156,0, 172,6.

EXAMPLE 27: 1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-3-phenylpropane-1-he

1-[4-(2,4-dihydroxyphenyl)-piperidine-1-yl]-3-phenylpropane-1-he receives a manner analogous to the method of example 11c, but using 3-phenylpropionylamino.

1H NMR (DMSO, 400 MHz): 1,33 (m, 2H); and 1.63 (m, 2H); 2,50-2,70 (m, 3H); 2,80-3,0 (m, 4 H); to 3.92 (d, J=12,8 Hz, 1H); 4,53 (d, J=12,8 Hz, 1H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); 6.75 in (d, J=7.9 Hz, 1H); 7,15-7,29 (m, 5H); 8,97 (s, 1H); 9,11 (s, 1H).

13C NMR (DMSO, 100 MHz): 30,9, 31,6, 32,2, 33,9, 34,5, 42,0, 45,8, 102,4, 106,0, 122,1, 125,8, 126,7, 128,2, 128,4, 141,5, 155,2, 156,1, 169,5.

EXAMPLE 28: 2-forbindelse 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

2-forbindelse 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using 2-fermentalization.

1H NMR (DMSO, 400 MHz): 1,40 (m, 2H); and 1.63 (m, 2H); was 2.76 (t, J=13 Hz, 2H); 2,84 (m, 1H); was 4.02 (d, J=12.3 Hz, 2H); to 4.28 (d, J=5.5 Hz, 2H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); 6.73 x (d, J=7.9 Hz, 1H); 7.03 is (t, J=5.6 Hz, 1H); 7,16 (m, 2H); 7,28 (m, 2H); 8,96 (s, 1H); 9,13 (s, 1H).

13C NMR (DMSO, 100 MHz): 31,7, 34,7, 37,0, 44,4, 102,4, 106,0, 114,7, 122,4, 124,1, 126,7, 127,7, 128,2, 129,0, 155,2, 156,0, 157,2, 158,6, 161,0.

EXAMPLE 29: 3-forbindelse 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

3-forbindelse 4-(2,4-dihydroxyphenyl)piperidine-1-carbon is howling acid is produced by way similar to the method of example 12a, but using 3-fermentalization.

1H NMR (DMSO, 400 MHz): to 1.38 (m, 2H); and 1.63 (m, 2H); 2,73 (t, J=13 Hz, 2H); of 2.86 (m, 1H); Android 4.04 (d, J=12.3 Hz, 2H); to 4.23 (d, J=5.5 Hz, 2H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); 6,79 (d, J=7.9 Hz, 1H); 7,06 (m, 4H); 7,34 (m, 1H); 8,96 (s, 1H); 9,13 (s, 1H).

13C NMR (DMSO, 100 MHz): 31,8, 24,7, 43,1, 44,5, 102,5, 106,1, 113,0 & of 113.2, 113,5 & 113,7, 122,5, 123,0, 126,8, 130,0, 144,6, 155,3, 156,1, 157,3.

EXAMPLE 30: 4-forbindelse 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

4-forbindelse 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using 4-fermentalization.

1H NMR (DMSO, 400 MHz): to 1.38 (m, 2H); and 1.63 (m, 2H); a 2.71 (t, J=13 Hz, 2H); 2,84 (m, 1H); Android 4.04 (d, J=12.3 Hz, 2H); is 4.21 (d, J=5.5 Hz, 2H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); is 6.78 (d, J=7.9 Hz, 1H); 7,05 (t, J=5.6 Hz, 1H); 7,13 (m, 2H); 7,28 (m, 2H); 8,96 (s, 1H); 9,13 (s, 1H).

13C NMR (DMSO, 100 MHz): 31,7, 34,7, 42,8, 44,4, 102,4, 106,0, 114,7, 122,4, 126,7, 128,8, 137,4, 155,2, 156,0, 157,2, 159,7 & 162,1.

EXAMPLE 31: benzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

Benzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using benzylisothiocyanate.

1H NMR (DMSO, 400 MHz): 1,41 (m, 2H); and 1.63 (m, 2H); of 2.72 (t, J=13 Hz, 2H); to 2.85 (m, 1H); was 4.02 (d, J=12.3 Hz, 2H); 4,24 (d, J=5.5 Hz, 2H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); 6,79 (d, J=7.9 Hz, 1H); 7,05 (t, J=5.6 Hz, 1H); from 7.24 (m, 5H); 7,28 (m, 2H); 8,96 (s, 1H) 9,13 (s, 1H).

13C NMR (DMSO, 100 MHz): 31,7, 34,7, 43,5, 44,4, 102,4, 106,0, 122,4, 126,3, 126,7, 126,9, 128,0, 141,2, 155,2, 156,0, 157,3.

EXAMPLE 32: 2-methylbenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

2-methylbenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using 2-methylbenzenesulfonate.

1H NMR (DMSO, 400 MHz): 1,40 (m, 2H); of 1.62 (m, 2H); and 2.27 (s, 3H); 2,73 (t, J=13 Hz, 2H); to 2.85 (m, 1H); 4,10 (d, J=12.3 Hz, 2H); 4,22 (d, J=5.5 Hz, 2H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); 6,79 (d, J=7.9 Hz, 1H); 6.90 to (t, J=5.6 Hz, 1H); 7,09-7,20 (m, 4H); 7,28 (m, 2H); 9 (USS, 1H); 9,12 (USS, 1H).

13C NMR (DMSO, 100 MHz): 18,6, 31,8, 34,7, 41,4, 44,5, 102,4, 106,0, 122,4, 125,5, 126,2, 126,7, 126,9, 129,6, 135,0, 138,7, 155,2, 156,0, 157,3.

EXAMPLE 33: 3-methylbenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

3-methylbenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using 3-methylbenzenesulfonate.

1H NMR (DMSO, 400 MHz): 1,40 (m, 2H); of 1.62 (m, 2H); of 2.28 (s, 3H); of 2.72 (t, J=13 Hz, 2H); of 2.86 (m, 1H); was 4.02 (d, J=12.3 Hz, 2H); 4,20 (d, J=5.5 Hz, 2H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); is 6.78 (d, J=7.9 Hz, 1H); 7,00-7,06 (m, 4H); 7.18 in (t, J=7,6 Hz, 1H); 8,99 (s, 1H); 9,13 (s, 1H).

13C NMR (DMSO, 100 MHz): 21,0, 31,7, 34,7, 43,4, 44,5, 102,4, 106,0, 122,5, 124,1, 126,7, 126,9, 127,6, 127,9, 136,9, 141,1, 155,2, 156,0, 157,3.

EXAMPLE 34: 4-methylbenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

4-methylbenzylamine 4-(2,4-dihydroxy who enyl)piperidine-1-carboxylic acid is obtained by way similar to the method of example 12a, but using 4-methylbenzenesulfonate.

1H NMR (DMSO, 400 MHz): 1,41 (m, 2H); of 1.62 (m, 2H); and 2.27 (s, 3H); a 2.71 (t, J=13 Hz, 2H); 2,84 (m, 1H); 4,08 (d, J=12 Hz, 2H); 4,19 (d, J=5.5 Hz, 2H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); is 6.78 (d, J=7.9 Hz, 1H); 6,99 (t, J=5.6 Hz, 1H); for 7.12 (2D, J=8 Hz, 4H); 8,96 (s, 1H); 9,13 (s, 1H).

13C NMR (DMSO, 100 MHz): 20,8, 31,9, 34,9, 43,4, 44,6, 102,6, 106,2, 122,7, 126,9, 127,2, 128,7, 135,4, 138,4, 155,4, 156,3, 157,5.

EXAMPLE 35: 2-methoxybenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

2-methoxybenzylamine 4-(2,4-dihydroxyphenyl)-piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using 2-methoxybenzylideneamino.

1H NMR (DMSO, 400 MHz): 1,41 (m, 2H); and 1.63 (m, 2H); to 2.74 (t, J=13 Hz, 2H); of 2.86 (m, 1H); 3,79 (s, 3H); 4,11 (d, J=12.3 Hz, 2H); 4,22 (d, J=5.5 Hz, 2H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); 6,79-to 6.95 (m, 4H); 7,13-7,22 (m, 2H); 9,00 (USS, 1H); 9,14 (USS, 1H).

13C NMR (DMSO, 100 MHz): 31,7, 34,7, 38,3, 44,5, 55,2, 102,4, 106,0, 110,1, 119,9, 122,5, 126,7, 126,9, 127,3, 128,6, 155,2, 156,1, 156,3, 157,4.

EXAMPLE 36: 3-methoxybenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

3-methoxybenzylamine 4-(2,4-dihydroxyphenyl)-piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using 3-methoxybenzylideneamino.

1H NMR (DMSO, 400 MHz): 1,41 (m, 2H); and 1.63 (m, 2H); of 2.72 (t, J=13 Hz, 2H); of 2.86 (m, 1H); to 3.73 (s, 3H); 4.09 to (d, J=12.3 Hz, 2H); is 4.21 (d, J=5.5 Hz, 2H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); 6,79 (m, 4H; 7,03 (t, J=5.6 Hz, 1H); 7,22 (t, J=8 Hz, 1H); 9,02 (USS, 1H); 9,10 (USS, 1H).

