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WO2004071504A1 - Compounds which are modulators of the ppar-type receptors and their use in cosmetic or pharmaceutical compositions - Google Patents

Compounds which are modulators of the ppar-type receptors and their use in cosmetic or pharmaceutical compositions Download PDF

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Publication number
WO2004071504A1
WO2004071504A1 PCT/EP2004/002198 EP2004002198W WO2004071504A1 WO 2004071504 A1 WO2004071504 A1 WO 2004071504A1 EP 2004002198 W EP2004002198 W EP 2004002198W WO 2004071504 A1 WO2004071504 A1 WO 2004071504A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
phenylsulphanyl
ethyl
acetate
acetic acid
Prior art date
Application number
PCT/EP2004/002198
Other languages
French (fr)
Inventor
Philippe Diaz
Etienne Thoreau
Johannes Voegel
Isabelle Carlavan
Pascale Mauvais
Original Assignee
Galderma Research & Development, S.N.C.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from FR0350025A external-priority patent/FR2850968B1/en
Application filed by Galderma Research & Development, S.N.C. filed Critical Galderma Research & Development, S.N.C.
Priority to CA002512757A priority Critical patent/CA2512757A1/en
Priority to EP04709628A priority patent/EP1596853A1/en
Publication of WO2004071504A1 publication Critical patent/WO2004071504A1/en
Priority to US11/202,019 priority patent/US20060052627A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the invention relates, as novel and useful industrial products, to a
  • PPAR Activated Receptor
  • the activity of the PPAR-type receptors has been the subject of 0 numerous studies. There may be mentioned, as a guide, 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 , in which a large number of bibliographic references relating to PPAR-type receptors is listed. There may also be 5 mentioned, as a guide, the dossier entitled “The PPARs: From orphan receptors to Drug Discovery", Timothy M. Willson, Peter J. Brown, Daniel D. Sternbach, and Brad R. Henke, J. Med. Chem., 2000, Vol. 43, p. 527-550.
  • the PPAR receptors activate transcription by binding to elements of DNA sequences, called peroxisome proliferator response elements (PPRE), in 0 the form of a heterodimer with the retinoid X receptors (called RXRs).
  • PPRE peroxisome proliferator response elements
  • PPAR ⁇ Three human PPAR subtypes have been identified and described: PPAR ⁇ , PPAR ⁇ and PPAR ⁇ (or NUC1 ).
  • PPAR ⁇ is mainly expressed in the liver while PPAR ⁇ is ubiquitous. It is described in Patent Application WO98/32444 that PPAR ⁇ selective 5 compounds play a role in the barrier function and the differentiation of the stratum corneum.
  • PPAR ⁇ is the most widely studied of the three subtypes. All the references suggest a critical role of the PPAR ⁇ receptors in the regulation of differentiation of adipocytes, where it is highly expressed. It also plays a key role in systemic lipid homeostasis.
  • PPAR ⁇ -selective compounds such as prostaglandin-J2 or -D2 are potential active agents for treating obesity and diabetes.
  • One of the aims of the present invention is to provide a novel class of PPAR-modulating compounds.
  • Ar-i represents an optionally substituted radical of formula:
  • Ar 2 represents an optionally substituted radical of formula:
  • R1 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;
  • 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 from 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, an aralkyl radical, a polyether radical, a monohydroxyalkyl radical, a polyhydroxyalkyl radical, a radical COR5 or CSR5;
  • - Y represents an oxygen or sulphur atom, or the radical N-R4; R4 having the meanings given below,
  • R4 represents a hydrogen atom, an alkyl radical having from 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, a polyether radical, an aralkyl radical or forms, with R1 and the nitrogen atom of Y, a heterocycle or a heteroaryl;
  • R5 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, a radical R6-N-R7 or a radical O-R8;
  • R6, R7 and R8 having the meanings given below, - R6 and R7 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, an aralkyl radical or alternatively, taken together, form a heterocycle; - R8 represents 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 or an aralkyl radical;
  • R9 represents a hydrogen atom, a radical -COR12, an alkyl radical having from 1 to 12 carbon atoms, a polyether radical, an aryl radical or an aralkyl radical; R12 having the meanings given below,
  • R10 and R11 which are identical or different, represent a hydrogen atom, an alkyl radical having from 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 heteroatoms and preferably the rings are dithianyl, dioxanyl, dithiolanyl, dioxolanyl or cyclopropanyl radicals;
  • - A represents an S, O or Se atom or a radical N-R13;
  • R13 having the meanings given below, - R12 represents an alkyl radical having from 1 to 12 carbon atoms;
  • R13 represents a hydrogen atom, an alkyl radical having from 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, a polyether radical or an aralkyl radical; and when R2 represents a hydrogen atom, R5 is different from an aryl radical and R3 is different from a hydrogen atom, and the optical and geometric isomers of the said compounds of formula (I) and their salts.
  • the compounds according to the invention are provided in the form of salts, they are salts of an alkali or alkaline-earth metal, zinc salts, or salts of an organic amine.
  • hydroxyl radical is understood to mean the -OH radical.
  • alkyl radical having from 1 to 12 carbon atoms is understood to mean a hydrogenated or fluorinated, linear or cyclic, optionally branched, radical containing 1 to 12 carbon atoms which may be interrupted by one or more heteroatoms, and preferably the alkyl radicals having from 1 to 12 carbon atoms are methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, octyl, decyl or cyclohexyl radicals.
  • the expression monohydroxyalkyl radical is understood to mean a radical having 1 to 6 carbon atoms, and preferably having from 2 to 3 carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.
  • the expression polyhydroxyalkyl radical is understood to mean 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 or 2,3,4,5-tetrahydroxypentyl radicals, or the pentaerythritol residue.
  • polyether radical is understood to mean a polyether radical having from 1 to 6 carbon atoms interrupted by at least one oxygen atom such as methoxymethoxy, ethoxymethoxy or methoxyethoxymethoxy radicals.
  • alkoxy radical having from 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 from 1 to 12 carbon atoms.
  • aryl radical is understood to mean a phenyl, biphenyl, cinnamyl or naphthyl radical which may be mono- or disubstituted with a halogen atom, a radical CF 3 , 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 or benzoyl group or an amino functional group optionally protected by an acetyl or 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 with a halogen atom, a radical CF 3 , 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 or benzoyl group or an amino functional group optionally protected by an acetyl or benzoyl group or optionally substituted with at least one alkyl having from 1 to 12 carbon atoms.
  • heteroaryl radical is preferably understood to mean an aryl radical interrupted by one or more heteroatoms, such as the pyridyl, furyl, thienyl, isoxazolyl, oxadiazolyl, oxazolyl, isothiazolyl, quinazolinyl, benzothiadiazolyl, benzimidazole, indolyl or benzofuran radical, optionally substituted with at least one halogen, an alkyl having from 1 to 12 carbon atoms, an alkoxy having from 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 or benzoyl group or an amino functional group optionally protected by an acetyl or benzoyl group or optionally substituted with at least one alkyl having from 1
  • heterocycle is preferably understood to mean the morpholino, piperidino, piperazino, 2-oxopiperidin-1-yl and 2-oxopyrrolidin-1-yl radicals optionally substituted with at least one alkyl group having from 1 to 12 carbon atoms, an alkoxy having from 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 or benzoyl group or an amino functional group optionally protected by an acetyl or benzoyl group or optionally substituted with at least one alkyl having from 1 to 12 carbon atoms.
  • the compounds of general formula (I) may be obtained ( Figure 1) by coupling a thiol, an alcohol, an amine or a seleniated derivate (depend on X value) with an aromatic iodinated compound, using a metal catalyst such as nickel or palladium derivatives, in the presence of a hydride donor such as sodium borohydride and if necessary a base.
  • a metal catalyst such as nickel or palladium derivatives
  • a hydride donor such as sodium borohydride and if necessary a base.
  • diaryl amine compounds the copper or palladium catalyzed amination (Tetrahedron 58, (2002) 2041-2075)of the nitro aniline compound with aryl halogenide may be used, followed by the reduction of the nitro to the corresponding amino group.
  • diaryl ether coupling of the corresponding alkoxide catalyzed by palladium may be used.
  • Concerning the preparation of diaryl ketone compounds palladium catalysed conversion of halogenoaryl derivatives compound to the corresponding organotin derivatives followed by a palladium catalysed coupling with acyl chloride derivative may afford the target product.
  • the ketone might be protected in order to avoid problem during reductive amination.
  • the next step is a reductive amination of the preceding amine and of an aldehyde, which may be carried out with isolation of the intermediate imine or otherwise, followed by reduction of the latter by the action of a reducing agent such as NaBH 3 CN.
  • the alkylated amine obtained can then be subjected to the action of an isocyanate or an isothiocyanate in a solvent such as dichloromethane to give the corresponding urea or thiourea. It can also be further alkylated by reductive amination reaction in the presence of an aldehyde under the same conditions as above.
  • the amide may also be formed by the action of an acid in the presence of a coupling agent such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) in the presence of a base such as DIEA or an acyl halide and a base.
  • a coupling agent such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) in the presence of a base such as
  • the derivatives obtained are then saponified by the action, for example, of a base such as NaOH to give the corresponding acids.
  • a base such as NaOH
  • the compounds according to the invention have PPAR-type receptor modulating properties. This activity on the PPAR ⁇ , ⁇ and ⁇ receptors is measured in a transactivation test and quantified by the dissociation constant Kdapp (apparent), as described in Example 142.
  • the preferred compounds of the present invention have a dissociation constant of less than or equal to 1 000 nM, and advantageously of less than or equal to 500 nM.
  • the subject of the present invention is also, as a medicament, the compounds of formula (I) as described above.
  • the subject of the present invention is the use of the compounds of formula (I) for manufacturing a composition intended for regulating and/or restoring the metabolism of skin lipids.
  • any dermal or epidermal proliferations whether benign or malignant, whether of viral origin or not, such as verruca vulgaris, verruca plana and epidermodysplasia verruciformis, oral or florid papillomatoses, T lymphoma, and proliferations which may be induced by ultraviolet radiation, in particular in the case of baso- and spinocellular epitheliomas, and any precancerous skin lesions such as keratoacanthomas;
  • pigmentation disorders such as hyperpigmentation, melasma, hypopigmentation or vitiligo
  • lipid metabolism conditions such as obesity, hyperlipidaemia, non-insulin-dependent diabetes or X syndrome
  • immune system disorders such as asthma, diabetes mellitus type I, multiple sclerosis, or other selective dysfunctions of the immune system
  • the subject of the present invention is also a pharmaceutical composition
  • a pharmaceutical composition comprising, in a physiologically acceptable medium, at least one compound of formula (I) as defined above.
  • composition according to the invention may be carried out enterally, parenterally, topically or ocularly.
  • pharmaceutical composition is packaged in a form suitable for application by the topical route.
  • the composition may be provided in the form of tablets, gelatin capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, suspensions of lipid or polymeric microspheres or nanospheres or vesicles allowing controlled release.
  • the composition may be provided in the form of solutions or suspensions for perfusion 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.
  • the compounds are used by the systemic route 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.
  • the pharmaceutical composition according to the invention is more particularly intended for the treatment of the skin and the mucous membranes and may be provided in the form of salves, creams, milks, ointments, powders, impregnated pads, syndets, solutions, gels, sprays, mousses, suspensions, lotions, sticks, shampoos or washing bases. It may also be provided in the form of suspensions of lipid or polymeric microspheres or nanospheres or vesicles or of polymeric patches and of hydrogels allowing controlled release.
  • This composition for the topical route may be provided in anhydrous form, in aqueous form or in the form of an emulsion.
  • the compounds are used by the topical route at a concentration which is generally 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 care, and more particularly for regulating and/or restoring skin lipid metabolism.
  • the subject of the invention is therefore also the cosmetic use of a composition
  • a composition comprising, in a physiologically acceptable carrier, at least one of the compounds of formula (I) for body or hair care.
  • the cosmetic composition according to the invention containing, in a cosmetically acceptable carrier, at least one compound of formula (I) or one of its optical or geometric isomers or one of its salts, may be provided in particular in the form of a cream, a milk, a lotion, a gel, suspensions of lipid or polymeric microspheres or nanospheres or vesicles, impregnated pads, solutions, sprays, mousses, sticks, soaps, shampoos or washing bases.
  • the concentration of compound of formula (I) in the cosmetic composition is preferably between 0.001% and 3% by weight, relative to the total weight of the composition.
  • compositions as described above may in addition contain inert additives, or even pharmacodynamically active additives as regards the pharmaceutical compositions, or combinations of these additives, and in particular:
  • - preservatives such as esters of parahydroxybenzoic acid
  • - stabilizers such as esters of parahydroxybenzoic acid
  • antioxidants such as ⁇ -tocopherol, butylated hydroxyanisole or butylated hydroxytoluene, Super Oxide Dismutase, Ubiquinol or certain metal chelators;
  • - depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid
  • - moisturizing agents such as glycerol, PEG 400, thiamorpholinone, and its derivatives, or urea;
  • antiseborrhoeic 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 4,5-polymethylene-3-isothiazolidones
  • agents promoting hair regrowth such as Minoxidil (2,4-diamino-6- piperidinopyrimidine 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;
  • - corticosteroids or oestrogens - corticosteroids or oestrogens; - ⁇ -hydroxy acids and ⁇ -keto acids or their derivatives, such as lactic, malic, citric, glycolic, mandelic, tartaric, glyceric and ascorbic acids, and their salts, amides or esters, or ⁇ -hydroxy acids or their derivatives, such as salicylic acid and its salts, amides or esters; - ion channel, such as potassium channel, blockers;
  • compositions in combination with medicaments known to interfere with the immune system (for example cyclosporine, FK 506, glucocorticoids, monoclonal antibodies, cytokines or growth factors, and the like).
  • medicaments known to interfere with the immune system for example cyclosporine, FK 506, glucocorticoids, monoclonal antibodies, cytokines or growth factors, and the like.
  • the gradient contains 3 entries which are Time A% B% Flow rate Curve
  • EXAMPLE 1 Ethyl 4-(3-aminophenylsulphanyl)phenyllacetate a) Ethyl 4-iodophenylacetate 1.25 ml (0.023 mol) of concentrated sulphuric acid are added dropwise to a mixture of 6.14 g (0.023 mol) of 4-iodophenylacetic acid in 50 ml of ethanol. The reaction medium is then heated under reflux for 7 h, and then concentrated in a rotary evaporator under vacuum. Water is added to the residue obtained. The solution is neutralized by adding sodium bicarbonate. The desired product is extracted by adding ethyl ether.
  • Example 2 In a manner similar to Example 1(b), by reacting ethyl 4-iodophenylacetate (2.5 g, 0.01 mol), 30 mi of THF, borohydride polymer supported Amberlite ® IRA400 resin (2.5 mmol/g) (Aldrich: 32864-2) (13.5 g), bis(bipyridine)nickel (II) bromide (125 mg) (Organometallics 1985, 4, 657-661) and 4,4'-dithiodianiline (1.7 g, 0.013 mol), 1.1 g (42%) of the expected derivative is obtained in the form of a yellow oil.
  • EXAMPLE 3 4-r3-.3-Phenylpropylamino)phenylsulphanyllphenyl ⁇ acetic acid a) Ethyl ⁇ 4-[3-(3-phenylpropylamino)phenylsulphanyl1phenyl)acetate A solution of 3-phenylpropionaldehyde (257 mg, 1.91 mmol) and acetic acid (1 ml) is added to a solution of ethyl [4-(3-aminophenylsulphanyl)phenyl]acetate (Example 1(b)) (550 mg, 1.91 mmol) in 15 ml of DMF.
  • Example 3(a) the product is obtained by reacting ethyl ⁇ 4-[3-(3-phenylpropylamino)phenylsulphanyl]phenyl ⁇ acetate (Example 3(a)) (50 mg), sodium hydroxide (80 mg), water (500 ⁇ l) and ethanol (500 ⁇ l) in THF (3 ml).
  • EXAMPLE 4 (4- 3-rBis.3-phenylpropynaminolphenyl- sulphanyllphenvDacetic acid
  • the product is obtained by reacting ethyl (4- ⁇ 3-[bis(3-phenylpropyl)amino]phenylsulphanyl ⁇ phenyl)acetate obtained in (Example 3(a)) (50 mg), sodium hydroxide (80 mg), water (500 ⁇ l) and ethanol (500 ⁇ l) in THF (3 ml).
  • Example 1(b) In a manner similar to Example 3(a), by reacting 3-phenylacetaldehyde (230 mg, 1.91 mmol), acetic acid (1 ml), ethyl [4-(3-aminophenylsulphanyl)phenyl]acetate (Example 1(b)) (550 mg, 1.91 mmol) in 15 ml of DMF and 241 mg of sodium cyanoborohydride (3.83 mmol), 643 mg (86%) of the expected derivative are obtained in the form of a colourless oil and 26 mg (10%) of ethyl [4-(3-diphenethylaminophenylsulphanyl)phenyl]acetate. b) r4-(3-Phenethylamino)phenylsulphanylphenyllacetic acid
  • Example 1(c) the product is obtained by reacting ethyl [4-(3-phenethylamino)phenylsulphanylphenyl]acetate
  • Example 5(a) (50 mg), sodium hydroxide (80 mg), water (500 ⁇ l) and ethanol (500 ⁇ l) in THF (3 ml).
  • Example 5(a) the product is obtained by reacting ethyl [4-(3-diphenethylaminophenylsulphanyl)phenyl]acetate obtained in Example 5(a) (50 mg), sodium hydroxide (80 mg), water (500 ⁇ l) and ethanol (500 ⁇ l) in THF (3 ml).
  • EXAMPLE 7 r4-(3-Heptylaminophenylsulphanyl)phenvHacetic acid a) Ethyl r4-(3-heptylaminophenylsulphanyl)phenyllacetate In a manner similar to Example 3(a), by reacting heptaldehyde
  • Example 7(a) the product is obtained by reacting ethyl [4-(3-heptylaminophenylsulphanyl)phenyl]acetate (Example 7(a)) (50 mg), sodium hydroxide (80 mg), water (500 ⁇ l) and ethanol (500 ⁇ l) in THF (3 ml).
  • Example 7(a) the product is obtained by reacting ethyl [4-(3-diheptylaminophenylsulphanyl)phenyl]acetate obtained in Example 7(a) (50 mg), sodium hydroxide (80 mg), water (500 ⁇ l) and ethanol (500 ⁇ l) in THF (3 ml).
  • Example 9(a) the product is obtained by reacting ethyl [4-(3-butylaminophenylsulphanyl)phenyl]acetate (Example 9(a)) (50 mg), sodium hydroxide (80 mg), water (500 ⁇ l) and ethanol (500 ⁇ l) in THF (3 ml).
  • Example 9(a) the product is obtained by reacting ethyl [4-(3-dibutylaminophenylsulphanyl)phenyl]acetate obtained in Example 9(a) (50 mg, 0.174 mmol), sodium hydroxide (80 mg), water (500 ⁇ l) and ethanol (500 ⁇ l) in THF (3 ml).
  • EXAMPLE 11 ⁇ 4-f4-(3-Phenylpropylamino)phenylsulphanvHphenyl acetic acid a) Ethyl ⁇ 4-[4-(3-phenylpropylamino)phenylsulphanyllphenyl)acetate
  • Example 2(a) In a manner similar to Example 3(a), by reacting 3-phenylpropionaldehyde (128 mg, 0.96 mmol), acetic acid (1 ml), ethyl [4-(4-aminophenylsulphanyl)phenyl]acetate (Example 2(a)) (275 mg, 0.96 mmol) in 15 ml of DMF 120 mg and sodium cyanoborohydride (1.91 mmol), 307 mg (79%) of the expected derivative and 55 mg (11%) of ethyl (4- ⁇ 4-[bis(3-phenyipropyl)amino]phenylsulphanyl ⁇ phenyl)acetate are obtained.
  • Example 11(a) the product is obtained by reacting ethyl ⁇ 4-[4-(3-phenylpropylamino)phenylsulphanyl]phenyl ⁇ acetate (Example 11(a)) (50 mg), sodium hydroxide (80 mg), water (500 ⁇ l) and ethanol (500 ⁇ l) in THF (3 ml).
  • EXAMPLE 12 .4-(4-rBis.3-phenylpropynamino1phenyl- sulphanyl)phenyl)acetic acid
  • Example 11(a) the product is obtained by reacting ethyl (4- ⁇ 4-[bis(3-phenylpropyl)amino]phenylsulphanyl ⁇ phenyl)acetate obtained in Example 11(a) (50 mg), sodium hydroxide (80 mg), water (500 ⁇ l) and ethanol (500 ⁇ l) in THF (3 ml).
  • Example 2(a) In a manner similar to Example 3(a), by reacting phenylacetaldehyde (115 mg, 0.96 mmol), acetic acid (1 ml), ethyl [4-(4-aminophenylsulphanyl)phenyl]acetate (Example 2(a)) (275 mg, 0.96 mmol) in 15 ml of DMF and 241 mg of sodium cyanoborohydride (3.83 mmol), 311 mg (83%) of the expected derivative are obtained in the form of a colourless oil and 17 mg (4%) of ethyl [4-(4-diphenethylaminophenylsulphanyl)phenyl]acetate.
  • Example 1(c) the product is obtained by reacting ethyl [4-(4-phenethylaminophenylsulphanyl)phenyl]acetate
  • Example 13(a) (50 mg), sodium hydroxide (80 mg), water (500 ⁇ l) and ethanol (500 ⁇ l) in THF (3 ml).
  • Example 13(a) the product is obtained by reacting ethyl [4-(4-diphenethylaminophenylsulphanyl)phenyl]acetate obtained in Example 13(a) (50 mg), sodium hydroxide (80 mg), water (500 ⁇ l) and ethanol (500 ⁇ l) in THF (3 ml).
  • Example 15(a) ethyl [4-(4-heptylaminophenylsulphanyl)phenyl]acetate (Example 15(a)) (50 mg), sodium hydroxide (80 mg), water (500 ⁇ l) and ethanol (500 ⁇ l) in THF (3 ml).
  • Example 15(a) the product is obtained by reacting ethyl [4-(4-diheptylaminophenylsulphanyl)phenyl]acetate obtained in Example 15(a) (50 mg), sodium hydroxide (80 mg), water (500 ⁇ l) and ethanol (500 ⁇ l) in THF (3 ml).
  • EXAMPLE 17 r4-(4-Dibutylaminophenylsulphanyl)phenyl1acetic acid a) Ethyl f4-(4-dibutylaminophenylsulphanvhphenvnacetate
  • Example 17(a) the product is obtained by reacting ethyl [4-(4-dibutylaminophenylsulphanyl)phenyl]acetate (Example 17(a)) (50 mg), sodium hydroxide (80 mg), water (500 ⁇ l) and ethanol (500 ⁇ l) in THF (3 ml).
  • Table 1 Results of analysis of the products of Examples 1b to 17b
  • Examples 18 to 141 were obtained by parallel chemistry. The reactions of a starting amine and a starting isocyanate are performed in several reactors simultaneously according to the operating protocol described below.
  • the starting amine (see Table 3) is introduced into each 5 ml reactor. 2 ml of dichloromethane are added. Next, 0.062 mmol of isocyanate (see Table 4) are added. The reactors are stirred for 7 h at room temperature. 0.062 mmol of isocyanates are added if the starting amine has not completely disappeared (TLC monitoring). In this case, the stirring is continued for 12 h at room temperature.
  • reaction media are concentrated to dryness for 2 h at 40°C in a centrifugal evaporator under vacuum.
  • the products are purified by filtration on silica cartridges (6 ml), 1 :DCM, 2:DCM 80/AcOEt 20, and then concentrated to dryness, 2 h at 40°C in a centrifugal evaporator.
  • Table 2 Starting amines
  • Compounds 18a to 141a are the esters corresponding to the acids 18b to 141b obtained before the saponification step.
  • EXAMPLE 142 - CROSS CURVE PPAR TRANSACTIVATION TEST The activation of receptors with 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 as quantity of luminescence produced after incubating the cells in the presence of a reference agonist.
  • the ligands will displace the agonist from its site.
  • the measurement of the activity is performed by quantification of the light produced. This measurement makes it possible to determine the modulatory 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 called apparent Kd (KdApp in nM).
  • cross curves for the product to be tested against a reference agonist are produced in a 96-well plate: 10 concentrations of the test product plus a concentration 0 are placed in a line, and 7 concentrations of the agonist plus one concentration 0 are placed in a column. This represents 88 measurement points for 1 product and 1 receptor. The 8 remaining wells are used for repeatability controls.
  • 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-difluorophenyl)-1-heptylureido]ethylJphenylsulphanyl)- 2-methylpropionic acid for PPAR ⁇ , ⁇ 2-methyl-4-[4-methyl-
  • the HeLN cell lines used are stable transfectants containing the plasmids ERE- ⁇ Glob-Luc-SV-Neo (reporter gene) and PPAR ( ⁇ , ⁇ , ⁇ ) Gal-hPPAR. These cells are inoculated into 96-well plates in an amount of 10 000 cells per well in 100 ⁇ l of DMEM medium free of phenol red and supplemented with 10% lipid- free calf serum. The plates are then incubated at 37°C, 7% CO 2 for 16 hours.
  • test products and of the reference ligand are added in an amount 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 turning over and
  • n.a. means not active

