FR2850967A1 - New Peroxisome Proliferator-Activated Receptor modulators useful in treatment of dermatological, lipid metabolism, inflammatory and immune system disorders, cancerous and pre-cancerous states, diabetes, and hypertension - Google Patents

Abstract

Peroxisome Proliferator-Activated Receptor (PPAR) modulators (I), their optical and geometric isomers, and their salts are new. [Image] : Peroxisome Proliferator-Activated Receptor (PPAR) modulators of formula (I), their optical and geometric isomers, and their salts are new. Ar1 : an optionally substituted phenyl, pyridine, pyrazine, pyridazine, pyrimidine; Z : a group meta to X in ring Ar1 and of formula -CH2-CO-Y-R1; Ar2 : an optionally substituted phenyl, pyridine, pyrazine, pyridazine, pyrimidine or ring of formula (k) - (n); R1 : H, 1-12C alkyl, aryl, heteroaryl, aralkyl, polyether, monohydroxy alkyl, or polyhydroxy alkyl; R2 : H, 1-12C alkyl, aryl, heteroaryl, aralkyl, polyether, monohydroxy alkyl, polyhydroxy alkyl, COR5 or CSR5; Y : O, S or NR4; R4 : H, 1-12C alkyl, aryl, heteroaryl, aralkyl, polyether, or together with R1 and the N atom of Y forms a heterocycle or heteroaryl group; R5 : 1-12C alkyl, aryl, heteroaryl, aralkyl, polyether, alkoxy, monohydroxy alkyl, or polyhydroxy alkyl, R6-N-R7 or O-R8; R6, R7 : H, 1-12C alkyl, aryl, heteroaryl, aralkyl, polyether, monohydroxy alkyl, or polyhydroxy alkyl, or taken together they form a heterocycle; R8 : H, 1-12C alkyl, aryl, heteroaryl, aralkyl, polyether, monohydroxy alkyl, or polyhydroxy alkyl; X : S, SO, SO2, Se, O, NR9, CO, HO-CR11, or R10-C-R11; R9 : H, COR12, 1-12C alkyl, polyether, aryl, or aralkyl; R10, R11 : H, 1-12C alkyl, aryl, heteroaryl, aralkyl, alkoxy, polyether, monohydroxy alkyl, polyhydroxy alkyl, or taken together form a ring that may be interrupted by hetero atoms; A : S, O, Se, or NR13; R12 : 1-12C alkyl; R13 : H, 1-12C alkyl, aryl, heteroaryl, aralkyl, or polyether. ACTIVITY : Dermatological; Antiseborrheic; Antiinflammatory; Cytostatic; Antidiabetic; Hypotensive; Anorectic; Antilipemic; Antiarteriosclerotic. MECHANISM OF ACTION : Peroxisome Proliferator-Activated Receptor (PPAR) modulators.

Description

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The present invention relates to a new class of Peroxisome ProliferatorActivated Receptor (PPARs) receptor-modulating compounds as new and useful industrial products. It also relates to their process of preparation and their use in pharmaceutical compositions intended for use in human or veterinary medicine, or even in cosmetic compositions.

The activity of PPAR receptors has been the subject of numerous studies. As an indication, the publication entitled "Differential Expression of Peroxisome Proliferator-Activated Receptor Subtypes During the Differentiation of Human Keratinocytes", Michel Rivier et al., J. Invest. Dermatol 111,1998, p 1116-1121, which lists a large number of bibliographic references relating to PPAR receptors. Another example is the "PPARs: From Orphan Receptors to Drug Discovery", Timothy M. Willson, Peter J.

Brown, Daniel D. Sternbach, and Brad R. Henke, J. Med. Chem., 2000, Vol.43, p. 527-550.

PPAR receptors activate transcription by binding to DNA sequence elements, called peroxisome proliferator response elements (PPREs), as a heterodimer with retinoid X receptors (called RXRs).

Three subtypes of human PPARs have been identified and described: PPARa, PPARy and PPAR # (or NUC1).

PPARa is mainly expressed in the liver whereas PPAR 8 is ubiquitous.

It is disclosed in WO98 / 32444 that the PPARα selective compounds play a role in the barrier function and differentiation of the stratum corneum.

PPARy is the most studied of the three subtypes. All references suggest a critical role of PPARy in the regulation of adipocyte differentiation, where it is strongly expressed. It also plays a key role in systemic lipid homeostasis.

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

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 One of the aims of the present invention is to propose a new class of PPAR modulator compounds.

dans laquelle - Ar1 représente un radical éventuellement substitué de formule :

- Z représente le substituant :

étant entendu que Z est positionné en méta par rapport à X sur le cycle Ar1 ;
R1 et Y ayant les significations données ci-après, - Ar2 représente un radical éventuellement substitué de formule : Thus, the present invention relates to compounds of the following general formula (I):

in which - Ar1 represents an optionally substituted radical of formula:

Z represents the substituent:

it being understood that Z is positioned in meta with respect to X on the cycle Ar1;
R1 and Y having the meanings given below, - Ar2 represents an optionally substituted radical of formula:

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- R1 représente un atome d'hydrogène, un radical alkyle ayant de 1 à 12 atomes de carbone, un radical aryle, un radical hétéroaryle, un radical aralkyle, un radical polyéther, un radical monohydroxyalkyle ou un radical polyhydroxyalkyle ; - R2 représente un atome d'hydrogène, un radical alkyle ayant de 1 à 12 atomes de carbone, un radical aryle, un radical hétéroaryle, un radical aralkyle, un radical polyéther, un radical monohydroxyalkyle ou un radical polyhydroxyalkyle ; - R3 représente un atome d'hydrogène, un radical alkyle ayant de 1 à 12 atomes de carbone, un radical aryle, un radical hétéroaryle, un radical aralkyle, un radical polyéther, un radical monohydroxyalkyle, un radical polyhydroxyalkyle, un radical COR5 ou CSR5 ;
R5 ayant les significations données ci-après, - Y représente un atome d'oxygène, de soufre ou le radical N-R4 ;
R4 ayant les significations données ci-après, - R4 représente un atome d'hydrogène, un radical alkyle ayant de 1 à 12 atomes de carbone, un radical aryle, un radical hétéroaryle, un radical polyéther, un radical aralkyle ou forme avec R1 et l'atome d'azote de Y, un hétérocycle ou un hétéroaryle ; - R5 représente un radical aryle, un radical hétéroaryle, un radical aralkyle, un radical alkyle ayant de 1 à 12 atomes de carbone, un radical polyéther, un radical alkoxy, un radical monohydroxyalkyle, un radical polyhydroxyalkyle, un radical R6-N-R7 ou un radical O-R8 ;
R6, R7 et R8 ayant les significations données ci-après,

R1 represents a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, an aralkyl radical, a polyether radical, a monohydroxyalkyl radical or a polyhydroxyalkyl radical; R2 represents a hydrogen atom, an alkyl radical having from 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, an aralkyl radical, a polyether radical, a monohydroxyalkyl radical or a polyhydroxyalkyl radical; - R3 represents a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, an aralkyl radical, a polyether radical, a monohydroxyalkyl radical, a polyhydroxyalkyl radical, a COR5 or CSR5 radical; ;
R5 having the meanings given below, Y represents an oxygen atom, sulfur or the radical N-R4;
R 4 having the meanings given below, R 4 represents a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, a polyether radical, an aralkyl radical or forms with R 1 and the nitrogen atom of Y, a heterocycle or a heteroaryl; R 5 represents an aryl radical, a heteroaryl radical, an aralkyl radical, an alkyl radical having from 1 to 12 carbon atoms, a polyether radical, an alkoxy radical, a monohydroxyalkyl radical, a polyhydroxyalkyl radical or an R6-N-R7 radical; or an O-R8 radical;
R6, R7 and R8 having the meanings given below,

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R 6 and R 7 may be identical or different and represent a hydrogen atom, an alkyl radical having from 1 to 12 carbon atoms, a monohydroxyalkyl radical, a polyhydroxyalkyl radical, a polyether radical, an aryl radical, a heteroaryl radical, a aralkyl radical or taken together form a heterocycle; - R8 represents a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, a monohydroxyalkyl radical, a polyhydroxyalkyl radical, a polyether radical, an aryl radical, a heteroaryl radical, or an aralkyl radical; X represents an S atom, an S = O radical, an O = S = O radical, a Se atom, an O atom, an N-R9 radical, a C = O radical or an HO-C radical; -R11or an R10-CR11 radical;
R9, R10 and R11 having the meanings given below, - R9 represents a hydrogen atom, a -COR12 radical, an alkyl radical having 1 to 12 carbon atoms, a polyether radical, an aryl radical or an aralkyl radical;
R12 having the meanings given below, - R10 and R11 identical or different represent a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, an aralkyl radical, a monohydroxyalkyl radical; a polyhydroxyalkyl radical, a polyether radical, an alkoxy radical, or R10 and R11 taken together can form a ring optionally interrupted by hetero atoms; A represents an S, O or Se atom or an N-R13 radical;
R13 having the meanings given below, - R12 represents an alkyl radical having 1 to 12 carbon atoms; - R13 represents a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, an aryl radical, a polyether radical, a heteroaryl radical, or an aralkyl radical; and the optical and geometric isomers of said compounds of formula (I) and their salts.

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In particular, when the compounds according to the invention are in the form of salts, they are salts of an alkali metal or alkaline earth metal, zinc salts, or salts of an organic amine.

According to the present invention, the term "hydroxyl radical" means the radical -OH.

According to the present invention, an alkyl radical having 1 to 12 carbon atoms means a radical containing 1 to 12 carbon atoms, hydrogenated or fluoro, linear or cyclic, optionally branched, which can be interrupted by one or more heteroatoms, and preferably the alkyl radicals having from 1 to 12 carbon atoms are the methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, octyl, decyl or cyclohexyl radicals.

By monohydroxyalkyl radical is meant a radical having 1 to 6 carbon atoms and preferably having 2 to 3 carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.

By polyhydroxyalkyl radical is meant a radical containing from 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5- tetrahydroxypentyl or the remainder of pentaerythritol.

By polyether radical is meant a polyether radical having from 1 to 6 carbon atoms interrupted by at least one oxygen atom such as the methoxymethoxy, ethoxymethoxy or methoxyethoxymethoxy radicals.

Alkoxy radical having 1 to 7 carbon atoms is understood to mean a radical containing from one to seven carbon atoms, such as the methoxy, ethoxy, isopropyloxy, tert-butoxy, hexyloxy, benzyloxy or phenoxy radicals, which may be optionally substituted with an alkyl radical. having 1 to 12 carbon atoms.

By aryl radical is meant a phenyl, biphenyl, cinnamyl or naphthyl radical which may be mono- or disubstituted by a halogen atom, a CF3 radical, an alkyl radical having from 1 to 12 carbon atoms, an alkoxy radical having 1 to 7 carbon atoms, a nitro functional group, a polyether radical, an aryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl radical optionally protected by an acetyl, benzoyl group or an optionally protected amino function

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 by an acetyl, benzoyl group or optionally substituted with at least one alkyl having from 1 to 12 carbon atoms.

Aralkyl radical is understood to mean a benzyl, phenethyl or naphthalen-2-ylmethyl radical which may be mono- or disubstituted by a halogen atom, a CF 3 radical, an alkyl radical having from 1 to 12 carbon atoms, an alkoxy radical having from 1 to 7 carbon atoms, a nitro functional group, a polyether radical, an aryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl radical optionally protected by an acetyl, benzoyl group or an amino function optionally protected by an acetyl, benzoyl group or optionally substituted by at least one alkyl having from 1 to 12 carbon atoms.

By heteroaryl radical is meant an aryl radical interrupted by one or more heteroatoms, such as the radical pyridyl, furyl, thienyl, isoxazolyl, oxadiazolyl, oxazolyl, isothiazolyl, quinozalinyl, benzothiadiazolyl, benzimidazole, indolyl, benzofuran, optionally substituted by at least one halogen. , an alkyl having 1 to 12 carbon atoms, an alkoxy having 1 to 7 carbon atoms, an aryl radical, a nitro functional group, a polyether radical, a heteroaryl radical, a benzoyl radical, an alkyl ester group, an acid carboxylic acid, a hydroxyl optionally protected with an acetyl group, benzoyl or an amino function optionally protected with an acetyl, benzoyl group or optionally substituted with at least one alkyl having from 1 to 12 carbon atoms.

By heterocycle is preferably meant a morpholino, piperidino, piperazino, 2-oxo-piperidin-1-yl and 2-oxo-pyrrolidin-1-yl radical, optionally substituted by at least one alkyl having from 1 to 12 carbon atoms. an alkoxy having 1 to 7 carbon atoms, an aryl radical, a nitro functional group, a polyether radical, a heteroaryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl optionally protected by an acetyl group, benzoyl or an amino function optionally protected by an acetyl, benzoyl group or optionally substituted by at least one alkyl having from 1 to 12 carbon atoms.

Among the compounds of formula (I) above falling within the scope of the present invention, mention may notably be made of the following compounds (alone or as a mixture): 1b. Ethyl 3- (4-aminophenylsulfanyl) -phenyl] -acetate

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4b. Acide {3-[3-(3-phényl-propylamino)-phénylsulfanyl]-phényl}-acétique 5a. [3-(3-Heptylamino-phénylsulfanyl)-phényl]-acétate d'éthyle 5b. Acide [3-(3-heptylamino-phénylsulfanyl)-phényl]-acétique 6a. [3-(3-Butylamino-phénylsulfanyl)-phényl]-acétate d'éthyle 6b. Acide [3-(3-butylamino-phénylsulfanyl)-phényl]-acétique 7a. [3-(4-Heptylamino-phénylsulfanyl)-phényl]-acétate d'éthyle 7b. Acide [3-(4-heptylamino-phénylsulfanyl)-phényl]-acétique 8a. [3-(4-Butylamino-phénylsulfanyl)-phényl]-acétate d'éthyle 8b. Acide [3-(4-butylamino-phénylsulfanyl)-phényl]-acétique 9a. [3-(4-Phénéthylamino-phénylsulfanyl)-phényl]-acétate d'éthyle 9b. Acide [3-(4-phénéthylamino-phénylsulfanyl)-phényl]-acétique 10a. {3-[4-(3-Phényl-propylamino)-phénylsulfanyl]-phényl}-acétate d'éthyle 10b. Acide {3-[4-(3-phényl-propylamino)-phénylsulfanyl]-phényl}-acétique 11a. (3-{4-[3-Phénéthyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl}-phényl)-acétate d'éthyle 11 b. Acide (3-{4-[3-phénéthyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl} -phényl)acétique 12a. (3-{4-[3-Benzyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl}-phényl)-acétate d'éthyle 12b. Acide (3-{4-[3-benzyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl}-phényl)-acétique

13a. (3-{4-[3-Cyclohexyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl}-phényl)-acétate d'éthyle 13b. Acide (3-{4-[3-cyclohexyl-1-(3-phényl-propyl)-uréido]-phénylsuIfanyl}-phényl)- acétique 14a. (3-{4-[3-Butyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl}-phényl)-acétate d'éthyle 14b. Acide (3-{4-[3-Butyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl}-phényl)-acétique 15a. (3-{4-[3-Hexyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl}-phényl)-acétate d'éthyle