13C NMR (DMSO, 100 MHz): 31,7, 34,7, 43,4, 44,5, 54,9, 102,4, 106,0, 111,6, 112,6, 119,1, 122,5, 126,7, 129,0, 142,9, 155,2, 156,0, 157,3, 159,2.

EXAMPLE 37: 4-methoxybenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

4-methoxybenzylamine 4-(2,4-dihydroxyphenyl)-piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using 4-methoxybenzylideneamino.

1H NMR (DMSO, 400 MHz): 1,41 (m, 2H); of 1.62 (m, 2H); 2,70 (t, J=13 Hz, 2H); 2,84 (m, 1H); and 3.72 (s, 3H); 4,08 (d, J=12 Hz, 2H); 4.16 the (d, J=5.5 Hz, 2H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); is 6.78 (d, J=7.9 Hz, 1H); 6.87 in (d, J=8 Hz, 2H); for 7.12 (t, J=5.6 Hz, 1H); to 7.18 (d, J=8 Hz, 2H); 9,06 (s, 2H).

13C NMR (DMSO, 100 MHz): 31,7, 34,7, 42,9, 44,4, 55,0, 102,4, 106,0, 113,4, 122,4, 126,7, 128,3, 133,2, 155,2, 156,1, 157,3, 157,9.

EXAMPLE 38: ((S)-1-p-triletal)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

((S)-1-p-triletal)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using ((S)-1-isocyanatomethyl)-4-methylbenzene.

1H NMR (DMSO, 400 MHz): 1,35 (d, J=7,1 Hz, 3H); to 1.38 (m, 2H); of 1.62 (m, 2H); and 2.26 (s, 3H); to 2.67 (t, J=13 Hz, 2H); and 2.83 (m, 1H); 4,11 (d, J=12.3 Hz, 2H); 4,84 (m, 1H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); to 6.67 (d, J=7.9 Hz, 1H); 6,77 (d, J=8,3 Hz, 1H); to 7.09 (d, J=8 Hz, 2H); 7,20 (d, J=8 Hz, 2H); 8,96 (s, 1H); 9,12 (s, 1H).

13C NMR (DMSO, 100 MHz): 18,5, 20,6, 22,9, 31,8, 34,7, 44,4, 49,0, 102,4, 106,0, 122,5, 125,8, 126,7, 128,5, 135,0, 143,2, 155,2, 156,0, 156,6.

EXAMPLE 39: [(S)-1-(4-Fortini is)ethyl]amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

[(S)-1-(4-forfinal)ethyl]amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using 1-fluoro-4-((S)-1-isocyanatomethyl)benzene.

1H NMR (DMSO, 400 MHz): 1,35 (d, J=7,1 Hz, 3H); to 1.38 (m, 2H); of 1.62 (m, 2H); to 2.67 (t, J=13 Hz, 2H); and 2.83 (m, 1H); 4.09 to (d, J=12.3 Hz, 2H); 4,84 (m, 1H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); 6,74 (d, J=7.9 Hz, 1H); is 6.78 (d, J=8,3 Hz, 1H); to 7.09 (t, J=8,9 Hz, 2H); 7,35 (m, 2H); 8,96 (s, 1H); 9,12 (s, 1H).

13C NMR (DMSO, 100 MHz): 22,8, 31,7, 34,7, 44,4, 48,7, 102,4, 106,0, 114,5, 122,4, 126,7, 127,8, 142,4, 155,2, 156,0, 156,5, 160,7 (d, J=241 Hz).

EXAMPLE 40: (S)-indan-1-alamid 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

(S)-indan-1-alamid 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using (S)-1-isocyanatobenzene.

1H NMR (DMSO, 400 MHz): to 1.38 (m, 2H); of 1.62 (m, 2H); to 1.86 (m, 1H); of 2.36 (m, 1H); 2,68-of 2.93 (m, 5H); 4,13 (d, J=12.3 Hz, 2H); 5,23 (m, 1H); 6,14 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); of 6.71 (d, J=7,9 Hz, 1H); to 6.80 (d, J=8,3 Hz, 1H); 7,20 (m, 4H); 9,07 (USS, 2H).

13C NMR (DMSO, 100 MHz): 29,6, 31,7, 33,2, 34,7, 44,5, 55,3, 102,4, 106,0, 122,5, 123,9, 124,3, 126,1, 126,7, 126,9, 142,6, 145,4, 155,2, 156,0, 157,4.

EXAMPLE 41: ((S)-1-naphthalen-1-retil)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

((S)-1-naphthalen-1-retil)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using 1-((S)-1-isocyanatomethyl)naphtalene.

1H NMR (DSO, 400 MHz): to 1.37 (m, 2H); for 1.49 (d, J=7,1 Hz, 3H); of 1.62 (m, 2H); 2,70 (t, J=13 Hz, 2H); 2,84 (m, 1H); to 4.14 (t, J=12 Hz, 2H); to 5.66 (m, 1H); 6,13 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); 6.75 in (d, J=7.9 Hz, 1H); 6,91 (d, J=7.7 Hz, 1H); 7,53 (m, 4H); 7,79 (d, J=8 Hz, 1H); to 7.93 (d, J=8 Hz, 1H); is 8.16 (d, J=8 Hz, 1H); 8,97 (s, 1H); 9,13 (s, 1H).

13C NMR (DMSO, 100 MHz): 22,0, 31,7, 34,6, 44,6, 45,5, 102,4, 106,0, 122,2, 122,5, 123,3, 125,3, 125,4, 125,9, 126,7, 126,7, 128,5, 130,4, 133,3, 141,8, 155,2, 156,0, 156,5.

EXAMPLE 42: ((S)-1-naphthalen-2-retil)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

((S)-1-naphthalen-2-retil)amide 4-(2,4-dihydroxyphenyl)-piperidine-1-carboxylic acid obtained by the method similar to the method of example 23a, but using (S)-1-naphthalen-2-ylethylamine, and then repeating the sequence 23b and 23c.

1H NMR (DMSO, 400 MHz): 1,35 (m, 2H); of 1.46 (d, J=7,1 Hz, 3H); of 1.62 (m, 2H); 2,70 (t, J=13 Hz, 2H); to 2.85 (m, 1H); 4,14 (d, J=12.9 Hz, 2H); free 5.01 (m, 1H); 6,13 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); 6,77 (d, J=7.9 Hz, 1H); 6,85 (d, J=7.7 Hz, 1H); 7,43 is 7.50 (m, 3H); to 7.77 (s, 1H); a 7.85 (m, 3H); 8,97 (s, 1H); 9,13 (s, 1H).

13C NMR (DMSO, 100 MHz): 22,6, 31,2, 34,6, 44,5, 49,5, 102,4, 106,0, 122,5, 123,8, 125,1, 125,3, 125,9, 126,7, 127,4, 127,5, 131,9, 132,8, 143,8, 155,2, 156,0, 156,7.

EXAMPLE 43: [(S)-1-(4-methoxyphenyl)ethyl]amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

[(S)-1-(4-methoxyphenyl)ethyl]amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using 1-((S)-1-isocyanatomethyl)-4-methoxybenzene.

1H NMR (DMSO, 400 MHz): 1,33 (d, J=7,1 Hz, 3H); to 1.38 (m, 2H); of 1.62 (m, 2H); 2,66 (who, J=13 Hz, 2H); and 2.83 (m, 1H); and 3.72 (s, 3H); 4,06 (d, J=12.3 Hz, 2H); rate 4.79 (m, 1H); 6,13 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); only 6.64 (d, J=7.9 Hz, 1H); is 6.78 (d, J=8,3 Hz, 1H); 6,85 (d, J=8,6 Hz, 2H); 7.23 percent (d, J=8.6 Hz, 2H); 8,96 (s, 1H); 9,13 (s, 1H).

13C NMR (DMSO, 100 MHz): 22,9, 31,7, 34,7, 44,4, 48,6, 55,0, 102,4, 106,0, 113,3, 122,5, 126,7, 127,0, 138,2, 155,2, 156,0, 156,6, 157,7.

EXAMPLE 44: [(S)-1-(3-methoxyphenyl)ethyl]amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

[(S)-1-(3-methoxyphenyl)ethyl]amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid obtained by the method similar to the method of example 12a, but using 1-((S)-1-isocyanatomethyl)-3-methoxybenzene.

1H NMR (DMSO, 400 MHz): 1,33 (d, J=7,1 Hz, 3H); to 1.38 (m, 2H); of 1.62 (m, 2H); in 2.68 (t, J=13 Hz, 2H); 2,84 (m, 1H); to 3.73 (s, 3H); 4,10 (d, J=12.3 Hz, 2H); to 4.81 (m, 1H); 6,13 (DD, J=8,4 & 2,4 Hz, 1H); of 6.26 (d, J=2.4 Hz, 1H); 6,70-6,79 (m, 5H); 7,20 (t, J=8,1 Hz, 1H); 8,96 (s, 1H); 9,13 (s, 1H).