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Abstract

The invention relates to novel compounds which correspond to the general formula (I), their method of preparation, and their use in pharmaceutical compositions intended for use in human or veterinary medicine (in dermatology and in the field of cardiovascular diseases, immune diseases and/or diseases linked to lipid metabolism), or in cosmetic compositions.

Description

COMPOUNDS WHICH ARE MODULATORS OF THE PPAR-TYPE RECEPTORS AND THEIR USE IN COSMETIC OR PHARMACEUTICAL COMPOSITIONS
The invention relates, as novel and useful industrial products, to a
5 novel class of compounds which are modulators of the Peroxisome Proliferator-
Activated Receptor (PPAR) type receptors. It also relates to their method of preparation and to their use in pharmaceutical compositions for use in human or veterinary medicine, or alternatively in cosmetic compositions.
The activity of the PPAR-type receptors has been the subject of 0 numerous studies. There may be mentioned, as a guide, 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 , in which a large number of bibliographic references relating to PPAR-type receptors is listed. There may also be 5 mentioned, as a guide, the dossier entitled "The PPARs: From orphan receptors to Drug Discovery", Timothy M. Willson, Peter J. Brown, Daniel D. Sternbach, and Brad R. Henke, J. Med. Chem., 2000, Vol. 43, p. 527-550.
The PPAR receptors activate transcription by binding to elements of DNA sequences, called peroxisome proliferator response elements (PPRE), in 0 the form of a heterodimer with the retinoid X receptors (called RXRs).
Three human PPAR subtypes have been identified and described: PPARα, PPARγ and PPARδ (or NUC1 ).
PPARα is mainly expressed in the liver while PPARδ is ubiquitous. It is described in Patent Application WO98/32444 that PPARα selective 5 compounds play a role in the barrier function and the differentiation of the stratum corneum.
PPARγ is the most widely studied of the three subtypes. All the references suggest a critical role of the PPARγ receptors in the regulation of differentiation of adipocytes, where it is highly expressed. It also plays a key role in systemic lipid homeostasis.
It has in particular been described in Patent Application WO 96/33724 that PPARγ-selective compounds, such as prostaglandin-J2 or -D2, are potential active agents for treating obesity and diabetes.
One of the aims of the present invention is to provide a novel class of PPAR-modulating compounds.
Thus, the present invention relates to compounds corresponding to the following general formula (I):
(I)
Figure imgf000003_0001
in which
Ar-i represents an optionally substituted radical of formula:
Figure imgf000003_0002
Z represents the substituent:
O
Y
~R1
it being understood that Z is at the para position with respect to X on the ring An; R1 and Y having the meanings given below, Ar2 represents an optionally substituted radical of formula:
Figure imgf000004_0001
- R1 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;
- 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 from 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, an aralkyl radical, a polyether radical, a monohydroxyalkyl radical, a polyhydroxyalkyl radical, a radical COR5 or CSR5;
R5 having the meanings given below,
- Y represents an oxygen or sulphur atom, or the radical N-R4; R4 having the meanings given below,
- R4 represents a hydrogen atom, an alkyl radical having from 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, a polyether radical, an aralkyl radical or forms, with R1 and the nitrogen atom of Y, a heterocycle or a heteroaryl;
- R5 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, a radical R6-N-R7 or a radical O-R8;
R6, R7 and R8 having the meanings given below, - R6 and R7 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, an aralkyl radical or alternatively, taken together, form a heterocycle; - R8 represents 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 or an aralkyl radical;
- X represents an S atom, a radical S=O, a radical O=S=O, an Se atom, an O atom, a radical N-R9, a radical C=O, a radical HO-C-R11 or a radical R10-C- R11 ;
R9, R10 and R11 having the meanings given below,
- R9 represents a hydrogen atom, a radical -COR12, an alkyl radical having from 1 to 12 carbon atoms, a polyether radical, an aryl radical or an aralkyl radical; R12 having the meanings given below,
- R10 and R11, which are identical or different, represent a hydrogen atom, an alkyl radical having from 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 heteroatoms and preferably the rings are dithianyl, dioxanyl, dithiolanyl, dioxolanyl or cyclopropanyl radicals;
- A represents an S, O or Se atom or a radical N-R13;
R13 having the meanings given below, - R12 represents an alkyl radical having from 1 to 12 carbon atoms;
- R13 represents a hydrogen atom, an alkyl radical having from 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, a polyether radical or an aralkyl radical; and when R2 represents a hydrogen atom, R5 is different from an aryl radical and R3 is different from a hydrogen atom, and the optical and geometric isomers of the said compounds of formula (I) and their salts.
In particular, when the compounds according to the invention are provided in the form of salts, they are salts of an alkali or alkaline-earth metal, zinc salts, or salts of an organic amine.
According to the present invention, the expression hydroxyl radical is understood to mean the -OH radical.
According to the present invention, the expression alkyl radical having from 1 to 12 carbon atoms is understood to mean a hydrogenated or fluorinated, linear or cyclic, optionally branched, radical containing 1 to 12 carbon atoms which may be interrupted by one or more heteroatoms, and preferably the alkyl radicals having from 1 to 12 carbon atoms are methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, octyl, decyl or cyclohexyl radicals.
The expression monohydroxyalkyl radical is understood to mean a radical having 1 to 6 carbon atoms, and preferably having from 2 to 3 carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical. The expression polyhydroxyalkyl radical is understood to mean 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 or 2,3,4,5-tetrahydroxypentyl radicals, or the pentaerythritol residue.
The expression polyether radical is understood to mean a polyether radical having from 1 to 6 carbon atoms interrupted by at least one oxygen atom such as methoxymethoxy, ethoxymethoxy or methoxyethoxymethoxy radicals.
The expression alkoxy radical having from 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 from 1 to 12 carbon atoms. The expression aryl radical is understood to mean a phenyl, biphenyl, cinnamyl or naphthyl radical which may be mono- or disubstituted with a halogen atom, a radical CF3, 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 or benzoyl group or an amino functional group optionally protected by an acetyl or benzoyl group or optionally substituted with at least one alkyl having from 1 to 12 carbon atoms.
The expression aralkyl radical is understood to mean a benzyl, phenethyl or naphthalen-2-ylmethyl radical which may be mono- or disubstituted with a halogen atom, a radical CF3, 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 or benzoyl group or an amino functional group optionally protected by an acetyl or benzoyl group or optionally substituted with at least one alkyl having from 1 to 12 carbon atoms.
The expression heteroaryl radical is preferably understood to mean an aryl radical interrupted by one or more heteroatoms, such as the pyridyl, furyl, thienyl, isoxazolyl, oxadiazolyl, oxazolyl, isothiazolyl, quinazolinyl, benzothiadiazolyl, benzimidazole, indolyl or benzofuran radical, optionally substituted with at least one halogen, an alkyl having from 1 to 12 carbon atoms, an alkoxy having from 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 or benzoyl group or an amino functional group optionally protected by an acetyl or benzoyl group or optionally substituted with at least one alkyl having from 1 to 12 carbon atoms.
The expression heterocycle is preferably understood to mean the morpholino, piperidino, piperazino, 2-oxopiperidin-1-yl and 2-oxopyrrolidin-1-yl radicals optionally substituted with at least one alkyl group having from 1 to 12 carbon atoms, an alkoxy having from 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 or benzoyl group or an amino functional group optionally protected by an acetyl or benzoyl group or optionally substituted with 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, the following compounds may be mentioned in particular (alone or as a mixture): 1 b. Ethyl [4-(3-aminophenylsulphanyl)phenyl]acetate 2. Ethyl [4-(4-aminophenylsulphanyl)phenyl]acetate
3a. Ethyl {4-[3-(3-phenylpropylamino)phenylsulphanyl]phenyl}acetate 3b. {4-[3-(3-Phenylpropylamino)phenylsulphanyl]phenyl}acetic acid 4a. Ethyl (4-{3-[bis(3-phenylpropyl)amino]phenylsulphanyl}phenyl)acetate 4b. (4-{3-[Bis(3-phenylpropyl)amino]phenylsuphanyl}phenyl)acetic acid 5a. Ethyl [4-(3-Phenethylamino)phenylsulphanylphenyl]acetate 5b. [4-(3-Phenethylamino)phenylsulphanylphenyl]acetic acid 6a. Ethyl [4-(3-Diphenethylaminophenylsulphanyl)phenyl]acetate 6b. [4-(3-Diphenethylaminophenylsulphanyl)phenyl]acetic acid
7a. Ethyl [4-(3-heptylaminophenylsulphanyl)phenyl]acetate
7b. [4-(3-Heptylaminophenylsulphanyl)phenyl]acetic acid
8a. Ethyl [4-(3-diheptylaminophenylsulphanyl)phenyl]acetate 8b. [4-(3-Diheptylaminophenylsulphanyl)phenyl]acetic acid
9a. Ethyl [4-(3-butylaminophenylsulphanyl)phenyl]acetate
9b. [4-(3-Butylaminophenylsulphanyl)phenyl]acetic acid
10a. Ethyl [4-(3-dibutylaminophenylsulphanyl)phenyl]acetate
10b. [4-(3-Dibutylaminophenylsulphanyl)phenyl]acetic acid 11a. Ethyl {4-[4-(3-phenylpropylamino)phenylsulphanyl]phenyl}acetate
11b. {4-[4-(3-Phenylpropylamino)phenylsulphanyl]phenyl}acetic acid
12a. Ethyl (4-{4-[bis(3-phenylpropyl)amino]phenylsulphanyl}phenyl)acetate
12b. (4-{4-[Bis(3-phenylpropyl)amino]phenylsulphanyl}phenyl)acetic acid
13a. Ethyl [4-(4-phenethylaminophenylsulphanyl)phenyl]acetate 13b. [4-(4-Phenethylaminophenylsulphanyl)phenyl]acetic acid
14a. Ethyl [4-(4-diphenethylaminophenylsulphanyl)phenyl]acetate
14b. [4-(4-Diphenethylaminophenylsulphanyl)phenyl]acetic acid
15a. Ethyl [4-(4-heptylaminophenylsulphanyl)phenyl]acetate
15b. [4-(4-Heptylaminophenylsulphanyl)phenyl]acetic acid 16a. Ethyl [4-(4-diheptylaminophenylsulphanyl)phenyl]acetate
16b. [4-(4-Diheptylaminophenylsulphanyl)phenyl]acetic acid
17a. Ethyl [4-(4-dibutylaminophenylsulphanyl)phenyl]acetate
17b. [4-(4-Dibutylaminophenylsulphanyl)phenyl]acetic acid
18a. Ethyl (4-{3-[3-benzyl-1-(3-phenylpropyl)ureido]phenylsulphanyl}- phenyl)acetate
18b. (4-{3-[3-Benzyl-1 -(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid 19a. Ethyl (4-{3-[3-phenyl-1-(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetate
19b. (4-{3-[3-Phenyl-1 -(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid 20a. Ethyl (4-{3-[3-(2,3-dichlorophenyl)-1-(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetate
20b. (4-{3-[3-(2,3-Dichlorophenyl)-1 -(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetic acid
21a. Ethyl (4-{3-[3-heptyl-1-(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetate
21b. (4-{3-[3-Heptyl-1-(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid
22a. Ethyl (4-{3-[3-phenethyl-1-(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetate 22b. (4-{3-[3-Phenethyl-1 -(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid
23a. Ethyl (4-{3-[1-(3-phenylpropyl)-3-(4-trifluoro- methylphenyl)ureido]phenylsulphanyl}phenyl)acetate
23b. (4-{3-[1 -(3-Phenylpropyl)-3-(4-trifluoro- methylphenyl)ureido]phenylsulphanyl}phenyl)acetic acid
24a. Ethyl (4-{3-[3-(4-methoxyphenyl)-1-(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetate
24b. (4-{3-[3-(4-Methoxyphenyl)-1 -(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetic acid 25a. Ethyl (4-{3-[3-adamantan-1-yl-1-(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetate
25b. (4-{3-[3-Adamantan-1 -yl-1 -(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetic acid
26a. Ethyl (4-{3-[3-(2-phenoxyphenyl)-1-(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetate
26b. (4-{3-[3-(2-Phenoxyphenyl)-1 -(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetic acid
27a. Ethyl (4-{3-[3-allyl-1-(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetate
27b. (4-{3-[3-Allyl-1 -(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid
28a. Ethyl (4-{3-[3-cyclohexyl-1-(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetate
28b. (4-{3-[3-Cyclohexyl-1 -(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetic acid
29a. Ethyl (4-{3-[3-(2-nitrophenyl)-1-(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetate 29b. (4-{3-[3-(2-Nitrophenyl)-1-(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetic acid
30a. Ethyl (4-{3-[3-hexyl-1-(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetate
30b. (4-{3-[3-Hexyl-1 -(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid 31a. Ethyl (4-{3-[3-naphthalen-2-yl-1-(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetate
31 b. (4-{3-[3-Naphthalen-2-yl-1-(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetic acid
32a. Ethyl (4-{3-[3-(2-ethoxyphenyl)-1-(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetate
32b. (4-{3-[3-(2-Ethoxyphenyl)-1 -(3-phenylpropyl)ureido]- pheny!sulphanyl}phenyl)acetic acid 33a. Ethyl (4-{3-[3-(4-butoxyphenyl)-1-(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetate
33b. (4-{3-[3-(4-Butoxyphenyl)-1 -(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetic acid 34a. Ethyl (4-{3-[3-pentyl-1-(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetate
34b. (4-{3-[3-Pentyl-1-(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid
35a. Ethyl (4-{3-[3-butyl-1-(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetate
35b. (4-{3-[3-Butyl-1 -(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid
36a. Ethyl (4-{3-[3-(4-dimethylaminophenyl)-1-(3- phenylpropyl)ureido]phenylsulphanyl}phenyl)acetate
36b. (4-{3-[3-(4-Dimethylaminophenyl)-1 -(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetic acid
37a. Ethyl {4-[3-(3-benzyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetate
37b. {4-[3-(3-Benzyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid
38a. Ethyl {4-[3-(1-phenethyl-3-phenylureido)phenylsulphanyl]phenyl}acetate
38b. {4-[3-(1-Phenethyl-3-phenylureido)phenylsulphanyl]phenyl}acetic acid 39a. Ethyl (4-{3-[3-(2,3-dichlorophenyl)-1-phenethylureido]- phenylsulphanyl}phenyl)acetate
39b. (4-{3-[3-(2,3-Dichlorophenyl)-1 -phenethylureido]- phenylsulphanyl}phenyl)acetic acid
40a. Ethyl {4-[3-(3-heptyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetate 40b. {4-[3-(3-Heptyl-1-phenethylureido)phenylsulphanyl]phenyl}acetic acid
41a. Ethyl {4-[3-(1,3-diphenethylureido)phenylsulphanyl]phenyl}acetate
41 b. {4-[3-(1 ,3-Diphenethylureido)phenylsulphanyl]phenyl}acetic acid 42a. Ethyl (4-{3-[1-phenethyl-3-(4-trifluoromethyl- phenyl)ureido]phenylsulphanyl}phenyl)acetate
42b. (4-{3-[1 -Phenethyl-3-(4-trifluoromethylphenyl)- ureido]phenylsulphanyl}phenyl)acetic acid 43a. Ethyl (4-{3-[3-(4-methoxyphenyl)-1-phenethyl- ureido]phenylsulphanyl}phenyl)acetate
