ZA200403797B - Biphenylmethyl-thiazolidinediones and analogues and their use as PPAR-gamma activators. - Google Patents

Biphenylmethyl-thiazolidinediones and analogues and their use as PPAR-gamma activators. Download PDF

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ZA200403797B
ZA200403797B ZA200403797A ZA200403797A ZA200403797B ZA 200403797 B ZA200403797 B ZA 200403797B ZA 200403797 A ZA200403797 A ZA 200403797A ZA 200403797 A ZA200403797 A ZA 200403797A ZA 200403797 B ZA200403797 B ZA 200403797B
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ylmethyl
biphenyl
radical
dioxothiazolidin
methyl
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ZA200403797A
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Jean-Michel Bernardon
Laurence Clary
Eric Terranova
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Galderma Res & Dev
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/007—Preparations for dry skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
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    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
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Description

DIPHENTLMETHYL-THIAZOLIDINENTONES. AND ANALOGUES AND =~
THEIR USE AS PPAR-GAMMA ACTIVATORS
The invention relates, as novel and useful industrial products, to biaromatic compounds which are activators of receptors of the Peroxisome Proliferator-
Activated Receptor type of subtype y (PPARy). 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 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 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 the form of a heterodimer with the retinoid X receptors (called
RXRs) .
Three human PPAR subtypes have been identified and described: PPARa, PPARy and PPARS (or
NUCL).
PPARa is mainly expressed in the liver while
PPARS is ubiquitous.
PPARy is the most widely studied of the three subtypes. All the references suggest a critical role of the PPARy 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 PPARy-selective compounds, such as prostaglandin-J2 or -D2, are potential active agents for treating obesity and diabetes.
Moreover, the applicant has already described in Patent Application FR98/02894 the use of PPARy- activating compounds in the preparation of a pharmaceutical composition, the composition being intended for treating skin disorders linked to an abnormality of differentiation of epidermal cells.
One of the aims of the present invention is to provide novel PPARy-activating compounds exhibiting a better biological activity than the prior art compounds.
Thus, the present invention relates to biaromatic compounds corresponding to the following general formula:
R. oA or ,
XR, in which: - Ry represents a radical of the following formulae (a) or (b):
O @) ~A A ~ 5 (a Rs (b)
Rs and R¢ having the meanings given below, - R; and R3, which may be identical or different, represent a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms, an aryl radical, a halogen atom, a radical -OR;, a polyether radical, a nitro radical or an amino radical which may be optionally substituted with alkyl radicals having from 1 to 6 carbon atoms;
Rs having the meaning given below, - X represents the bonds having the following structures:
8. 2200473797 -CH,-N (Rg) -CO- =N (Rg) ~CO-N (Rg) = -N (Rg) ~CO-CH,~- -N (Rg) -CH,-CO- which may be read from left to right or conversely
Rg and Ry having the meanings given below, - Rgq represents: - a phenyl, benzyl, phenethyl, thienyl, furyl or pyridyl radical, all these radicals being substituted with a group Rig,
Rip having the meanings given below, - a pyrrolyl, pyrazinyl, naphthyl, biphenyl, indolyl, indenyl, benzothienyl, benzofuryl, benzothiazolyl or quinolyl radical, it being possible for all these radicals to be mono- or disubstituted with a group Rj; and/or Rj,
R;; and R;; having the meanings given below, - a radical =-(CHy),— (CO) q4R13, n, gq and R;3 having the meanings given below, - an adamantyl, diphenylmethyl, diphenylethyl, diphenylpropyl, diphenylbutyl, cyclopropylmethyl, cyclopentylethyl, 2-benzimidazolyl- ethyl, cyclohexylmethyl, phenoxyphenyl, 9H-fluorenyl, benzyloxyphenyl, 4-heptyloxyphenyl, or 4-(6-methyl-2- benzothiazolyl)phenyl radical,
