EP1596853A1 - Composes modulateurs des recepteurs du type ppar et leur utilisation dans des preparations pharmaceutiques et cosmetiques - Google Patents

Composes modulateurs des recepteurs du type ppar et leur utilisation dans des preparations pharmaceutiques et cosmetiques

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Publication number
EP1596853A1
EP1596853A1 EP04709628A EP04709628A EP1596853A1 EP 1596853 A1 EP1596853 A1 EP 1596853A1 EP 04709628 A EP04709628 A EP 04709628A EP 04709628 A EP04709628 A EP 04709628A EP 1596853 A1 EP1596853 A1 EP 1596853A1
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EP
European Patent Office
Prior art keywords
phenyl
phenylsulphanyl
ethyl
acetate
acetic acid
Prior art date
Legal status (The legal status 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 status listed.)
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Application number
EP04709628A
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German (de)
English (en)
Inventor
Philippe Le Jardin de Saint-Antoine DIAZ
Etienne Thoreau
Johannes Voegel
Isabelle Carlavan
Pascale Mauvais
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Galderma Research and Development SNC
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Galderma Research and Development SNC
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Priority claimed from FR0350025A external-priority patent/FR2850968B1/fr
Application filed by Galderma Research and Development SNC filed Critical Galderma Research and Development SNC
Publication of EP1596853A1 publication Critical patent/EP1596853A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des nouveaux composés représentés par la formule générale(I), leur procédé de préparation et leur utilisation dans des préparations pharmaceutiques destinées à être utilisées chez l'homme, en médecine vétérinaire (en dermatologie et dans le domaine des maladies cardiovasculaires, des maladies immunitaires et/ou des maladies liées au métabolisme lipidique) ou dans des préparations cosmétiques.
EP04709628A 2003-02-12 2004-02-10 Composes modulateurs des recepteurs du type ppar et leur utilisation dans des preparations pharmaceutiques et cosmetiques Withdrawn EP1596853A1 (fr)

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Application Number Priority Date Filing Date Title
FR0350025A FR2850968B1 (fr) 2003-02-12 2003-02-12 NOUVEAUX COMPOSES MODULATEURS DES RECEPTEURS DE TYPE PPARs ET LEUR UTILISATION DANS DES COMPOSITIONS COSMETIQUES OU PHARMACEUTIQUES
FR0350025 2003-02-12
US45383503P 2003-03-12 2003-03-12
US453835P 2003-03-12
PCT/EP2004/002198 WO2004071504A1 (fr) 2003-02-12 2004-02-10 Composes modulateurs des recepteurs du type ppar et leur utilisation dans des preparations pharmaceutiques et cosmetiques

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EP1596853A1 true EP1596853A1 (fr) 2005-11-23

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WO2006117664A1 (fr) 2005-05-04 2006-11-09 Pronova Biopharma Norge As Nouveaux derives de dha et utilisation de ceux ci en tant que medicaments
WO2008053331A1 (fr) 2006-11-01 2008-05-08 Pronova Biopharma Norge A/S Lipides oméga-3 à substitution alpha en tant qu'activateurs ou modulateurs du récepteur activé par proliférateurs de peroxisome (ppar)
EP2129646A2 (fr) * 2006-11-01 2009-12-09 Pronova Biopharma Norge AS Composes lipidiques omega-3
EP2102139A2 (fr) * 2006-11-01 2009-09-23 Pronova Biopharma Norge AS Composes du lipide omega-3

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US6525093B1 (en) * 1999-11-08 2003-02-25 Calyx Therapeutics Inc. Compounds to treat diabetes and associated conditions

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