43b. (4-{3-[3-(4-Methoxyphenyl)-1-phenethylureido]- phenylsulphanyl}phenyl)acetic acid
44a. Ethyl {4-[3-(3-adamantan-1-yl-1-phenethylureido)- phenylsulphanyl]phenyl}acetate
44b. {4-[3-(3-Adamantan-1 -yl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid
45a. Ethyl (4-{3-[1-phenethyl-3-(2-phenoxyphenyl)- ureido]phenylsulphanyl}phenyl)acetate 45b. (4-{3-[1-Phenethyl-3-(2-phenoxyphenyl)ureido]- phenylsulphanyl}phenyl)acetic acid
46a. Ethyl {4-[3-(3-allyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetate
46b. {4-[3-(3-Allyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid
47a. Ethyl {4-[3-(3-cyclohexyl-1-phenethylureido)- phenylsulphanyl]phenyl}acetate
47b. {4-[3-(3-Cyclohexyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid
48a. Ethyl (4-{3-[3-(2-nitrophenyl)-1-phenethylureido]~ phenylsulphanyl}phenyl)acetate
48b. (4-{3-[3-(2-Nitrophenyl)-1-phenethylureido]phenylsulphanyl}phenyl)acetic acid
49a. Ethyl {4-[3-(3-hexyl-1-phenethylureido)phenylsulphanyl]phenyl}acetate
49b. {4-[3-(3-Hexyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid 50a. Ethyl {4-[3-(3-naphthalen-2-yl-1-phenethylureido)- phenylsulphanyl]phenyl}acetate
50b. {4-[3-(3-Naphthalen-2-yl-1-phenethylureido)phenylsulphanyl]phenyl}acetic acid 51a. Ethyl (4-{3-[3-(2-ethoxyphenyl)-1-phenethyl- ureido]phenylsulphanyl}phenyl)acetate
51 b. (4-{3-[3-(2-Ethoxyphenyl)-1-phenethylureido]- phenylsulphanyl}phenyl)acetic acid
52a. Ethyl (4-{3-[3-(4-butoxyphenyl)-1-phenethyl- ureido]phenylsulphanyl}phenyl)acetate
52b. (4-{3-[3-(4-Butoxyphenyl)-1 -phenethylureido]- phenylsulphanyl}phenyl)acetic acid
53a. Ethyl {4-[3-(3-pentyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetate
53b. {4-[3-(3-Pentyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid 54a. Ethyl {4-[3-(3-butyl-1-phenethylureido)phenylsulphanyl]phenyl}acetate
54b. {4-[3-(3-Butyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid
55a. Ethyl (4-{3-[3-(4-dimethylaminophenyl)-1- phenethylureido]phenylsulphanyl}phenyl)acetate
55b. (4-{3-[3-(4-Dimethylaminophenyl)-1 -phenethyl- ureido]phenylsulphanyl}phenyl)acetic acid
56a. Ethyl {4-[3-(3-benzyl-1 -heptylureido)phenylsulphanyl]phenyl}acetate
56b. {4-[3-(3-Benzyl-1 -heptylureido)phenylsulphanyl]phenyl}acetic acid
57a. Ethyl {4-[3-(1-heptyl-3-phenylureido)phenylsulphanyl]phenyl}acetate
57b. {4-[3-(1-Heptyl-3-phenylureido)phenylsulphanyl]phenyl}acetic acid 58a. Ethyl {4-[3-(1,3-diheptylureido)phenylsulphanyl]phenyl}acetate
58b. {4-[3-(1 ,3-Diheptylureido)phenylsulphanyl]phenyl}acetic acid
59a. Ethyl {4-[3-(1-heptyl-3-phenethylureido)phenylsulphanyl]phenyl}acetate 59b. {4-[3-(1-Heptyl-3-phenethylureido)phenylsulphanyl]phenyl}acetic acid
60a. Ethyl (4-{3-[1-heptyl-3-(4-trifluoromethylphenyl)- ureido]phenylsulphanyl}phenyl)acetate
60b. (4-{3-[1 -Heptyl-3-(4-trifluoromethylphenyl)- ureido]phenylsulphanyl}phenyl)acetic acid
61a. Ethyl (4-{3-[1-heptyl-3-(4-methoxyphenyl)ureido]- phenylsulphanyl}phenyl)acetate
61b. (4-{3-[1-Heptyl-3-(4-methoxyphenyl)ureido]phenylsulphanyl}phenyl)acetic acid 62a. Ethyl {4-[3-(3-adamantan-1 -yl-1 -heptylureido)- phenylsulphanyl]phenyl}acetate
62b. {4-[3-(3-Adamantan-1 -yl-1 -heptylureido)phenylsulphanyl]phenyl}acetic acid
63a. Ethyl (4-{3-[1-heptyl-3-(2-phenoxyphenyl)ureido]- phenylsulphanyl}phenyl)acetate 63b. (4-{3-[1 -Heptyl-3-(2-phenoxyphenyl)ureido]phenylsulphanyl}phenyl)acetic acid
64a. Ethyl {4-[3-(3-allyl-1 -heptylureido)phenylsulphanyl]phenyl}acetate
64b. {4-[3-(3-Allyl-1 -heptylureido)phenylsulphanyl]phenyl}acetic acid
65a. Ethyl {4-[3-(3-cyclohexyl-1 -heptylureido)phenylsulphanyl]phenyl}acetate 65b. {4-[3-(3-Cyclohexyl-1-heptylureido)phenylsulphanyl]phenyl}acetic acid
66a. Ethyl (4-{3-[1-heptyl-3-(2-nitrophenyl)ureido]- phenylsulphanyl}phenyl)acetate
66b. (4-{3-[1 -Heptyl-3-(2-nitrophenyl)ureido]phenylsulphanyl}phenyl)acetic acid
67a. Ethyl {4-[3-(1-heptyl-3-hexylureido)phenylsulphanyl]phenyl}acetate 67b. {4-[3-(1-Heptyl-3-hexylureido)phenylsulphanyl]phenyl}acetic acid
68a. Ethyl {4-[3-(1-heptyl-3-naphthalen-2-ylureido)- phenylsulphanyl]phenyl}acetate 68b. {4-[3-(1-Heptyl-3-naphthalen-2-ylureido)phenylsulphanyl]phenyl}acetic acid
69a. Ethyl (4-{3-[3-(2-ethoxyphenyl)-1-heptylureidoJ- phenylsulphanyl}phenyl)acetate
69b. (4-{3-[3-(2-Ethoxyphenyl)-1-heptylureido]phenylsulphanyl}phenyl)acetic acid
70a. Ethyl (4-{3-[3-(4-butoxyphenyl)-1-heptylureido]- phenylsulphanyl}phenyl)acetate
70b. (4-{3-[3-(4-Butoxyphenyl)-1-heptylureido]phenylsulphanyl}phenyl)acetic acid 71a. Ethyl {4-[3-(1-heptyl-3-pentylureido)phenylsulphanyl]phenyl}acetate
71 b. {4-[3-(1-Heptyl-3-pentylureido)phenylsulphanyl]phenyl}acetic acid
72a. Ethyl {4-[3-(3-butyl-1 -heptylureido)phenylsulphanyl]phenyl}acetate
72b. {4-[3-(3-Butyl-1 -heptylureido)phenylsulphanyl]phenyl}acetic acid
73a. Ethyl (4-{3-[3-(4-dimethylaminophenyl)-1-heptyl- ureido]phenylsulphanyl}phenyl)acetate
73b. (4-{3-[3-(4-Dimethylaminophenyl)-1 -heptylureido]- phenylsulphanyl}phenyl)acetic acid
74a. Ethyl {4-[3-(3-benzyl-1 -butylureido)phenylsulphanyl]phenyl}acetate
74b. {4-[3-(3-Benzyl-1 -butylureido)phenylsulphanyl]phenyl}acetic acid 75a. Ethyl {4-[3-(1-butyl-3-phenylureido)phenylsulphanyl]phenyl}acetate
75b. {4-[3-(1-Butyl-3-phenylureido)phenylsulphanyl]phenyl}acetic acid
76a. Ethyl (4-{3-[1-butyl-3-(2,3-dichlorophenyl)- ureido]phenylsulphanyl}phenyl)acetate
76b. (4-{3-[1-Butyl-3-(2,3-dichlorophenyl)ureido]phenylsulphanyl}phenyl)acetic acid
77a. Ethyl {4-[3-(1-butyl-3-heptylureido)phenylsulphanyl]phenyl}acetate
77b. {4-[3-(1-Butyl-3-heptylureido)phenylsulphanyl]phenyl}acetic acid 78a. Ethyl {4-[3-(1-butyl-3-phenethylureido)phenylsulphanyl]phenyl}acetate
78b. {4-[3-(1-Butyl-3-phenethylureido)phenylsulphanyl]phenyl}acetic acid
79a. Ethyl (4-{3-[1-butyl-3-(4-trifluoromethylphenyl)- ureido]phenylsulphanyl}phenyl)acetate 79b. (4-{3-[1-Butyl-3-(4-trifluoromethylphenyl)ureido]- phenylsulphanyl}phenyl)acetic acid
80a. Ethyl (4-{3-[1-butyl-3-(4-methoxyphenyl)ureido]- phenylsulphanyl}phenyl)acetate
80b. (4-{3-[1-Butyl-3-(4-methoxyphenyl)ureido]phenylsulphanyl}phenyl)acetic acid
81a. Ethyl {4-[3-(3-adamantan-1 -yl-1 -butylureido)- phenylsulphanyl]phenyl}acetate
81 b. {4-[3-(3-Adamantan-1-yl-1-butylureido)phenylsulphanyl]phenyl}acetic acid
82a. Ethyl (4-{3-[1-butyl-3-(2-phenoxyphenyl)ureido]- phenylsulphanyl}phenyl)acetate
82b. (4-{3-[1-Butyl-3-(2-phenoxyphenyl)ureido]phenylsulphanyl}phenyl)acetic acid
83a. Ethyl {4-[3-(3-allyl-1 -butylureido)phenylsulphanyl]phenyl}acetate
83b. {4-[3-(3-Allyl-1 -butylureido)phenylsulphanyl]phenyl}acetic acid 84a. Ethyl {4-[3-(1-butyl-3-cyclohexylureido)phenylsulphanyl]phenyl}acetate
84b. {4-[3-(1-Butyl-3-cyclohexylureido)phenylsulphanyl]phenyl}acetic acid
85a. Ethyl (4-{3-[1-butyl-3-(2-nitrophenyl)ureido]phenylsulphanyl}phenyl)acetate
85b. (4-{3-[1 -Butyl-3-(2-nitrophenyl)ureido]phenylsulphanyl}phenyl)acetic acid
86a. Ethyl {4-[3-(1-butyl-3-hexylureido)phenylsulphanyl]phenyl}acetate 86b. {4-[3-(1-Butyl-3-hexylureido)phenylsulphanyl]phenyl}acetic acid
87a. Ethyl {4-[3-(1-butyl-3-naphthalen-2-ylureido)- phenylsulphanyl]phenyl}acetate 87b. {4-[3-(1-Butyl-3-naphthalen-2-ylureido)phenylsulphanyl]phenyl}acetic acid
88a. Ethyl (4-{3-[1-butyl-3-(2-ethoxyphenyl)ureido]- phenylsulphanyl}phenyl)acetate
88b. (4-{3-[1 -Butyl-3-(2-ethoxyphenyl)ureido]phenylsulphanyl}phenyl)acetic acid 89a. Ethyl (4-{3-[3-(4-butoxyphenyl)-1-butylureido]- phenylsulphanyl}phenyl)acetate
89b. (4-{3-[3-(4-Butoxyphenyl)-1 -butylureido]phenylsulphanyl}phenyl)acetic acid
90a. Ethyl {4-[3-(1-butyl-3-pentylureido)phenylsulphanyl]phenyl}acetate
90b. {4-[3-(1-Butyl-3-pentylureido)phenylsulphanyl]phenyl}acetic acid 91a. Ethyl {4-[3-(1,3-dibutylureido)phenylsulphanyl]phenyl}acetate
91 b. {4-[3-(1 ,3-Dibutylureido)phenylsulphanyl]phenyl}acetic acid
92a. Ethyl (4-{4-[3-benzyl-1-(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetate
92b. (4-{4-[3-Benzyl-1-(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid
93a. Ethyl (4-{4-[3-heptyl-1-(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetate
93b. (4-{4-[3-Heptyl-1-(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid 94a. Ethyl (4-{4-[3-phenethyl-1-(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetate
94b. (4-{4-[3-Phenethyl-1-(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid
95a. Ethyl (4-{4-[1-(3-phenylpropyl)-3-(4-tri- fluoromethylphenyl)ureido]phenylsulphanyl}phenyl)acetate
95b. (4-{4-[1 -(3-Phenylpropyl)-3-(4-tri- fluoromethylphenyl)ureido]phenylsulphanyl}phenyl)acetic acid 96a. Ethyl (4-{4-[3-(2-phenoxyphenyl)-1-(3-phenyl- propyl)ureido]phenylsulphanyl}phenyl)acetate
96b. (4-{4-[3-(2-Phenoxyphenyl)-1 -(3-phenyl- propyl)ureido]phenylsulphanyl}phenyl)acetic acid 97a. Ethyl (4-{4-[3-allyl-1-(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetate
97b. (4-{4-[3-Allyl-1 -(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid
98a. Ethyl (4-{4-[3-cyclohexyl-1-(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetate 98b. (4-{4-[3-Cyclohexyl-1-(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetic acid
99a. Ethyl (4-{4-[3-(2-nitrophenyl)-1-(3-phenyl- propyl)ureido]phenylsulphanyl}phenyl)acetate
99b. (4-{4-[3-(2-Nitrophenyl)-1 -(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetic acid
100a. Ethyl (4-{4-[3-hexyl-1-(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetate
100b. (4-{4-[3-Hexyl-1-(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid 101a. Ethyl (4-{4-[3-naphthalen-2-yl-1-(3-phenyl- propyl)ureido]phenylsulphanyl}phenyl)acetate
101b. (4-{4-[3-Naphthalen-2-yl-1 -(3-phenyl- propyl)ureido]phenylsulphanyl}phenyl)acetic acid
102a. Ethyl (4-{4-[3-(2-ethoxyphenyl)-1 -(3-phenyl- propyl)ureido]phenylsulphanyl}phenyl)acetate
102b. (4-{4-[3-(2-Ethoxyphenyl)-1 -(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetic acid 103a. Ethyl (4-{4-[3-(4-butoxyphenyl)-1-(3-phenyl- propyl)ureido]phenylsulphanyl}phenyl)acetate
103b. (4-{4-[3-(4-Butoxyphenyl)-1 -(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetic acid 104a. Ethyl (4-{4-[3-pentyl-1-(3-phenylpropyl)- ureido]pheny!sulphanyl}phenyl)acetate
104b. (4-{4-[3-Pentyl-1 -(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid
105a. Ethyl (4-{4-[3-butyl-1-(3-phenylpropyl)ureido]- phenylsulphanyl}phenyl)acetate
105b. (4-{4-[3-Butyl-1 -(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid
106a. Ethyl {4-[4-(3-benzyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetate
106b. {4-[4-(3-Benzyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid 107a. Ethyl {4-[4-(1-phenethyl-3-phenylureido)phenylsulphanyl]phenyl}acetate
107b. {4-[4-(1-Phenethyl-3-phenylureido)phenylsulphanyl]phenyl}acetic acid
108a. Ethyl (4-{4-[3-(2,3-dichlorophenyl)-1-phenethyl- ureido]phenylsulphanyl}phenyl)acetate
108b. (4-{4-[3-(2,3-Dichlorophenyl)-1 -phenethylureido]- phenylsulphanyl}phenyl)acetic acid
109a. Ethyl {4-[4-(3-heptyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetate
109b. {4-[4-(3-Heptyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid
110a. Ethyl {4-[4-(1 ,3-diphenethylureido)phenylsulphanyl]phenyl}acetate
110b. {4-[4-(1 ,3-Diphenethylureido)phenylsulphanyl]phenyl}acetic acid 111a. Ethyl (4-{4-[1-phenethyl-3-(4-trifluoro- methylphenyl)ureido]phenylsulphanyl}phenyl)acetate
111b. (4-{4-[1 -Phenethyl-3-(4-trif luoromethyl- phenyl)ureido]phenylsulphanyl}phenyl)acetic acid
112a. Ethyl (4-{4-[3-(4-methoxyphenyl)-1 -phenethyl- ureido]phenylsulphanyl}phenyl)acetate
112b. (4-{4-[3-(4-Methoxyphenyl)-1 -phenethylureido]- phenylsulphanyl}phenyl)acetic acid
113a. Ethyl {4-[4-(3-adamantan-1 -yl-1 -phenethyl- ureido)phenylsulphanyl]phenyl}acetate
113b. {4-[4-(3-Adamantan-1 -yl-1 -phenethylureido)- phenylsulphanyl]phenyl}acetic acid 114a. Ethyl (4-{4-[1-phenethyl-3-(2-phenoxyphenyl)- ureido]phenylsulphanyl}phenyl)acetate
114b. (4-{4-[1 -Phenethyl-3-(2-phenoxyphenyl)ureido]- phenylsulphanyl}phenyl)acetic acid
115a. Ethyl {4-[4-(3-allyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetate 115b. {4-[4-(3-Allyl-1-phenethylureido)phenylsulphanyl]phenyl}acetic acid
116a. Ethyl {4-[4-(3-cyclohexyl-1 -phenethylureido)- phenylsulphanyl]phenyl}acetate
116b. {4-[4-(3-Cyclohexyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid 117a. Ethyl (4-{4-[3-(2-nitrophenyl)-1 -phenethyl- ureido]phenylsulphanyl}phenyl)acetate
117b. (4-{4-[3-(2-Nitrophenyl)-1 -phenethylureido]phenylsulphanyl}phenyl)acetic acid
118a. Ethyl {4-[4-(3-hexyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetate 118b. {4-[4-(3-Hexyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid
119a. Ethyl {4-[4-(3-naphthalen-2-yl-1 -phenethyl- ureido)phenylsulphanyl]phenyl}acetate 119b. {4-[4-(3-Naphthalen-2-yl-1 -phenethylureido)- phenylsulphanyl]phenyl}acetic acid
120a. Ethyl (4-{4-[3-(2-ethoxyphenyl)-1-phenethyl- ureido]phenylsulphanyl}phenyI)acetate 120b. (4-{4-[3-(2-Ethoxyphenyl)-1-phenethylureido]- phenylsulphanyl}phenyl)acetic acid
121 a. Ethyl (4-{4-[3-(4-butoxyphenyl)-1 -phenethyl- ureido]phenylsulphanyl}phenyl)acetate
121 b. (4-{4-[3-(4-Butoxyphenyl)-1 -phenethylureido]- phenylsulphanyl}phenyl)acetic acid
122a. Ethyl {4-[4-(3-pentyI-1 -phenethylureido)phenylsulphanyl]phenyl}acetate
122b. {4-[4-(3-Pentyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid
123a. Ethyl {4-[4-(3-butyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetate
123b. {4-[4-(3-Butyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid 124a. Ethyl {4-[4-(3-benzyl-1-heptylureido)phenyIsulphanyl]phenyl}acetate
124b. {4-[4-(3-Benzyl-1 -heptylureido)phenylsulphanyl]phenyl}acetic acid
125a. Ethyl {4-[4-(1-heptyl-3-phenylureido)phenylsulphanyl]phenyl}acetate
125b. {4-[4-(1-Heptyl-3-phenylureido)phenylsulphanyI]phenyl}acetic acid
126a. Ethyl (4-{4-[3-(2,3-dichlorophenyl)-1-heptyl- ureido]phenylsulphanyl}phenyl)acetate
126b. (4-{4-[3-(2,3-Dichlorophenyl)-1-heptylureido]- phenylsulphanyl}phenyl)acetic acid
127a. Ethyl {4-[4-(1 ,3-diheptylureido)phenylsulphanyl]phenyl}acetate
127b. {4-[4-(1 ,3-Diheptylureido)phenylsulphanyl]phenyl}acetic acid 128a. Ethyl {4-[4-(1-heptyl-3-phenethylureido)phenylsulphanyl]phenyl}acetate
128b. {4-[4-(1-Heptyl-3-phenethylureido)phenylsulphanyl]phenyl}acetic acid
129a. Ethyl (4-{4-[1-heptyl-3-(4-trifluoro- methylphenyl)ureido]phenylsulphanyl}phenyl)acetate
129b. (4-{4-[1 -Heptyl-3-(4-trif luoromethyl- phenyl)ureido]phenylsulphanyl}phenyl)acetic acid
130a. Ethyl (4-{4-[1-heptyl-3-(4-methoxyphenyl)ureido]- phenylsulphanyl}phenyl)acetate
130b. (4-{4-[1 -Heptyl-3-(4-methoxyphenyl)ureido]phenylsulphanyl}phenyl)acetic acid
131a. Ethyl {4-[4-(3-adamantan-1-yl-1-heptylureido)- phenylsulphanyl]phenyl}acetate 131b. {4-[4-(3-Adamantan-1 -yl-1 -heptylureido)phenylsulphanyl]phenyl}acetic acid
132a. Ethyl (4-{4-[1-heptyl-3-(2-phenoxyphenyl)- ureido]phenylsulphanyl}phenyl)acetate
132b. (4-{4-[1 -Heptyl-3-(2-phenoxyphenyl)ureido]phenylsulphanyl}phenyl)acetic acid
133a. Ethyl {4-[4-(3-allyl-1 -heptylureido)phenylsulphanyl]phenyl}acetate
133b. {4-[4-(3-Allyl-1 -heptylureido)phenylsulphanyl]phenyl}acetic acid
134a. Ethyl {4-[4-(3-cyclohexyl-1 -heptylureido)phenylsulphanyl]phenyl}acetate
134b. {4-[4-(3-Cyclohexyl-1 -heptylureido)phenylsulphanyl]phenyl}acetic acid 135a. Ethyl (4-{4-[1-heptyl-3-(2-nitrophenyl)ureido]- phenylsulphanyl}phenyl)acetate
135b. (4-{4-[1 -Heptyl-3-(2-nitrophenyl)ureido]phenylsulphanyl}phenyl)acetic acid
136a. Ethyl {4-[4-(1-heptyl-3-hexylureido)phenylsulphanyl]phenyl}acetate 136b. {4-[4-(1-Heptyl-3-hexylureido)phenylsulphanyl]phenyl}acetic acid