15b. Acide (3-{4-[3-hexyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl}-phényl)-acétique 16a. {3-[4-(1,3-Diphénéthyl-ureido)-phénylsulfanyl]-phényl}-acétate d'éthyle 16b. Acide {3-[4-(1 ,3-diphénéthyl-ureido)-phénylsulfanyl]-phényl}-acétique 17a. {3-[4-(3-Benzyl-1-phénéthyl-ureido)-phénylsulfanyl]-phényl}-acétate d'éthyle 1 C. [3- (4-Amino-phenylsulfanyl) -phenyl] -acetic acid 2a. [3- (3-Amino-phenylsulfanyl) -phenyl] -acetate ethyl 2b. [3- (3-Amino-phenylsulfanyl) -phenyl] -acetic acid 3a. Ethyl 3- (3-phenethylamino-phenylsulfanyl) -phenyl] -acetate 3b. [3- (3-Phenethylamino-phenylsulfanyl) -phenyl] -acetic acid 4a. Ethyl {3- [3- (3-phenyl-propylamino) -phenylsulfanyl] -phenyl} -acetate

4b. {3- [3- (3-phenyl-propylamino) -phenylsulfanyl] -phenyl} -acetic acid 5a. Ethyl 3- (3-heptylamino-phenylsulfanyl) -phenyl] -acetate 5b. [3- (3-Heptylamino-phenylsulfanyl) -phenyl] -acetic acid 6a. Ethyl 3- (3-butylamino-phenylsulfanyl) -phenyl] -acetate 6b. [3- (3-Butylamino-phenylsulfanyl) -phenyl] -acetic acid 7a. Ethyl 3- (4-heptylamino-phenylsulfanyl) -phenyl] -acetate 7b. [3- (4-Heptylamino-phenylsulfanyl) -phenyl] -acetic acid 8a. Ethyl 3- (4-butylamino-phenylsulfanyl) -phenyl] -acetate 8b. [3- (4-Butylamino-phenylsulfanyl) -phenyl] -acetic acid 9a. Ethyl 3- (4-phenethylamino-phenylsulfanyl) -phenyl] -acetate 9b. [3- (4-Phenethylamino-phenylsulfanyl) -phenyl] -acetic acid 10a. Ethyl {3- [4- (3-phenylpropylamino) phenylsulfanyl] phenyl} -acetate 10b. {3- [4- (3-phenyl-propylamino) -phenylsulfanyl] -phenyl} -acetic acid 11a. Ethyl 3- {4- [3-phenethyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetate 11b. (3- {4- [3-Phenethyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid 12a. Ethyl 3- {4- [3-Benzyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetate 12b. (3- {4- [3-Benzyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid

13a. Ethyl 3- {4- [3-cyclohexyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetate 13b. (3- {4- [3-Cyclohexyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid 14a. Ethyl 3- {4- [3-butyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetate 14b. (3- {4- [3-Butyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid 15a. Ethyl (3- {4- [3-hexyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetate

15b. (3- {4- [3-hexyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid 16a. Ethyl {3- [4- (1,3-diphenethyl-ureido) -phenylsulfanyl] -phenyl} -acetate 16b. {3- [4- (1,3-Diphenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 17a. Ethyl {3- [4- (3-Benzyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetate

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17b. Acide {3-[4-(3-benzyl-1-phénéthyl-ureido)-phénylsulfanyl]-phényl}-acétique 18a. {3-[4-(3-Cyclohexyl-1-phénéthyl-ureido)-phénylsulfanyl]-phényl}-acétate d'éthyle 18b. Acide {3-[4-(3-cyclohexyl-1-phénéthyl-ureido)-phénylsulfanyl]-phényl}-acétique 19a. {3-[4-(3-Butyl-1-phénéthyl-ureido)-phénylsulfanyl]-phényl}-acétate d'éthyle

19b. Acide {3-[4-(3-butyl-1-phénéthyl-ureido)-phénylsulfanyl]-phényl}-acétique 20a. {3-[4-(3-Hexyl-1-phénéthyl-ureido)-phénylsulfanyl]-phényl}-acétate d'éthyle 20b. Acide {3-[4-(3-hexyl-1-phénéthyl-ureido)-phénylsulfanyl]-phényl}-acétique 21a. {3-[4-(1-Heptyl-3-phénéthyl-ureido)-phénylsulfanyl]-phényl}-acétate d'éthyle 21 b. Acide {3-[4-(1-heptyl-3-phénéthyl-ureido)-phénylsulfanyl]-phényl}-acétique

22a. {3-[4-(1-Butyl-3-phénéthyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 22b. Acide {3-[4-(1-butyl-3-phénéthyl-uréido)-phénylsulfanyl]-phényl}-acétique 23a. {3-[3-(1,3-diphénéthyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 23b. Acide {3-[3-{1,3-diphénéthyl-uréido)-phénylsulfanyl]-phényl}-acétique 24a. (3-{3-[3-phénéthyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl} -phényl)- acétate d'éthyle 24b. Acide (3-{3-[3-phénéthyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl} -phényl)acétique 25a. {3-[3-(1-heptyl-3-phénéthyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 25b. Acide {3-[3-(1-heptyl-3-phénéthyl-uréido)-phénylsulfanyl]-phényl}-acétique 26a. {3-[3-(1-butyl-3-phénéthyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 26b. Acide {3-[3-(1-butyl-3-phénéthyl-uréido)-phénylsulfanyl]-phényl}-acétique 27a. {3-[4-(3-benzyl-1-heptyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 27b. Acide {3-[4-(3-benzyl-1-heptyl-uréido)-phénylsulfanyl]-phényl}-acétique

28a. {3-[ 4-(3-benzyl-1-butyl-uréido )-phénylsulfanyl]-phényl}- acétate d'éthyle 28b. Acide {3-[4-(3-benzyl-1-butyl-uréido)-phénylsulfanyl]-phényl}-acétique 29a. {3-[3-(3-benzyl-1-phénéthyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 29b. Acide {3-[3-(3-benzyl-1-phénéthyl-uréido)-phénylsulfanyl]-phényl}-acétique 30a. (3-{3-[3-benzyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl}-phényl)- acétate d'éthyle 30b. Acide (3-{3-[3-benzyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl}-phényl)-acétique 31a. {3-[3-(3-benzyl-1-heptyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 31 b. Acide {3-[3-(3-benzyl-1-heptyl-uréido)-phénylsulfanyl]-phényl}-acétique 32a. {3-[3-(3-benzyl-1-butyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 32b. Acide {3-[3-(3-benzyl-1-butyl-uréido)-phénylsulfanyl]-phényl}-acétique 33a. {3-[4-(3-cyclohexyl-1-heptyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 33b. Acide {3-[4-(3-cyclohexyl-1-heptyl-uréido)-phénylsulfanyl]-phényl}-acétique

34a. {3-[4-(1-butyl-3-cyclohexyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle

17b. {3- [4- (3-Benzyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 18a. Ethyl {3- [4- (3-cyclohexyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetate 18b. {3- [4- (3-Cyclohexyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 19a. Ethyl {3- [4- (3-butyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetate

19b. {3- [4- (3-Butyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 20a. Ethyl {3- [4- (3-hexyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetate 20b. {3- [4- (3-hexyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 21a. Ethyl {3- [4- (1-heptyl-3-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetate 21b. {3- [4- (1-heptyl-3-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid

22a. {3- [4- (1-Butyl-3-phenethyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 22b. {3- [4- (1-Butyl-3-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 23a. {3- [3- (1,3-diphenethyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 23b. {3- [3- (1,3-Diphenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 24a. (3- {3- [3-phenethyl-1- (3-phenyl-propyl) -ureido] -phenyl-sulfanyl} -phenyl) -ethyl acetate 24b. (3- {3- [3-Phenethyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid 25a. {3- [3- (1-heptyl-3-phenethyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 25b. {3- [3- (1-heptyl-3-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 26a. {3- [3- (1-Butyl-3-phenethyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 26b. {3- [3- (1-Butyl-3-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 27a. {3- [4- (3-Benzyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 27b. {3- [4- (3-Benzyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid

28a. {3- [4- (3-Benzyl-1-butylureido) -phenylsulfanyl] -phenyl} -ethyl acetate 28b. {3- [4- (3-Benzyl-1-butylureido) -phenylsulfanyl] -phenyl} -acetic acid 29a. {3- [3- (3-Benzyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 29b. {3- [3- (3-Benzyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 30a. (3- {3- [3-Benzyl-1- (3-phenyl-propyl) -ureido] -phenyl-sulfanyl} -phenyl) -ethyl acetate 30b. (3- {3- [3-Benzyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid 31a. {3- [3- (3-Benzyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 31 b. {3- [3- (3-Benzyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 32a. {3- [3- (3-Benzyl-1-butylureido) -phenylsulfanyl] -phenyl} -ethyl acetate 32b. {3- [3- (3-Benzyl-1-butylureido) -phenylsulfanyl] -phenyl} -acetic acid 33a. {3- [4- (3-cyclohexyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 33b. {3- [4- (3-Cyclohexyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid

34a. {3- [4- (1-Butyl-3-cyclohexyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate

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34b. Acide {3-[4-(1-butyl-3-cyclohexyl-uréido)-phénylsulfanyl]-phényl}-acétique 35a. {3-[3-(3-cyclohexyl-1-phénéthyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 35b. Acide {3-[3-(3-cyclohexyl-1-phénéthyl-uréido)-phénylsulfanyl]-phényl}-acétique 36a. (3-{3-[3-cyclohexyl-1-(3-phényl-propyl)-uréido ]-phénylsulfanyl} -phényl)- acétate d'éthyle 36b. Acide (3-{3-[3-cyclohexyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl} -phényl)- acétique 37a. {3-[3-(3-cyclohexyl-1-heptyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 37b. Acide {3-[3-(3-cyclohexyl-1-heptyl-uréido)-phénylsulfanyl]-phényl}-acétique 38a. {3-[3-(1-butyl-3-cyclohexyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 38b. Acide {3-[3-(1-butyl-3-cyclohexyl-uréido)-phénylsulfanyl]-phényl}-acétique 39a. Acide {3-[4-(3-butyl-1-heptyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 39b. Acide {3-[4-(3-butyl-1-heptyl-uréido)-phénylsulfanyl]-phényl}-acétique 40a. {3-[4-(1,3-dibutyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 40b. Acide {3-[4-(1 ,3-dibutyl-uréido)-phénylsulfanyl]-phényl}-acétique 41a. {3-[3-(3-butyl-1-phénéthyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle

41 b. Acide {3-[3-(3-butyl-1-phénéthyl-uréido)-phénylsulfanyl]-phényl}-acétique 42a. (3-{3-[3-butyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl}-phényl)- acétate d'éthyle 42b. Acide (3-{3-[3-butyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl}-phényl)-acétique 43a. {3-[3-(3-butyl-1-heptyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 43b. Acide {3-[3-(3-butyl-1-heptyl-uréido)-phénylsulfanyl]-phényl}-acétique 44a. {3-[3-(1,3-dibutyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 44b. Acide {3-[3-(1 ,3-dibutyl-uréido)-phénylsulfanyl]-phényl}-acétique 45a. {3-[4-(1-heptyl-3-hexyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 45b. Acide {3-[4-(1-heptyl-3-hexyl-uréido)-phénylsulfanyl]-phényl}-acétique 46a. {3-[4-(1-butyl-3-hexyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 46b. Acide {3-[4-(1-butyl-3-hexyl-uréido)-phénylsulfanyl]-phényl}-acétique 47a. {3-[3-(3-hexyl-1-phénéthyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle

47b. Acide {3-[3-(3-hexyl-1-phénéthyl-uréido)-phénylsulfanyl]-phényl}-acétique 48a. (3-{3-[3-hexyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl}-phényl)- acétate d'éthyle 48b. Acide (3-{3-[3-hexyl-1-(3-phényl-propyl)-uréido]-phénylsulfanyl}-phényl)-acétique 49a. {3-[3-(1-heptyl-3-hexyl-uréido)-phénylsulfanyl]-phényl}- acétate d'éthyle 49b. Acide {3-[3-(1-heptyl-3-hexyl-uréido)-phénylsulfanyl]-phényl}-acétique 50a. {3-[3-(1-butyl-3-hexyl-uréido) -phénylsulfanyl] -phényl} - acétate d'éthyle 50b. Acide {3-[3-(1-butyl-3-hexyl-uréido) -phénylsulfanyl] -phényl} -acétique

34b. {3- [4- (1-Butyl-3-cyclohexyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 35a. {3- [3- (3-cyclohexyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 35b. {3- [3- (3-Cyclohexyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 36a. (3- {3- [3-Cyclohexyl-1- (3-phenyl-propyl) -ureido] -phenyl-sulfanyl} -phenyl) -ethyl acetate 36b. (3- {3- [3-Cyclohexyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid 37a. {3- [3- (3-cyclohexyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 37b. {3- [3- (3-Cyclohexyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 38a. {3- [3- (1-Butyl-3-cyclohexyl-ureido) -phenylsulfanyl] -phenyl} -acetate 38b. {3- [3- (1-Butyl-3-cyclohexyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 39a. {3- [4- (3-Butyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 39b. {3- [4- (3-Butyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 40a. {3- [4- (1,3-dibutyl-ureido) -phenylsulfanyl] -phenyl} -acetate 40b. {3- [4- (1,3-dibutyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 41a. {3- [3- (3-Butyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate

41 b. {3- [3- (3-Butyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 42a. (3- {3- [3-Butyl-1- (3-phenyl-propyl) -ureido] -phenyl-sulfanyl} -phenyl) -ethyl acetate 42b. (3- {3- [3-Butyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid 43a. {3- [3- (3-Butyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 43b. {3- [3- (3-Butyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 44a. {3- [3- (1,3-dibutyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 44b. {3- [3- (1,3-dibutyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 45a. {3- [4- (1-heptyl-3-hexyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 45b. {3- [4- (1-heptyl-3-hexyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 46a. {3- [4- (1-butyl-3-hexyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 46b. {3- [4- (1-Butyl-3-hexyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 47a. {3- [3- (3-hexyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate

47b. {3- [3- (3-hexyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 48a. (3- {3- [3-hexyl-1- (3-phenyl-propyl) -ureido] -phenyl-sulfanyl} -phenyl) -ethyl acetate 48b. (3- {3- [3-Hexyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid 49a. {3- [3- (1-heptyl-3-hexyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 49b. {3- [3- (1-heptyl-3-hexyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 50a. {3- [3- (1-Butyl-3-hexyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 50b. {3- [3- (1-Butyl-3-hexyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid

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 A general description of the preparation of the compounds of the general formula of Figure 1 attached is given below.

The reaction scheme described in FIG. 1 is a general diagram allowing the compounds according to the invention to be obtained.

The compounds of general formula (I) can be obtained (FIG. 1) by coupling of thiol with an aromatic iodine, by use of a metal catalyst such as: nickel or palladium derivatives, in the presence of a donor of hydride such as sodium borohydride and if necessary a base. The next step is a reductive amination of the above amine and an aldehyde, which can be carried out with isolation of the intermediate imine or not and then reduction of the latter by action of a reducing agent such as NaBH3CN. The alkylated amine obtained can then be subjected to the action of an isocyanate or an isothiocyanate in a solvent such as dichloromethane to yield the corresponding urea or thiourea. It can also be alkylated, again by reductive amination reaction in the presence of an aldehyde in the same conditions as above. The amide can also be formed by the action of an acid in the presence of coupling agent such as O- (7-azabenzotriazol-1-yl) -N, N, N ', N' tetramethyluronium hexafluorophosphate (HATU) in presence of a base like DIE) or an acyl halide and a base. The derivatives obtained are then saponified by the action of, for example, a base such as NaOH to give the corresponding acids.

The compounds according to the invention exhibit PPAR receptor modulating properties. This activity on PPARα receptors, γ and γ, is measured in a transactivation test and quantified by the dissociation constant Kdapp (apparent), as described in Example 51.