-a radical -(CHz)qa-O-Rys, i n and R;3 having the meanings given below, - Rs represents a hydroxyl radical or an alkoxy 5 radical having from 1 to 9 carbon atoms, Co - Rg represents an alkyl radical having from 1 to 6 carbon atoms, a radical OR;4 or a radical SRiqg,
Ris having the meanings given below, - Ry represents a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms, an aryl radical or an aralkyl radical, - Rg represents a hydrogen atom or an alkyl radical having from 1 to 6 carbon atoms, - Rg represents a hydrogen atom or an alkyl radical having from 1 to 6 carbon atoms, - Ryo represents: a radical -S(0)mRis a radical -(CH;)p-CORjs a radical -O-R;y m, p, Ris, Ris and Ry; having the meanings given below, - R;; and Rj; represent a halogen atom, a radical
CFi3, an alkyl radical having from 1 to 12 carbon atoms, an alkoxy radical having from 1 to 9 carbon atoms, a polyether radical, a nitro functional group, a hydroxyl radical optionally protected by an acetyl or benzoyl group, an amino functional group optionally substituted with at least one alkyl having from 1 to 12 carbon
£.°2004/3797 c . atoms or with a radical -CONH-R;4, or protected by an acetyl or benzoyl group, a radical -S(O).Ris, a radical (CH2) p-CORy4 or a radical -ORyq, m, p, Ris, Ris, Riz and Rys having the meanings given below, - n may take the values ranging from 1 to 9, - q may take the values 0 or 1, - Ris represents a radical -ORjg, a radical -N (Rig) {Rz0), an aryl radical, an aralkyl radical or a heteroaryl radical,
Rig, Rig and Rpg having the meanings given below, - m may take the values 0, 1 or 2, - p may take the values 0, 1 or 2, - Rig represents an alkyl radical having from 1 to 12 carbon atoms, a radical CFi3, an aryl radical or an aralkyl radical, - R35 represents an alkyl radical having from 1 to 12 carbon atoms, an aryl radical or an aralkyl radical, - R15 represents an alkyl radical having from 1 to 12 carbon atoms, a radical -OR;;, a radical -N(R32) (R23), an aryl radical or an aralkyl radical,
R;1, Rzz and Ry3 having the meanings given below, - Ry7 represents an aryl radical or an aralkyl radical,
- Rig represents a hydrogen atom or an alkyl radical having from 1 to 12 carbon atoms, ’ - Rig and Ryo, which may be identical or different, represent a hydrogen atom, an alkyl radical having from 1 to 12 carbon atoms, or taken together may form a Co heterocycle, - Ry; represents a hydrogen atom or an alkyl radical having from 1 to 12 carbon atoms, - Ry2 and Rz3, which may be identical or different, represent a hydrogen atom, an alkyl radical having from 1 to 12 carbon atoms, or taken together may form a heterocycle, - Ruy represents a phenyl, diphenylmethyl, diphenylpropyl, diphenylbutyl, biphenylyl, phenoxyphenyl, 9H-fluorenyl, 4-benzyloxyphenyl, 4-heptyloxyphenyl, or 4-(6-methyl-2- benzothiazolyl)phenyl radical.
The present invention also relates to the salts of the compounds of formula (I) when R; contains a carboxylic acid functional group and the optical and geometric isomers of the said compounds of formula (I).
When the compounds according to the invention are provided in the form of a salt, this is preferably a salt of an alkali or alkaline-earth metal, or alternatively a zinc salt or salts of an organic amine.
According to the present invention:
The expression alkyl radical having from 1 to 6 carbon atoms is preferably understood to mean the methyl, ethyl, isoprepyl, butyl, tert-butyl and hexyl radicals. . 5 The expression alkyl radical having from 1 to 12 carbon atoms is preferably understood to mean the methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, octyl, decyl and dodecyl radicals.
The expression polyether radical is preferably understood toc mean a radical having from 1 to 6 carbon atoms interrupted by at least one oxygen atom such as the methoxymethoxy, ethoxymethoxy and methoxyethoxymethoxy radicals.
The expression halogen atom is preferably understood to mean a fluorine, chlorine or bromine atom.
The expression alkoxy radical having from 1 to 9 carbon atoms is preferably understood to mean the methoxy, ethoxy, isopropyloxy, tert-butoxy and hexyloxy radicals.