137a. Ethyl {4-[4-(1-heptyl-3-naphthalen-2-ylureido)- phenylsulphanyl]phenyl}acetate 137b. {4-[4-(1-Heptyl-3-naphthalen-2-ylureido)phenylsulphanyl]phenyl}acetic acid
138a. Ethyl (4-{4-[3-(2-ethoxyphenyl)-1-heptylureido]- phenylsulphanyl}phenyl)acetate 138b. (4-{4-[3-(2-Ethoxyphenyl)-1 -heptylureido]phenylsulphanyl}phenyl)acetic acid
139a. Ethyl (4-{4-[3-(4-butoxyphenyl)-1-heptylureido]- phenylsulphanyl}phenyl)acetate 139b. (4-{4-[3-(4-Butoxyphenyl)-1 -heptylureido]phenylsulphanyl}phenyl)acetic acid
140a. Ethyl {4-[4-(1-heptyl-3-pentylureido)phenylsulphanyl]phenyI}acetate 140b. {4-[4-(1-Heptyl-3-pentylureido)phenylsulphanyl]phenyl}acetic acid 141a. Ethyl {4-[4-(3-butyl-1 -heptylureido)phenylsulphanyl]phenyl}acetate 141 b. {4-[4-(3-Butyl-1 -heptylureido)phenylsulphanyl]phenyl}acetic acid. A general description of the preparation of the compounds of general formula of the appended Figure 1 is given below.
The reaction scheme described in Figure 1 is a general scheme allowing the production of the compounds according to the invention.
The compounds of general formula (I) may be obtained (Figure 1) by coupling a thiol, an alcohol, an amine or a seleniated derivate (depend on X value) with an aromatic iodinated compound, using a metal catalyst such as nickel or palladium derivatives, in the presence of a hydride donor such as sodium borohydride and if necessary a base. Concerning diaryl amine compounds, the copper or palladium catalyzed amination (Tetrahedron 58, (2002) 2041-2075)of the nitro aniline compound with aryl halogenide may be used, followed by the reduction of the nitro to the corresponding amino group. Concerning the preparation of diaryl ether coupling of the corresponding alkoxide catalyzed by palladium may be used. Concerning the preparation of diaryl ketone compounds, palladium catalysed conversion of halogenoaryl derivatives compound to the corresponding organotin derivatives followed by a palladium catalysed coupling with acyl chloride derivative may afford the target product. The ketone might be protected in order to avoid problem during reductive amination. The next step is a reductive amination of the preceding amine and of an aldehyde, which may be carried out with isolation of the intermediate imine or otherwise, followed by reduction of the latter by the 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 give the corresponding urea or thiourea. It can also be further alkylated by reductive amination reaction in the presence of an aldehyde under the same conditions as above. The amide may also be formed by the action of an acid in the presence of a coupling agent such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) in the presence of a base such as DIEA or an acyl halide and a base. The derivatives obtained are then saponified by the action, for example, of a base such as NaOH to give the corresponding acids. The sulphated compounds (X: S) oxydated by the action of metachloroperbenzoic acid (MCPBA) in the presence of dichloromethane.
The compounds according to the invention have PPAR-type receptor modulating properties. This activity on the PPARα, δ and γ receptors is measured in a transactivation test and quantified by the dissociation constant Kdapp (apparent), as described in Example 142. The preferred compounds of the present invention have a dissociation constant of less than or equal to 1 000 nM, and advantageously of less than or equal to 500 nM. The subject of the present invention is also, as a medicament, the compounds of formula (I) as described above.
The subject of the present invention is the use of the compounds of formula (I) for manufacturing a composition intended for regulating and/or restoring the metabolism of skin lipids.
The compounds according to the invention are particularly suitable in the fields of the following treatments:
1) for treating dermatological conditions linked to a keratinization disorder related to cell differentiation and proliferation, in particular to treat acne vulgaris, comedo- type acne, polymorphic acne, acne rosacea, nodulocystic acne, acne conglobata, senile acne, secondary acne such as solar acne, acne medicamentosa or occupational acne;
2) for treating other types of keratinization disorders, in particular ichthyosis, ichthyosiform states, Darrier's disease, keratosis palmaris et plantaris, leukoplasia and leukoplasiform states, cutaneous or mucosal (buccal) lichen;
3) for treating other dermatological conditions with an inflammatory immunoallergic component, with or without cell proliferation disorder, and in particular all the forms of psoriasis, whether cutaneous, mucosal or ungual, and even psoriatic rheumatism, or cutaneous atopy, such as eczema or respiratory atopy or gingival hypertrophy;
4) for treating any dermal or epidermal proliferations whether benign or malignant, whether of viral origin or not, such as verruca vulgaris, verruca plana and epidermodysplasia verruciformis, oral or florid papillomatoses, T lymphoma, and proliferations which may be induced by ultraviolet radiation, in particular in the case of baso- and spinocellular epitheliomas, and any precancerous skin lesions such as keratoacanthomas;
5) for treating 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 conditions with an immunological component; 7) in the treatment of skin disorders due to exposure to UV radiation and for repairing or combating skin ageing, whether photoinduced or chronological or for reducing actinic keratoses and pigmentations, or any pathologies associated with chronological or actinic ageing, such as xerosis;
8) for combating sebaceous function disorders such as acne hyperseborrhoea, simple seborrhoea, or seborrhoeic dermatitis;
9) for preventing or treating cicatrization 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 lipid metabolism conditions, such as obesity, hyperlipidaemia, non-insulin-dependent diabetes or X syndrome;
12) in the treatment of inflammatory conditions such as arthritis;
13) in the treatment or prevention of cancerous or precancerous states;
14) in the prevention or treatment of alopecia of different origins, in particular alopecia due to chemotherapy or to radiation;
15) in the treatment of immune system disorders, such as asthma, diabetes mellitus type I, multiple sclerosis, or other selective dysfunctions of the immune system; and
16) in the treatment of conditions of the cardiovascular system such as arteriosclerosis or hypertension.
The subject of the present invention is also a pharmaceutical 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 application by the topical route.
By the enteral route, the composition may be provided in the form of tablets, gelatin capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, suspensions of lipid or polymeric microspheres or nanospheres or vesicles allowing controlled release. By the parenteral route, the composition may be provided in the form of solutions or suspensions for perfusion 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. The compounds are used by the systemic route 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.
By the topical route, the pharmaceutical composition according to the invention is more particularly intended for the treatment of the skin and the mucous membranes and may be provided in the form of salves, creams, milks, ointments, powders, impregnated pads, syndets, solutions, gels, sprays, mousses, suspensions, lotions, sticks, shampoos or washing bases. It may also be provided in the form of suspensions of lipid or polymeric microspheres or nanospheres or vesicles or of polymeric patches and of hydrogels allowing controlled release. This composition for the topical route may be provided in anhydrous form, in aqueous form or in the form of an emulsion.
The compounds are used by the topical route at a concentration which is generally 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 care, and more particularly for regulating and/or restoring skin lipid metabolism.
The subject of the invention is therefore also 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 care.
The cosmetic composition according to the invention containing, in a cosmetically acceptable carrier, at least one compound of formula (I) or one of its optical or geometric isomers or one of its salts, may be provided in particular in the form of a cream, a milk, a lotion, a gel, suspensions of lipid or polymeric microspheres or nanospheres or vesicles, impregnated pads, solutions, sprays, mousses, sticks, soaps, shampoos or washing bases. The concentration of compound of formula (I) in the cosmetic composition is preferably between 0.001% and 3% by weight, relative to the total weight of the composition.
The pharmaceutical and cosmetic compositions as described above may in addition contain inert additives, or even pharmacodynamically active additives as regards the pharmaceutical compositions, or combinations of these additives, and in particular:
- wetting agents;
- flavour enhancers;
- preservatives such as esters of parahydroxybenzoic acid; - stabilizers;
- moisture regulators;
- pH regulators; - osmotic pressure modifiers;
- emulsifiers;
- UV-A and UV-B screening agents;
- antioxidants, such as α-tocopherol, butylated hydroxyanisole or butylated hydroxytoluene, Super Oxide 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;
- antiseborrhoeic 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 4,5-polymethylene-3-isothiazolidones;
- agents promoting hair regrowth, such as Minoxidil (2,4-diamino-6- piperidinopyrimidine 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, β-carotene;
- antipsoriatic agents such as anthralin and its derivatives;
- 5,8,11 ,14-eicosatetraynoic and 5,8,11-eicosatriynoic acids, their esters and amides; - retinoids, that is to say ligands for the RAR or RXR receptors, which may be natural or synthetic;
- corticosteroids or oestrogens; - α-hydroxy acids and α-keto acids or their derivatives, such as lactic, malic, citric, glycolic, mandelic, tartaric, glyceric and ascorbic acids, and their salts, amides or esters, or β-hydroxy acids or their derivatives, such as salicylic acid and its salts, amides or esters; - ion channel, such as potassium channel, blockers;
- or alternatively, more particularly for pharmaceutical compositions, in combination with medicaments known to interfere with the immune system (for example cyclosporine, FK 506, glucocorticoids, monoclonal antibodies, cytokines or growth factors, and the like). Of course, persons skilled in the art will be careful to choose the possible compound(s) to be added to these compositions such that the advantageous properties intrinsically attached to the present invention are not or not substantially impaired by the addition envisaged.
Several examples of production of active compounds of formula (I) according to the invention, results of biological activity thereof and various concrete formulations based on such compounds, will now be given by way of illustration and without being limiting in any manner.
EXAMPLES The products were analysed by HPLC/Mass. Column: 2.1X5 mm,
3 μ, High purity C18 Hypersil.
Mobile phase: A (CH3CN/0.1 v/v HCO2H); B (H2O/0.1 v/v HCO2H),
Waters Alliance 2790 LC Mobile Phase
Solvents A% 35.0 Solvent A B% 65.0 Solvent B
Flow rate (ml/min) 0.450
Analytical time (min) 5.00 Column temperature (°C) 60
Maximum column temperature (°C) 10
Waters Alliance 2790 LC Rapid Equilibration System time (min) 0.30 Re-equilibration time (min) 0.50
The gradient contains 3 entries which are Time A% B% Flow rate 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: Ethyl 4-(3-aminophenylsulphanyl)phenyllacetate a) Ethyl 4-iodophenylacetate 1.25 ml (0.023 mol) of concentrated sulphuric acid are added dropwise to a mixture of 6.14 g (0.023 mol) of 4-iodophenylacetic acid in 50 ml of ethanol. The reaction medium is then heated under reflux for 7 h, and then concentrated in a rotary evaporator under vacuum. Water is added to the residue obtained. The solution is neutralized by adding sodium bicarbonate. The desired product is extracted by adding ethyl ether. The organic phase is washed with water, dried over magnesium sulphate and concentrated in a rotary evaporator. The product is purified by filtration on a silica column, eluted with a dichloromethane 8/heptane 2 mixture. After evaporation of the solvents, 6.2 g (96%) of the expected compound are recovered in the form of a colourless oil. b) Ethyl f4-(3-aminophenylsulphanv0phenvπacetate
A solution of 3-aminothiophenol (2 g, 0.016 mol) in 30 ml of THF is added over a mixture of borohydride polymer supported Amberlite® IRA400 resin (2.5 mmol/g) (Aldrich: 32864-2) (16.2 g, 0.04 mol), bis(bipyridine)nickel (II) bromide (150 mg) (Organometallics 1985, 4, 657-661) and ethyl 4-iodophenylacetate (3 g, 0.011 mol) in ethanol (120 ml). The mixture is stirred under reflux for 3 h and 12 h at room temperature. The reaction medium is filtered and the filtrate concentrated in a rotary evaporator under vacuum. The product is purified by chromatography on a silica column (dichloromethane 5/ heptane 5). After evaporation of the solvents, the expected compound 2.2 g (70%), is isolated in the form of a yellow oil.
1H NMR (CDCI3, 400 MHz): 1.28 (3H, t), 3.61 (2H, s), 4.18 (2H, q), 6.57 (1 H, Ar, d), 6.66 (1H, Ar, s), 6.75 (1H, Ar, d), 7.09 (1H, Ar, t), 7.23 (2H, Ar, d), 7.335 (2H, Ar, d).
EXAMPLE 2: Ethyl r4-(4-aminophenylsulphanyl)phenvπacetate
In a manner similar to Example 1(b), by reacting ethyl 4-iodophenylacetate (2.5 g, 0.01 mol), 30 mi of THF, borohydride polymer supported Amberlite® IRA400 resin (2.5 mmol/g) (Aldrich: 32864-2) (13.5 g), bis(bipyridine)nickel (II) bromide (125 mg) (Organometallics 1985, 4, 657-661) and 4,4'-dithiodianiline (1.7 g, 0.013 mol), 1.1 g (42%) of the expected derivative is obtained in the form of a yellow oil. 1H NMR (CDCIs, 400 MHz): 1.26 (3H, t), 3.55 (2H, s), 4.15 (2H, q), 6.67 (2H, Ar, d), 7.10 (2H, Ar, d), 7.15 (2H, Ar, d), 7.32 (2H, Ar, d).
EXAMPLE 3: 4-r3-.3-Phenylpropylamino)phenylsulphanyllphenyl}acetic acid a) Ethyl {4-[3-(3-phenylpropylamino)phenylsulphanyl1phenyl)acetate A solution of 3-phenylpropionaldehyde (257 mg, 1.91 mmol) and acetic acid (1 ml) is added to a solution of ethyl [4-(3-aminophenylsulphanyl)phenyl]acetate (Example 1(b)) (550 mg, 1.91 mmol) in 15 ml of DMF. DMF 241 mg and sodium cyanoborohydride (3.83 mmol) are added and the mixture is stirred for 12 h at room temperature. After extracting with ethyl ether, the organic phase is washed 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, 601 mg (77%) of the expected derivative and 100 mg (10%) of ethyl
(4-{3-[bis(3-phenylpropyl)amino]phenylsulphanyl}phenyl)acetate are obtained. 1H NMR (CDCI3, 400 MHz): 1.29 (3H, t), 1.91 to 1.99 (2H, m), 2.74 (2H, t), 3.13 (2H, t), 3.63 (2H, s), 3.69 (1 H, NH, s), 4.20 (2H, q), 6.5 (1H, Ar, d), 6.61 (1 H, Ar, s), 6.71 (1H, Ar, d), 7.11 (1 H, Ar, t), 7.21 to 7.26 (5H, Ar, m), 7.33 (4H, Ar, t). b) (4-[3-(3-Phenylpropylamino)phenylsulphanyl1phenyl}acetic acid
In a manner similar to Example 1(c), the product is obtained by reacting ethyl {4-[3-(3-phenylpropylamino)phenylsulphanyl]phenyl}acetate (Example 3(a)) (50 mg), sodium hydroxide (80 mg), water (500 μl) and ethanol (500 μl) in THF (3 ml).