The preferred compounds of the present invention have a dissociation constant less than or equal to 1000 nM, and advantageously less than or equal to 500 nM for at least one of the PPARs subtypes.

The present invention also relates to the compounds of formula (1) as described above.

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 The present invention relates to the use of the compounds of formula (I) for producing a composition intended to regulate and / or restore the metabolism of cutaneous lipids.

The compounds according to the invention are particularly suitable in the following treatment areas: 1) for treating dermatological disorders related to a keratinization disorder relating to differentiation and proliferation, in particular to treat acne vulgaris, comedoniennes, polymorphs, rosaceae, nodulocystic acnes, conglobata, senile acnes, secondary acnes such as solar acne, medicated or occupational, 2) to treat other types of disorders of keratinization, including ichthyosis, ichthyosiform states, the disease of Darrier, palmoplantar keratoderma, leukoplakia and leukoplasiform states, cutaneous or mucosal lichen (buccal), 3) to treat other dermatological conditions with an inflammatory immunoallergic component, with or without cell proliferation disorder, and especially all the forms of psoriasis, be it cutaneous, mucous or ungual , and even psoriatic arthritis, or cutaneous atopy, such as eczema or atopy respiratory or gingival hypertrophy, 4) to treat all epidermal or dermal proliferations whether benign or malignant, that whether or not they are of viral origin such as common warts, flat warts and verruciform epidermodysplasia, oral or florid papillomatoses, T-cell lymphoma, and proliferations that can be induced by ultraviolet rays, especially in the case of epithelioma baso and squamous cell, as well as any precancerous skin lesions such as keratoacanthomas, 5) to treat other dermatological disorders such as immune dermatoses such as lupus erythematosus, bullous immune diseases and collagen diseases, such as scleroderma, 6) in the treatment of dermatological or general affections with an immunological component, 7) in the treatment of cutaneous disorders of the skin. s exposure to UV radiation as well as to repair or fight against aging of the skin, be it photoinduced or chronological, or to reduce actinic pigmentations and keratoses, or any pathologies associated with chronological or actinic aging, such as xerosis,

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 8) for controlling sebum function disorders such as acne hyperseborrhoea, simple seborrhea, or seborrheic dermatitis, 9) for preventing or treating healing disorders, or for preventing or repairing stretch marks , 10) in the treatment of pigmentation disorders, such as hyperpigmentation, melasma, hypopigmentation or vitiligo, 11) in the treatment of diseases of lipid metabolism, such as obesity, hyperlipidemia, diabetes noninsulin-dependent or syndrome X, 12) in the treatment of inflammatory conditions such as arthritis, 13) in the treatment or prevention of cancerous or precancerous conditions, 14) in the prevention or treatment of alopecia of different origins, including alopecia due to chemotherapy or radiation, 15) in the treatment of disorders of the immune system, such as asthma, type I diabetes mellitus, multiple sclerosis, or other s dysfunctional immune system, or 16) in the treatment of cardiovascular system conditions such as arteriosclerosis or hypertension.

The present invention also relates to a pharmaceutical or cosmetic composition comprising, in a physiologically acceptable medium, at least one compound of formula (I) as defined above.

The administration of the composition according to the invention may be carried out enterally, parenterally, topically or ocularly. Preferably, the pharmaceutical composition is packaged in a form suitable for topical application.

Enterally, the composition, more particularly the pharmaceutical composition, may be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres. or lipid or polymeric vesicles for controlled release.

Parenterally, the composition may be in the form of solutions or suspensions for infusion or injection.

The compounds according to the invention are generally administered at a daily dose of about 0.001 mg / kg to 100 mg / kg of body weight, in 1 to 3 doses.

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 The compounds are used systemically at a concentration generally of between 0.001 and 10% by weight, preferably between 0.01 and 1% by weight, relative to the weight of the composition.

Topically, the pharmaceutical composition according to the invention is more particularly intended for the treatment of skin and mucous membranes and may be in the form of ointments, creams, milks, ointments, powders, impregnated swabs, syndets, solutions, gels, sprays, foams, suspensions, stick lotions, shampoos, or washing bases. It can also be in the form of suspensions of microspheres or nanospheres or lipid or polymeric vesicles or polymeric patches and hydrogels allowing controlled release. This topical composition may be in anhydrous form, in aqueous form or in the form of an emulsion.

The compounds are used topically at a concentration generally of between 0.001 and 10% by weight, preferably between 0.01 and 1% by weight, relative to the total weight of the composition.

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

The invention therefore also relates to the cosmetic use of a composition comprising, in a physiologically acceptable carrier, at least one of the compounds of formula (I) for body or hair hygiene.

The cosmetic composition according to the invention containing, in a cosmetically acceptable support, at least one compound of formula (I) or one of its optical or geometrical isomers or one of its salts, can be in particular in the form of a cream, a milk, a lotion, a gel, suspensions of microspheres or nanospheres or lipid or polymeric vesicles, soaked swabs, solutions, sprays, foams, sticks, soaps, shampoos or washing bases.

The concentration of compound of formula (I) in the cosmetic composition is between 0.001 and 3% by weight, relative to the total weight of the composition.

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 The pharmaceutical and cosmetic compositions as described above may also contain inert additives, or even pharmacodynamically active additives for pharmaceutical compositions, or combinations of these additives, and especially: wetting agents; - flavor enhancers; preserving agents such as esters of parahydroxybenzoic acid; stabilizing agents; humidity regulating agents; pH regulating agents; osmotic pressure modifying agents; emulsifying agents; UV-A and UV-B filters; antioxidants, such as α-tocopherol, butylhydroxyanisole or butylhydroxytoluene, superoxide dismutase, ubiquinol or certain metal chelators; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; - emollients; moisturizing agents such as glycerol, PEG 400, thiamorpholinone, and its derivatives or urea; anti-seborrhoeic or anti-acne agents, such as S-carboxymethylcysteine, S-benzylcysteamine, their salts or their derivatives, or benzoyl peroxide; antibiotics such as erythromycin and its esters, neomycin, clindamycin and its esters, tetracyclines; antifungal agents such as ketoconazole or polymethylene-4,5-isothiazolidones-3; agents promoting the regrowth of hair, such as Minoxidil (2,4-diamino-6-piperidino-pyrimidine-3-oxide) and its derivatives, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) ) and phenytoin (5,4-diphenylimidazolidine 2,4-dione); nonsteroidal anti-inflammatory agents; carotenoids and, in particular, 0-carotene; anti-psoriatic agents such as anthralin and its derivatives; - eicosa-5,8,11,14-tetraynoic and eicosa-5,8,11-triynoic acids, their esters and amides;

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 retinoids, that is to say ligands of the RAR or RXR receptors, natural or synthetic; corticosteroids or estrogens; α-hydroxy acids and α-keto acids or their derivatives, such as lactic, malic, citric, glycolic, mandelic, tartaric, glyceric or ascorbic acids, as well as their salts, amides or esters, or p-hydroxy acids or their derivatives, such as salicylic acid and its salts, amides or esters; ion channel blockers such as potassium channels; or even more particularly for pharmaceutical compositions, in combination with medicaments known to interfere with the immune system (for example cyclosporin, FK 506, glucocorticoids, monoclonal antibodies, cytokines or growth factors). .).

Of course, those skilled in the art will take care to choose the optional compound (s) to be added to these compositions in such a way that the advantageous properties intrinsically attached to the present invention are not or not substantially impaired by the envisaged addition.

Several examples of obtaining active compounds of formula (1) according to the invention, as well as biological activity results for such compounds and various concrete formulations to be given by way of illustration will now be given by way of illustration and without any limiting nature. basis of its compounds.

EXAMPLES The products were analyzed by HPLC / Mass. Column: 2.1X5 mm, 3, High purity C18 Hypersil.

Mobile phase: A (CH3CN / 0.1v / v HC02H); B (H20 / O.1v / v HCO2H), Waters Alliance 2790 LC Mobile Phase Solvents A% 35. 0 Solvent A
B% 65. 0 Solvent B Flow (ml / min) 0. 450 Analysis time (mins) 5.00

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EXEMPLE 1 : Acide [3-(4-Amino-phénylsulfanvl)-phényil-acétique a) 3-mercaptophényl acétate d'éthyle 6. 5 ml (0. 12 mol) d'acide sulfurique concentré sont additionnés goutte à goutte sur un mélange de 10 g (0.06moi) d'acide 3-mercaptophényl acétique dans 200 ml d'éthanol. Le milieu réactionnel est ensuite chauffé à reflux pendant 4h. 1 ml d'acide sulfurique concentré est additionnés goutte à goutte afin de compléter la réaction. Le milieu réactionnel est chauffé 3 h à reflux puis concentré à l'évaporateur rotatif sous vide. De l'eau est additionnée au résidu obtenu. La solution est neutralisée par addition de bicarbonate de sodium. Le produit désiré est extrait par addition d'éther éthylique. La phase organique est lavée à l'eau, séchée par du sulfate de magnésium et concentrée à l'évaporateur rotatif. Le produit est purifié par chromatographie sur colonne de silice, éluée par du dichlorométhane. Après évaporation des solvants, on recueille 10. 15 g (86%) du composé attendu, sous la forme d'une huile jaune.

b) r3-(4-Amino-phénvlsulfanyl)-phénvn-acétate d'éthyle Une solution de 3-mercaptophényl acétate d'éthyle (2. 5 g, 12.7 mmol) dans 10 ml de THF est additionné sur un mélange de résine borohydride polymer supported Amberlite IRA400 (2. 5 mmol/g) (Aldrich : 32864-2) (10. 1 g, 25.4mmol), de Bis(bipyridine)nickel (II) bromide (105. 3 mg) (Organometallics 1985,4, 657-661) et de 4-iodoaniline (1. 8 g, 8.5 mmol) dans l'éthanol (90ml). Le mélange est agité à reflux 3h. Le milieu réactionnel est filtré et le filtrat concentré à l'évaporateur rotatif sous vide. Le produit est purifié par chromatographie sur colonne de silice (dichlorométhane). Après évaporation des solvants, le composé attendu 524 mg (73%), est isolé sous la forme d'une huile jaune. Column Temperature (C) 60 Temperature Column Limit (C) 10 Waters Alliance 2790 LC Rapid Equilibration System Time (mins) 0.30 Rebalancing Time (mins) 0.50 The gradient contains 3 entries that are: Time A% B % Flow Curve 0. 00 5. 0 65. 0 0. 450 1 3. 00 95. 0 5. 0 0. 450 6 5. 00 95. 0 5. 0 0. 450 6

EXAMPLE 1 [3- (4-Amino-phenylsulfanyl) -phenyl-acetic acid a) 3-mercaptophenyl ethyl acetate 6. 5 ml (0. 12 mol) of concentrated sulfuric acid are added dropwise to a mixture 10 g (0.06 mol) of 3-mercaptophenyl acetic acid in 200 ml of ethanol. The reaction medium is then heated under reflux for 4 hours. 1 ml of concentrated sulfuric acid is added dropwise to complete the reaction. The reaction medium is heated for 3 hours under reflux and then concentrated on a rotary evaporator under vacuum. Water is added to the resulting residue. The solution is neutralized by the addition of sodium bicarbonate. The desired product is extracted by addition of ethyl ether. The organic phase is washed with water, dried with magnesium sulfate and concentrated on a rotary evaporator. The product is purified by chromatography on a silica column, eluted with dichloromethane. After evaporation of the solvents, 10 15 g (86%) of the expected compound are collected in the form of a yellow oil.

b) Ethyl 3- (4-aminophenylsulfanyl) phenyl-ethyl acetate A solution of ethyl 3-mercaptophenyl acetate (2.5 g, 12.7 mmol) in 10 ml of THF is added to a mixture of borohydride resin. polymer supported Amberlite IRA400 (2.5 mmol / g) (Aldrich: 32864-2) (10. 1 g, 25.4mmol), Bis (bipyridine) nickel (II) bromide (105.3 mg) (Organometallics 1985.4 657-661) and 4-iodoaniline (1. 8 g, 8.5 mmol) in ethanol (90 ml). The mixture is stirred at reflux for 3 hours. The reaction medium is filtered and the filtrate is concentrated by rotary evaporation in vacuo. The product is purified by chromatography on a silica column (dichloromethane). After evaporation of the solvents, the expected compound 524 mg (73%) is isolated in the form of a yellow oil.

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c) Acide r3-(4-Amino-phénylsulfanyl)-phénvll-acétique Un mélange de produit 1(b) (50 mg, 0.174 mmol), de soude (50 mg), d'eau (50 NI) et d'éthanol (50 l) dans le THF (2.5 ml) est agité 24 h à température ambiante. Le milieu réactionnel est acidifié par addition d'une solution d'acide chlorhydrique 2N et extrait à l'éther éthylique. La phase organique est lavée à l'eau, séchée sur sulfate de magnésium et concentrée à l'évaporateur rotatif sous vide. Le produit est obtenu sous forme d'un solide jaune (44mg), 98%.

1 H NMR (CDCl 3, 400MHz): 1.22 (3H, t), 3.50 (2H, s), 3.65 (2H, NH 2, s), 4.11 (2H, q), 6.65. (2H, Ar, d), 6.99 (2H, Ar, t), 7.04 (1H, Ar, s), 7.14 (1H, Ar, t), 7.28 (2H, Ar , d)

c) 3- (4-Amino-phenylsulfanyl) -phenyl-acetic acid A mixture of product 1 (b) (50 mg, 0.174 mmol), sodium hydroxide (50 mg), water (50 NI) and ethanol (50 l) in THF (2.5 ml) is stirred for 24 h at room temperature. The reaction medium is acidified by addition of a 2N hydrochloric acid solution and extracted with ethyl ether. The organic phase is washed with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum. The product is obtained in the form of a yellow solid (44 mg), 98%.

EXAMPLE 2: α- (3-Amino-phenylsulfanyl) -phenyl-acetic acid α) β- (3-Amino-phenylsulfanyl) -phenyl-ethyl acetate Analogously to Example 1 (b), by reaction of 3-mercaptophenyl ethyl acetate (3 g, 15.3 mmol), 10 ml of THF, amberlite IRA400 supported borohydride polymer (2. 5 mmol / g) (Aldrich: 32864-2) (12.24 g, 30.6 mmol), of Bis (bipyridine) nickel (II) bromide (127 mg) (Organometallics 1985, 4, 657-661) and 3iodoaniline (2.2 g, 10.2 mmol), 2.38 g (54%) of the expected derivative are obtained. in the form of a yellow oil.

b) Acide f3-(3-Amino-phénvlsulfanyl)-phénvn-acétique De manière analogue à l'exemple 1(c), par réaction de [3-(3-Amino-phénylsulfanyl)phényl]-acétate d'éthyle (50 mg, 0.174 mmol), de soude (50 mg), d'eau (50 NI) et d'éthanol (50 NI) dans le THF (2.5 ml), on obtient 39 mg (87%) du dérivé attendu sous forme d'un solide jaune.

1H NMR (CDCl3, 400MHz): 1.22 (3H, t), 3.54 (4H, s), 4.12 (2H, q), 6.50 (1H, Ar, d), 6.653 (1H; , Ar, s), 6.71 (1H, Ar, d), 7.05 (1H, Ar, t), 7.10 to 7.20 (1H, Ar, m), 7.22 (2H; , Ar, d), 7.27 (1H, Ar, s)

(b) 3- (3-Amino-phenylsulfanyl) -phenyl-acetic acid Analogous to Example 1 (c), by reaction of ethyl [3- (3-aminophenylsulfanyl) phenyl] acetate (50.degree. mg, 0.174 mmol), sodium hydroxide solution (50 mg), water (50 NI) and ethanol (50 NI) in THF (2.5 mL), 39 mg (87%) of the expected derivative are obtained in the form of a yellow solid.