13C NMR (DMSO, 100 MHz): 22,9, 31,8, 34,6, 44,4, 49,3, 54,9, 102,4, 106,0, 111,3, 111,8, 118,2, 122,5, 126,7, 129,0, 148,0, 155,2, 156,0, 156,7, 159,1.

EXAMPLE 45: (S)-2-amino-1-[4-(2,4-dihydroxyphenyl)-piperidine-1-yl]-3-phenylpropane-1-he

(S)-2-amino-1-[4-(2,4-dihydroxyphenyl)-piperidine-1-yl]-3-phenylpropane-1-he receives a manner analogous to the method of example 26, but using Z-D-phenylalanine.

1H NMR (DMSO, 400 MHz): 0,6 (m, 1H); 1,09 (m, 1H); 1.30 and a 1.75 (m, 5H); 2,56-of 2.97 (m, 4H); of 3.94 (m, 2H); 4,51 (d, J=12,8 Hz, 1H); 6,11 (m, 1H); 6,24 (m, 1H); 6,57 & 6,77 (d, J=8,3 Hz, 1H); 7.18 in-7,40 (m, 5H); 8,97 (s, 1H); 9,11 & to 9.15 (s, 1H).

13C NMR (DMSO, 100 MHz): (shortness of rotation) 31,6, 32,3, 31,1, 34,6, 42,0, 42,2, 42,7, 45,3, 45,6, 51,3, 51,6, 102,3 105,9, 121,9, 126,0, 126,7, 127,9, 128,1, 129,4, 138,5, 155,0, 156,0, 172,6.

EXAMPLE 46: ((S)-1-phenylethyl)amide 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid

a) 1,5-bis(benzyloxy)-2-fluoro-4-nitrobenzene

2,82 g (70,6 mmol, 2.5 EQ.) 60% sodium hydride are added to a solution of 7.6 g (70,6 mmol, 2.5 EQ.) benzyl alcohol in 100 ml of tetrahydrofuran. The reaction mixture was stirred at ambient temperature for 1.5 hours, and then in solution in 50 ml of tetrahydrofuran are added dropwise 5.0 g (28,2 mmol, 1 EQ.) 1,2,4-Cryptor-5-nitrobenzene. The reaction mixture is refluxed for 3 hours. The reaction mixture is treated with 150 ml of 1 M hydrochloric acid and extracted with ethyl acetate. The combined organic phases are washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel, carrying out elution with heptane/ethyl acetate 90/10. Obtain 1.68 g of 1,5-bis(benzyloxy)-2-fluoro-4-nitrobenzene. Yield=17%.

(b) 1,5-bis(benzyloxy)-2-fluoro-4-aminobenzoyl

508 mg (9.5 mmol, 2 EQ.) ammonium chloride followed of 2.23 g (a 34.2 mmol, 7.2 EQ.) powdered zinc is added to a solution of 1.68 g (of 4.75 mmol, 1 EQ.) 1,5-bis(benzyloxy)-2-fluoro-4-nitrobenzene in 50 ml of water. The reaction mixture is refluxed for 4 hours. The cooled reaction mixture is extracted with ethyl acetate. The organic phase is combined washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel, carrying out elution with heptane/ethyl acetate 85/15. Obtain 930 mg of 1,5-bis(benzyloxy)-2-fluoro-4-aminobenzene. Yield=61%.

c) 1,5-bis(benzyloxy)-2-fluoro-4-iadanza

7 ml of 6M hydrochloric acid is added to the solution 3,20 g (9.9 mmol, 1 EQ.) 1,5-bis(benzyloxy)-2-fluoro-4-aminobenzoyl in 40 ml of N,N-dimethylformamide, cooled to 0°C. In solution in 7 ml of water is added 683 mg (9.9 mmol, 1 EQ.) sodium nitrite and the reaction mixture stirred at 0°C for 1 hour. In solution in 8 ml of water is added 1.64 g (9.9 mmol, 1 EQ.) of potassium iodide, followed 190 mg (1.0 mmol, 0.1 EQ.) iodide of copper, and then the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was treated with a saturated solution of ammonium chloride and extracted with ethyl acetate. The combined organic phases are washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel, carrying out elution with heptane/dichloromethane 75/25. Get 3,59 g of 1,5-bis(benzyloxy)-2-fluoro-4-yogashala. Yield=68%.

(d) tert-butyl ether 4-(2,4-bis(benzyloxy)-5-forfinal)piperidine-1-carboxylic acid

In the solution 3,59 g (compared to 8.26 mmol, 1 EQ.) 1,5-bis(benzyloxy)-2-fluoro-4-th is benzole in 40 ml of tetrahydrofuran added to 4.0 ml (9.9 mmol, 1.2 EQ.) 2.5 M n-utility in hexane, cooled to -70°C. the Reaction mixture was stirred at -70°C for 25 minutes in solution in 20 ml of tetrahydrofuran type of 1.97 g (9.9 mmol, 1.2 EQ.) 1-boc-4-piperidone. The reaction mixture was stirred at -70°C for 1 hour and then leave for the night to return to ambient temperature. The reaction mixture was added 30 ml of a saturated solution of ammonium chloride, after which it add 4 ml of 2 M hydrochloric acid, then stirred for 20 minutes and then extracted with ethyl acetate. The combined organic phases, dried over magnesium sulfate and evaporated. The residue is subjected to chromatography on silica gel, carrying out elution with heptane/ethyl acetate 95/5, then heptane/ethyl acetate 75/25 (0.1% TEA).

Obtain 860 mg of a mixture of tert-butyl ester 4-(2,4-bis(benzyloxy)-5-forfinal)piperidine-1-carboxylic acid (25%) and 1-boc-4-piperidone in the form of a yellow oil, which crystallizes. Output=5%.

e) tert-butyl ester 4-(5-fluoro-2,4-dihydroxyphenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid

A mixture of 860 mg (0.42 mmol, 1 EQ.) 35% tert-butyl ester 4-(2,4-bis(benzyloxy)-5-forfinal)piperidine-1-carboxylic acid in 10 ml of ethyl acetate in the presence of 200 mg of 10% palladium on coal stirred at ambient temperature under hydrogen pressure of 500 kPa for 17 hours. Add 5 ml of methanol and the reaction is ionic mixture was stirred at ambient temperature under hydrogen pressure of 500 kPa for 29 hours. The reaction mixture was filtered through filter paper and the filtrate is evaporated. The residue is subjected to chromatography on silica gel, carrying out elution with heptane/ethyl acetate 60/40. Get 192 mg tert-butyl ester 4-(5-fluoro-2,4-dihydroxyphenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid. Output=100%.

f) tert-butyl ether 4-(2,4-bis(benzyloxy)-5-forfinal)piperidine-1-carboxylic acid

241 mg (1,74 mmol, 3 EQ.) potassium carbonate (325 mesh) is added to a solution of 181 mg (of 0.58 mmol, 1 EQ.) tert-butyl ester 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid in 3 ml of acetone. Added dropwise 152 μl (1.28 mmol, 2.2 EQ.) benzylbromide. The reaction mixture is heated at 50°C for 20 hours. The solvent is evaporated and then the residue is treated with a mixture of water/ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with sodium hydrogen carbonate solution and then a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel, carrying out elution with heptane/ethyl acetate 85/15.

Obtain 188 mg of tert-butyl ester 4-(2,4-bis(benzyloxy)-5-forfinal)piperidine-1-carboxylic acid. Yield=66%.

g) 4-(2,4-bis(benzyloxy)-5-forfinal)piperidine

280 μl (3.7 mmol, 10 EQ.) triperoxonane acid added to a solution of 184 mg (0,37 mmol who, 1 EQ.) tert-butyl ester 4-(2,4-bis(benzyloxy)-5-forfinal)piperidine-1-carboxylic acid in 3 ml of dichloromethane. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture is treated with 10 ml of water, and then extracted with dichloromethane. The combined organic phases are washed with saturated sodium hydrogen carbonate solution and then a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated. Receive 150 mg of 4-(2,4-bis(benzyloxy)-5-forfinal)piperidine. Output=100%.

h) ((S)-1-phenylethyl)amide 4-(2,4-bis(benzyloxy)-5-forfinal)piperidine-1-carboxylic acid

65 μl (0.45 mmol, 1.2 EQ.) (S)-(-)-phenylacrylate added to a solution of 147 mg (from 0.37 mmol, 1 EQ.) 4-(2,4-bis(benzyloxy)-5-forfinal)of piperidine in 3 ml of tetrahydrofuran in the presence of 64 μl (from 0.37 mmol, 1 EQ.) dimethylethylamine. The reaction mixture was stirred at ambient temperature for 50 minutes. The reaction is stopped by adding 5 ml of water, and then extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate. The solvent is evaporated and the residue is subjected to chromatography on silica gel, carrying out elution with heptane/ethyl acetate 60/40. Obtain 178 mg phenylamide 4-(2,4-bis(benzyloxy)-5-forfinal)piperidine-1-carboxylic acid. Yield=89%.

i) ((S)-1-phenylethyl)amide 4-(5-fluoro-2,4-dihydroxyphenyl)PI is Eridan-1-carboxylic acid

A mixture of 174 mg (0.32 mmol, 1 EQ.) phenylamide 4-(2,4-bis(benzyloxy)-5-forfinal)piperidine-1-carboxylic acid in 1 ml of ethyl acetate and 2 ml of methanol in the presence of 51 mg (30% by mass) of 10% palladium on coal stirred at ambient temperature under atmospheric pressure of hydrogen for 8 hours. The reaction mixture was filtered through filter paper and the filtrate is evaporated. The residue is subjected to chromatography on silica gel, carrying out elution with heptane/ethyl acetate 30/70. Obtain 83 mg of ((S)-1-phenylethyl)amide 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid. Yield=72%.