EXAMPLE 4: (4- 3-rBis.3-phenylpropynaminolphenyl- sulphanyllphenvDacetic acid In a manner similar to Example 1(c), the product is obtained by reacting ethyl (4-{3-[bis(3-phenylpropyl)amino]phenylsulphanyl}phenyl)acetate obtained in (Example 3(a)) (50 mg), sodium hydroxide (80 mg), water (500 μl) and ethanol (500 μl) in THF (3 ml).
EXAMPLE 5: r4-.3-Phenylethylamino)phenylsulphanylphenyllacetic acid a) Ethyl r4-(3-phenylethylamino)phenylsulphanylphenyllacetate
In a manner similar to Example 3(a), by reacting 3-phenylacetaldehyde (230 mg, 1.91 mmol), acetic acid (1 ml), ethyl [4-(3-aminophenylsulphanyl)phenyl]acetate (Example 1(b)) (550 mg, 1.91 mmol) in 15 ml of DMF and 241 mg of sodium cyanoborohydride (3.83 mmol), 643 mg (86%) of the expected derivative are obtained in the form of a colourless oil and 26 mg (10%) of ethyl [4-(3-diphenethylaminophenylsulphanyl)phenyl]acetate. b) r4-(3-Phenethylamino)phenylsulphanylphenyllacetic acid
In a manner similar to Example 1(c), the product is obtained by reacting ethyl [4-(3-phenethylamino)phenylsulphanylphenyl]acetate
(Example 5(a)) (50 mg), sodium hydroxide (80 mg), water (500 μl) and ethanol (500 μl) in THF (3 ml).
EXAMPLE 6: r4-.3-Diphenethylaminophenylsulphanyl)phenyl1acetic acid
In a manner similar to Example 1(c), the product is obtained by reacting ethyl [4-(3-diphenethylaminophenylsulphanyl)phenyl]acetate obtained in Example 5(a) (50 mg), sodium hydroxide (80 mg), water (500 μl) and ethanol (500 μl) in THF (3 ml).
EXAMPLE 7: r4-(3-Heptylaminophenylsulphanyl)phenvHacetic acid a) Ethyl r4-(3-heptylaminophenylsulphanyl)phenyllacetate In a manner similar to Example 3(a), by reacting heptaldehyde
(219 mg, 1.91 mmol), acetic acid (1 ml), ethyl
[4-(3-aminophenylsulphanyl)phenyl]acetate (Example 1(b)) (550 mg, 1.91 mmol) in 15 ml of DMF and 241 mg of sodium cyanoborohydride (2.71 mmol), 330 mg (45%) of the expected derivative are obtained in the form of a colourless oil and 64 mg (7%) of ethyl [4-(3-diheptylaminophenylsulphanyl)phenyl]acetate.
1H NMR (CDCIg, 400 MHz): 0.93 (3H, t), 1.28 (3H, t), 1.32 to 1.41 (8H, m), 1.57 to 1.64 (2H, m), 3.07 (2H, t), 3.06 (2H, t), 3.60 (2H, s), 4.18 (2H, q), 6.49 (1 H, Ar, d), 6.61 (1 H, Ar, s), 6.68 (1H, Ar, d), 7.11 (1 H, Ar, t), 7.23 (2H, Ar, d), 7.32 (2H, Ar, d). b) -O-Heptylaminophenylsulphanvπphenvnacetic acid
In a manner similar to Example 1(c), the product is obtained by reacting ethyl [4-(3-heptylaminophenylsulphanyl)phenyl]acetate (Example 7(a)) (50 mg), sodium hydroxide (80 mg), water (500 μl) and ethanol (500 μl) in THF (3 ml).
EXAMPLE 8: r4-.3-Diheptylaminophenylsulphanyl)phenvπacetic acid
In a manner similar to Example 1(c), the product is obtained by reacting ethyl [4-(3-diheptylaminophenylsulphanyl)phenyl]acetate obtained in Example 7(a) (50 mg), sodium hydroxide (80 mg), water (500 μl) and ethanol (500 μl) in THF (3 ml).
EXAMPLE 9: r4-(3-ButylaminophenylsulphanvQphenyl1acetic acid a) Ethyl r4-(3-butylaminophenylsulphanyl)phenvnacetate
In a manner similar to Example 3(a), by reacting butyraldehyde (138 mg, 1.91 mmol), acetic acid (1 ml), ethyl
[4-(3-aminophenylsulphanyl)phenyl]acetate (Example 1(b)) (550 mg, 1.91 mmol) in 15 ml of DMF and 241 mg of sodium cyanoborohydride (2.71 mmol), 140 mg (21%) of the expected derivative are obtained in the form of a colourless oil and 464 mg (61%) of ethyl [4-(3-dibutylaminophenylsulphanyl)phenyl]acetate. 1H NMR (CDCI3, 400 MHz): 0.97 (3H, t), 1.28 (3H, t), 1.39 to 1.45 (2H, m), 1.57 to 1.61 (2H, m), 3.08 (2H, t), 3.62 (2H, s), 3.67 (1 H, NH, s), 4.12 (2H, q), 6.51 (1H, Ar, d), 6.61 (1 H, Ar, s), 6.69 (1 H, Ar, d), 7.11 (1 H, Ar, t), 7.23 (2H, Ar, d), 7.33 (2H, Ar, d). b) r4-(3-Butylaminophenylsulphanyl)phenyl1acetic acid
In a manner similar to Example 1(c), the product is obtained by reacting ethyl [4-(3-butylaminophenylsulphanyl)phenyl]acetate (Example 9(a)) (50 mg), sodium hydroxide (80 mg), water (500 μl) and ethanol (500 μl) in THF (3 ml).
EXAMPLE 10: r4-(3-Dibutylaminophenylsulphanyl)phenyllacetic acid
In a manner similar to Example 1(c), the product is obtained by reacting ethyl [4-(3-dibutylaminophenylsulphanyl)phenyl]acetate obtained in Example 9(a) (50 mg, 0.174 mmol), sodium hydroxide (80 mg), water (500 μl) and ethanol (500 μl) in THF (3 ml).
EXAMPLE 11 : {4-f4-(3-Phenylpropylamino)phenylsulphanvHphenyl acetic acid a) Ethyl {4-[4-(3-phenylpropylamino)phenylsulphanyllphenyl)acetate
In a manner similar to Example 3(a), by reacting 3-phenylpropionaldehyde (128 mg, 0.96 mmol), acetic acid (1 ml), ethyl [4-(4-aminophenylsulphanyl)phenyl]acetate (Example 2(a)) (275 mg, 0.96 mmol) in 15 ml of DMF 120 mg and sodium cyanoborohydride (1.91 mmol), 307 mg (79%) of the expected derivative and 55 mg (11%) of ethyl (4-{4-[bis(3-phenyipropyl)amino]phenylsulphanyl}phenyl)acetate are obtained. 1H NMR (CDCI3, 400 MHz): 1.27 (3H, t), 1.96 to 2.03 (2H, m), 2.77 (2H, t), 3.19 (2H, t), 3.56 (2H, s), 3.86 (1 H, NH, s), 4.16 (2H, q), 6.58 (1 H, Ar, d), 7.09 (2H, Ar, d), 7.15 (2H, Ar, d), 7.23 to 7.26 (3H, Ar, m), 7.32 to 7.36 (4H, Ar, m). b) (4-[4-(3-Phenylpropylamino)phenylsulphanyljphenyl)acetic acid
In a manner similar to Example 1(c), the product is obtained by reacting ethyl {4-[4-(3-phenylpropylamino)phenylsulphanyl]phenyl}acetate (Example 11(a)) (50 mg), sodium hydroxide (80 mg), water (500 μl) and ethanol (500 μl) in THF (3 ml). EXAMPLE 12: .4-(4-rBis.3-phenylpropynamino1phenyl- sulphanyl)phenyl)acetic acid
In a manner similar to Example 1(c), the product is obtained by reacting ethyl (4-{4-[bis(3-phenylpropyl)amino]phenylsulphanyl}phenyl)acetate obtained in Example 11(a) (50 mg), sodium hydroxide (80 mg), water (500 μl) and ethanol (500 μl) in THF (3 ml).
EXAMPLE 13: r4-(4-Phenethylaminophenylsulphanyl)phenyllacetic acid a) Ethyl [4-(4-phenethylaminophenylsulphanyl)phenyriacetate
In a manner similar to Example 3(a), by reacting phenylacetaldehyde (115 mg, 0.96 mmol), acetic acid (1 ml), ethyl [4-(4-aminophenylsulphanyl)phenyl]acetate (Example 2(a)) (275 mg, 0.96 mmol) in 15 ml of DMF and 241 mg of sodium cyanoborohydride (3.83 mmol), 311 mg (83%) of the expected derivative are obtained in the form of a colourless oil and 17 mg (4%) of ethyl [4-(4-diphenethylaminophenylsulphanyl)phenyl]acetate. 1H NMR (CDCI3, 400 MHz): 1.29 (3H, t), 2.97 (2H, t), 3.45 (2H, t), 3.58 (2H, s), 3.95 (1H, NH, s), 4.18 (2H, q), 6.32 (2H, Ar, d), 7.12 (2H, Ar, d), 7.18 (2H, Ar, d), 7.27 to 7.30 (3H, Ar, m), 7.36 to 7.40 (4H, Ar, m). b) [4-(4-Phenethylaminophenylsulphanyl)phenyr|acetic acid
In a manner similar to Example 1(c), the product is obtained by reacting ethyl [4-(4-phenethylaminophenylsulphanyl)phenyl]acetate
(Example 13(a)) (50 mg), sodium hydroxide (80 mg), water (500 μl) and ethanol (500 μl) in THF (3 ml).
EXAMPLE 14: r4-.4-Diphenethylaminophenylsulphanyl)phenvπacetic acid
In a manner similar to Example 1(c), the product is obtained by reacting ethyl [4-(4-diphenethylaminophenylsulphanyl)phenyl]acetate obtained in Example 13(a) (50 mg), sodium hydroxide (80 mg), water (500 μl) and ethanol (500 μl) in THF (3 ml).
EXAMPLE 15: r4-(4-Heptylaminophenylsulphanyl)phenyllacetic acid a) Ethyl f4-(4-heptylaminophenylsulphanvDphenyl1acetate
In a manner similar to Example 3(a), by reacting heptaldehyde (109 mg, 0.96 mmol), acetic acid (1 ml), ethyl
[4-(4-aminophenylsulphanyl)phenyl]acetate (Example 2(a)) (275 mg, 0.96 mmol) in 15 ml of DMF and 241 mg of sodium cyanoborohydride (2.71 mmol), 250 mg (68%) of the expected derivative are obtained in the form of a colourless oil and 43 mg (9%) of ethyl [4-(4-diheptylaminophenylsulphanyl)phenyl]acetate. 1H NMR (CDCI3, 400 MHz): 0.92 (3H, t), 1.28 (3H, t), 1.30 to 1.43 (8H, m), 1.63 to 1.67 (2H, m), 3.14 (2H, t), 3.55 (2H, s), 3.86 (1 H, NH, s), 4.15 (2H, q), 6.60 (2H, Ar, d), 7.08 (2H, Ar, d), 7.15 (2H, Ar, d), 7.35 (2H, Ar, d). b) r4-(4-HeptylaminophenylsulphanvDphenyllacetic acid
In a manner similar to Example 1(c), the product is obtained by reacting ethyl [4-(4-heptylaminophenylsulphanyl)phenyl]acetate (Example 15(a)) (50 mg), sodium hydroxide (80 mg), water (500 μl) and ethanol (500 μl) in THF (3 ml).
EXAMPLE 16: r4-(4-Diheptylaminophenylsulphanvπphenyllacetic acid
In a manner similar to Example 1(c), the product is obtained by reacting ethyl [4-(4-diheptylaminophenylsulphanyl)phenyl]acetate obtained in Example 15(a) (50 mg), sodium hydroxide (80 mg), water (500 μl) and ethanol (500 μl) in THF (3 ml). EXAMPLE 17: r4-(4-Dibutylaminophenylsulphanyl)phenyl1acetic acid a) Ethyl f4-(4-dibutylaminophenylsulphanvhphenvnacetate
In a manner similar to Example 3(a), by reacting butyraldehyde
(69 mg, 0.96 mmol), acetic acid (1 ml), ethyl [4-(4-aminophenylsulphanyl)phenyl]acetate (Example 2(a)) (275 mg, 0.96 mmol) in 15 ml of DMF and 241 mg of sodium cyanoborohydride (2.71 mmol), 313 mg
(82%) of ethyl [4-(4-dibutylaminophenylsulphanyl)phenyl]acetate are obtained. b) f4-(4-Dibutylaminophenylsulphanyl)phenvπacetic acid
In a manner similar to Example 1(c), the product is obtained by reacting ethyl [4-(4-dibutylaminophenylsulphanyl)phenyl]acetate (Example 17(a)) (50 mg), sodium hydroxide (80 mg), water (500 μl) and ethanol (500 μl) in THF (3 ml). Table 1: Results of analysis of the products of Examples 1b to 17b
Figure imgf000040_0001
Figure imgf000041_0002
EXAMPLES 18 TO 141: SYNTHESIS OF EXAMPLES 18 to 141
Examples 18 to 141 were obtained by parallel chemistry. The reactions of a starting amine and a starting isocyanate are performed in several reactors simultaneously according to the operating protocol described below.
A. Formation of urea for the [4-(aminophenylsulphanyl)phenyl]acetic acid derivatives
Operating protocol: The starting amine (see Table 3) is introduced into each 5 ml reactor. 2 ml of dichloromethane are added. Next, 0.062 mmol of isocyanate (see Table 4) are added. The reactors are stirred for 7 h at room temperature. 0.062 mmol of isocyanates are added if the starting amine has not completely disappeared (TLC monitoring). In this case, the stirring is continued for 12 h at room temperature.
The reaction media are concentrated to dryness for 2 h at 40°C in a centrifugal evaporator under vacuum. The products are purified by filtration on silica cartridges (6 ml), 1 :DCM, 2:DCM 80/AcOEt 20, and then concentrated to dryness, 2 h at 40°C in a centrifugal evaporator. Table 2: Starting amines
Figure imgf000041_0001
Figure imgf000042_0001
Table 3: Starting isocyanates
Figure imgf000043_0002
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
OjH
HF. n at
Figure imgf000047_0003
The CM acid sium um. and t nder
Figure imgf000047_0001
Figure imgf000047_0004
Table 4: Analysis of the products of Examples 18b to 141b
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Compounds 18a to 141a are the esters corresponding to the acids 18b to 141b obtained before the saponification step.
EXAMPLE 142 - CROSS CURVE PPAR TRANSACTIVATION TEST The activation of receptors with 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 as quantity of luminescence produced after incubating the cells in the presence of a reference agonist. The ligands will displace the agonist from its site. The measurement of the activity is performed by quantification of the light produced. This measurement makes it possible to determine the modulatory 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 called apparent Kd (KdApp in nM).
To determine this constant, "cross curves" for the product to be tested against a reference agonist are produced in a 96-well plate: 10 concentrations of the test product plus a concentration 0 are placed in a line, and 7 concentrations of the agonist plus one concentration 0 are placed in a column. This represents 88 measurement points for 1 product and 1 receptor. The 8 remaining wells are used for repeatability controls.
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-difluorophenyl)-1-heptylureido]ethylJphenylsulphanyl)- 2-methylpropionic acid for PPARα, {2-methyl-4-[4-methyl-
2-(4-trifluoromethylphenyl)thiazol-5-ylmethylsulphanylJphenoxyJacetic acid for PPARδ and 5-{4-[2-(methylpyridin-2-ylamino)ethoxy]benzyl}thiazolidine-2,4-dione for PPARγ. Measurements are also carried out for the controls total agonist with the same products.
The HeLN cell lines used are stable transfectants containing the plasmids ERE-βGlob-Luc-SV-Neo (reporter gene) and PPAR (α, δ, γ) Gal-hPPAR. These cells are inoculated into 96-well plates in an amount of 10 000 cells per well in 100 μl of DMEM medium free of phenol red and supplemented with 10% lipid- free calf serum. The plates are then incubated at 37°C, 7% CO2 for 16 hours.
The various dilutions of the test products and of the reference ligand are added in an amount of 5 μl per well. The plates are then incubated for 18 hours at 37°C, 7% CO2. The culture medium is removed by turning over and
100 μl of a 1 :1 PBS/Luciferin mixture are added to each well. After 5 minutes, the plates are read by the luminescence reader.
These cross curves make it possible to determine the AC50 values
(concentrations at which 50% activation is observed) for the reference ligand at various concentrations of test product. These AC50 values are used to calculate the Schild regression by plotting a straight line corresponding to the Schild equation ("quantitation in receptor pharmacology" Terry P. Kenakin, Receptors and Channels, 2001, 371-385) which leads to Kd app values being obtained (in nM).
Transactivation results:
Figure imgf000063_0001
n.a. means not active
EXAMPLE 143 - COMPOSITIONS
Various concrete formulations based on the compounds according to the invention have been illustrated in this example.
A- ORAL ROUTE
(a) 0.2 g tablet
- Compound of Example 2a 0.001 g - Starch 0.114 g
- Bicalcium 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 vials
- Compound of Example 7b 0.001 g
- Glycerine 0.500 g
- Sorbitol at 70% 0.500 g
- Sodium saccharinate 0.010 g
- Methyl para-hydroxybenzoate 0.040 g
- Flavouring qs
- Purified water qs 5 ml
(c) 0.8 g tablet
- Compound of Example 45b 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 vials
- Compound of Example 115a 0.200 g
- Glycerine 1.000 g
- Sorbitol at 70% 1.000 g
- Sodium saccharinate 0.010 g
- Methyl para-hydroxybenzoate 0.080 g
- Flavouring qs
- Purified water qs 10 ml
B- TOPICAL ROUTE
(a) Salve
- Compound of Example 76b 0.020 g
- Isopropyl myristate 81.700 g
- Fluid liquid paraffin 9.100 g
- Silica ("Aerosil 200" sold by DEGUSSA) 9.180 g
(b) Salve
- Compound of Example 95a 0.300 g
- Petroleum jelly qs 100 g
(c) Nonionic water-in-oil cream
- Compound of Example 46a 0.100 g
- Mixture of emulsifying lanolin alcohols, waxes and oils ("anhydrous eucerin" sold by BDF)
39.900 g
- Methyl para-hydroxybenzoate 0.075 g
- Propyl para-hydroxybenzoate 0.075 g
- Sterile demineralized water qs 100 g (d) Lotion Compound of Example 57a 0.100 g Polyethylene glycol (PEG 400) 69.900 g Ethanol at 95% 30.000 g
(e) Hydrophobic salve
- Compound of Example 21b 0.300 g
- Isopropyl myristate 36.400 g
- Silicone oil ("Rhodorsil 47 V 300" sold by RHONE-POULENC) 36.400 g - Beeswax 13.600 g
- Silicone oil ("Abil 300,000 cst" sold by GOLDSCHMIDT) qs 100 g
(f) Nonionic oil-in-water cream
- Compound of Example 19a 1.000 g
- Cetyl alcohol 4.000 g
- Glyceryl monostearate 2.500 g
- PEG 50 stearate 2.500 g
- Shea butter 9.200 g
- Propylene glycol 2.000 g
- Methyl para-hydroxybenzoate 0.075 g
- Propyl para-hydroxybenzoate 0.075 g
- Sterile demineralized water qs 100 g