EXAMPLE 3: 3- (3-Phenethylamino-Dienylsulfanyl) -H-phenyl) -acetinium a) -3- (3-Phenethylamino-phenylsulfanyl) -phenyl-ethyl acetate A solution of phenylacetaldehyde (163 mg, 1.357 mmol) and acetic acid ( 1 ml) is added to a solution of ethyl [3- (3-aminophenylsulfanyl) -phenyl] -acetate (Example 2 (a)) (390.1.36 mmol) in 15 ml of DMF 170. 54 mg of sodium cyanoborohydride (2.71 mmol) are added and the mixture is stirred for 12 hours at room temperature After extraction with ethyl ether, the organic phase is washed

<Desc / Clms Page number 18>

 with water, dried over magnesium sulphate and concentrated in a rotary evaporator under vacuum. The product is purified by chromatography on a silica column (dichloromethane 7 / heptane 3). After evaporation of the solvents, the expected compound 170 mg (34%) is isolated in the form of a yellow oil.

b) Acide r3-(3-Phénéthvlamino-phénvlsulfanvl)-phényll-acétique Un mélange de [3-(3-Phénéthylamino-phénylsulfanyl)-phényl]-acétate d'éthyle (47 mg), d'une solution de soude à 35% (100 NI) et de 50ul d'éthanol dans le THF (2ml) est agité à température ambiante 4 jours. Après acidification par 5 ml d'une solution d'acide chlorhydrique 1 N, extraction à l'éther éthylique, la phase organique est lavée à l'eau, séchée sur sulfate de magnésium et concentrée à l'évaporateur rotatif sous vide. Après évaporation du solvant, le composé attendu 40 mg (92%), est isolé sous la forme d'une huile jaune.

1 H NMR (CDCl 3, 400MHz): 1.21 (3H, t), 2.85 (2H, t), 3.32 (2H, t), 3.53 (2H, s), 4.09 (2H, m.p. q), 6.46 (1H, Ar, d), 6.60 (1H, Ar, s), 6.66 (1H, Ar, d), 7.06 to 7.29 (10H, Ar , m)

b) 3- (3-Phenethylamino-phenylsulfanyl) -phenyl-acetic acid A mixture of ethyl [3- (3-phenethylamino-phenylsulfanyl) -phenyl] -acetate (47 mg), a sodium hydroxide solution, % (100 NI) and 50ul of ethanol in THF (2ml) is stirred at room temperature for 4 days. After acidification with 5 ml of a 1N hydrochloric acid solution, extraction with ethyl ether, the organic phase is washed with water, dried over magnesium sulphate and concentrated in a rotary evaporator under vacuum. After evaporation of the solvent, the expected compound 40 mg (92%) is isolated in the form of a yellow oil.

EXAMPLE 4 {3-R3- (3-Phenylpropyl) amino) -phenyl) -benzyl-dienv)} acetic acid a) 3- [3- (3-Phenyl-aroa) -l-phenylsulfanyll-ahen-ethyl acetate Analogous to Example 3 (a), by reaction of 3-phenylpropionaldehyde (182 mg, 1.357 mmol), acetic acid (1 ml), [3- (3-aminophenylsulfanyl) -phenyl] - ethyl acetate (Example 2 (a)) (390.136 mmol) in 15 ml of DMF 170, 54 mg and sodium cyanoborohydride (2.71 mmol), 364 mg (66%) of the expected derivative are obtained. a colorless oil.

b) Acide {3-f3-(3-Phénvl-propylamino)-phénvlsulfanvll-phénvl)-acétique De manière analogue à l'exemple 3 (b), par réaction de {3-[3-(3-Phényl-propylamino)phénylsulfanyl]-phényl}-acétate d'éthyle (25 mg, 0.062 mmol), d'une solution de soude à 35% (100 l) et de 50ul d'éthanol dans le THF (2ml), on obtient 17 mg (73%) du dérivé attendu sous forme d'une huile jaune.

1H NMR (CDCl3, 400MHz): 1.19 (3H, t), 1.18-1.88 (2H, m), 2.64 (2H, t), 3.03 (2H, t), 3, 50 (2H, s), 4.09 (2H, q), 6.39 (1H, Ar, d), 6.54 (1H, Ar, s), 6.64 (1H, Ar, d ), 7.04 to 7.26 (10H, Ar, m).

(b) {3 - [3- (3-Phenylpropylamino) phenyl] sulfanyl] phenyl} acetic acid Analogous to Example 3 (b), by reaction of {3- [3- (3-phenylpropylamino)} phenylsulfanyl] -phenyl} -acetate (25 mg, 0.062 mmol), a 35% sodium hydroxide solution (100 l) and 50ul of ethanol in THF (2 ml), 17 mg (73%) are obtained. %) of the expected derivative as a yellow oil.

EXAMPLE 5 [3- (3-Heptylamino-phenylsulfanyl) -phenyl-acetic acid a) [3- (3-Heptylamino-phenylsulfanyl) -phenyl-ethyl acetate

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 Analogous to Example 3 (a), by reaction of heptaldehyde (155 mg, 1.357 mmol), acetic acid (1 ml), [3- (3-aminophenylsulfanyl) -phenyl] -acetate, and ethyl (Example 2 (a)) (390.136 mmol) in 15 ml of DMF and 170.54 mg of sodium cyanoborohydride (2.71 mmol), 217 mg (42%) of the expected derivative is obtained in the form of an oil. colorless.

b) Acide F3-(3-Heptylamino-phénylsulfanvl)-phényll-acétique De manière analogue à l'exemple 3 (b), par réaction de [3-(3-Heptylaminophénylsulfanyl)-phényl]-acétate d'éthyle (40 mg, 0.10 mmol), d'une solution de soude à 35% (100 l) et de 50 l d'éthanol dans le THF (2ml), on obtient 34 mg (93%) du dérivé attendu sous forme d'une huile jaune.

1H NMR (CDCl3, 400MHz): 0.88 (3H, t), 1.22 (3H, t), 1.27 to 1.31 (8H, m), 1.52 to 1.59 (2H, m). ), 3.03 (2H, t), 3.44 (1H, NH, s), 3.54 (2H, s), 4.12 (2H, q), 6.45 (1H, Ar, d), 6.58 (1H, Ar, s), 6.65 (1H, Ar, d), 7.07 (1H, Ar, t), 7.11 (1H, Ar, t) , 7.21 (2H, Ar, d), 7.26 (1H, Ar, s).

b) F3- (3-Heptylamino-phenylsulfanyl) -phenyl-acetic acid Analogously to Example 3 (b), by reaction of ethyl [3- (3-heptylaminophenylsulfanyl) -phenyl] -acetate (40 mg 0.10 mmol), a 35% sodium hydroxide solution (100 l) and 50 l of ethanol in THF (2 ml) give 34 mg (93%) of the expected derivative in the form of a yellow oil. .

EXAMPLE 6 [3- (3-Butylamino-phenylsulfanyl) -phenyl-acetic acid a) [3- (3-butylamino-phenylsulfanyl) -phenyl-ethyl acetate Analogously to Example 3 (a), reaction of butyraldehyde (97.9 mg, 1.357 mmol), acetic acid (1 ml), ethyl [3- (3-aminophenylsulfanyl) -phenyl] acetate (Example 2 (a)) (390 1.36 mmol) in 15 ml of DMF and 170.54 mg of sodium cyanoborohydride (2.71 mmol) gives 319 mg (69%) of the expected derivative as a colorless oil.

b) Acide f3-(3-Butv)amino-phénvisu!fanv))-phénvi1-acétic)ue De manière analogue à l'exemple 3 (b), par réaction de [3-(3-Butylamino-phénylsulfanyl)phényl]-acétate d'éthyle (30 mg, 0.087 mmol), d'une solution de soude à 35% (100 l) et de 50 l d'éthanol dans le THF (2ml), on obtient 19 mg (89%) du dérivé attendu sous forme d'une huile jaune.

1 H NMR (CDCl 3, 400MHz): 0.91 (3H, t), 1.21 (3H, t), 1.32 to 1.42 (2H, m), 1.49 to 1.56 (2H, m.p. m), 3.02 (2H, t), 3.52 (3H, s), 4.11 (2H, q), 6.44 (1H, Ar, d), 6.57 (1H, Ar , s), 6.64 (1H, Ar, d), 7.06 (1H, Ar, t), 7.11 (1H, Ar, t), 7.18 (2H, Ar, d). 7.26 (1H, Ar, s).

(b) 3- (3-Butyl) amino-phenylsulfonyl) phenyl-acetic acid Analogous to Example 3 (b), by reaction of [3- (3-butylamino-phenylsulfanyl) phenyl] ethyl acetate (30 mg, 0.087 mmol), a 35% sodium hydroxide solution (100 l) and 50 l of ethanol in THF (2 ml) give 19 mg (89%) of the derivative. expected in the form of a yellow oil.

EXAMPLE 7: 3- (4-Heptylamino-phenylsulfanyl) -phenyl-acetic acid a) -3- (4-Heptylamino-phenylsulfanyl) -phenyl-ethyl acetate Analogously to Example 3 (a), by reaction of heptaldehyde (160.5 mg, 1.15 mmol), acetic acid (1 ml), ethyl [3- (4-aminophenylsulfanyl) -phenyl] -acetate

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 (Example 1b) (330 mg, 1.15 mmol) in 15 ml of DMF and 144. 5 mg of sodium cyanoborohydride (2.3 mmol) and addition of 160.5 μl of heptaldehyde after 4 hours of stirring, 343 mg (77%) are obtained of the expected derivative in the form of a colorless oil.

b) Acide f3-(4-Heptylamino-phénylsulfanyl)-phényll-acétiaue De manière analogue à l'exemple 3 (b), par réaction de [3-(4-Heptylaminophénylsulfanyl)-phényl]-acétate d'éthyle (45 mg, 0.12 mmol), d'une solution de soude à 35% (100 NI) et de 50 l d'éthanol dans le THF (2ml), on obtient 30 mg (72%) du dérivé attendu sous forme d'une huile jaune.

1H NMR (CDCl3, 400MHz): 0.88 (3H, t), 1.22 (3H, t), 1.28 to 1.41 (6H, m), 1.58 to 1.63 (2H, m.p. m), 3.10 (2H, t), 3.50 (2H, s), 4.11 (2H, q), 6.58 (2H, Ar, d), 6.98 (2H, Ar, t). ), 7.03 (1H, Ar, s), 7.13 (1H, Ar, t), 7.32 (2H, Ar, d)

b) 3- (4-Heptylamino-phenylsulfanyl) -phenyl-acetic acid Analogous to Example 3 (b), by reaction of ethyl [3- (4-heptylaminophenylsulfanyl) -phenyl] acetate (45 mg. 0.12 mmol), a 35% sodium hydroxide solution (100 Nl) and 50 l of ethanol in THF (2 ml) give 30 mg (72%) of the expected derivative in the form of a yellow oil. .

EXAMPLE 8: 3- (4-Butylamino-phenylsulfanyl) phenyl-acetic acid a) 3- (4-Butylamino-phenylsulfanyl) -phenyl-ethyl acetate Analogously to Example 3 (a), by reaction of butyraldehyde (103.6 mg, 1.15 mmol), acetic acid (1 ml), ethyl [3- (4-aminophenylsulfanyl) -phenyl] acetate (Example 1b) (330 mg, 1.15 mmol) in 1 ml of DMF and 144. 5 mg of sodium cyanoborohydride (2.71 mmol) give 223 mg (66%) of the expected derivative as a colorless oil.

b) Acide f3-(4-Butvlamino-phénvlsulfanvl)-phényll-acétique De manière analogue à l'exemple 3 (b), par réaction de [3-(4-Butylamino-phénylsulfanyl)phényl]-acétate d'éthyle (20 mg, 0.06 mmol), d'une solution de soude à 35% (100 NI) et de 50 l d'éthanol dans le THF (2ml), on obtient 19 mg (100%) du dérivé attendu sous forme d'une huile jaune.

1 H NMR (CDCl 3, 400MHz): 0.95 (3H, t), 1.21 (3H, t), 1.37 to 1.46 (2H, m), 1.55 to 1.63 (2H, m.p. m), 3.10 (2H, t), 3.49 (2H, s), 3.76 (1H, NH, s), 4.105 (2H, q), 6.56 (2H, Ar, d), 6.95 (2H, Ar, t), 7.03 (1H, Ar, s), 7.12 (1H, Ar, t), 7.30 (2H, Ar, d).

(b) 3- (4-Butylamino-phenylsulfanyl) -phenyl-acetic acid Analogous to Example 3 (b), by reaction of ethyl [3- (4-butylamino-phenylsulfanyl) phenyl] acetate ( mg, 0.06 mmol), a 35% sodium hydroxide solution (100 Nl) and 50 l of ethanol in THF (2 ml) give 19 mg (100%) of the expected derivative in the form of an oil. yellow.

EXAMPLE 9: 3- (4-Phenethylamino-phenylsulfanyl) -phenyl-acetic acid a) - (4-Phenethylamino-phenylsulfanyl) -phenyl-ethyl acetate Analogously to Example 3 (a), by reaction of phenylacetaldehyde (115 mg, 1. 15 mmol), acetic acid (1 ml), ethyl [3- (4-aminophenylsulfanyl) -phenyl] acetate (Example 1b) (330 mg, 1.15 mmol) in 15 ml of DMF and 120. 15 mg of sodium cyanoborohydridE (2. 3 mmol) and addition of 33.5 μl of phenylacetaldehyde after 4 h

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 stirring, 503 mg of the expected derivative and residual amine are obtained. The mixture is solubilized in 15 ml of DMF, and 400 mg of PS-benzaldehyde resin, acetic acid (1 ml) of sodium cyanoborohydride (58 mg) are added. The solution is stirred for 48 hours at room temperature. After extraction with ethyl ether, the organic phase is washed with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum.

The product is purified by filtration on a silica column (dichloromethane / heptane 2). After evaporation of the solvents, the expected compound 276 mg (34%) is isolated in the form of a yellow oil.

b) Acide r3-(4-Phénéthvlamino-phénvlsulfanvl)-phényll-acétiaue De manière analogue à l'exemple 3 (b), par réaction de [3-(4-Phénéthylaminophénylsulfanyl)-phényl]-acétate d'éthyle (24 mg, 0.06 mmol), d'une solution de soude à 35% (100 l) et de 50ul d'éthanol dans le THF (2ml), on obtient 18 mg (81%) du dérivé attendu sous forme d'une huile jaune.

1H NMR (CDCl3, 400MHz): 1.18 (3H, t), 2.86 (2H, t), 3.55 (2H, t), 3.47 (2H, s), 4.08 (2H, q), 6.53 (2H, Ar, d), 6.96 (2H, Ar, t), 7.03 (1H, Ar, s), 7.11 (1H, Ar, t), 7.17; to 7.22 (3H, Ar, m), 7.39 (4H, Ar, t)

b) 3- (4-Phenethylamino-phenylsulfanyl) -phenyl-acetic acid Analogous to Example 3 (b), by reaction of ethyl [3- (4-phenethylaminophenylsulfanyl) -phenyl] -acetate (24 mg. 0.06 mmol), a 35% sodium hydroxide solution (100 l) and 50 μl of ethanol in THF (2 ml) give 18 mg (81%) of the expected derivative in the form of a yellow oil.