1H NMR (DMSO, 400 MHz): 1,35-1,45 (m, 5H); 1,53 (m, 2H); to 2.67 (t, J=13 Hz, 2H); and 2.83 (m, 1H); 4,11 (d, J=12.3 Hz, 2H); a 4.83 (m, 1H); to 6.43 (d, J=8.0 Hz, 1H); 6.73 x (m, 2H); 7,14-7,40 (m, 5H); 9,11 (s, 1H); 9,40 (s, 1H).

13C NMR (DMSO, 100 MHz): 23,0, 31,6, 34,6, 44,2, 49,3, 104,5, 113,3 (d, J=19 Hz), 122,4, (d, J=5 Hz), 125,9, 126,1, 127,9, 142,4, 144,6 (d, J=228 Hz), 146,3, 150,4, 155,5.

EXAMPLE 47: (R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylethanone

(R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylethanone receive in a manner analogous to the method of example 26, but using (R)-hydroxyphenylarsonic acid.

1H NMR (DMSO, 400 MHz): (shortness of rotation) of 0.6 (m, 0,5H); 1,30-1,70 (m, 3,5H); 2,5-3 (m, 2H); 4.0 a (m, 1H); 4,51 (m, 1H); lower than the 5.37-to 5.57 (m, 2H); 6,07 (m, 1H); 6,24 (m, 1H); 6.48 in & 6,72 (2D, J=8,2 Hz, 1H); 7.29 trend-7,38 (m, 5H); 8,98 (2s, 1H); 9,11 (2s, 1H)

13C NMR (DMSO, 100 MHz): (limited rotation) 30,9 & 31,4, 31,5 & 31,, 34,1 & 34,4, 42,9, 45,2, 71,1, 102,4, 105,9, 121,8, 126,3, 126,4, 126,9, 127,5, 128,1, 128,3, 128,4, 128,9, 140,5, 155,1, 156,1, 170,0.

EXAMPLE 48: (S)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylethanone

(S)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylethanone receive in a manner analogous to the method of example 26, but using (S)-hydroxyphenylarsonic acid.

1H NMR (DMSO, 400 MHz): (shortness of rotation) of 0.6 (m, 0,5H); 1,30-1,70 (m, 3,5H); 2,5-3 (m, 2H); 4.0 a (m, 1H); 4,51 (m, 1H); lower than the 5.37-to 5.57 (m, 2H); 6,07 (m, 1H); 6,24 (m, 1H); 6.48 in & 6,72 (2D, J=8,2 Hz, 1H); 7.29 trend-7,38 (m, 5H); 8,98 (2s, 1H); 9,11 (2s, 1H)

13C NMR (DMSO, 100 MHz): (limited rotation) 30,9 & 31,4, 31,5 & 31,9, 34,1 & 34,4, 42,9, 45,2, 71,1, 102,4, 105,9, 121,8, 126,3, 126,4, 126,9, 127,5, 128,1, 128,3, 128,4, 128,9, 140,5, 155,1, 156,1, 170,0.

EXAMPLE 49: (R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-3-phenylpropane-1-he

(R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-3-phenylpropane-1-he receives a manner analogous to the method of example 26, but using (R)-2-hydroxy-3-phenylpropionic acid.

1H NMR (DMSO, 400 MHz): (limited rotation) 1,04 is 1.70 (m, 4H); 2,50-to 3.34 (m, 5H); was 4.02 (m, 1H); to 4.52 (m, 2H); equal to 4.97 (m, 1H); 6,14 (d, J=8,2 Hz, 1H); of 6.25 (m, 1H); 6,67 & 6,782 (2D, J=8,2 Hz, 1H); 7,14-7,28 (m, 5H); 8,97 (2C, 1H); 9.15, with (2s, 1H).

13C NMR (DMSO, 100 MHz): (limited rotation) 31,6 & 31,7, 34,5 & 34,7, 40,3 & 40,6, 42,5, 45,6, 68,6 & 68,9, 102,5, 106,1, 122,1, 126,1, 126,8, 128,1, 129,6, 138,1 & 138,4, 155,3, 156,2, 171,0.

EXAMPLE 50: (S)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-3-phenylpropane-1-he

(S)-1-[4(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-3-phenylpropane-1-he get way similar to the method of example 26, but using (S)-2-hydroxy-3-phenylpropionic acid.

1H NMR (DMSO, 400 MHz): (limited rotation) 1,04 is 1.70 (m, 4H); 2,50-to 3.34 (m, 5H); was 4.02 (m, 1H); to 4.52 (m, 2H); equal to 4.97 (m, 1H); 6,14 (d, J=8,2 Hz, 1H); of 6.25 (m, 1H); 6,67 & 6,782 (2D, J=8,2 Hz, 1H); 7,14-7,28 (m, 5H); 8,97 (2C, 1H); 9.15, with (2s, 1H).

13C NMR (DMSO, 100 MHz): (limited rotation) 31,6 & 31,7, 34,5 & 34,7, 40,3 & 40,6, 42,5, 45,6, 68,6 & 68,9, 102,5, 106,1, 122,1, 126,1, 126,8, 128,1, 129,6, 138,1 & 138,4, 155,3, 156,2, 171,0.

EXAMPLE 51: Analysis of inhibition tyrosinase activity

The activity of the inhibitors was measured using a lysate of B16F1 cells (line melanoma mice). In the presence of substrate L-tyrosine, tyrosinase present in these cells, catalyzes hydroxylation of L-tyrosine with receiving L-DOPA, and then the oxidation of L-DOPA with getting dauphinee. In the presence of MBTH (3-methyl-2-benzothiazolinone) dopamine is captured so that it forms a pink complex that absorbs at 520 nm.

B16F1 cells were cultured in DMEM + 10% fetal calf serum + 10-9M α-MSH for 4 days at 37°C in 7% CO2. They are treated with trypsin, washed in PBS, counted and precipitate. The residue is treated with 107cells/ml lyse buffer (10 mm sodium phosphate, pH 6.8 and 1% Igepal) and the suspension is treated with ultrasound for 10 seconds. After centrifugation for 30 minutes at 4000 rpm./minutes of the obtained supernatant extending t the cell lysate, used as a source of tyrosinase in enzymatic analysis.

Tests conducted in two iterations in 384-well tablets in total volume of 50 µl. Each hole contains:

to 40 μl of a solution containing 1.25 mm L-tyrosine, and 6.25 μm L-DOPA (cofactor) and 3.75 mm MBTH in buffer B (62,25 mm sodium phosphate, pH 6.8 and 2.5% dimethylformamide),

to 5 μl of inhibitor dissolved in DMSO,

- 5 ál of cell lysate diluted to 1/2 in 50 mm buffer Tris-HCl, pH 7.5.

Tablet incubated at 37°C and after 6 hours of incubation carried out spectrophotometric scanning at 520 nm. To avoid any possible absorption products, the system uses the corrected optical density (optical density at the time of 6 hours the optical density at time zero).

Inhibitors evaluated in terms of "dose-response" in order to calculate the IC50(dose inhibiting 50% of the enzymatic activity).

In each experiment, add a few internal controls:

control 100% activity: 5 ál of inhibitor replace 5 μl DMSO,

control 50% of the activity: 5 ál of inhibitor replace 5 ál phenyltoloxamine at 300 μm in DMSO,

control 0% activity: substrate L-tyrosine is replaced by buffer B.

The results obtained for the compounds according to the invention, are shown in table A:

Table A
NameStructureThe tyrosine hydroxylase/Dopa-oxidase IC50(µm)
4-butylnitrone (retinol)3
The connection 480,2
Connection 240,15

EXAMPLE 52: analysis of the inhibition of melanogenesis

Inhibition of melanogenesis measured in human melanoma cells MNT1 in accordance with the Protocol, adapted from Reigner et al., Cell Mol. Biol. (1999) 45:969-980. The analysis is based on the simultaneous inclusion of 2 radioactively labeled markers:14C-thiouracil is included in the newly synthesized melanin and reflects melanogenesis, whereas3H-leucine is included in proteins and reflects cell viability, and thus, testing the toxicity of the compounds.

The MNT1 cells were seeded in 96-well plates in the presence of test compounds and radioactive isotopes. After incubation for 24 h at 37°C the cells are washed and measure the number 2 radioactive isotopes. The test connection is anywayt in terms of "dose-response" to calculate the IC50for inhibition of melanogenesis based on the inclusion of14C, which standardizes on inclusion of3H. Also on the basis of including3H calculate IC50cellular toxicity.