Claims

1. Compounds, characterized in that they correspond to the following formula (I):
Figure imgf000067_0001
(I)
in which
- An represents an optionally substituted radical of formula:
Figure imgf000067_0002
Z represents the substituent:
O
Y
R1
it being understood that Z is at the para position with respect to X on the ring Aη; R1 and Y having the meanings given below, - Ar2 represents an optionally substituted radical of formula: 67
Figure imgf000068_0001
- R1 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; - 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 from 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, an aralkyl radical, a polyether radical, a monohydroxyalkyl radical, a polyhydroxyalkyl radical, a radical COR5 or CSR5;
R5 having the meanings given below,
- Y represents an oxygen or sulphur atom, or the radical N-R4;
R4 having the meanings given below, - R4 represents a hydrogen atom, an alkyl radical having from 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, a polyether radical, an aralkyl radical or forms, with R1 and the nitrogen atom of Y, a heterocycle or a heteroaryl;
- R5 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, a radical R6-N-R7 or a radical O-R8;
R6, R7 and R8 having the meanings given below,
- R6 and R7 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, an aralkyl radical or alternatively, taken together, form a heterocycle;
- R8 represents 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 or an aralkyl radical;
- X represents an S atom, a radical S=O, a radical O=S=O, an Se atom, an O atom, a radical N-R9, a radical C=O, a radical HO-C-R11 or a radical R10-C- R11 ; R9, R10 and R11 having the meanings given below,
- R9 represents a hydrogen atom, a radical -COR12, an alkyl radical having from 1 to 12 carbon atoms, a polyether radical, an aryl radical or an aralkyl radical;
R12 having the meanings given below, - R10 and R11 , which are identical or different, represent a hydrogen atom, an alkyl radical having from 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 heteroatoms and preferably the rings are dithianyl, dioxanyl, dithiolanyl, dioxolanyl or cyclopropanyl radicals;
- A represents an S, O or Se atom or a radical N-R13;
R13 having the meanings given below,
- R12 represents an alkyl radical having from 1 to 12 carbon atoms; - R13 represents a hydrogen atom, an alkyl radical having from 1 to 12 carbon atoms, an aryl radical, a heteroaryl radical, a polyether radical or an aralkyl radical; and when R2 represents a hydrogen atom, R5 is different from an aryl radical and
R3 is different from a hydrogen atom, and the optical and geometric isomers of the said compounds of formula (I) and their salts.
2. Compounds according to Claim 1 , characterized in that they are provided in the form of salts of an alkali 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 from 1 to 12 carbon atoms are chosen from hydrogenated or fluorinated, linear or cyclic, optionally branched radicals containing 1 to 12 carbon atoms which may be interrupted by one or more heteroatoms, and preferably the alkyl radicals having from 1 to 12 carbon atoms are methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, octyl, decyl or cyclohexyl radicals.
4. Compounds according to any one of Claims 1 to 3, characterized in that the monohydroxyalkyl radicals are chosen from the radicals having 1 to 6 carbon atoms and preferably having from 2 to 3 carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.
5. Compounds according to any one of Claims 1 to 3, characterized in that the polyhydroxyalkyl radicals are chosen from the radicals containing from 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl or 2,3,4,5-tetrahydroxypentyl radicals or the pentaerythritol residue.
6. Compounds according to any one of the preceding claims, characterized in that the polyether radicals are chosen from the polyether radicals having from 1 to 6 carbon atoms interrupted by at least one oxygen atom such as methoxymethoxy, ethoxymethoxy or methoxyethoxymethoxy radicals.
7. Compounds according to any one of the preceding claims, characterized in that the alkoxy radical having from 1 to 7 carbon atoms is chosen from the group consisting of methoxy, ethoxy, isopropyloxy, tert-butoxy, hexyloxy, benzyloxy or phenoxy radicals, which may be optionally substituted with an alkyl radical having from 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 with a halogen atom, a radical CF3, 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 or benzoyl group or an amino functional group optionally protected by an acetyl or benzoyl group or optionally substituted with 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-2-ylmethyl radical which may be mono- or disubstituted with a halogen atom, a radical CF3, 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 or benzoyl group or an amino functional group optionally protected by an acetyl or 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, oxadiazolyl, oxazolyl, isothiazolyl, quinazolinyl, benzothiadiazolyl, benzimidazole, indolyl or benzofuran radical, optionally substituted with at least one halogen, an alkyl having from 1 to 12 carbon atoms, an alkoxy having from 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 or benzoyl group or an amino functional group optionally protected by an acetyl or benzoyl group or optionally substituted with at least one alkyl having from 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-oxopiperidin-1-yl and 2-oxopyrrolidin- 1-yl radical optionally substituted with at least one alkyl group having from 1 to 12 carbon atoms, an alkoxy having from 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 or benzoyl group or an amino functional group optionally protected by an acetyl or benzoyl group or optionally substituted with at least one alkyl having from 1 to 12 carbon atoms.
12. Compounds according to Claim 1 , characterized in that they are chosen, alone or in the form of mixtures, from the group consisting of:
1b. Ethyl [4-(3-aminophenylsulphanyl)phenyl]acetate 2. Ethyl [4-(4-aminophenylsulphanyl)phenyl]acetate 3a. Ethyl {4-[3-(3-phenylpropylamino)phenylsulphanyl]phenyl}acetate 3b. {4-[3-(3-Phenylpropylamino)phenylsulphanyl]phenyl}acetic acid 4a. Ethyl (4-{3-[bis(3-phenylpropyl)amino]phenylsulphanyl}phenyl)acetate 4b. (4-{3-[Bis(3-phenylpropyl)amino]phenylsuphanyl}phenyl)acetic acid 5a. Ethyl [4-(3-Phenethylamino)phenylsulphanylphenyl]acetate 5b. [4-(3-Phenethylamino)phenylsulphanylphenyl]acetic acid
6a. Ethyl [4-(3-Diphenethylaminophenylsulphanyl)phenyl]acetate
6b. [4-(3-Diphenethylaminophenylsulphanyl)phenyl]acetic acid
7a. Ethyl [4-(3-heptylaminophenylsulphanyl)phenyl]acetate 7b. [4-(3-Heptylaminophenylsulphanyl)phenyl]acetic acid
8a. Ethyl [4-(3-diheptylaminophenylsulphanyl)phenyl]acetate
8b. [4-(3-Diheptylaminophenylsulphanyl)phenyl]acetic acid
9a. Ethyl [4-(3-butylaminophenylsulphanyl)phenylJacetate
9b. [4-(3-Butylaminophenylsulphanyl)phenyl]acetic acid 10a. Ethyl [4-(3-dibutylaminophenylsulphanyl)phenyl]acetate
10b. [4-(3-Dibutylaminophenylsulphanyl)phenyl]acetic acid
11a. Ethyl {4-[4-(3-phenylpropylamino)phenylsulphanyl]phenyl}acetate
11 b. {4-[4-(3-Phenylpropylamino)phenylsulphanyl]phenylJacetic acid
12a. Ethyl (4-{4-[bis(3-phenylpropyl)amino]phenylsulphanylJphenyI)acetate 12b. (4-{4-[Bis(3-phenylpropyl)amino]phenylsulphanyl}phenyl)acetic acid
13a. Ethyl [4-(4-phenethylaminophenylsulphanyl)phenyl]acetate
13b. [4-(4-Phenethylaminophenylsulphanyl)phenyl]acetic acid
14a. Ethyl [4-(4-diphenethylaminophenylsulphanyl)phenyl]acetate
14b. [4-(4-Diphenethylaminophenylsulphanyl)phenyl]acetic acid 15a. Ethyl [4-(4-heptylaminophenylsulphanyl)phenyl]acetate
15b. [4-(4-Heptylaminophenylsulphanyl)phenyl]acetic acid
16a. Ethyl [4-(4-diheptylaminophenylsulphanyl)phenylJacetate
16b. [4-(4-Diheptylaminophenylsulphanyl)phenyl]acetic acid
17a. Ethyl [4-(4-dibutylaminophenylsulphanyl)phenyl]acetate 17b. [4-(4-Dibutylaminophenylsulphanyl)phenyl]acetic acid
18a. Ethyl (4-{3-[3-benzyI-1 -(3-phenylpropyl)ureido]phenylsulphanylJ- phenyl)acetate 18b. (4-{3-[3-Benzyl-1 -(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid
19a. Ethyl (4-{3-[3-phenyl-1-(3-phenylpropyl)ureidoJ- phenylsulphanyljphenyl)acetate 19b. (4-{3-[3-Phenyl-1 -(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid
20a. Ethyl (4-{3-[3-(2,3-dichlorophenyl)-1-(3-phenylpropyl)- ureido]phenylsulphanylJphenyl)acetate
20b. (4-{3-[3-(2,3-Dichlorophenyl)-1 -(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetic acid
21a. Ethyl (4-{3-[3-heptyl-1-(3-phenylpropyl)ureidoJ- phenylsulphanyljphenyl)acetate
21b. (4-{3-[3-Heptyl-1-(3-phenylpropyl)ureido]phenylsulphanylJphenyl)acetic acid 22a. Ethyl (4-{3-[3-phenethyl-1-(3-phenylpropyl)ureidoJ- phenylsulphanyljphenyl)acetate
22b. (4-{3-[3-Phenethyl-1-(3-phenylpropyl)ureido]phenylsulphanylJphenyl)acetic acid
23a. Ethyl (4-{3-[1-(3-phenylpropyl)-3-(4-trifluoro- methylphenyl)ureido]phenylsulphanyl}phenyl)acetate
23b. (4-{3-[1 -(3-Phenylpropyl)-3-(4-trifluoro- methylphenyl)ureido]phenylsulphanyl}phenyl)acetic acid
24a. Ethyl (4-{3-[3-(4-methoxyphenyl)-1-(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetate 24b. (4-{3-[3-(4-Methoxyphenyl)-1-(3-phenylpropyl)- ureido]phenylsulphanylJphenyl)acetic acid
25a. Ethyl (4-{3-[3-adamantan-1-yl-1-(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetate
25b. (4-{3-[3-Adamantan-1 -yl-1 -(3-phenylpropyl)ureidoJ- phenylsulphanyl}phenyl)acetic acid
26a. Ethyl (4-{3-[3-(2-phenoxyphenyl)-1-(3-phenylpropyl)- ureido]phenylsulphanylJphenyl)acetate
26b. (4-{3-[3-(2-Phenoxyphenyl)-1 -(3-phenylpropyl)- ureido]phenylsulphanylJphenyl)acetic acid
27a. Ethyl (4-{3-[3-allyl-1-(3-phenylpropyl)ureidoJ- phenylsulphanyljphenyl)acetate 27b. (4-{3-[3-Allyl-1-(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid
28a. Ethyl (4-{3-[3-cyclohexyl-1-(3-phenylpropyl)ureidoJ- phenylsulphanyl}phenyl)acetate
28b. (4-{3-[3-Cyclohexyl-1-(3-phenylpropyl)ureidoJ- phenylsulphanyl}phenyl)acetic acid 29a. Ethyl (4-{3-[3-(2-nitrophenyl)-1-(3-phenylpropyl)- ureido]phenylsulphanylJphenyl)acetate
29b. (4-{3-[3-(2-Nitrophenyl)-1-(3-phenylpropyl)ureidoJ- phenylsulphanyl}phenyl)acetic acid
30a. Ethyl (4-{3-[3-hexyl-1-(3-phenylpropyl)ureidoJ- phenylsulphanyljphenyl)acetate
30b. (4-{3-[3-Hexyl-1 -(3-phenylpropyl)ureido]phenylsulphanylJphenyl)acetic acid
31a. Ethyl (4-{3-[3-naphthalen-2-yl-1-(3-phenylpropyl)ureidoJ- phenylsulphanyl}phenyl)acetate
31 b. (4-{3-[3-Naphthalen-2-yl-1 -(3-phenylpropyl)ureidoJ- phenylsulphanyl phenyl)acetic acid
32a. Ethyl (4-{3-[3-(2-ethoxyphenyl)-1-(3-phenylpropyl)- ureido]phenylsulphanylJphenyl)acetate 32b. (4-{3-[3-(2-Ethoxyphenyl)-1 -(3-phenylpropyl)ureidoJ- phenylsulphanyl}phenyl)acetic acid
33a. Ethyl (4-{3-[3-(4-butoxyphenyl)-1-(3-phenylpropyl)- ureidoJphenylsulphanyl}phenyl)acetate 33b. (4-{3-[3-(4-Butoxyphenyl)-1-(3-phenylpropyl)- ureido]phenylsuIphanyl}phenyl)acetic acid
34a. Ethyl (4-{3-[3-pentyl-1-(3-phenylpropyl)ureidoJ- phenylsulphanyljphenyl)acetate
34b. (4-{3-[3-Pentyl-1-(3-phenylpropyl)ureido]phenylsulphanylJphenyl)acetic acid
35a. Ethyl (4-{3-[3-butyl-1-(3-phenylpropyl)ureidoJ- phenylsulphanyl}phenyl)acetate
35b. (4-{3-[3-Butyl-1 -(3-phenylpropyl)ureidoJphenylsulphanylJphenyl)acetic acid
36a. Ethyl (4-{3-[3-(4-dimethylaminophenyI)-1-(3- phenylpropyl)ureido]phenylsulphanyl}phenyl)acetate
36b. (4-{3-[3-(4-Dimethylaminophenyl)-1 -(3-phenylpropyl)- ureido]phenylsulphanylJphenyl)acetic acid
37a. Ethyl {4-[3-(3-benzyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetate
37b. {4-[3-(3-Benzyl-1 -phenethylureido)phenylsulphanyl]phenylJacetic acid 38a. Ethyl {4-[3-(1-phenethyl-3-phenylureido)phenylsulphanyl]phenyl}acetate
38b. {4-[3-( 1 -Phenethyl-3-phenylureido)phenylsulphanyl]phenyl}acetic acid
39a. Ethyl (4-{3-[3-(2,3-dichlorophenyl)-1-phenethylureidoJ- phenylsulphanyl}phenyl)acetate
39b. (4-{3-[3-(2,3-Dichlorophenyl)-1 -phenethylureidoj- phenylsulphanyljphenyl)acetic acid
40a. Ethyl {4-[3-(3-heptyl-1 -phenethylureido)phenylsulphanylJphenyl}acetate
40b. {4-[3-(3-Heptyl-1 -phenethylureido)phenylsulphanyl]phenylJacetic acid 41a. Ethyl {4-[3-(1 ,3-diphenethylureido)phenylsulphanyl]phenyl}acetate
41 b. {4-[3-(1 ,3-Diphenethylureido)phenylsulphanyl]phenyl}acetic acid
42a. Ethyl (4-{3-[1-phenethyl-3-(4-trifluoromethyl- phenyl)ureido]phenylsulphanyl}phenyl)acetate 42b. (4-{3-[1-Phenethyl-3-(4-trifluoromethylphenyl)- ureidoJphenylsulphanyl}phenyl)acetic acid
43a. Ethyl (4-{3-[3-(4-methoxyphenyl)-1-phenethyl- ureido]phenylsulphanyl}phenyl)acetate
43b. (4-{3-[3-(4-Methoxyphenyl)-1 -phenethylureido]- phenylsulphanyljphenyl)acetic acid
44a. Ethyl {4-[3-(3-adamantan-1-yl-1-phenethylureido)- phenylsulphanyljphenyljacetate
44b. {4-[3-(3-Adamantan-1 -yl-1 -phenethylureido)phenylsulphanyl]phenylJacetic acid 45a. Ethyl (4-{3-[1-phenethyl-3-(2-phenoxyphenyl)- ureido]phenylsulphanylJphenyl)acetate
45b. (4-{3-[1 -Phenethyl-3-(2-phenoxyphenyl)ureidoJ- phenylsulphanyljphenyl)acetic acid
46a. Ethyl {4-[3-(3-allyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetate 46b. {4-[3-(3-Allyl-1-phenethylureido)phenylsulphanyl]phenyl}acetic acid
47a. Ethyl {4-[3-(3-cyclohexyl-1-phenethylureido)- phenylsulphanyljphenyljacetate
47b. {4-[3-(3-Cyclohexyl-1 -phenethylureido)phenylsulphanyl]phenylJacetic acid
48a. Ethyl (4-{3-[3-(2-nitrophenyl)-1-phenethylureidoJ- phenylsulphanyl}phenyl)acetate
• 48b. (4-{3-[3-(2-Nitrophenyl)-1-phenethylureido]phenylsulphanyl}phenyl)acetic acid 49a. Ethyl {4-[3-(3-hexyl-1-phenethylureido)phenylsulphanyl]phenyl}acetate
49b. {4-[3-(3-Hexyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid
50a. Ethyl {4-[3-(3-naphthalen-2-yl-1-phenethylureido)- phenylsulphanyljphenyljacetate 50b. {4-[3-(3-Naphthalen-2-yl-1-phenethylureido)phenylsulphanyl]phenyl}acetic acid
51a. Ethyl (4-{3-[3-(2-ethoxyphenyl)-1-phenethyl- ureido]phenylsulphanylJphenyl)acetate
51 b. (4-{3-[3-(2-Ethoxyphenyl)-1 -phenethylureidoj- phenylsulphanyl}phenyl)acetic acid
52a. Ethyl (4-{3-[3-(4-butoxyphenyl)-1-phenethyl- ureido]phenylsulphanylJphenyl)acetate
52b. (4-{3-[3-(4-Butoxyphenyl)-1 -phenethylureidoj- phenylsulphanyljphenyl)acetic acid 53a. Ethyl {4-[3-(3-pentyl-1-phenethylureido)phenylsulphanyl]phenylJacetate
53b. {4-[3-(3-Pentyl-1 -phenethylureido)phenylsulphanyl]phenylJacetic acid
54a. Ethyl {4-[3-(3-butyl-1 -phenethylureidojphenylsulphanyljphenyljacetate
54b. {4-[3-(3-Butyl-1-phenethylureido)phenylsulphanyl]phenyl}acetic acid
55a. Ethyl (4-{3-[3-(4-dimethylaminophenyl)-1- phenethylureido]phenylsulphanyl}phenyl)acetate
55b. (4-{3-[3-(4-DimethylaminophenyI)-1 -phenethyl- ureido]phenylsulphanyl}phenyl)acetic acid
56a. Ethyl {4-[3-(3-benzyl-1 -heptylureido)phenylsulphanyl]phenyl}acetate
56b. {4-[3-(3-Benzyl-1 -heptylureido)phenylsulphanyl]phenyl}acetic acid 57a. Ethyl {4-[3-(1-heptyl-3-phenylureido)phenylsulphanyl]phenyl}acetate ■
57b. {4-[3-(1-Heptyl-3-phenylureido)phenylsulphanyl]phenyl}acetic acid
58a. Ethyl {4-[3-(1 ,3-diheptylureido)phenylsulphanyl]phenyl}acetate 58b. {4-[3-(1 ,3-Diheptylureido)phenylsulphanyl]phenylJacetic acid
59a. Ethyl {4-[3-(1-heptyl-3-phenethylureido)phenylsulphanyl]phenylJacetate
59b. {4-[3-(1-Heptyl-3-phenethylureido)phenylsulphanyl]phenyl}acetic acid
60a. Ethyl (4-{3-[1-heptyl-3-(4-trifluoromethylphenyl)- ureidoJphenylsulphanyl}phenyl)acetate
60b. (4-{3-[1-Heptyl-3-(4-trifluoromethylphenyl)- ureido]phenylsulphanyl}phenyl)acetic acid
61a. Ethyl (4-{3-[1-heptyl-3-(4-methoxyphenyl)ureidoJ- phenylsulphanyl}phenyl)acetate 61b. (4-{3-[1-Heptyl-3-(4-methoxyphenyl)ureido]phenylsulphanyl}phenyl)acetic acid
62a. Ethyl {4-[3-(3-adamantan-1-yl-1-heptylureido)- phenylsulphanyljphenyljacetate
62b. {4-[3-(3-Adamantan-1 -yl-1 -heptylureido)phenylsulphanyl]phenylJacetic acid 63a. Ethyl (4-{3-[1-heptyl-3-(2-phenoxyphenyl)ureidoJ- phenylsulphanyl}phenyl)acetate
63b. (4-{3-[1-Heptyl-3-(2-phenoxyphenyl)ureido]phenylsulphanyl}phenyl)acetic acid
64a. Ethyl {4-[3-(3-allyl-1 -heptylureido)phenylsulphanyl]phenyl}acetate 64b. {4-[3-(3-Allyl-1-heptylureido)phenylsulphanyl]phenyl}acetic acid
65a. Ethyl {4-[3-(3-cyclohexyl-1 -heptylureido)phenylsulphanyl]phenylJacetate
65b. {4-[3-(3-Cyclohexyl-1 -heptylureido)phenylsulphanyl]phenylJacetic acid