EXAMPLE 10: D3-4- (3-Phenylpropylamino) -phenylsulfanyll-phenyl-acetic acid a) {3-r4- (3-phenyl-propylamino) -phenylsulfanyl-phenyl) -acetate acetate A suspension of molecular sieve ( 1 g), 3-phenylpropionaldehyde (280 mg, 2.1 mmol) in THF (5 ml) is added to a solution of ethyl [3- (4-aminophenylsulfanyl) phenyl] acetate (Example 1b) ( 500 mg, 1.74 mmol) in 20 ml of ethanol and 10 ml of THF. The mixture is stirred for 24 hours at room temperature. After filtration, 98.7 mg of sodium borohydride (2.71 mmol) are added to the filtrate. After stirring 24h and extraction with ethyl ether, the organic phase is washed with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum. The product is purified by chromatography on a silica column (dichloromethane 7 / heptane 3). After evaporation of the solvents, the expected compound is isolated in the form of a yellow oil.

b) Acide {3-r4-(3-Phénv!-propv!amino)-phénv)suifanvi1-phény!}-acétiQue De manière analogue à l'exemple 3 (b), par réaction de {3-[4-(3-Phényl-propylamino)- phénylsulfanyl]-phényl}- acétate d'éthyle (30 mg, 0.07 mmol), d'une solution de soude à 1 H NMR (CDCl 3, 400MHz): 1.21 (3H, t), 1.91 to 1.98 (2H, m), 2.72 (2H, t), 3.14 (2H, t), 3; , 49 (2H, s), 4.06 to 4.13 (2H, m), 6.527 (2H, Ar, d), 7.00 (2H, Ar, t), 7.03 (1H, Ar, s). ), 7.13 (1H, Ar, t), 7.18 to 7.29 (3H, Ar, m), 7.27 to 7.31 (4H, Ar, m).

b) {3- [4- (3-Phenylpropylamino) phenyl] sulfanyl] phenyl} acetic acid Analogously to Example 3 (b), by reaction of {3- [4- ( 3-Phenyl-propylamino) phenylsulfanyl] -phenyl} -acetate (30 mg, 0.07 mmol) of a sodium hydroxide solution.

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 35% (100 NI) and 50 l of ethanol in THF (2 ml) gives 22 mg (96%) of the expected derivative as a yellow oil.

Table 1: Product Analysis Results of Examples 1-10

<Tb>
<tb> EXAMPLE <SEP> HPLC <SEP> Spectrometry <SEP> of <SEP> Mass
<tb> (% <SEP> total <SEP> of <SEP> the area) <SEP> (ES) <SEP> (M + H +)
<tb> 1b <SEP> 92 <SEP> 260 <SEP>
<tb> 2b <SEP> 97 <SEP> 260 <SEP>
<tb> 3b <SEP> 87 <SEP> 364 <SEP>
<tb> 4b <SEP> 92 <SEP> 378 <SEP>
<tb> 5b <SEP> 93 <SEP> 358 <SEP>
<tb> 6b <SEP> 89 <SEP> 315 <SEP>
<tb> 7b <SEP> 90 <SEP> 358 <SEP>
<tb> 8b <SEP> 95 <SEP> 316 <SEP>
<tb> 9b <SEP> 89 <SEP> 364 <SEP>
<tb> 10b <SEP> 96 <SEP> 378
<Tb>
EXAMPLES 11 TO 20: SYNTHESIS OF COMPOUNDS 11 TO 20 Examples 11 to 20 were obtained by parallel chemistry. The reactions of a starting amine and a starting isocyanate are carried out in several reactors simultaneously according to the operating procedure described below.

Protocole opératoire : 0. 123 mmol, (50mg) de {3-[4-(3-Phényl-propylamino)-phénylsulfanyl]-phényl}-acétate d'éthyle (composé de l'exemple 10a) est introduit dans chaque réacteur de 5ml. 2ml de A. Formation of Urea for Ethyl {3- [4- (3-Phenyl-propylamino) -phenylsulfanyl] phenyl} -acetate (Compound of Example 10a)

Operating protocol: 0. 123 mmol, (50 mg) of ethyl {3- [4- (3-phenyl-propylamino) -phenylsulfanyl] -phenyl} -acetate (compound of Example 10a) is introduced into each reaction vessel. 5ml. 2ml of

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 dichloromethane are added. Then 0.247 mmol of the isocyanate (see Table 2) are added. The reactors are stirred for 7 hours at room temperature. 0.247 mmol of isocyanates are added if the starting amine has not completely disappeared (TLC control). In this case stirring is continued for 12 hours at room temperature.

The reaction media are concentrated to dryness, 2 h at 40 ° C., in the vacuum evaporator. The products are purified by filtration on silica cartridges (6ml), 1: DCM, 2: DCM 80 / AcOEt 20, then concentrated to dryness, 2h at 40 ° C on the centrifugal evaporator (see Table 3 for the quantities obtained).

CHEMISTRY Structure MW n (mmol) Mole m (mg)X2 2éq équivalent PHÉNÉTHYL 147.18 0.247 2X2 36.2 ISOCYANATE 0 1 I ''1 BENZYL 133.15 0.247 2X2 32.99 ISOCYANATE 0 -: 133'15 '247 CYCLOHEXYL / N 125.17 0.247 2X2 30.92 ISOCYANATE O ISOCYANATE 0 99.13 0.247 2X2 24.49 HEXYL ISOCYANATE /'... o 127.19 0.247 2X2 31.42 Tableau 3 : Quantités obtenues

Table 2: Starting Isocyanates

CHEMISTRY Structure MW n (mmol) Mole m (mg) X2 2equivalent PHENETHYL 147.18 0.247 2X2 36.2 ISOCYANATE 0 1 I '' 1 BENZYL 133.15 0.247 2X2 32.99 ISOCYANATE 0 -: 133'15 '247 CYCLOHEXYL / N 125.17 0.247 2X2 30.92 ISOCYANATE O ISOCYANATE 0 99.13 0.247 2X2 24.49 HEXYL ISOCYANATE / '... o 127.19 0.247 2X2 31.42 Table 3: Quantities obtained

<Tb>
<tb> Example <SEP> Name <SEP> isocyanate <SEP> Quantity
<tb> isocyanate
<Tb>

11a (3-{4-[3-Phénéthyl-1-(3-phényl- phénéthyl isocyanate 52

11a (3- {4- [3-Phenethyl-1- (3-phenylphenethyl) isocyanate

<Tb>
<tb> propyl) -ureido] -phenylsulfanyl} phenyl) -acetate <SEP> of ethyl
<tb> 12a <SEP> (3- {4- [3-Benzyl-1- (3-phenyl-propyl) - <SEP> benzyl <SEP> isocyanate <SEP> 67
<Tb>

uréidoJ-phénylsulfanyl}-phényl)-

uréidoJ-phenylsulfanyl} phenyl) -

<Tb>
<tb> acetate <SEP> of ethyl
<tb> 13a <SEP> (3- {4- [3-Cyclohexyl-1- (3-phenyl) <SEP> cyclohexyl <SEP> isocyanate <SEP> 34
<tb> propyl) -ureido] -phenylsulfanyl} phenyl
<tb>) -acetate <SEP> of ethyl
<tb> 14a <SEP> (3- {4- [3-Butyl-1- (3-phenyl-propyl) - <SEP> n-butyl <SEP> isocyanate <SEP> 28
<tb> ureido] -phenylsulfanyl} -phenyl) acetate <SEP> of ethyl
<tb> 15a <SEP> (3- {4- [3-Hexyl-1- (3-phenyl-propyl) - <SEP> hexyl <SEP> isocyanate <SEP> 52
<tb> ureido] -phenylsulfanyl} -phenyl) -
<tb> ~~~~~~~ <SEP> acetate <SEP> ethyl <SEP> ~~~~~
<Tb>

<Desc / Clms Page number 24>

Protocole opératoire : 0. 128 mmol, (50mg) de [3-(4-Phénéthylamino-phénylsulfanyl)-phényl]-acétate d'éthyle (composé de l'exemple 9a) est introduit dans chaque réacteur de 5ml. 2ml de dichlorométhane sont additionnés. Puis 0.255 mmol de l'isocyanate (voir tableau 4) sont additionnés. Les réacteurs sont agités 7h à température ambiante. 0.255 mmol d'isocyanates sont ajoutés si l'amine de départ n'a pas totalement disparue (contrôle CCM). Dans ce cas l'agitation est poursuivie 12 h à température ambiante. B. Formation of Urea for Ethyl 3- (4-Phenethylamino-phenylsulfanyl) -phenyl] Acetate (Compound of Example 9a)

Operating Procedure: 0. 128 mmol, (50 mg) of ethyl [3- (4-phenethylamino-phenylsulfanyl) -phenyl] -acetate (compound of Example 9a) is introduced into each 5 ml reactor. 2ml of dichloromethane are added. Then 0.255 mmol of the isocyanate (see Table 4) are added. The reactors are stirred for 7 hours at room temperature. 0.255 mmol of isocyanates are added if the starting amine has not completely disappeared (TLC control). In this case stirring is continued for 12 hours at room temperature.

The reaction media are concentrated to dryness, 2 h at 40 ° C., in the vacuum evaporator. The products are purified by filtration on silica cartridges (6ml), 1: DCM, 2: DCM 80 / AcOEt 20, then concentrated to dryness, 2h at 40 ° C on the centrifugal evaporator (see Table 5 for the quantities obtained).

chemistry Structure MW n (mmol) Mole m (mg)X2 2éq équivalent phénéthyl isocyanate 0 -1 11 147.18 0.255 2X2 37.53 ,l\ N -o benzyl isocyanate N r\ 133.15 0.255 2X2 31.5 0 cyclohexyl isocyanate 11/1,N 125.17 0.255 2X2 32.57 |U l| | l Table 4: Starting Isocyanate

Chemistry Structure MW n (mmol) Mole m (mg) X2 2 equivalent phenethyl isocyanate 0-1 11 147.18 0.255 2X2 37.53, 1 N -o benzyl isocyanate Nr 133.15 0.255 2X2 31.5 0 cyclohexyl isocyanate 11/1, N 125.17 0.255 2X2 32.57 | U l | | l

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n-butyl isocyanate "Il/N 99.13 0.255 2X2 28.73 o hexyl isocyanate N/ 0 127.19 0.255 2X2 37.15 Tableau 5 :quantités obtenues

n-butyl isocyanate "II / N 99.13 0.255 2X2 28.73 o hexyl isocyanate N / 0 127.19 0.255 2X2 37.15 Table 5: Quantities obtained

<Tb>
<tb> Example <SEP> Name <SEP> isocyanate <SEP> Quantity
<tb> 16a <SEP> {3- [4- (1,3-Diphenethyl-ureido) - <SEP> phenethyl <SEP> 52
<tb> phenylsulfanyl] -phenyl} -acetate <SEP> isocyanate
<tb> ethyl
<tb> 17a <SEP> {3- [4- (3-Benzyl-1-phenethyl) <SEP> benzyl <SEP> isocyanate <SEP> 67
<Tb>

ureido)-phénylsulfanyl]-phényl}-

ureido) phenylsulfanyl] phenyl} -

<Tb>
<tb> acetate <SEP> of ethyl
<tb> 18a <SEP> {3- [4- (3-Cyclohexyl-1-phenethyl) <SEP> cyclohexyl <SEP> 45
<tb> ureido) -phenylsulfanyl] -phenyl} - <SEP> isocyanate
<tb> acetate <SEP> of ethyl
<tb> 19a <SEP> {3- [4- (3-Butyl-1-phenethyl-ureido) - <SEP> n-butyl <SEP> isocyanate <SEP> 47
<Tb>

phénylsulfanyl]-phényl}-acétate

phenylsulfanyl] phenyl} acetate

<Tb>
<tb> ethyl
<tb> 20a <SEP> {3- [4- (3-Hexyl-1-phenethyl-ureido) - <SEP> hexyl <SEP> isocyanate <SEP> 46
<Tb>

phénylsulfanylJ-phényl}-acétate

phénylsulfanylJ-phenyl} -acetate

Les esters obtenus précédemment (exemple 11a à 20a des tableaux 3 et 5) sont solubilisés dans 2 ml de THF. 100 l d'éthanol sont introduits. 100 l d'une solution de soude à 35% est ensuite ajoutée. Le mélange est agité à température ambiante 48 heures. L'avancement de la réaction est contrôlé par chromatographie sur couche mince (DCM 80/ AcOEt 20). Après extraction à l'éther, acidification avec une solution d'acide chlorhydrique 1 N, la phase organique est lavée 2 fois a l'eau, séchée sur sulfate de magnésium et concentrée à sec, à l'évaporateur centrifuge sous vide. Les produits sont purifiés par filtration sur cartouches de silices (6ml) si nécessaire, puis concentrés à sec, 2h à 40 C à l'évaporateur centrifuge sous vide. Les produits finaux sont analysés par HPLC couplée Masse (Tableau 6). <Tb>
<tb> ethyl
<Tb>
C. Saponification

The esters obtained previously (example 11a to 20a of Tables 3 and 5) are solubilized in 2 ml of THF. 100 l of ethanol are introduced. 100 l of a 35% sodium hydroxide solution is then added. The mixture is stirred at room temperature for 48 hours. The progress of the reaction is monitored by thin layer chromatography (DCM 80 / AcOEt 20). After extraction with ether, acidification with a 1N hydrochloric acid solution, the organic phase is washed twice with water, dried over magnesium sulphate and concentrated to dryness, using a vacuum centrifugal evaporator. The products are purified by filtration on silica cartridges (6ml) if necessary, then concentrated to dryness, 2h at 40 ° C in the vacuum centrifugal evaporator. The final products are analyzed by coupled HPLC Mass (Table 6).