Thus, this analysis makes it possible to distinguish between products that specifically inhibit melanogenesis from products that are cytotoxic to melanocytes.

NameFormulaIC50of melanogenesisIC50toxicity
4-butylnitrone (retinol)15-mm55 microns
The connection 480.7 mcm>999 microns
Connection 240,3 ám>999 microns

EXAMPLE 53: Drugs

This example illustrates a variety of drugs are based on compounds according to the invention.

LOCALLY
(a) Ointment
Connection 160,020 g
- Isopropylmyristate81,700 g
Liquid vaseline oil9,100 g
- Silicon dioxide (Aerosil 200)9,180 g
(b) Ointment
Connection 60,300 g
White vaseline oil, pharmaceutical purityin quantity, sufficient for 100 g
(c) non-ionic cream water-in-oil
Connection 160,100 g
A mixture of emulsive lanolin alcohols, waxes and oils (anhydrous eucerin)39,900 g
- Methyl parahydroxybenzoate0.075 g
- Sodium propyl parahydroxybenzoate0.075 g
- Sterile demineralized water(d) Lotion
Connection 60,100 g
- Polyethylene glycol (PEG 400)69,900 g
- 95% ethanol30,000 g
(e) Hydrophobic ointment
Connection 220,300 g
- isopropylmyristate36,400 g
- Silicone oil (rodosil 47 V 300)36,400 g
- Beeswax13,600 g
- Silicone oil (Abil to 300,000 cSt)in quantity, sufficient for 100 g
(f) non-ionic cream oil-in-water
Connection 41,000 g
- Cetyl alcohol4,000 g
- Glycerylmonostearate2,500 g
- PEG 50 stearate 2,500 g
- Shea butter9,200 g
- Propylene glycol2,000 g
- Methyl parahydroxybenzoate0.075 g
- Sodium propyl parahydroxybenzoate0.075 g
- Sterile demineralized waterin quantity, sufficient for 100 g

1. Compounds of General formula (I)below;

where R1 represents:
- C1-C5-alkilany radical,
- C3-C6-cycloalkenyl radical,
- arrowy radical,
- arrowy radical, substituted by one or more groups selected from C1-C5the alkyl, a C1-C5alkoxygroup, fluorine atom and triptorelin group,
- Uralkaliy radical,
- C1-C5-alkoxy radical,
- amine moiety corresponding to the structure (a):

where R2 represents:
is hydrogen,
- C1-C5-alkilany radical,
- C3-C6-cycloalkenyl radical,
- arrowy radical,
- arrowy radical, substituted by one or more groups selected from C1-C5the alkyl, a C1-C5- pyridyloxy radical,
- Uralkaliy radical,
radical corresponding to the structure (b):

where the value of R can represent 1 or 2, the moiety corresponding to the structure (s)

where R4 represents:
- carboxymethoxy, SOON3or carboxitherapy, -COOEt, radical,
- C1-C3-alkilany radical,
is hydrogen,
and R5 represents:
- unsubstituted arrowy radical or arrowy radical, substituted by one or more groups selected from C1-C5of alkyl, C1-C5alkoxygroup, fluorine atom and triptorelin group,
- C3-C6-cycloalkenyl radical,
- pyridyl,
and R3 represents:
is hydrogen,
- C1-C5-alkilany radical;
or R1 can also represent a radical corresponding to the formula (d):

where R6 represents:
is hydrogen,
- C1-C5-alkilany radical,
- C3-C6-cycloalkenyl radical,
- arrowy radical,
- arrowy radical, substituted by one or more groups selected from C1-C5of alkyl, C1-C5alkoxygroup, fluorine atom and triptorelin group,
- pyridyloxy radical,
- Uralkaliy radical,
R7 before the hat is:
is hydrogen,
- C1-C5-alkilany radical, and
R8 represents:
is hydrogen,
is hydroxyl,
- amine radical,
- C1-C3-alkoxy radical;
Y represents hydrogen or fluorine, and
the value of m and n can represent 0, 1 or 2,
and isomeric and enantiomeric forms of the compounds of formula (I).

2. The compound according to claim 1, characterized in that:
- R1 is Uralkaliy radical or an amine radical, corresponding to structure (a):

where R2 represents:
- C1-C5-alkilany radical,
- Uralkaliy radical or
radical corresponding to the structure (s):

where R4 represents:
- carboxymethoxy, SOON3or carboxitherapy, -COOEt, radical,
- C1-C3-alkilany radical,
and R5 represents:
- unsubstituted arrowy radical or arrowy radical, substituted by one or more groups selected from C1-C5of alkyl, C1-C5alkoxygroup, fluorine atom and triptorelin group, and
R3 represents hydrogen,
- Y represents a hydrogen atom or fluorine,
- m=1 and n=1,
and isomeric and enantiomeric forms of the compounds of formula (I).

3. The compound according to claim 1 or 2, characterized in that it is selected from the group consisting of:
1: tert-bout the business ester 3-(2,4-dihydroxyphenyl)azetidin-1-carboxylic acid
2: [3-(2,4-dihydroxyphenyl)azetidin-1-yl]phenylmethanone
3: pentylamine 3-(2,4-dihydroxyphenyl)azetidin-1-carboxylic acid
4: tert-butyl ether 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid
5: isobutyl ester 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid
6: cyclohexylamine 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid
7: phenylamide 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid
8: (4-forfinal)amide 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid
9: (4-triptoreline)amide 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid
10: ethyl ester of 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
11: [4-(2,4-dihydroxyphenyl)piperidine-1-yl]phenylmethanone
12: butylamide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
13: propylamide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
14: 1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]butane-1-it
15: 1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-methylpropan-1-it
16: phenylamide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
17: (4-forfinal)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
18: p-tolylamino 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
19: phenethylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
20: (3-forfinal)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic to the slots
21: ((R)-1-phenylethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
22: methylphenylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
23: pyridine-2-ylamide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
24: ((S)-1-phenylethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
25: ((S)-1-phenylpropyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
26: (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-3-phenylpropane-1-it
27: 1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-3-phenylpropane-1-it
28: 2-formanilide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
29: 3-formanilide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
30: 4-formanilide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
31: benzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
32: 2-methylbenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
33: 3-methylbenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
34: 4-methylbenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
35: 2-methoxybenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
36: 3-methoxybenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
37: 4-methoxybenzylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
38: ((S)-1-p-triletal)amide 4-(2,4-dihydroxide the l)piperidine-1-carboxylic acid
39: [(S)-1-(4-forfinal)ethyl]amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
40: (S)-indan-1-ylamide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
41: ((S)-1-naphthalen-1-retil)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
42: ((S)-1-naphthalen-2-retil)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
43: [(S)-1-(4-methoxyphenyl)ethyl]amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
44: [(S)-1-(3-methoxyphenyl)ethyl]amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
45: (S)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-3-phenylpropane-1-it
46: ((S)-1-phenylethyl)amide 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
47: (R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylethanone
48: (S)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylethanone
49: (R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-3-phenylpropane-1-it
50: (S)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-3-phenylpropane-1-it
51: (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-(4-forfinal)ethanone
52: (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-phenylethanone
53: (S)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-phenylethanone
54: (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-(4-triptoreline)ethanone
55: 2-amino-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-phenylbut-1-it
56: (S)-1-[4-(2,4-dihydrox is phenyl)piperidine-1-yl]-2-methoxy-2-phenylethanone
57: ((S)-1-cyclohexylethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
58: (1,2,3,4-tetrahydronaphthalen-1-yl)amide of 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
59: methyl ester of (R)-{[4-(2,4-dihydroxyphenyl)piperidine-1-carbonyl]amino}phenylacetic acid
60: (pyridine-3-ylmethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
61: (pyridin-4-ylmethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
62: benzylamine 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
63: butylamide 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
64: (3-forfinal)amide 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
65: phenethylamine 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
66: methyl ester of (R)-{[4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carbonyl]amino}phenylacetic acid
67: (S)-indan-1-ylamide 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
68: [(S)-1-(4-methoxyphenyl)ethyl]amide 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
69: ((S)-1-cyclohexylethyl)amide 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
70: (R)-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylethanone
71: (S)-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylethanone
72: (R)-2-amino-1-[4-(5-fluoro-2,4-dihydroxyphenyl)-piperidine-1-yl]2-phenylethanone
73: (S)-2-amino-1-[4-(5-fluoro-2,4-dihydroxyphenyl)-piperidine-1-yl]-2-phenylethanone
74: (R)-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylpropane-1-it
75: (S)-1-[4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylpropane-1-it
76: (R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylpropane-1-it
77: (S)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylpropane-1-it
78: methyl ester of (R)-{[4-(2,4-dihydroxyphenyl)piperidine-1-carbonyl]amino}-(4-forfinal)acetic acid
79: methyl ester (S)-{[4-(2,4-dihydroxyphenyl)piperidine-1-carbonyl]amino}-(4-forfinal)acetic acid
80: (R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-methyl-3-phenylpropane-1-it
81: (S)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-methyl-3-phenylpropane-1-it
82: (pyridine-3-ylmethyl)amide-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
83: (pyridin-4-ylmethyl)amide 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
84: ((R)-1-phenylethyl)amide (5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
85: (R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylbutane-1-it
86: (S)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-phenylbutane-1-it
87: (S)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-(4-forfinal)-2-hydroxyethane
88: (R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-(4-forfinal)-2-hydroxyethane
89: (S)-1-[4-(2,4-Digi roxiprin)piperidine-1-yl]-2-hydroxy-2-(3-methoxyphenyl)ethanone
90: (R)-1-[4-(2,4-dihydroxyphenyl)piperidine-1-yl]-2-hydroxy-2-(3-methoxyphenyl)ethanone
91: cyclohexylethylamine 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
92: cyclohexylethylamine 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
93: (2-ethylbutyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
94: (2-ethylbutyl)amide 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
95: cyclopentylmethyl 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
96: cyclopentylmethyl 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
97: (6-methylpyridin-3-ylmethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
98: (4-methylpyridin-3-ylmethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
99: (5-methylpyridin-3-ylmethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
100: (2-methylpyridin-3-ylmethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
101: (2,6-dimethylpyridin-4-ylmethyl)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
102: (2-pyridin-2-retil)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
103: (2-pyridin-3-retil)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid
104: (2-pyridin-4-retil)amide 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid.