66a. Ethyl (4-{3-[1-heptyl-3-(2-nitrophenyl)ureidoJ- phenylsulphanyl}phenyl)acetate 66b. (4-{3-[1-Heptyl-3-(2-nitrophenyl)ureido]phenylsulphanyl}phenyl)acetic acid
67a. Ethyl {4-[3-(1-heptyl-3-hexylureido)phenylsulphanyl]phenyl}acetate
67b. {4-[3-(1-Heptyl-3-hexylureido)phenylsulphanyl]phenyl}acetic acid 68a. Ethyl {4-[3-(1-heptyl-3-naphthalen-2-ylureido)- phenylsulphanyljphenyljacetate
68b. {4-[3-(1-Heptyl-3-naphthalen-2-ylureido)phenylsulphanyl]phenyl}acetic acid
69a. Ethyl (4-{3-[3-(2-ethoxyphenyl)-1-heptylureidoJ- phenylsulphanyl}phenyl)acetate
69b. (4-{3-[3-(2-Ethoxyphenyl)-1-heptylureido]phenylsulphanyl}phenyl)acetic acid
70a. Ethyl (4-{3-[3-(4-butoxyphenyl)-1-heptylureidoJ- phenylsulphanyl}phenyl)acetate 70b. (4-{3-[3-(4-Butoxyphenyl)-1-heptylureido]phenylsulphanyl}phenyl)acetic acid
71a. Ethyl {4-[3-(1-heptyl-3-pentylureido)phenylsulphanyl]phenylJacetate
71b. {4-[3-(1-Heptyl-3-pentylureido)phenylsulphanyl]phenyl}acetic acid
72a. Ethyl {4-[3-(3-butyl-1 -heptylureido)phenylsuIphanyl]phenylJacetate 72b. {4-[3-(3-Butyl-1-heptylureido)phenylsulphanyl]phenylJacetic acid
73a. Ethyl (4-{3-[3-(4-dimethylaminophenyl)-1-heptyl- ureido]phenylsulphanylJphenyl)acetate
73b. (4-{3-[3-(4-Dimethylaminophenyl)-1 -heptylureidoj- phenylsulphanyl}phenyl)acetic acid 74a. Ethyl {4-[3-(3-benzyl-1-butylureido)phenylsulphanyl]phenylJacetate
74b. {4-[3-(3-Benzyl-1 -butylureido)phenylsulphanyl]phenyl}acetic acid
75a. Ethyl {4-[3-(1 -butyl-3-phenylureido)phenylsulphanylJphenyl}acetate
75b. {4-[3-(1-Butyl-3-phenylureido)phenylsulphanyl]phenyl}acetic acid
76a. Ethyl (4-{3-[1-butyl-3-(2,3-dichlorophenyl)- ureidoJphenylsulphanyl}phenyl)acetate
76b. (4-{3-[1-Butyl-3-(2,3-dichlorophenyl)ureido]phenylsulphanylJphenyl)acetic acid 77a. Ethyl {4-[3-(1-butyl-3-heptylureido)phenylsulphanyl]phenylJacetate
77b. {4-[3-(1-Butyl-3-heptylureido)phenylsulphanyl]phenyl}acetic acid
78a. Ethyl {4-[3-(1-butyl-3-phenethylureido)phenylsulphanyl]phenyl}acetate
78b. {4-[3-(1-Butyl-3-phenethylureido)phenylsulphanyl]phenyl}acetic acid 79a. Ethyl (4-{3-[1-butyl-3-(4-trifluoromethylphenyl)- ureido]phenylsulphanylJphenyl)acetate
79b. (4-{3-[1 -Butyl-3-(4-trifluoromethylphenyl)ureidoJ- phenylsulphanyljphenyl)acetic acid
80a. Ethyl (4-{3-[1-butyl-3-(4-methoxyphenyl)ureidoJ- phenylsulphanyljphenyl)acetate
80b. (4-{3-[1-Butyl-3-(4-methoxyphenyl)ureido]phenylsulphanylJphenyl)acetic acid
81a. Ethyl {4-[3-(3-adamantan-1-yl-1-butylureido)- phenylsulphanyljphenyljacetate 81 b. {4-[3-(3-Adamantan-1-yl-1-butylureido)phenylsulphanyl]phenylJacetic acid
82a. Ethyl (4-{3-[1-butyl-3-(2-phenoxyphenyl)ureidoJ- phenylsulphanyl}phenyl)acetate
82b. (4-{3-[1-Butyl-3-(2-phenoxyphenyl)ureido]phenylsulphanylJphenyl)acetic acid 83a. Ethyl {4-[3-(3-allyl-1-butylureido)phenylsulphanyl]phenyl}acetate
83b. {4-[3-(3-Allyl-1 -butylureido)phenylsulphanyl]phenylJacetic acid
84a. Ethyl {4-[3-(1 -butyl-3-cyclohexylureido)phenylsulphanylJphenyl}acetate
84b. {4-[3-(1-Butyl-3-cyclohexylureido)phenylsulphanyl]phenyl}acetic acid
85a. Ethyl (4-{3-[1-butyl-3-(2-nitrophenyl)ureido]phenylsulphanyl}phenyl)acetate 85b. (4-{3-[1-Butyl-3-(2-nitrophenyl)ureido]phenylsulphanyl}phenyl)acetic acid
86a. Ethyl {4-[3-(1 -butyl-3-hexylureido)phenylsulphanyl]phenyl}acetate
86b. {4-[3-(1-Butyl-3-hexylureido)phenylsulphanylJphenyl}acetic acid 87a. Ethyl (4-[3-(1-butyl-3-naphthalen-2-ylureido)- phenylsulphanyljphenyljacetate
87b. {4-[3-(1 -Butyl-3-naphthalen-2-ylureido)phenylsulphanyl]phenylJacetic acid
88a. Ethyl (4-{3-[1-butyl-3-(2-ethoxyphenyl)ureidoJ- phenylsulphanyl}phenyl)acetate
88b. (4-{3-[1 -Butyl-3-(2-ethoxyphenyl)ureido]phenylsulphanylJphenyl)acetic acid
89a. Ethyl (4-{3-[3-(4-butoxyphenyl)-1-butylureidoJ- phenylsulphanyljphenyl)acetate
89b. (4-{3-[3-(4-Butoxyphenyl)-1 -butylureido]phenylsulphanylJphenyl)acetic acid 90a. Ethyl {4-[3-(1-butyl-3-pentylureido)phenylsulphanyl]phenylJacetate
90b. {4-[3-(1-Butyl-3-pentylureido)phenylsulphanylJphenylJacetic acid
91a. Ethyl {4-[3-(1 ,3-dibutylureido)phenylsulphanyl]phenyl}acetate
91 b. {4-[3-(1 ,3-Dibutylureido)phenylsulphanyl]phenyl}acetic acid
92a. Ethyl (4-{4-[3-benzyl-1-(3-phenylpropyl)ureidoJ- phenylsulphanyljphenyl)acetate
92b. (4-{4-[3-Benzyl-1-(3-phenylpropyl)ureido]phenylsulphanylJphenyl)acetic acid
93a. Ethyl (4-{4-[3-heptyl-1-(3-phenylpropyl)ureidoJ- phenylsulphanyl}phenyl)acetate 93b. (4-{4-[3-Heptyl-1 -(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid
94a. Ethyl (4-{4-[3-phenethyl-1-(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetate
94b. (4-{4-[3-Phenethyl-1-(3-phenylpropyl)ureido]phenylsulphanylJphenyl)acetic acid
95a. Ethyl (4-{4-[1-(3-phenylpropyl)-3-(4-tri- fluoromethylphenyl)ureido]phenylsulphanyl}phenyl)acetate 95b. (4-{4-[1 -(3-Phenylpropyl)-3-(4-tri- fluoromethylphenyl)ureido]phenylsulphanylJphenyl)acetic acid
96a. Ethyl (4-{4-[3-(2-phenoxyphenyl)-1-(3-phenyl- propyl)ureido]phenylsulphanyl}phenyl)acetate 96b. (4-{4-[3-(2-Phenoxyphenyl)-1-(3-phenyl- propyl)ureidoJphenylsulphanylJphenyl)acetic acid
97a. Ethyl (4-{4-[3-allyl-1-(3-phenylpropyl)ureidoJ- phenylsulphanyl phenyl)acetate
97b. (4-{4-[3-Allyl-1 -(3-phenylpropyl)ureido]phenylsulphanylJphenyl)acetic acid 98a. Ethyl (4-{4-[3-cyclohexyl-1-(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetate
98b. (4-{4-[3-Cyclohexyl-1 -(3-phenylpropyl)ureidoJ- phenylsulphanyl}phenyl)acetic acid
99a. Ethyl (4-{4-[3-(2-nitrophenyl)-1-(3-phenyl- propyl)ureido]phenylsulphanylJphenyl)acetate
99b. (4-{4-[3-(2-Nitrophenyl)-1-(3-phenylpropyl)- ureido]phenylsulphanylJphenyl)acetic acid
100a. Ethyl (4-{4-[3-hexyl-1-(3-phenylpropyl)- ureido]phenylsulphanylJphenyl)acetate 100b. (4-{4-[3-Hexyl-1 -(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid
101a. Ethyl (4-{4-[3-naphthalen-2-yl-1-(3-phenyl- propyl)ureido]phenylsulphanyl}phenyl)acetate
101b. (4-{4-[3-Naphthalen-2-yl-1-(3-phenyl- propyl)ureido]phenylsulphanylJphenyl)acetic acid
102a. Ethyl (4-{4-[3-(2-ethoxyphenyl)-1-(3-phenyl- propyl)ureido]phenylsulphanyl}phenyl)acetate 102b. (4-{4-[3-(2-Ethoxyphenyl)-1 -(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetic acid
103a. Ethyl (4-{4-[3-(4-butoxyphenyl)-1-(3-phenyl- propyl)ureido]phenylsulphanyl}phenyl)acetate 103b. (4-{4-[3-(4-Butoxyphenyl)-1-(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetic acid
104a. Ethyl (4-{4-[3-pentyl-1-(3-phenylpropyl)- ureido]phenylsulphanyl}phenyl)acetate
104b. (4-{4-[3-Pentyl-1 -(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid
105a. Ethyl (4-{4-[3-butyl-1-(3-phenylpropyl)ureido]- phenylsulphanyljphenyl)acetate
105b. (4-{4-[3-Butyl-1 -(3-phenylpropyl)ureido]phenylsulphanyl}phenyl)acetic acid 106a. Ethyl {4-[4-(3-benzyl-1-phenethylureido)phenylsulphanyl]phenylJacetate
106b. {4-[4-(3-Benzyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid
107a. Ethyl {4-[4-(1-phenethyl-3-phenylureido)phenylsulphanyl]phenyl}acetate
107b. {4-[4-(1-Phenethyl-3-phenylureido)phenylsulphanyl]phenyl}acetic acid
108a. Ethyl (4-{4-[3-(2,3-dichlorophenyl)-1-phenethyl- ureido]phenylsulphanyl}phenyl)acetate
108b. (4-{4-[3-(2,3-Dichlorophenyl)-1 -phenethylureido]- phenylsulphanyl phenyl)acetic acid
109a. Ethyl {4-[4-(3-heptyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetate
109b. {4-[4-(3-Heptyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid 110a. Ethyl {4-[4-(1 ,3-diphenethylureido)phenylsulphanyl]phenyl}acetate
110b. {4-[4-(1 ,3-Diphenethylureido)phenylsulphanyl]phenyl}acetic acid
111a. Ethyl (4-{4-[1 -phenethyl-3-(4-trifluoro- methylphenyl)ureido]phenylsulphanylJphenyl)acetate
111b. (4-{4-[1 -Phenethyl-3-(4-trifluoromethyl- phenyl)ureido]phenylsulphanyl}phenyl)acetic acid
112a. Ethyl (4-{4-[3-(4-methoxyphenyl)-1 -phenethyl- ureido]phenylsulphanylJphenyl)acetate
112b. (4-{4-[3-(4-Methoxyphenyl)-1 -phenethylureido]- phenylsulphanyl}phenyl)acetic acid
113a. Ethyl {4-[4-(3-adamantan-1-yl-1-phenethyl- ureido)phenylsulphanyl]phenyl}acetate 113b. {4-[4-(3-Adamantan-1-yl-1-phenethylureido)- phenylsulphanyljphenyljacetic acid
114a. Ethyl (4-{4-[1 -phenethyl-3-(2-phenoxyphenyl)- ureido]phenylsulphanylJphenyl)acetate
114b. (4-{4-[1 -Phenethyl-3-(2-phenoxyphenyl)ureido]- phenylsulphanyljphenyl)acetic acid
115a. Ethyl {4-[4-(3-allyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetate
115b. {4-[4-(3-Allyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid
116a. Ethyl {4-[4-(3-cyclohexyl-1 -phenethylureido)- phenylsulphanyljphenyljacetate 116b. {4-[4-(3-Cyclohexyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid
117a. Ethyl (4-{4-[3-(2-nitrophenyl)-1 -phenethyl- ureido]phenylsulphanyl}phenyl)acetate
117b. (4-{4-[3-(2-Nitrophenyl)-1-phenethylureido]phenylsulphanyl}phenyl)acetic acid
118a. Ethyl {4-[4-(3-hexyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetate
118b. {4-[4-(3-Hexyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetic acid 119a. Ethyl {4-[4-(3-naphthalen-2-yl-1 -phenethyl- ureido)phenylsulphanyl]phenylJacetate
119b. {4-[4-(3-Naphthalen-2-yl-1 -phenethylureido)- phenylsulphanyljphenyljacetic acid 120a. Ethyl (4-{4-[3-(2-ethoxyphenyl)-1-phenethyl- ureido]phenylsulphanyl}phenyl)acetate
120b. (4-{4-[3-(2-Ethoxyphenyl)-1-ρhenethylureido]- phenylsulphanyljphenyl)acetic acid
121a. Ethyl (4-{4-[3-(4-butoxyphenyl)-1 -phenethyl- ureido]phenylsulphanyl}phenyl)acetate
121b. (4-{4-[3-(4-Butoxyphenyl)-1-phenethylureido]- phenylsulphanyljphenyl)acetic acid
122a. Ethyl {4-[4-(3-pentyl-1 -phenethylureido)phenylsulphanyl]phenyl}acetate
122b. {4-[4-(3-Pentyl-1 -phenethylureido)phenylsulphanyl]phenylJacetic acid 123a. Ethyl {4-[4-(3-butyl-1-phenethylureido)phenylsulphanyl]phenyl}acetate
123b. {4-[4-(3-Butyl-1 -phenethylureido)phenylsulphanyl]phenylJacetic acid
124a. Ethyl {4-[4-(3-benzyl-1-heptylureido)phenylsulphanyl]phenyl}acetate
124b. {4-[4-(3-Benzyl-1 -heptylureido)phenylsulphanyl]phenyl}acetic acid
125a. Ethyl {4-[4-(1-heptyl-3-phenylureido)phenylsulphanyl]phenylJacetate 125b. {4-[4-(1-Heptyl-3-phenylureido)phenylsulphanyl]phenyl}acetic acid
126a. Ethyl (4-{4-[3-(2,3-dichlorophenyl)-1-heptyl- ureido]phenylsulphanyl}phenyl)acetate
126b. (4-{4-[3-(2,3-Dichlorophenyl)-1 -heptylureido]- phenylsulphanyl}phenyl)acetic acid 127a. Ethyl {4-[4-(1 ,3-diheptylureido)phenylsulphanyl]phenyl}acetate
127b. {4-[4-(1 ,3-Diheptylureido)phenylsulphanyl]phenylJacetic acid
128a. Ethyl {4-[4-(1-heptyl-3-phenethylureido)phenylsulphanyl]phenyl}acetate 128b. {4-[4-(1-Heptyl-3-phenethylureido)phenylsulphanyl]phenylJacetic acid
129a. Ethyl (4-{4-[1-heptyl-3-(4-trifluoro- methylphenyl)ureido]phenylsulphanylJphenyl)acetate
129b. (4-{4-[1 -Heptyl-3-(4-trifluoromethyl- phenyl)ureido]phenylsulphanylJphenyl)acetic acid
130a. Ethyl (4-{4-[1 -heptyl-3-(4-methoxyphenyl)ureido]- phenylsulphanyl}phenyl)acetate
130b. (4-{4-[1 -Heptyl-3-(4-methoxyphenyl)ureido]phenylsulphanyl}phenyl)acetic acid 131a. Ethyl {4-[4-(3-adamantan-1 -yl-1 -heptylureido)- phenylsulphanyl]phenyl}acetate
131b. {4-[4-(3-Adamantan-1-yl-1-heptylureido)phenylsulphanyl]phenyl}acetic acid
132a. Ethyl (4-{4-[1-heptyl-3-(2-phenoxyphenyl)- ureido]phenylsulphanyl}phenyl)acetate
132b. (4-{4-[1 -Heptyl-3-(2-phenoxyphenyl)ureido]phenylsulphanyl}phenyl)acetic acid
133a. Ethyl {4-[4-(3-allyl-1-heptylureido)phenylsulphanyl]phenylJacetate
133b. {4-[4-(3-Allyl-1 -heptylureido)phenylsulphanyl]phenyl}acetic acid 134a. Ethyl {4-[4-(3-cyclohexyl-1-heptylureido)phenylsulphanyl]phenyl}acetate
134b. {4-[4-(3-Cyclohexyl-1-heptylureido)phenylsulphanyl]phenyl}acetic acid
135a. Ethyl (4-{4-[1-heptyl-3-(2-nitrophenyl)ureido]- phenylsulphanyl}phenyl)acetate
135b. (4-{4-[1 -Heptyl-3-(2-nitrophenyl)ureido]phenylsulphanylJphenyl)acetic acid
136a. Ethyl {4-[4-(1-heptyl-3-hexylureido)phenylsulphanyl]phenyl}acetate
136b. {4-[4-(1-Heptyl-3-hexylureido)phenylsulphanyl]phenyl}acetic acid 137a. Ethyl {4-[4-(1-heptyl-3-naphthalen-2-ylureido)- phenylsulphanyljphenyljacetate
137b. {4-[4-(1-Heptyl-3-naphthalen-2-ylureido)phenylsulphanyl]phenyl}acetic acid 138a. Ethyl (4-{4-[3-(2-ethoxyphenyl)-1-heptylureido]- phenylsulphanyljphenyl)acetate
138b. (4-{4-[3-(2-Ethoxyphenyl)-1 -heptylureido]phenylsulphanyl}phenyl)acetic acid
139a. Ethyl (4-{4-[3-(4-butoxyphenyl)-1 -heptylureido]- phenylsulphanyljphenyl)acetate
139b. (4-{4-[3-(4-Butoxyphenyl)-1 -heptylureido]phenylsulphanylJphenyl)acetic acid
140a. Ethyl {4-[4-(1 -heptyl-3-pentylureido)phenylsulphanyl]phenylJacetate
140b. {4-[4-(1-Heptyl-3-pentylureido)phenylsulphanyl]phenylJacetic acid 141a. Ethyl {4-[4-(3-butyl-1-heptylureido)phenylsulphanyl]phenylJacetate
141 b. {4-[4-(3-Butyl-1 -heptylureido)phenylsulphanyl]phenylJacetic acid.
13. Cosmetic composition, characterized in that it comprises, in a physiologically acceptable carrier, at least one compound as defined in any one of Claims 1 to 12.
14. Composition according to Claim 13, characterized in that the concentration of compound(s) according to any one of Claims 1 to 12 is between 0.001 and 3% by weight relative to the total weight of the composition.
15. Cosmetic use of a composition as defined in either of
Claims 13 and 14 for body or hair care.
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 intended for regulating and/or restoring skin lipid metabolism.
18. Use of a compound according to any one of Claims 1 to 12, in the manufacture of a composition intended for the treatment: - of dermatological conditions linked to a cicatrisation disorder related to cell differentiation and proliferation, in particular to treat acne vulgaris, comedo-type acne, polymorphic acne, acne rosacea, nodulocystic acne, acne conglobata, senile acne, secondary acne such as solar acne, acne medicamentosa or occupational acne, - of ichthyosis, ichthyosiform states, Darrier's disease, keratosis palmaris et plantaris, leukoplasia and leukoplasiform states, cutaneous or mucosal (buccal) lichen,
- of dermatological conditions with an inflammatory immunoallergic component, with or without cell proliferation disorder, in particular cutaneous, mucosal or icatr psoriasis, psoriatic rheumatism, or cutaneous atopy, such as eczema or respiratory atopy or gingival hypertrophy,
- of dermal or epidermal proliferations whether benign or malignant, whether of viral origin or not, such as verruca vulgaris, verruca plana and epidermodysplasia verruciformis, oral or florid papillomatoses, T lymphoma, - of proliferations which may be induced by ultraviolet radiation, in particular baso- and spinocellular epithelioma,
- of precancerous skin lesions, in particular keratoacanthomas,
- of immune dermatoses, in particular lupus erythematosus,
- of bullous immune diseases, - of collagen diseases, in particular scleroderma,
- of dermatological or general conditions with an immunological component,
- of skin disorders due to exposure to UV radiation, skin ageing, photoinduced or chronological or actinic pigmentations and keratoses, or any pathologies associated with chronological or actinic ageing, in particular xerosis,
- of sebaceous function disorders, in particular acne hyperseborrhoea, simple seborrhoea or seborrhoeic dermatitis, - of icatrisation disorders or of stretch marks, of pigmentation disorders, such as hyperpigmentation, melasma, hypopigmentation or vitiligo,
- of lipid metabolism conditions such as obesity, hyperlipidaemia or non-insulin- dependent diabetes or X syndrome, - of inflammatory conditions such as arthritis,
- of cancerous or precancerous states,
- of alopecia of different origins, in particular alopecia due to chemotherapy or to radiation,
- of immune system disorders such as asthma, diabetes mellitus type I, multiple sclerosis, or other selective dysfunctions of the immune system, or
- of conditions 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. Composition according to Claim 19, characterized in that the concentration of compound(s) according to any one of Claims 1 to 12 is between 0.001 and 10% by weight relative to the total weight of the composition.
21. Composition according to Claim 19, characterized in that the concentration of compound(s) according to any one of Claims 1 to 12 is between 0.01 and 1 % by weight relative to the total weight of the composition.
PCT/EP2004/002198 2003-02-12 2004-02-10 Compounds which are modulators of the ppar-type receptors and their use in cosmetic or pharmaceutical compositions WO2004071504A1 (en)