Table 6: Product Analyzes of Examples 11b to 20b

<Desc / Clms Page number 26>

<Tb>
<tb> Example <SEP> Name <SEP> Ester <SEP> of <SEP> Start <SEP> Quantity <SEP> MW <SEP> HPLC <SEP> MASS
<tb> (mg) <SEP> (% <SEP> ES
<tb> total <SEP> (M + H +)
<tb>
<tb> the area)
<tb> 11b <SEP><SEP> Acid (3- {4- [3-Phenethyl-1- <SEP> (3- {4- [3-Phenethyl-1- (3- <SEP> 45 <SEP>) 524. <SEP> 68 <SEP> 95 <SEP> 525
(3-phenyl-propyl) -ureido] - (SEP) phenyl-propyl) -ureido] phenylsulfanyl} -phenyl) - (SEP) phenylsulfanyl} -phenyl) acetic acid <SEP> acetate <SEP> of ethyl
<tb> 12b <SEP><SEP> Acid (3- {4- [3-Benzyl-1- (3- <SEP> (3- {4- [3-Benzyl-1- (3-phenyl- <SEP > 57 <SEP> 510. <SEP> 66 <SEP> 96 <SEP> 511
<tb> phenyl-propyl) -ureido] - (SEP) propyl) -ureido] phenylsulfanyl} -phenyl) - (SEP) phenylsulfanyl} -phenyl) acetic acid <SEP> acetate <SEP> of ethyl
<tb> 13b <SEP><SEP> Acid (3- {4- [3-Cyclohexyl- <SEP> (3- {4- [3-cyclohexyl-1- (3- <SEP> 33 <SEP> 502. <SEP> 68 <SEP> 93 <SEP> 503
1- (3-phenyl-propyl) -ureido] - (SEP-phenyl-propyl) -ureido] phenylsulfanyl} phenyl) - (SEP) phenylsulfanyl) -phenyl) acetic acid SEP-acetate ethyl
<tb> 14b <SEP><SEP> Acid (3- {4- [3-Butyl-1- (3- <SEP> (3- {4- [3-Butyl-1- (3-phenyl-)] SEP > 23 <SEP> 476. <SEP> 64 <SEP> 93 <SEP> 477
<tb> phenyl-propyl) -Ureido] - (SEP) propyl) -ureido] phenylsulfanyl} -phenyl) - (SEP) phenylsulfanyl} -phenyl) acetic acid <SEP> acetate <SEP>
<tb> 15b <SEP><SEP> Acid (3- {4- [3-Hexyl-1- (3- <SEP> (3- {4- [3-Hexyl-1- (3-phenyl- <SEP) > 41 <SEP> 504. <SEP> 70 <SEP> 94 <SEP> 505
<tb> phenyl-propyl) -Ureido] - (SEP) propyl) -ureido] phenylsulfanyl} -phenyl) - (SEP) phenylsulfanyl} -phenyl) acetic acid <SEP> acetate <SEP>
<tb> 16b <SEP><SEP> {3- [4- (1,3- <SEP> {3- [4- (1,3-Diphenethyl) - <SEP> 39 <SEP> 510. <SEP> 66 <SEP> 94 <SEP> 511
<tb> diphenethyl-ureido) - (SEP) ureido) -phenylsulfanyl] phenylsulfanyl] phenyl} - SEP> phenyl} -acetate <SEP> ethyl
<tb> acetic
<tb> 17b <SEP><SEP> {3- [4- (3-Benzyl-1- <SEP> {3- [4- (3-Benzyl-1 <SEP> 52 <SEP> 496. SEP> 63 <SEP> 95 <SEP> 497
Phenethyl-ureido) Phenethyl-ureido phenylsulfanyl-phenyl-SEP-phenylsulfanyl-phenyl-acetic ethyl-SEP-acetate
<tb> 18b <SEP><SEP> {3- [4- (3-cyclohexyl-1- <SEP> {3- [4- (3-cyclohexyl-1- <SEP> 38 <SEP> 488. SEP> 65 <SEP> 91 <SEP> 489
Phenethyl urea) phenylsulfanyl phenylsulfanyl] phenyl} SEP phenylsulfanyl] phenyl} acetic acid SEP ethyl acetate <SEP>
<tb> 19b <SEP><SEP> {3- [4- (3-Butyl-1- <SEP> {3- [4- (3-Butyl-1-phenethyl)} - SEP> 37 <SEP> 462 <SEP> 62 <SEP> 93 <SEP> 463
<tb> Phenethyl-ureido) - <SEP> ureido) -phenylsulfanyl] phenylsulfanyl] -phenyl} - <SEP> phenyl} -acetate <SEP> of ethyl
<tb> acetic
<tb> 20b <SEP><SEP> {3- [4- (3-Hexyl-1- <SEP> {3- [4- (3-Hexyl-1-phenethyl)} - SEP> 36 <SEP> 490 <SEP> 67 <SEP> 95 <SEP> 491
Phenethyl-ureido) SEP-ureido phenylsulfanyl-phenyl-SEP-phenylsulfanyl-phenyl-acetic ethyl-SEP-ethyl acetate
<Tb>
EXAMPLES 21 TO 50: SYNTHESIS OF COMPOUNDS 21 TO 50 Examples 21 to 50 were obtained by parallel chemistry. The reactions of a starting amine and a starting isocyanate are carried out in several reactors simultaneously according to the operating procedure described below.

<Desc / Clms Page number 27>

Protocole opératoire : 0. 077 mmol d'amine (voir tableau 7) est introduite dans chaque réacteur de 5ml. 2ml de dichlorométhane sont additionnés. Puis 0.153 mmol de l'isocyanate (voir tableau 8) sont additionnés. Les réacteurs sont agités 7h à température ambiante. 0.062 mmol d'isocyanates sont ajoutés si l'amine de départ n'a pas totalement disparue (contrôle CCM). Dans ce cas l'agitation est poursuivie 12 h à température ambiante. A. Urea formation for [3- (Amino-phenylsulfanyl) -phenyl] -ethyl acetate derivatives

Operating protocol: 0. 077 mmol of amine (see Table 7) is introduced into each 5 ml reactor. 2ml of dichloromethane are added. Then 0.153 mmol of the isocyanate (see Table 8) are added. The reactors are stirred for 7 hours at room temperature. 0.062 mmol of isocyanates are added if the starting amine has not completely disappeared (TLC control). In this case stirring is continued for 12 hours at room temperature.

The reaction media are concentrated to dryness, 2 h at 40 ° C., in the vacuum evaporator. The products are purified by filtration on silica cartridges (6ml), 1: DCM, 2: DCM 80 / AcOEt 20, then concentrated to dryness, 2h at 40 ° C on the centrifugal evaporator.

Table 7: Starting Amines

<Tb>
<tb> N <SEP> example <SEP> Name <SEP> Mass <SEP> Number <SEP> of <SEP> Quantity
<tb> molar <SEP> mole <SEP> (mmol) <SEP> reactor <SEP> mg
<tb> 7a <SEP> [3- (4-Heptylamino-phenylsulfanyl) <SEP> -phenyl] - <SEP> 385. <SEP> 57 <SEP> 0. <SEP> 0766 <SEP> 29.53
<tb> acetate <SEP> of ethyl
<tb> 8a <SEP> [3- (4-Butylamino-phenylsulfanyl) -phenyl] - <SEP> 343. <SEP> 49 <SEP> 0. <SEP> 0766 <SEP> 26. <SEP> 31
<tb> acetate <SEP> of ethyl
<tb> 3a <SEP> [3- (3-Phenethylamino-phenylsulfanyl) - <SEP> 391. <SEP> 53 <SEP> 0. <SEP> 0766 <SEP> 29. <SEP> 99
<tb> phenyl] -acetate <SEP> of ethyl
<tb> 4a <SEP> {3- [3- (3-Phenylpropylamino) - <SEP> 405. <SEP> 56 <SEP> 0. <SEP> 0766 <SEP> 31. <SEP> 07
<tb> Phenylsulfanyl] -phenyl} -acetate <SEP> of ethyl
<tb> 5a <SEP> [3- (3-Heptylamino-phenylsulfanyl) <SEP> -phenyl] - <SEP> 385. <SEP> 57 <SEP> 0. <SEP> 0766 <SEP> 29.53
<tb> acetate <SEP> of ethyl
<tb> 6a <SEP> [3- (3-Butylamino-phenylsulfanyl) -phenyl] - <SEP> 343. <SEP> 49 <SEP> 0. <SEP> 0766 <SEP> 26. <SEP> 31
<tb> acetate <SEP> of ethyl
<Tb>
Table 8: Starting Isocyanates

<Tb>
<tb> CHEMISTRY <SEP> Structure <SEP> MW <SEP> N <SEP> Mole <SEP> m
<tb> (mmol) <SEP> equivalent <SEP> (mg) <SEP> X2
<tb> 2q
<Tb>

<Desc / Clms Page number 28>

Chacun des esters obtenus précédemment est solubilisé dans 2 ml de THF. 100ul d'éthanol sont ensuite introduits. 100 l d'une solution de soude à 35% est ensuite ajoutée. Le mélange est agité à température ambiante 48 h. L'avancement de la réaction est contrôlé par chromatographie sur couche mince (DCM 801 AcOEt 20). Après extraction à l'éther, acidification avec une solution d'acide chlorhydrique 1N, la phase organique est lavée 2 fois a l'eau, séchée sur sulfate de magnésium et concentrée à sec, à l'évaporateur centrifuge sous vide. Les produits sont purifiés par filtration sur cartouches de silices (6ml) si nécessaire, puis concentrés à sec, 2h à 40 C à l'évaporateur centrifuge sous vide. Les produits finaux sont analysés par HPLC couplée Masse (Tableau 9). <Tb>
<tb> PHENETHYL <SEP> 147. <SEP> 18 <SEP> 0. <SEP> 153 <SEP> 2 <SEP> 22.5
<tb> ISOCYANATE
<tb># N #
<tb> BENZYL <SEP> N <SEP>#<SEP> 133. <SEP> 15 <SEP> 0. <SEP> 153 <SEP> 2 <SEP> 20.4
<tb> ISOCYANATE <SEP> O # <SEP>#
<tb> CYCLOHEXYL <SEP> N # <SEP> 125. <SEP> 17 <SEP> 0.153 <SEP> 2 <SEP> 19.2
<tb> ISOCYANATE <SEP> O # <SEP>#
<tb> N-BUTYL <SEP> N # <SEP> 99.13 <SEP> 0.153 <SEP> 2 <SEP> 15.2
<tb> ISOCYANATE <SEP> O
<tb> HEXYL <SEP> O <SEP> 127. <SEP> 19 <SEP> 0. <SEP> 153 <SEP> 2 <SEP> 19.5
<tb> ISOCYANATE <SEP># N #
<Tb>
B. Saponification

Each of the esters obtained above is solubilized in 2 ml of THF. 100ul of ethanol are then introduced. 100 l of a 35% sodium hydroxide solution is then added. The mixture is stirred at room temperature for 48 h. The progress of the reaction is monitored by thin layer chromatography (DCM 801 AcOEt 20). After extraction with ether, acidification with a 1N hydrochloric acid solution, the organic phase is washed twice with water, dried over magnesium sulphate and concentrated to dryness, using a vacuum centrifugal evaporator. The products are purified by filtration on silica cartridges (6ml) if necessary, then concentrated to dryness, 2h at 40 ° C in the vacuum centrifugal evaporator. The final products are analyzed by coupled HPLC Mass (Table 9).

Table 9: Product Analyzes of Examples 21b through 50b

<Desc / Clms Page number 29>

<Tb>
<tb> Example <SEP> product <SEP> of arrival <SEP> Substrate <SEP> Isocyanate <SEP> Quantity <SEP> MW <SEP> HPLC <SEP> MASS
<tb> Product <SEP> of arrival <SEP> Substrate <SEP> Isocyanate <SEP> Obtained <SEP> (% <SEP> total <SEP> ES
<tb> amine <SEP> mg <SEP> of <SEP> (M + H +)
<tb> the area)
<tb> 21b <SEP><SEP> {3- [4- (1-Heptyl-3 <SEP> 7a <SEP> Phenethyl] <SEP> 31 <SEP> 504. <SEP> 69 <SEP> 92 <SEP> 505
<tb> phenethyl ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} acetic acid
<tb> 22b <SEP><SEP> {3- [4- (1-Butyl-3- <SEP> 8a <SEP> Phenethyl) <SEP> 34 <SEP> 462. <SEP> 61 <SEP> 92 <SEP> 463
<tb> phenethyl-ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} acetic acid <SEP> ~~~~~~~~~~~~~~~~~
<tb> 23b <SEP><SEP> {3- [3- (1,3- <SEP> 3a <SEP> Phenethyl) acid <SEP> 38 <SEP> 510. <SEP> 66 <SEP> 87 <SEP> 511
<tb> Diphenethyl-ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} -
<Tb>

~~~~~ acétique ~~~~~~~~~~~~~~~~~~~ ~~~~ ~~~~~

~~~~~ acetic ~~~~~~~~~~~~~~~~~~~ ~~~~ ~~~~~

<Tb>
<tb> 24b <SEP><SEP> Acid (3- {3- [3-Phenethyl-1- <SEP> 4a <SEP> Phenethyl] <SEP> 41 <SEP> 524. <SEP> 68 <SEP> 86 <SEP> 525
<tb> (3-phenyl-propyl) -ureido] - <SEP> isocyanate
<tb> phenylsulfanyl} -phenyl) -
<tb> ~~~~~ <SEP> acetic acid <SEP> ~~~~~~~~ <SEP> ~~~~ <SEP> ~~~~~
<tb> 25b <SEP><SEP> {3- [3- (1-Heptyl-3- <SEP> 5a <SEP> Phenethyl) acid <SEP> 38 <SEP> 504. <SEP> 69 <SEP> 90 <SEP> 505
<tb> phenethyl-ureido) - <SEP> isocyanate
<tb> Phenylsulfanyl] -phenyl} acetic acid <SEP> ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
<tb> 26b <SEP><SEP> {3- [3- (1-Butyl-3- <SEP> 6a <SEP> Phenethyl) acid <SEP> 33 <SEP> 462. <SEP> 61 <SEP> 89 <SEP> 463
<tb> phenethyl-ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} -
<tb> @ <SEP> acetic <SEP> ~~~~~~~~~~~~~~~~~ SEP> ~~~~~~~~~~~~
<tb> 27b <SEP><SEP> {3- [4- (3-Benzyl-1- <SEP> 7a <SEP> Benzyl <SEP> 33 <SEP> 490. <SEP> 67 <SEP> 96 <SEP> 491
<tb> heptyl ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} acetic acid <SEP> ~~~~~~~~ <SEP> ~~~~ <SEP> ~~~~~
<tb> 28b <SEP><SEP> {3- [4- (3-Benzyl-1- <SEP> 8a <SEP> Benzyl <SEP> 32 <SEP> 448. <SEP> 58 <SEP> 95 <SEP> 449
<tb> butyl ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} acetic acid <SEP> ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
<tb> 29b <SEP><SEP> {3- [3- (3-Benzyl-1- <SEP> 3a <SEP> Benzyl <SEP> 35 <SEP> 496. <SEP> 63 <SEP> 91 <SEP> 497
<tb> phenethyl-ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} acetic acid <SEP> ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
<tb> 30b <SEP><SEP> Acid (3- {3- [3-Benzyl-1- (3- <SEP> 4a <SEP> Benzyl <SEP> 38 <SEP> 510. <SEP> 66 <SEP > 91 <SEP> 511
<tb> phenyl-propyl) -ureido] - <SEP> isocyanate
<tb> phenylsulfanyl} -phenyl) acetic acid <SEP> ~~~~~~~~~~~~~~~~~~~ <SEP> ~~~~~~~~~
<tb> 31b <SEP><SEP> {3- [3- (3-Benzyl-1- <SEP> 5a <SEP> Benzyl <SEP> 33 <SEP> 490. <SEP> 67 <SEP> 95 <SEP> 491
<tb> heptyl ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} acetic acid
<tb> 32b <SEP><SEP> {3- [3- (3-Benzyl-1- <SEP> 6a <SEP> Benzyl <SEP> 35 <SEP> 448.58 <SEP> 93 <SEP> 449
<tb> butyl ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} acetic acid <SEP> ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
<tb> 33b <SEP><SEP> {3- [4- (3-Cyclohexyl-)} SE <7><SEP> Cyclohexyl <SEP> 27 <SEP> 482. <SEP> 69 <SEP> 87 <SEP> 483
<tb> 1-heptyl-ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] <SEP> -phenyl} acetic acid
<Tb>

<Desc / Clms Page number 30>

<Tb>
<tb> 34b <SEP><SEP> {3- [4- (1-Butyl-3- <SEP> 8a <SEP> Cyclohexyl <SEP> 25 <SEP> 440. <SEP> 61 <SEP> 81 <SEP> 441
<tb> cyclohexyl-ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} acetic acid
<tb> 35b <SEP><SEP> {3- [3- (3-Cyclohexyl-)} SEP> 3a <SEP> Cyclohexyl <SEP> 36 <SEP> 488. <SEP> 65 <SEP> 85 <SEP> 489
<tb> 1-phenethyl-ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] <SEP> -phenyl} acetic acid
<tb> 36b <SEP><SEP> Acid (3- {3- [3-Cyclohexyl- <SEP> 4a <SEP> Cyclohexyl <SEP> 35 <SEP> 502. <SEP> 68 <SEP> 87 <SEP> 503
<tb> 1- (3-phenyl-propyl) -ureido] - <SEP> isocyanate
<tb> phenylsulfanyl} -phenyl) <SEP> acetic acid
<tb> 37b <SEP><SEP> {3- [3- (3-Cyclohexyl-)} SEP> 5a <SEP> Cyclohexyl <SEP> 27 <SEP> 482. <SEP> 69 <SEP> 80 <SEP> 483
<tb> 1-heptyl-ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} acetic acid
<tb> 38b <SEP><SEP> {3- [3- (1-Butyl-3- <SEP> 6a <SEP>) Cyclohexyl <SEP> 27 <SEP> 440. <SEP> 61 <SEP> 87 <SEP> 441
<tb> cyclohexyl-ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} -
<Tb>

~~~~~ acétique ~~~~ ~~~~~~~ ~~~~~ ~~~ ~~~~ ~~~~~