4. The use of at least one compound according to any of the at one of claims 1 to 3 as a drug for the treatment and/or prevention of pigmentary disorders.

5. The use according to claim 4, where the specified connection has inhibiting tyrosinase activity.

6. The use according to claim 4, where pigmentary disorders selected from melasma, chloasma, lentigines, senile lentigo, irregular hyperpigmentation associated with the aging of the skin from UV rays, mesoscutal, postinflammatory hyperpigmentation due to scratches, burns, scars, dermatitis, contact Allergy; nevi, genetically defined hyperpigmentations, hyperpigmentations of metabolic or associated with drugs of origin, melanomas or other foci of hyperpigmentation.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or a pharmaceutically acceptable salt thereof, wherein G1 is phenyl or pyridyl, each of which is optionally additionally substituted by one substitute presented by T; G2 is phenyl, 1,3-thiazolyl or 1,3-oxazolyl, wherein G2 is bound to G1 in the para position in relation to a place of attachment of G1 to group NH in formula (I), wherein G2 means phenyl, G3 is bound to G2 in the para position of G2 in relation to G1, and wherein provided G2 represents 1,3-thiazolyl or 1,3-oxazolyl, G2 is bound to G1 in the position of 5 G2 and G3 is bound to G2 in the position of 2 G2; T in each case is independently specified in a group containing C1-6alkyl and halogen; G3 is presented by formula or by formula ; W1 is -C(R3)(R4)-C(R3)(R4)-, and W2 represents N; or W3 represents O; W4 is -C(R3)(R4) -; each R3 and R4 is hydrogen; each R5 and R6 kis hydrogen; Rc and Rd together with a carbon atom whereto attached, are a 4-5-member cycloalkyl or monocyclic heterocycle of formula ; wherein one hydrogen atoms attached to the carbon atom of the cycloalkyl ring and monocyclic heterocycle is optionally substituted by a radical specified in a group -C(O)O(R8); W5 is -CH2- or -CH2-CH2-; W6 is O or N(RX), wherein Rx is hydrogen, C1-6alkyl or -C(O)O(Rz); RZ in each case is independently C1-6alkyl; R8 is hydrogen; L1 is O; and X is hydrogen, C1-6alkyl, or - (CRgRh)u-C(O)O(R10); or L1 is -CH2- and X is -C(O)OH; R10 is hydrogen; or Q is G4 or Y1-Y3; or Q is described for formula wherein Z is phenyl; G4 is benzothiazole or benzoxazole optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of C1-6alkyl, halogen and -OR1; Y1 in each case is independently -C(O)-, -C(O)O- or -C(O)N(Rw)-, wherein the right side -C(O)O- and -C(O)N(Rw)- of the groups is attached to Y3 or (CRJRk)v, Y3 in each case is independently phenyl, benzyl, piperidinyl or bicyclo[4.2.0]octa-1,3,5-triene, wherein the phenyl and benzyl residues are optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of halogen and haloC1-6alkyl; Rg and Rh in each case is independently hydrogen, or C1-6alkyl; R1 in each case is independently halogenC1-6alkyl; Rw is hydrogen; and u means 1.

EFFECT: compounds being the type 1 diacylglycerol O-acyltransferase (DGAT-1) enzyme inhibitors.

7 cl, 1 tbl, 61 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 4-(4-cyano-2-thioaryl)- dihydropyrimidin-2-one derivatives of formula (I), a method for preparing and using them. In formula , , both A and E mean C-R7, wherein R7 mean hydrogen, Z means O, n means the number 0,1 or 2, R1 means (C1-C6)-alkyl which may be substituted by the group hydroxy, (C1-C4)-alkoxy,(C3-C6)-cycloalkyl, phenyl or 5- or 6-member heteroaryl with two heteroatoms specified in nitrogen or sulphur, or may be substituted up to three times by fluorine, or means (C3-C6)-cycloalkyl or phenyl, R2 means hydrogen, R3 means cyano or a group of formulas -C(=O)-R8, -C(=O)-O-R8 or -C(=O)-NH2, wherein R8 means (C1-C6)-alkyl or (C3-C6)-alkenyl, R4 means methyl or ethyl, or R3 and R4 are linked to each other and together form an annulated group of formula (II), R9 means hydrogen, (C1-C6)-alkyl or (C3-C6)-cycloalkyl with (C1-C6)-alkyl may be substituted by a hydroxy group, aminocarbonylamino or (C1-C4)-acylamino, R5 means hydrogen or (C1-C6)-alkyl. The other group and radical values are specified in the patent claim.

EFFECT: compounds possess the properties of a neutrophil elastase (HNE) inhibitor and can find application in treating and/or preventing pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pulmonary emphysema, mediated by neutrophil elastase (HNE) activity.

16 cl, 4 tbl, 10 dwg, 202 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein: X and Y independently mean a nitrogen atom or the chain -CR4-, wherein R4 means a nitrogen atom; A means an aryl or heteroaryl group, with the above aryl or heteroaryl groups are optionally substituted by one or more groups specified in a halogen atom, a hydroxyl group, (C1-C4)alkyl group, (C3-C5)cycloalkyl group, (C1-C4)alkoxy group optionally substituted by (C1-C4)alkoxy group, a halogen alkyl group, a halogen alkoxy group; W means a halogen atom; Z means (C1-C4)alkylene group optionally substituted by one or more groups specified in a halogen atom and (C1-C4)alkyl group; B means the group -NR4R5, wherein R4 and R5 independently mean (C1-C4)alkyl group; R1 and R2 mean: - or R1 means a hydrogen atom and R2 mean (C1-C4)alkyl group, - or R1 and R2 together with a carbon atom whereto attached form a mono- or polycyclic system specified in: (C3-C8)cycloalkyl group, a bicyclic bridge group or a tetracyclic bridge group; the above system may be substituted by one or more hydroxyl groups; R3 means either the group C(O)R5, wherein R5 means (C1-C4)alkoxygroup optionally substituted by (C1-C4)alkoxygroup, or the group NR6R7, wherein R6 and R7 independently mean a hydrogen atom, (C1-C4)alkyl group, (C3-C5)cycloalkyl group, (C1-C4)alkylsulphonyl group, a halogenalkyl group, or the group -CH2XR8, wherein: - X means an oxygen atom and R8 means a hydrogen atom or (C1-C4)alkyl group, - or the nitrile group (CN); p means an integer equal to 0 or 1; the aryl group represents an aromatic monocyclic group containing 5 or 6 carbon atoms; the above cycle may be fused with a partially saturated heterocyclic group containing 5 or 6 atoms, including one or two heteroatoms, such as an oxygen atom; the heteroaryl group represents an aromatic cyclic group containing 5 or 6 atoms, including one or two heteroatoms, such as nitrogen; in the form of a base or an additive salt with an acid or base, as well as to their enantiomers and diastereoisomers, including to their racemic mixtures. Besides, the invention refers to methods for preparing the compound of formula I, as well as to a therapeutic agent and a pharmaceutical composition which possess antagonist action on an urotensin II receptor and contain the compound of formula I.

EFFECT: there are prepared and described the new compounds which possess urotensin II receptor antagonist action.