The expression aryl radical is preferably understood to mean a phenyl, biphenyl, cinnamyl or naphthyl radical which may be mono- or disubstituted with a halogen atom, a radical CF;, 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 preferably understood to mean a benzyl or phenethyl 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 6 carbon atoms, a nitro functional group, a polyether radical, 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, 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, an aryl 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, an aryl 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 to 1 to 12 carbon atoms.
Among the compounds corresponding to the above general formula (I), the following may be mentioned, alone or as a mixture: 1- methyl 7-{{4'-(2,4-dioxothiazolidin-5-ylmethyl) - biphenyl-3-ylmethyl]methylcarbamoyl}theptanocate; 2- methyl 9-{[4'-(2,4-dioxothiazolidin-5-ylmethyl) - biphenyl-3-ylmethyl]methylcarbamoyl}nonanoate; 3- methyl N-[4'-(2,4~dioxothiazolidin-5~ylmethyl)- biphenyl-3-ylmethyl]-N-methylterephthalamate;
£. 2004/3797
4- 3-cyclopentyl-N-{4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylpropionamide; 5~ N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methylnaphthalene-1l-carboxamide; 6- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl~3- } ylmethyl]-N-methylnaphthalene-2-carboxamide; 7- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-2-phenoxyacetamide; 8- N-[4'-(2,4-dioxothiazolidin~5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-l-methyl-1H-pyrrole-2-carboxamide; 9- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyladamantane-l-carboxamide; 10- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]~N-methylbiphenyl~4-carboxamide; 11- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methylbenzo[b]thiophene-2-carboxamide; 12- N-[4'~(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-6-oxo-6-phenylhexanamide; 13- 4-dimethylamino-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-1- carboxamide; 14- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-4-methanesulphonyl-N-methylbenzamide; 15- N-[4'-(2,4~-dioxothiazolidin-5-ylmethyl)biphenyl-3- vylmethyl]-N-methyl-4-(l-phenylmethanoyl)benzamide;
oc Lul 4/3797
1l6- 6-(2-methoxyethoxymethoxy)-N-[4'-(2,4~- dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N- methylnaphthalene-2-carboxamide; 17- 6-hydroxy-N-[4'-(2,4-dioxothiazolidin-5-ylmethyl) -
biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide; 18- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4-methylsulphanylbenzamide;
19- (S)-3-(3'-{[(l-biphenyl-4-ylmethanoyl)methyl- amino]methyl }biphenyl-4-yl)-2—-ethoxypropionic acid;
20- (S)-2-ethoxy-3-(3'-{[methyl- (6-0x0-6- phenylhexanoyl) amino]methyl }biphenyl-4-yl) propionic acid; 21- 1-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- yl] -1-methyl-3-naphthalen-2-ylurea;
22- 3-(4-dimethylaminophenyl)-1-[4'~(2,4- dioxothiazolidin-5-ylmethyl)biphenyl~-3-ylj-1- methylurea; 23- (S) -2-ethoxy-3-{3'-[({1-([6-(2-methoxyethoxymeth- oxy) naphthalen-2-yllmethanoyl}methylamino)methyl]bi-
phenyl-4-yl}propionic acid;
24- 6-{(methoxymethoxy)-N-[4'-(2,4-dioxothiazolidin~-5- yvlmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2~ carboxamide;
25- 6-(methoxycarbonyl)-N-[4'-(2,4-dioxothiazolidin-5-
vylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- carboxamide;
26-~ 6- (propyloxy)-N-[4'~-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2-
B carboxamide; 27- 6-(hexyloxy)-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- oo carboxamide; -28- 6-(nonyloxy)-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide; 29- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4'~propylbiphenyl-2-carboxamide; 30- N-{4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4-phenoxybenzamide; 31- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-7-oxo~7-phenylheptanamide; 32- (6-{[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl- 3-ylmethyl]lmethylcarbamoyl}naphthalen-2-yloxy)acetic acid; 33- (6-{[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl- 3-ylmethyl]lmethylcarbamoyl}naphthalen-2-yloxy)acetic acid methyl ester; 34- 6-methoxy-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide; 35- o6-acetoxy-N-{4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- carboxamide;