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US11/202,019 US20060052627A1 (en) 2003-02-12 2005-08-12 Novel modulators of the PPAR-type receptors and cosmetic/pharmaceutical compositions comprised thereof

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FR0350025A FR2850968B1 (en) 2003-02-12 2003-02-12 NOVEL MODULATING COMPOUNDS OF PPAR-TYPE RECEPTORS AND THEIR USE IN COSMETIC OR PHARMACEUTICAL COMPOSITIONS
FR0350025 2003-02-12
US45383503P 2003-03-12 2003-03-12
US60/453,835 2003-03-12

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WO2008132552A3 (en) * 2006-11-01 2009-01-15 Pronova Biopharma Norge As Omega-3 lipid compounds
US8399516B2 (en) 2006-11-01 2013-03-19 Pronova Biopharma Norge As Alpha-substituted omega-3 lipids that are activators or modulators of the peroxisome proliferators-activated receptor (PPAR)
US8618165B2 (en) 2005-05-04 2013-12-31 Pronova Biopharma Norge As Compounds
RU2509071C2 (en) * 2006-11-01 2014-03-10 Пронова Биофарма Норге Ас Novel lipid compounds

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WO2001034094A2 (en) * 1999-11-08 2001-05-17 Calyx Therapeutics, Inc. Novel compounds to treat diabetes and associated conditions

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WO2001034094A2 (en) * 1999-11-08 2001-05-17 Calyx Therapeutics, Inc. Novel compounds to treat diabetes and associated conditions

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
US8618165B2 (en) 2005-05-04 2013-12-31 Pronova Biopharma Norge As Compounds
WO2008132552A3 (en) * 2006-11-01 2009-01-15 Pronova Biopharma Norge As Omega-3 lipid compounds
US8399516B2 (en) 2006-11-01 2013-03-19 Pronova Biopharma Norge As Alpha-substituted omega-3 lipids that are activators or modulators of the peroxisome proliferators-activated receptor (PPAR)
RU2509071C2 (en) * 2006-11-01 2014-03-10 Пронова Биофарма Норге Ас Novel lipid compounds

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