~~~~~ acetic ~~~~~~~~~~~ ~~~~~ ~~~ ~~~~ ~~~~~

<Tb>
<tb> 39b <SEP><SEP> {3- [4- (3-Butyl-1- <SEP> 7a <SEP> Butyl] acid <SEP> 24 <SEP> 456. <SEP> 65 <SEP> 82 <SEP> 457
<tb> heptyl ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} acetic acid <SEP> ~~~~~ <SEP> ~~~~~~~~~~~~
<tb> 40b <SEP><SEP> {3- [4- (1,3-Dibutyl) <SEP> 8a <SEP> Butyl <SEP> 21 <SEP> 414. <SEP> 57 <SEP> 78 <SEP> 415
<tb> ureido) -phenylsulfanyl] - <SEP> isocyanate
<Tb>

phényl}-acétique ~~~~~~~ ~~~~~ ~~~ ~~~~~~~~~

phenyl} -acetic ~~~~~~~~~~~~~~~~~~~~~~~~

<Tb>
<tb> 41 <SEP> b <SEP><SEP> {3- [3- (3-Butyl-1- <SEP> 3a <SEP> Butyl} acid>SEP> 29 <SEP> 462. <SEP> 61 <SEP> 83 <SEP> 463
<tb> phenethyl-ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} acetic acid <SEP> ~~~~ <SEP> ~~~~~~~ <SEP> ~~~~~ <SEP> ~~~ <SEP> ~~~~ <SEP> ~~~~~
<tb> 42b <SEP><SEP> Acid (3- {3- [3-Butyl-1- (3- <SEP> 4a <SEP> Butyl <SEP> 25 <SEP> 476. <SEP> 64 <SEP > 81 <SEP> 477
<tb> phenyl-propyl) -ureido] - <SEP> isocyanate
<tb> phenylsulfanyl} -phenyl) -
<tb> ~~~~~ <SEP> acetic acid <SEP> ~~~~~~~~ <SEP> ~~~~ <SEP> ~~~~~
<tb> 43b <SEP><SEP> {3- [3- (3-Butyl-1- <SEP> 5a <SEP> Butyl] acid <SEP> 22 <SEP> 456. <SEP> 65 <SEP> 75 <SEP> 457
<tb> heptyl ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} acetic acid <SEP> ~~~~~~~~~~~ <SEP> ~~~~~ <SEP> ~~~ <SEP> ~~~~ <SEP> ~~~ ~~
<tb> 44b <SEP><SEP> {3- [3- (1,3-Dibutyl- <SEP> 6a <SEP> Butyl] acid>SEP> 22 <SEP> 414. <SEP> 57 <SEP> 79 <SEP> 415
<tb> ureido) -phenylsulfanyl] - <SEP> isocyanate
<tb> phenyl} -acetic acid <SEP> ~~~~ <SEP> ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
<tb> 45b <SEP><SEP> {3- [4- (1-Heptyl-3- <SEP> 7a <SEP> Hexyl <SEP> 23 <SEP> 484. <SEP> 70 <SEP> 82 <SEP> 485
<tb> hexyl-ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} acetic acid <SEP> ~~~~~~~~~~~~ <SEP> ~~~~~
<tb> 46b <SEP><SEP> {3- [4- (1-Butyl-3- <SEP> 8a <SEP> Hexyl <SEP> 21 <SEP> 442. <SEP> 62 <SEP> 83 <SEP> 443
<tb> hexyl-ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} -
<tb> ~~~~~ <SEP> acetic acid <SEP> ~~~~~~~ <SEP> ~~~~~ <SEP> ~~~ <SEP> ~~~~ <SEP> ~~~~ ~
<tb> 47b <SEP><SEP> {3- [3- (3-Hexyl-1- <SEP> 3a <SEP> Hexyl <SEP> 30 <SEP> 490. <SEP> 67 <SEP> 83 <SEP> 491
<tb> phenethyl-ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} -
<tb> ~~~~~ <SEP> acetic acid <SEP> ~~~~ <SEP> ~~~~~
<Tb>

<Desc / Clms Page number 31>

<Tb>
<tb> 48b <SEP><SEP> Acid (3- {3- [3-Hexyl-1- (3- <SEP> 4a <SEP> Hexyl <SEP> 27 <SEP> 504.69 <SEP> 81 <SEP> 505
<tb> phenyl-propyl) -ureido] - <SEP> isocyanate
<tb> phenylsulfanyl} -phenyl) acetic
<tb> 49b <SEP><SEP> {3- [3- (1-Heptyl-3- <SEP> 5a <SEP> Hexyl <SEP> 29 <SEP> 484. <SEP> 70 <SEP> 82 <SEP> 485
<tb> hexyl-ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} -
<tb> ~~~~~ <SEP> acetic acid <SEP> ~~~~~~~~~~~~~~~~~~~~~~~~ SEP
<tb> 50b <SEP><SEP> {3- [3- (1-Butyl-3- <SEP> 6a <SEP> Hexyl <SEP> 24 <SEP> 442. <SEP> 62 <SEP> 78 <Acid SEP> 443
<tb> hexyl-ureido) - <SEP> isocyanate
<tb> phenylsulfanyl] -phenyl} acetic acid
<Tb>
Compounds 21a to 50a are esters corresponding to acids 21b to 50b prior to the saponification reaction.

EXAMPLE 51 Transactivation Cross-Curve Transactivation Test The activation of the receptors by an agonist (activator) in HeLN cells leads to the expression of a reporter gene, luciferase, which, in the presence of a substrate, generates light. The modulation of the receptors is measured by quantifying the luminescence produced after incubation of the cells in the presence of a reference agonist. The ligands will move the agonist from his site. The measurement of the activity is done by the quantification of the produced light. This measurement makes it possible to determine the modulating activity of the compounds according to the invention by determining the constant which represents the affinity of the molecule for the receptor. Since this value can fluctuate according to the basal activity and the expression of the receptor, it is denoted Kd apparent (KdApp in nM).

To determine this constant, cross-curves of the product to be tested against a reference agonist are made in 96-well plate: concentrations of the test product plus a concentration 0 are arranged in line, and 7 concentrations of the agonist plus a concentration of 0. are arranged in column. This represents 88 measurement points for 1 product and 1 receiver. The remaining 8 wells are used for repeatability checks.

4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenoxy}-acétique pour PPARS et le 5-{4-[2-(Methyl-pyridin-2-yl-amino)-ethoxy]-benzyl}-thiazolidine-2,4dione pour PPARy. Des mesures sont également réalisées pour les témoins agoniste total avec les mêmes produits. In each well, the cells are in contact with a concentration of the product to be tested and a concentration of the reference agonist, 2- (4- {2- [3- (2,4-Difluoro-phenyl)) - 1heptyl-ureido] -ethyl} -phenylsulfanyl) -2-methylpropionic acid for PPARα, {2-Methyl-

4- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethylsulfanyl] -phenoxy} -acetic acid for PPARS and 5- {4- [2- (Methyl-pyridin-2-yl-amino) ) -ethoxy] -benzyl} -thiazolidine-2,4dione for PPARy. Measurements are also made for total agonist controls with the same products.

<Desc / Clms Page number 32>

 The HeLN cell lines used are stable transfectants containing the ERE-pGlob-Luc-SV-Neo plasmids (reporter gene) and PPAR (α, 8, γ) Gal-hPPAR. These cells are seeded in 96-well plates at a rate of 10,000 cells per well in 100 l of DMEM medium without phenol red and supplemented with 10% of delipidated calf serum. The plates are then incubated at 37 ° C, 7% CO2 for 16 hours.

The different dilutions of the products to be tested and the reference ligand are added at the rate of 5 l per well. The plates are then incubated for 18 hours at 37 ° C., 7% CO 2.

The culture medium is removed by inversion and 100 l of a 1: 1 PBS / Luciferine mixture is added to each well. After 5 minutes, the plates are read by the luminescence reader.

These crossed curves make it possible to determine the AC50 (concentration at which one observes 50% activation) of the reference ligand at different concentrations of product to be tested. These AC50s are used to calculate the Schild regression by plotting a line corresponding to the Schild equation in receptor pharmacology (Terry P.Kenakin, Receptors and Channels, 2001, 7, 371-385) which leads to Kd app values (in nM).

Transactivation results:

<Tb>
<tb> PPAR <SEP> alpha <SEP> PPARs <SEP> delta <SEP> PPAR <SEP> gamma <SEP>
<tb> Compounds <SEP> Kd <SEP> app <SEP> (nM) <SEP> Kd <SEP> app <SEP> (in <SEP> nM) <SEP> Kd <SEP> app <SEP> (in <SEP> nM)
<tb> Reference <SEP> 1 <SEP>: <SEP> acid2- (4- {2- [3- (2,4- <SEP> 200 <SEP> na <SEP> na
<Tb>

Difluoro-phenyl) -1-heptyl-ureido] ethyl} phenylsulfanyl) -2-methylpropionic acid
<tb> Reference <SEP> 2 <SEP>: <SEP> acid {2-Methyl-4- [4- <SEP> na <SEP> 10 <SEP> na
methyl-2- (4-trifluoromethyl-phenyl) thiazol-5-ylmethylsulfanyl] -phenoxy} acetic acid
<tb> Reference <SEP> 3 <SEP>: <SEP> 5- {4- [2- (Methyl- <SEP> na <SEP> na <SEP> 30
<tb> pyridin-2-yl-amino) -ethoxy] -benzyl} thiazolidine-2,4-dione
<tb> Example <SEP> 18b <SEP> 250 <SEP> 15 <SEP> 30
<tb> Example <SEP> 25b <SEP> na <SEP> 60 <SEP> 500
<Tb>
Na means non-active EXAMPLE 52 - COMPOSITIONS In this example, various concrete formulations based on the compounds according to the invention have been illustrated.

<Desc / Clms Page number 33>

ORAL (a) Tablet of 0.2 g - Compound of Example 2b 0.001 g - Starch 0.114 g - Dicalcium phosphate 0.020 g - Silica 0.020 g - Lactose 0.030 g - Talc 0.010 g - Magnesium stearate 0.005 g ( b) Oral suspension in 5 ml ampoules - Compound of Example 7a 0.001 g - Glycerine 0.500 g - 70% sorbitol 0.500 g - Sodium saccharinate 0.010 g - Methyl parahydroxybenzoate 0.040 g - Aroma qs - Purified water qs5 ml ( c) 0.8 g tablet - Compound of Example 1 b 0.500 g - Pregelatinized starch 0.100 g - Microcrystalline cellulose 0.115 g - Lactose 0.075 g - Magnesium stearate 0.010 g (d) Oral suspension in 10 ml ampoules - Compound of Example 21 b 0.200 g - Glycerin 1.000 g - 70% sorbitol 1.000 g - Sodium saccharinate 0.010 g - Methyl parahydroxybenzoate 0.080 g - Aroma qs - Purified water qs 10 ml

<Desc / Clms Page number 34>

 B- TOPICAL ROUTE (a) Ointment - Compound of Example 42b 0.020 g - Isopropyl myristate 81.700 g - Fluid Vaseline oil 9.100 g - Silica ("Aerosil 200" sold by DEGUSSA) 9.180 g (b) Ointment - Compound of Example 37a 0.300 g - White Vaseline codex qs 100 g (c) Cream Water-in-Nonionic Oil - Compound of Example 19b 0.100 g - Mixture of lanolin alcohols emulsifiers, waxes and oils ( "Anhydrous Eucerin" sold by BDF) 39,900 g - Methyl parahydroxybenzoate 0.075 g - Propyl parahydroxybenzoate 0.075 g - Sterile demineralized water qs 100 g (d) Lotion - Compound of Example 7a 0.100 g - Polyethylene glycol (PEG 400) 69.900 g - 95% Ethanol 30,000 g (e) Hydrophobic Ointment - Compound of Example 16b 0.300 g - Isopropyl Miristate 36.400 g - Silicone Oil ("Rhodorsil 47 V 300" sold by RHONE-POULENC) 36.400 g - Wax of bee 13,600 g - Silicone oil ("Abil 300,000 cst" sold by GOLDSCHMIDT) qs 100 g (f) Non-ionic oil-in-water cream

<Desc / Clms Page number 35>

 - Compound of Example 31 b 1,000 g - Cetyl alcohol 4,000 g - Glycerol monostearate 2,500 g - PEG 50 stearate 2,500 g - Shea butter 9,200 g - Propylene glycol 2,000 g - Methyl parahydroxybenzoate 0,075 g - Propyl parahydroxybenzoate 0,075 g - Demineralized sterile water qs 100 g

Claims (21)

 in which - Ar1 represents an optionally substituted radical of formula:

 CLAIMS 1. Compounds characterized by the fact that they correspond to the following formula (I): R1 and Y having the meanings given below,  it being understood that Z is positioned in meta with respect to X on the cycle Ar1;

Z having the meaning given below, Z represents the substituent: <Desc / Clms Page number 37> R7 and R8 having the meanings given below, R 4 having the meanings given below, R 4 represents a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, a polyether radical, an aralkyl radical or forms with R 1 and the nitrogen atom of Y, a heterocycle or a heteroaryl; R 5 represents an aryl radical, a heteroaryl radical, an aralkyl radical, an alkyl radical having from 1 to 12 carbon atoms, a polyether radical, an alkoxy radical, a monohydroxyalkyl radical, a polyhydroxyalkyl radical or an R6-N-R7 radical; or an O-R8 radical; R5 having the meanings given below, Y represents an oxygen atom, sulfur or the radical N-R4;  R1 represents a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, an aralkyl radical, a polyether radical, a monohydroxyalkyl radical or a polyhydroxyalkyl radical; R2 represents a hydrogen atom, an alkyl radical having from 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, an aralkyl radical, a polyether radical, a monohydroxyalkyl radical or a polyhydroxyalkyl radical; - R3 represents a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, an aralkyl radical, a polyether radical, a monohydroxyalkyl radical, a polyhydroxyalkyl radical, a COR5 or CSR5 radical; ;