9 cl, 44 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel carboxyl- or hydroxyl-substituted benzimidazole derivatives of formula (I), or pharmaceutically acceptable salts thereof, where R1 is selected from and , R2 is hydrogen; R3 is cyclohexyl or bicyclo[2.2.1]heptyl; R4 is phenyl, which is substituted in the 4th position with a halogen or a lower fluoroalkyl, or a pyridyl, which is substituted with 1 or 2 substitutes independently selected from halogen and a lower alkoxy group; R5 and R6 independently denote hydrogen or fluorine; R7 and R9 are independently selected from a group consisting of hydrogen, lower alkyl, halogen, lower alkoxy group, lower fluoroalkyl, lower fluoroalkoxy group and cyano group; R8 is -(CR12R13)n-COOH, where n equals 0, 1 or 2, and R12 and R13 are independently hydrogen or lower alkyl, or -O-(CR14R15)p-COOH, where p equals 1 or 2, and R14 and R15 are independently hydrogen or lower alkyl, or R14 and R15 together with the carbon atom with which they are bonded form a cycloalkyl ring, or R8 is tetrazole; R10 is a hydroxy group or -(CH2)p-COOH, where p equals 0 or 1; m equals 0 or 1; R11 is -COOH. The invention also relates to specific carboxyl- or hydroxyl-substituted benzimidazole derivatives and a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel carboxyl- or hydroxyl-substituted benzimidazole derivatives, having selective activity with respect to farnesoid X receptor, are obtained.

26 cl, 126 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (I): or to its pharmaceutically acceptable ester, amide, carbamate, solvate or salt, including salt of such ester, amide or carbamate and solvate of such ester, amide, carbamate or salt, where values R1, R2, R3, R4, R5 and R6 are given in item of the formula, with the exception: 4-[3-(4,5-dihydro-1H-imidazol-2-yl)-2-(3,5-dimethylisoxazol-4-yl)indole-1-yl]phenol; 1-(4-hydroxyphenyl)-2-(4-methylimidazol-1-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-(1H-pyrazol-3-yl)-1H-indole-3-carbonitryl; 1-(3-chloro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-prop-1-inyl-1H-indole-3-carboxylic acid amide.

EFFECT: compounds I possess affinity of binding with estrogen receptor of p-subtype, which makes it possible to use them in pharmaceutical composition and in treatment or prevention of state, associated with disease or disorder, associated with activity of estrogen receptors of β-subtype.

27 cl, 271 ex

Organic compounds // 2491285

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein V is specified in -O- or a single bond; W is specified in -N(R5)C(O)-, -S(O)t- and -C(O)O-; X is specified in C(H) or N; Y is specified in S, N(H) or N(CH3); p means 0 or 2; t means 1 or 2; R1 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by 1 or 2 halogroups, C3-7cycloalkylC1-6alkyl, 2,3-dihydro-1H-indenyl, C6arC1-6alkyl optionally substituted by one or two halogroups and heteroarylC1-6alkyl, wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen optionally oxidated, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9-member bicyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen, oxygen and sulphur, wherein monocyclic heteroaryl of the heteroarylalkyl group may be optionally substituted by one or two substitutes independently specified in a group consisting a halogroup, a cyanogroup, C1-6alkyl, haloC1-6alkyl and C1-6alkyl-O-C(O)-; R2 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by phenoxy, hydroxy C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, phenyl optionally substituted by a halogroup, haloC1-6alkyl, C6arC1-6alkyl (optionally substituted by a halogroup, haloC1-6alkyl or haloC1-6alkoxygroup), 2-oxo-imidazolidinyl, heterocyclylC1-6alkyl and heteroarylC1-6alkyl, wherein heterocyclyl of heterocyclylalkyl means 5- or 6-member monocycle containing oxygen, and wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocycle containing 1-3 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9- or 10-member bicycle containing 1 to 2 heteroatoms specified in a group consisting of nitrogen and sulphur, wherein monocyclic heteroaryl of the heteroaryl alkyl group may be optionally substituted by 1 or 2 substitutes independently specified in a group consisting of a halogroup, C1-6alkyl, haloC1-6alkyl and phenyl optionally substituted by a halogroup; R3 is specified in a group consisting of hydrogen and alkyl; two adjacent R4 groups together with carbon atoms whereto attached can form phenyl; R5 means hydrogen; or a pharmaceutically acceptable salt thereof.

EFFECT: preparing the heterocyclic derivatives which modulate activity of stearoyl CoA desaturase, methods of using the above derivatives for modulating activity of stearoyl CoA desaturase and pharmaceutical compositions containing the above derivatives.

26 cl, 1 tbl, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new quinolone derivatives of general formula (1) or a pharmaceutically acceptable salts thereof, wherein R1 represents a hydrogen atom, a lower alkyl group, cyclo C3-8 alkyl, a lower alkyl group or a lower alkoxy, a lower alkyl group; R2 represents a hydrogen, a lower alkyl group or a halogen-substituted lower alkyl group; R3 represents a phenyl group, a difurylglyoxal group, a thienyl group or pyridyl group with each group of the above is optionally substituted by one or two groups specified in a group consisting of the following (1) to (16) in an aromatic or heterocyclic ring, presented by the above R3: (1) lower alkyl groups, (2) lower alkoxy groups, (3) halogen-substituted lower alkoxy groups; (4) a phenoxy group, (5) lower alkylthio groups, (6) a hydroxy group, (7) hydroxy lower alkyl groups, (8) halogen atoms, (9) lower alkanoyl groups, (10) lower alkoxycarbonyl groups, (11) amino groups optionally substituted by one or two lower alkyl groups, (12) carbamoyl groups optionally substituted by one or two lower alkyl groups, (13) cyclo C3-8 alkyl lower alkoxy groups, (14) pyrrolidinyl carbonyl groups, (15) morpholinyl carbonyl groups and (16) a carboxyl group; R1 represents a halogen atom; R5 represents a hydrogen atom or a halogen atom; R6 represents a hydrogen atom; and R7 represents any of the above groups (1) to (15): (1) a hydroxyl group, (2) a halogen atom, (3) a lower alkoxy group, (4) a halogen-substituted lower alkoxy group, (5) a hydroxy lower alkoxy group, (6) a lower alkoxy lower alkoxy group, (7) an amino group optionally substituted by one or two members specified in a group consisting of lower alkyl groups, lower alkoxy lower alkyl groups and cyclo C3-8 alkyl groups, (8) an amino lower alkoxy group optionally substituted in an amino group by one or two members specified in a group consisting of lower alkyl groups, lower alkanoyl group, lower alkyl sulphonyl groups and carbamoyl groups optionally substituted by one or two lower alkyl groups, (9) a cyclo C3-8 alkoxy group, (10) a cyclo C3-8 alkyl lower alkoxy group, (11) a tetrahydrofuryl lower alkoxy group, (12) a lower alkylthio group, (13) a heterocyclic group specified in a group consisting of morpholinyl groups, pyrrolidinyl groups, difurylglyoxal groups, thienyl groups and benzothienyl groups, (14) a phenyl lower alkoxy lower alkoxy group and (15) a pyrrolidinyl carbonyl group. Also, the invention refers to a pharmaceutical composition, and a preventive and/or therapeutic agent based on the compound of formula (1), using the compound of formula (1), a method of treating or preventing the above diseases, to a method of preparing the compound of formula (1).

EFFECT: there are prepared new quinolone derivatives effective for treating and/or preventing the neurodegenerative diseases, diseases caused by neurological dysfunction, or diseases induced by deterioration of mitochondrial function.

11 cl, 1 tbl, 104 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted quinoxaline-type piperidine compounds of formula or to a pharmaceutically acceptable derivative thereof, wherein: Y1 represents O; Q is specified in condensed benzo or pyridino; each R2 is independently specified in: (a) -halogen or -CN; (b) -(C1-C6)alkyl; a is an integer specified in 0, 1 or 2; a dash line in a 6-member ring containing a nitrogen atom which is condensed with Q group means the presence or absence of a bond, and when the dash line means the absence of the bond, then R3, and one R4 are absent; R3 is specified in: (a) -H; each R4 is independently specified in: (a) -H; or (b) - halogen or CN; or (c) -X, -(C1-C6)alkyl-X, -(5- or 6-member)heterocyclyl-X or -(5- or 6-member)heterocyclyl-(C1-C6)alkyl-X; or (d) -C(=Y)X, -C(=Y)T3, -C(=Y)YX, - C(=Y)YT3, -C(-Y)N(T1)(T2), -C(=Y)N(R9)CN, -C(=Y)N(R9)X, -C(=Y)N(R9)YH, -C(=Y)N(R9)YX, -C(=Y)N(R9)YCH2X, -C(-Y)N(R9)YCH2CH2X or -C(=Y)N(R9)S(K))2T3; or (e) -N(R9)X, -N(R9)-CH2X, -N(R9)-CH2CH2X, -N(R9)CH2N(R9)C(=N(R12))N(R12)2, -N(R9)-CH2CH2N(R9)C(=N(RI2))N(R12)2, -N(T1)(T2), -N(T3)C(=Y)T3, -N(T3)C(=Y)YT3, -N(T3)C(=Y)N(T1)(T2), -N(T3)S(=O)2T3 or -N(T3)S(=O)2N(T1)(T2); X represents: (a) -H, -( C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkoxy, -(C3-C7)cycloalkyl, -(5- or 6-member)heterocycle or -(7-10-member)bicycloheterocycle each of which is unsubstituted or substituted with 1, 2 or 3 of optionally substituted R8 groups; or (b) -phenyl, -naphthalenyl, or -(5- or 6-member)heteroaryl each of which is unsubstituted or substituted with 1 or 2 of independently specified in R7 groups; each Y is independently specified in O; A and B are independently specified in: (a) -H; or (c) A-B together can form a (C2-C6)bridge each can optionally contain -HC=CH- or -O- in a (C2-C6)bridge; wherein the 6-member ring containing a nitrogen atom which is condensed with Q group can be found in the endo- or exo- configuration in relation to the A-B bridge; or (d) A-B together can form the -CH2-N(Ra)-CH2- bridge wherein the 6-member ring containing a nitrogen atom is condensed with Q group, and can be found in the endo- or exo- configuration in relation to the A-B bridge; Ra is specified in -H or -(C1-C6)alkyl; Z represents -[(C1-C10)alkyl optionally substituted with R1]h-, wherein h is equal to 0 or 1; each R1 is independently specified in: (b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl3 -(C3-C7)cycloalkoxy, -(C6-C14)bicycloalkyl, -(C8-C10)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C7-C14)bicycloalkenyl, -(3-7-member)heterocyclyl each of which is unsubtituted or substituted with 1, 2 or 3 of independently specified in R8 groups;