 Ar 2 represents an optionally substituted radical of formula: <Desc / Clms Page number 38> R13 having the meanings given below, - R12 represents an alkyl radical having 1 to 12 carbon atoms; - R13 represents a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, an aryl radical, a polyether radical, a heteroaryl radical, or an aralkyl radical; and the optical and geometric isomers of said compounds of formula (I) and their salts. R12 having the meanings given below, R10 and R11idental or different represent a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, an aralkyl radical, a monohydroxyalkyl radical, a polyhydroxyalkyl radical, a polyether radical, an alkoxy radical, or R10 and R11 taken together can form a ring optionally interrupted by hetero atoms; A represents an S, O or Se atom or an N-R13 radical; R9, R10 and R11 having the meanings given below, - R9 represents a hydrogen atom, a -COR12 radical, an alkyl radical having 1 to 12 carbon atoms, a polyether radical, an aryl radical or an aralkyl radical;  R 6 and R 7 may be identical or different and represent a hydrogen atom, an alkyl radical having from 1 to 12 carbon atoms, a monohydroxyalkyl radical, a polyhydroxyalkyl radical, a polyether radical, an aryl radical, a heteroaryl radical, a aralkyl radical or taken together form a heterocycle; - R8 represents a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, a monohydroxyalkyl radical, a polyhydroxyalkyl radical, a polyether radical, an aryl radical, a heteroaryl radical, or an aralkyl radical; X represents an S atom, an S = O radical, an O = S = O radical, a Se atom, an O atom, an N-R9 radical, a C = O radical or an HO-C radical; -R11 or an R10-CR11 radical; <Desc / Clms Page number 39> 2. Compounds according to claim 1, characterized in that they are in the form of salts of an alkali metal or alkaline earth metal, zinc salts, or salts of an organic amine. 3. Compounds according to claim 1 or 2, characterized in that the alkyl radicals having 1 to 12 carbon atoms are chosen from a radical containing 1 to 12 carbon atoms, hydrogenated or fluoro, linear or cyclic, optionally branched, which can be interrupted by one or more heteroatoms, and preferably alkyl radicals having 1 to 12 carbon atoms are methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, octyl, decyl, or cyclohexyl radicals. 4. Compounds according to one of claims 1 to 3, characterized in that the monohydroxyalkyl radicals are chosen from radicals 5. Compounds according to one of claims 1 to 4, characterized in that the polyhydroxyalkyl radicals are chosen from radicals 6. Compounds according to any one of the preceding claims, characterized in that the polyether radicals are chosen from polyethers radicals having from 1 to 6 carbon atoms interrupted by at least one oxygen atom such as the methoxymethoxy, ethoxymethoxy radicals. or methoxyethoxymethoxy. 7. Compounds according to any one of the preceding claims, characterized in that the alkoxy radical having 1 to 7 carbon atoms is selected from the group consisting of methoxy, ethoxy, isopropyloxy, tert-butoxy, hexyloxy, benzyloxy radicals. or phenoxy, which may be optionally substituted by an alkyl radical having 1 to 12 carbon atoms. 8. Compounds according to any one of the preceding claims, characterized in that the aryl radical is chosen from a phenyl, biphenyl, cinnamyl or naphthyl radical which may be mono- or disubstituted by a halogen atom, a CF 3 radical, an alkyl radical having 1 to 12 carbon atoms, an alkoxy radical having 1 to 7 carbon atoms, a nitro functional group, a polyether radical, an aryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl radical optionally protected by an acetyl, benzoyl or amino group <Desc / Clms Page number 40>  optionally protected by an acetyl, benzoyl group or optionally substituted by at least one alkyl having from 1 to 12 carbon atoms. 9. Compounds according to any one of the preceding claims, characterized in that the aralkyl radical is chosen from a benzyl, phenethyl or naphthalen-2ylmethyl radical which may be mono- or disubstituted by a halogen atom, a CF 3 radical, an alkyl radical having 1 to 12 carbon atoms, an alkoxy radical having 1 to 7 carbon atoms, a nitro functional group, a polyether radical, an aryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl radical optionally protected by an acetyl, benzoyl or an amino group optionally protected by an acetyl, benzoyl group or optionally substituted with at least one alkyl having from 1 to 12 carbon atoms. 10. Compounds according to any one of the preceding claims, characterized in that the heteroaryl radical is chosen from the group consisting of an aryl radical interrupted by one or more heteroatoms, such as the pyridyl, furyl, thienyl, isoxazolyl or oxadiazolyl radical, oxazolyl, isothiazolyl, quinozalinyl, benzothiadiazolyl, benzimidazole, indolyl, benzofuran, optionally substituted by at least one halogen, an alkyl having 1 to 12 carbon atoms, an alkoxy having 1 to 7 carbon atoms, an aryl radical, a nitro, a polyether radical, a heteroaryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl optionally protected with an acetyl, benzoyl group or an amino function optionally protected by an acetyl, benzoyl or optionally substituted by less an alkyl having 1 to 12 carbon atoms. 11. Compounds according to any one of the preceding claims, characterized in that the heterocyclic radical is chosen from the group consisting of a morpholino, piperidino, piperazino, 2-oxo-piperidin-1-yl and 2-oxo-pyrrolidine radical. -1-yl, optionally substituted with at least one alkyl having 1 to 12 carbon atoms, an alkoxy having 1 to 7 carbon atoms, an aryl radical, a nitro functional group, a polyether radical, a heteroaryl radical, a radical benzoyl, an alkyl ester group, a carboxylic acid, a hydroxyl optionally protected with an acetyl group, benzoyl or an amino function optionally protected with an acetyl, benzoyl group or optionally substituted with at least one alkyl having from 1 to 12 carbon atoms. <Desc / Clms Page number 41>  13a. Ethyl 3- {4- [3-cyclohexyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetate 13b. (3- {4- [3-Cyclohexyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid 14a. Ethyl 3- {4- [3-butyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetate 14b. (3- {4- [3-Butyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid 15a. Ethyl (3- {4- [3-hexyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetate 15b. (3- {4- [3-hexyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid

 9a. Ethyl 3- (4-phenethylamino-phenylsulfanyl) -phenyl] -acetate 9b. [3- (4-Phenethylamino-phenylsulfanyl) -phenyl] -acetic acid 10a. Ethyl {3- [4- (3-phenylpropylamino) phenylsulfanyl] phenyl} -acetate 10b. {3- [4- (3-phenyl-propylamino) -phenylsulfanyl] -phenyl} -acetic acid 11a. Ethyl (3- {4- [3-phenethyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetate 11b. (3- {4- [3-Phenethyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid 12a. Ethyl 3- {4- [3-Benzyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetate 12b. (3- {4- [3-Benzyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid

 12. Compounds according to claim 1, characterized in that they are taken, alone or in mixtures, from the group consisting of: 1 b. [3- (4-Amino-phenylsulfanyl) -phenyl] ethyl acetate 1c. [3- (4-Amino-phenylsulfanyl) -phenyl] -acetic acid 2a. [3- (3-Amino-phenylsulfanyl) -phenyl] -acetate ethyl 2b. [3- (3-Amino-phenylsulfanyl) -phenyl] -acetic acid 3a. Ethyl 3- (3-phenethylamino-phenylsulfanyl) -phenyl] -acetate 3b. [3- (3-Phenethylamino-phenylsulfanyl) -phenyl] -acetic acid 4a. Ethyl 3- [3- (3-phenyl-propylamino) -phenylsulfanyl] -phenyl} -acetate 4b. {3- [3- (3-phenyl-propylamino) -phenylsulfanyl] -phenyl} -acetic acid 5a. Ethyl 3- (3-heptylamino-phenylsulfanyl) -phenyl] -acetate 5b. [3- (3-Heptylamino-phenylsulfanyl) -phenyl] -acetic acid 6a. Ethyl 3- (3-butylamino-phenylsulfanyl) -phenyl] -acetate 6b. [3- (3-Butylamino-phenylsulfanyl) -phenyl] -acetic acid 7a. Ethyl 3- (4-heptylamino-phenylsulfanyl) -phenyl] -acetate 7b. [3- (4-Heptylamino-phenylsulfanyl) -phenyl] -acetic acid 8a. Ethyl 3- (4-butylamino-phenylsulfanyl) -phenyl] -acetate 8b. [3- (4-Butylamino-phenylsulfanyl) -phenyl] -acetic acid <Desc / Clms Page number 42>  27b. {3- [4- (3-Benzyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 28a. {3- [4- (3-Benzyl-1-butylureido) -phenylsulfanyl] -phenyl} -ethyl acetate 28b. {3- [4- (3-Benzyl-1-butylureido) -phenylsulfanyl] -phenyl} -acetic acid 29a. {3- [3- (3-Benzyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 29b. {3- [3- (3-Benzyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 30a. (3- {3- [3-Benzyl-1- (3-phenyl-propyl) -ureido] -phenyl-sulfanyl} -phenyl) -ethyl acetate 30b. (3- {3- [3-Benzyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid a. {3- [3- (3-Benzyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 31 b. {3- [3- (3-Benzyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 32a. {3- [3- (3-Benzyl-1-butylureido) -phenylsulfanyl] -phenyl} -ethyl acetate 32b. {3- [3- (3-Benzyl-1-butylureido) -phenylsulfanyl] -phenyl} -acetic acid

 26a. {3- [3- (1-Butyl-3-phenethyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 26b. {3- [3- (1-Butyl-3-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 27a. {3- [4- (3-Benzyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate

 23a. {3- [3- (1,3-diphenethyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 23b. {3- [3- (1,3-Diphenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 24a. (3- {3- [3-phenethyl-1- (3-phenyl-propyl) -ureido] -phenyl-sulfanyl} -phenyl) -ethyl acetate 24b. (3- {3- [3-Phenethyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid 25a. {3- [3- (1-heptyl-3-phenethyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 25b. {3- [3- (1-heptyl-3-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid

 19b. {3- [4- (3-Butyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl) -acetic acid 20a. Ethyl {3- [4- (3-hexyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetate 20b. {3- [4- (3-hexyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 21a. Ethyl {3- [4- (1-heptyl-3-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetate 21b. {3- [4- (1-heptyl-3-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 22a. {3- [4- (1-Butyl-3-phenethyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 22b. {3- [4- (1-Butyl-3-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid

 16b. {3- [4- (1,3-Diphenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 17a. Ethyl {3- [4- (3-Benzyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetate 17b. {3- [4- (3-Benzyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 18a. Ethyl {3- [4- (3-cyclohexyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetate 18b. {3- [4- (3-Cyclohexyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 19a. Ethyl {3- [4- (3-butyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetate

 16a. Ethyl {3- [4- (1,3-diphenethyl-ureido) -phenylsulfanyl] -phenyl} -acetate <Desc / Clms Page number 43>  45b. {3- [4- (1-heptyl-3-hexyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 46a. {3- [4- (1-butyl-3-hexyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 46b. {3- [4- (1-Butyl-3-hexyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 47a. {3- [3- (3-hexyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 47b. {3- [3- (3-hexyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 48a. (3- {3- [3-hexyl-1- (3-phenyl-propyl) -ureido] -phenyl-sulfanyl} -phenyl) -ethyl acetate 48b. (3- {3- [3-hexyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyaryl-phenyl) -acetate 49a. {3- [3- (1-heptyl-3-hexyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 49b. {3- [3- (1-heptyl-3-hexyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid

 43b. {3- [3- (3-Butyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 44a. {3- [3- (1,3-dibutyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 44b. {3- [3- (1,3-Dibutyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 45a. {3- [4- (1-heptyl-3-hexyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate

 38a. {3- [3- (1-Butyl-3-cyclohexyl-ureido) -phenylsulfanyl] -phenyl} -acetate 38b. {3- [3- (1-Butyl-3-cyclohexyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 39a. {3- [4- (3-Butyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 39b. {3- [4- (3-Butyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 40a. {3- [4- (1,3-dibutyl-ureido) -phenylsulfanyl] -phenyl} -acetate 40b. {3- [4- (1,3-Dibutyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 41a. {3- [3- (3-Butyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 41 b. {3- [3- (3-Butyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 42a. (3- {3- [3-Butyl-1- (3-phenyl-propyl) -ureido] -phenyl-sulfanyl} -phenyl) -ethyl acetate 42b. (3- {3- [3-Butyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid 43a. {3- [3- (3-Butyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate

 34b. {3- [4- {1-butyl-3-cyclohexyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 35a. {3- [3- (3-cyclohexyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 35b. {3- [3- (3-Cyclohexyl-1-phenethyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 36a. (3- {3- [3-Cyclohexyl-1- (3-phenyl-propyl) -ureido] -phenyl-sulfanyl} -phenyl) -ethyl acetate 36b. (3- {3- [3-Cyclohexyl-1- (3-phenyl-propyl) -ureido] -phenylsulfanyl} -phenyl) -acetic acid 37a. {3- [3- (3-cyclohexyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 37b. {3- [3- (3-Cyclohexyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid

 33a. {3- [4- (3-cyclohexyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 33b. {3- [4- (3-Cyclohexyl-1-heptyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 34a. {3- [4- (1-Butyl-3-cyclohexyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate <Desc / Clms Page number 44>  50a. {3- [3- (1-Butyl-3-hexyl-ureido) -phenylsulfanyl] -phenyl} -ethyl acetate 50b. {3- [3- (1-Butyl-3-hexyl-ureido) -phenylsulfanyl] -phenyl} -acetic acid 13. Cosmetic composition, characterized in that it comprises, in a physiologically acceptable suppoi, at least one compound as defined in any one of claims 1 to 12. 14. A composition according to claim 13, characterized in that the concentration ei compound (s) according to one of claims 1 to 12 is between 0.001 and 3% e weight relative to the total weight of the composition. 15. Cosmetic use of a composition as defined in one of claims 13 or 14 for body or hair hygiene. 16. Compounds according to any one of claims 1 to 12 as a medicament. 17. Use of a compound according to any one of claims 1 to 12 in the manufacture of a composition for regulating and / or restoring the metabolism of cutaneous lipids. 18. Use of a compound according to any one of claims 1 to 12 in the manufacture of a composition for the treatment of: - dermatological conditions related to a disorder of keratinization on differentiation and proliferation including acnes vulgar, polymorphic comedones, rosaceae, nodulocystic acnes, conglobata, senile acnes, secondary acnes such as solar acne, medicinal or occupational, ichthyosis, ichthyosiform states, Darrier's disease, keratoderma: palmoplantaria , leukoplasias and leukoplasiform states, mucosal or mucosal lichen (buccal), dermatological disorders with an inflammatory immunoallergic component with or without a cell proliferation disorder, in particular mucosal or nail skin psoriasis, psoriatic arthritis, cutaneous atopy, such as eczema respiratory atopy or gingival hypertrophy, - Benign or malignant dermal or epidermal proliferations, of viral or non-viral origin, in particular common warts, flat warts epidermodysplasil verruciform, oral or florid papillomatoses, T-cell lymphoma, <Desc / Clms Page number 45>  - proliferations that can be induced by ultraviolet including baso and squamous epithelium, - precancerous skin lesions including keratoacanthomas, - immune dermatoses including lupus erythematosus, - bullous immune diseases, - collagen diseases including scleroderma - dermatological or general disorders with immunological component, - cutaneous disorders due to exposure to U.V radiation, skin aging, photoinduced or chronological or pigmentations and actinic keratoses or any pathologies associated with chronological aging. or actinic notammer xerosis, - disorders of the sebaceous function including hyperseborrhoea of acne, seborrhea simple or seborrheic dermatitis, - disorders of healing or stretch marks, - disorders of pigmentation, such as hyperpigmentation, melasma hypopigmentation or vitiligo, - d Lipid metabolism disorders, such as obesity, hyperlipidemia, non-insulin-dependent diabetes or X syndrome, inflammatory conditions such as arthritis, cancerous or precancerous conditions, alopecia. different origins, including alopecia due to chemotherapy or radiation, - disorders of the immune system, such as asthma, type I diabetes mellitus, sclerotic plaque, or other selective dysfunction of the immune system, or - disorders of the cardiovascular system such as arteriosclerosis or hypertension 19. Pharmaceutical composition, characterized in that it comprises, in a physiologically acceptable carrier, at least one of the compounds as defined in any one of claims 1 to 12. 20. The composition of claim 19, characterized in that the concentration e compound (s) according to one of claims 1 to 12 is between 0.001 and 10% e weight relative to the total weight of the composition. <Desc / Clms Page number 46> 21. The composition of claim 19, characterized in that the concentration of compound (s) according to one of claims 1 to 12 is between 0.01 and 1% by weight relative to the total weight of the composition.