or or (d) -phenyl, -naphthalenyl each of which is unsubstituted or substituted with R7 group; each R6 is optionally specified in -H; each R7 is independently specified in -(C1-C4)alkyl, -OR9, -C(halogen)3, -CH(halogen)2, -CH2(halogen), -CN, -halogen, -N(R9)2, -C(=O)OR9; each R8 is independently specified in -(C1-C4alkyl, tetrzolyl, imidazolyl, furanyl, -(C1-C6)alkylCOOR9, -OR9, -SR9, -C(halogen)3, -CH(halogen)2, -CH2(halogen), -CN, =O, -halogen, -N(R9)(C1-C6)alkylCOOR9, -N(R9)2, -N(R9)S(=O)2R12, -N(R9)C(=O)R12, -N(R9)C(=O)OR12, -C(=O)R9, -C(=O)N(T1)(T2), -C(=O)OR9, -OC(=O)R9, or -S(=O)2R9; each R9 is independently specified in -H, -(C1-C6)alkyl, -(C3-C8)cycloalkyl, -phenyl, -benzyl, -(5- to 6-member)heterocycle, -C(halogen)3; -CH(halogen)2 or -CH2(halogen); if h is equal to O, then R11 can be specified in -H, -C(=O)OR9 or -C(=O)N(R6)2 or R11 can be -(C1-C4)alkyl; if h is equal to 1, then R11 can be specified in -H; each R12 is independently specified in -H or -(C1-C4)alkyl; m is equal to an integer specified in 3, 4, 5, 6, 7, 8 or 9; each e and f is equal to an integer independently specified in 0 or 1, provided 2≤(e+f)≤5; each j and k is equal to an integer independently specified in 0 or 1, provided 1≤(j+k)≤4; each p is equal to an integer independently specified in 0 or 1; each T1, T2, and T3 is independently specified in -H or -(C1-C10)alkyl which is unsubstituted or substituted with 1, 2 or 3 from independently specified R8 groups, or T1 and T2 together can form 5- to 8-member ring wherein the number of ring atoms contains a nitrogen atom wherein T1 and T2 are bound; the above 5- to 8-member ring is unsubstituted or substituted with 1, 2 or 3 from independently specified R8 groups and optionally any carbon atom in the above 5- to 8-member ring is independently substituted with O or N(R6); each halogen is independently specified in -F, -CI, -Br or -I.

EFFECT: invention refers to the intermediate compounds of formula

, , for preparing the above compounds of formula (II), compositions containing the above compounds and to a method of treating or preventing a diseased state, such as a pain.

36 cl, 58 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: chemistry.

SUBSTANCE: described are novel chiral cis-imidazolines selected from a group which includes 2-{4-[(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-acetamide, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(1,1-dioxohexahydrothiopyran-4-yl)-piperazin-1-yl]-methanone, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(3-methanesulphonylpropyl)-piperazin-1-yl]-methanone, 2-{4-[(4S,5R)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-N,N-bis-(2-methoxyethyl)-acetamide. 2-{1-[(48;5K)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperidin-4-yl}-acetamide and others described by the general structural formula (I), and pharmaceutical composition containing said compounds.

EFFECT: compounds can be used as anti-cancer agents, particularly as agents for treating solid tumours.

8 cl, 217 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I) or to its stereoisomers, or to a pharmaceutically acceptable salt, wherein Ra represents H or (C1-C6)alkyl; Rb is specified in an optionally substituted group consisting of -(CH2)n-aryl, -CH(CH3)-aryl, -(CH2)n-arylaryl, -(CH2)n-arylheteroaryl, -(CH2)n-(C3-C8) cycloalkyl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl and -(C3-C8) cycloalkylaryl; or Ra and Rb taken together with a nitrogen atom form 2,3-dihydro-1H-isoindolyl, decahydroisoquinolinyl, optionally substituted piperidinyl or optionally substituted pyrrolidinyl; Y is specified in an an optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridinyl, -NH-(CH2)n-heterocyclyl, wherein NH is attached to carbonyl, and -heterocyclylaryl, wherein heterocyclyl is attached to carbonyl; and n is equal to 0, 1 or 2; wherein each heterocyclyl represents an independent non-aromatic ring system containing 3 to 12 ring atoms, and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; wherein each heteroaryl represents an independent non-aromatic ring system containing 3 to 12 ring atoms and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; and wherein the optional substitutes are independently specified in a group consisting of C1-C6-alkyl, C1-C6-alkoxy, halogen, CN, CF3, OCF3, NH2, NH(CH3), N(CH3)2, hydroxy, cyclohexyl, phenyl, pyrrolidinyl, -C(O)-piperidinyl, -N(H)-C(O)-C1-C6-alkyl and N(H)-S(O)2-C1-C6-alkyl. The invention also describes a pharmaceutical composition having chemokine receptor antagonist activity and a method of treating such diseases, such as rheumatoid arthritis, psoriasis, lupus, etc.

EFFECT: there are prepared and described new chemical compounds that can be used as chemokine receptor antagonists and, as such, may be used in treating certain pathological conditions and diseases, particularly inflammatory pathological conditions and diseases and proliferative disorders and conditions, eg rheumatoid arthritis, osteoarthritis, multiple sclerosis and asthma.

23 cl, 59 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new crystalline modifications of N-α-(2,4,6-triisopropylphenylsulphonyl)-3-hydroxyamidino-(L)-phenylalanine-4-ethoxycarbonyl piperazide and/or its salts. Such crystalline modifications have high stability particularly at low hygroscopicity compared to known amorphous forms of the compound.

EFFECT: invention relates to a method of obtaining such new crystalline modifications, to pharmaceutical compositions containing these new crystalline modifications and their use as an anti-tumour agent.

26 cl, 7 tbl, 13 ex, 20 dwg

FIELD: chemistry, pharmaceutical.

SUBSTANCE: invention pertains to compounds with formula I , where: n is an integer equal 1 or 2; p is an integer from 1 to 7; A is chosen from one or more radicals X and/or Y; X represents methylene group, substituted when necessary by one or two C1-6-alkyl groups; Y represents C2-alkenyl, C2-alkenyl; G represents a single bonds, oxygen or C=O. The compound can be used as ferment FAAH inhibitor for pain killing, inflammation or nerve-degenerative diseases. Description is given of the method of obtaining compounds, pharmaceutical compositions based on them and their use.

EFFECT: design of a method of obtaining alkylhomopiperazinecarboxylates and their use for pain killing, treating inflammation or nervous degenerative diseases.

11 cl, 2 tbl, 7 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

The invention relates to piperazinone derivatives, to processes for their production, to their use and to the containing pharmaceutical compositions

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new indanone derivatives which may be preferentially used for treating and/or preventing a medical state for which cholinesterase inhibition is desired.

EFFECT: there are presented the new indanone derivatives which may be preferentially used for treating and/or preventing a medical state for which cholinesterase inhibition is desired.

11 cl, 36 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a benzylpiperidine derivative of formula

, or a pharmaceutically acceptable salt thereof, which can be used as a medicinal agent such as an antidepressant. In formula (1), R1 is a hydrogen atom or a methyl group; R2 is a group bonded in the para- or meta-position relative a methylene group, and is a chlorine atom bonded in the para-position, a bromine atom bonded in the para-position, a methyl group bonded in the para-position, a chlorine atom bonded in the meta-position, or a bromine atom bonded n the meta-position; X is a methylene group or an oxygen atom; and n is an integer from 1 to 3.

EFFECT: obtaining a benzylpiperidine derivative.

11 cl, 34 ex, 14 tbl, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes new 4-{3-[4-(3-{4- [amino(butoxycarbonylimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}-N'-(butoxycarbonyl)benzamidine crystals. The technical result: type II, type III and type IV 4-{3-[4-(3-{4- [amino(butoxycarbonylimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}-N'-(butoxycarbonyl)benzamidine crystals are excellent as therapeutic ingredients for antimycotics due to the fact that they appear to be easy-to-use since, i.e. have greater mouldability.

EFFECT: preparing the therapeutic ingredients for antimycotics.

3 cl, 4 ex, 9 tbl, 4 dwg

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