36- 6-amino-N-[4'-(2,4-dioxothiazolidin-5- } ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide; 37- 6-acetylamino-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- carboxamide; 38- 1-hydroxy-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide;
39- 1l-methoxy-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide;
40- 6-bromo-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2-
carboxamide;
41- 6-carboxyl-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide;
42- 6-carboxyl-N-[4'-(2,4-dioxothiazolidin-~-5-
ylmethyl)biphenyl-3-ylmethyl]}-N-methylnaphthalene-2- carboxamide methyl ester;
43- 6-(3-phenylureido)-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide;
44-~ 3-hydroxy-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide;
45- 3-methoxy-N-[4'~(2,4-dioxothiazolidin~5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide; : - 46- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-
ylmethyl]-N-methyl-4'-hydroxybiphenyl-4-carboxamide; 47- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4'-methoxybiphenyl-4-carboxamide;
48- N-[{4'-(2,4~-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4'-propyloxybiphenyl-4-carboxamide;
4S9- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4'-hexyloxybiphenyl-4-carboxamide; 50- N-[4'-(2,4-dioxothiazolidin-5~-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4'-acetoxybiphenyl-4-carboxamide; 51- (4'-{[4'-(2,4-dioxothiazolidin-5-
ylmethyl)biphenyl-3-ylmethylimethylcarbamoyl}biphenyl- 4-yloxy)acetic acid;
52- (4'-{{4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3~ylmethyl]}methylcarbamoyl }biphenyl- 4-yloxy) acetic acid methyl ester;
53- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4'-methoxymethoxybiphenyl-4- carboxamide; 54- N-[4'-(2,4~-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4'-nonyloxybiphenyl-4-carboxamide;
55- N-[4'-(2,4~dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4'-(2-methoxyethoxy)biphenyl-4- carboxamide;
56- 3-biphenyl-4-yl1-1-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-y1]-1-methylurea; . 57- 1-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- yl]-3-(9H-flucren-2-yl)-l-methylurea;
58- 1-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- y1l]-3-(9H-fluoren-9-yl)-l-methylurea; 59- 3-benzhydryl-1-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-yl]-1-methylurea;
60- 1-{4'-(2,4-dioxothiazolidin~5-ylmethyl)biphenyl-3-
yll-l-methyl-3-(3-phenoxyphenyl)urea; 61- 1-[{4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- yl}-3-(4-heptyloxyphenyl)-1l-methylurea; 62~ 3-(4-benzyloxyphenyl)-1-[4'-(2,4-dioxothiazolidin- 5-ylmethyl)biphenyl-3-yl]-1-methylurea;
63- 1-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- yl]-1l-methyl-3-[4-(6-methylbenzothiazol-2- yl)phenyllurea; 64- 4'-(2-methoxyethoxymethoxy)-N-{4'-(2,4- dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-
methylbiphenyl-4-carboxamide; 65- 4'-hydroxy-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] ~-N-methylbiphenyl-4- carboxamide; 66- 1-[(4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl~3-
yll-3-(4-hexyloxyphenyl)-l-methylurea.
According to the present invention, the more particularly preferred compounds of formula (I) are oo those for -which: : : : . - R; represents the radical of formula (a) or the radical of formula (b) where Rs represents a hydroxyl ] radical and Rg represents the radical OR;4 and/or ~ X represents the linkage having the structure —-CH2-N (Rg) -CO- or -N(Rg)-CO-N(Rg)- read from left to right or conversely.
The subject of the present invention is also the methods for preparing the compounds of formula (I), in particular according to the reaction schemes given in Figures 1 and 2.
In Figure 1, the derivatives of formula (Ia) and (Ib) may be obtained respectively from the derivatives (2) and (4) by acylation of the amine functional group with an activated form of a carboxylic acid, for example an acid chloride (C1-CO-R4), in the presence of a tertiary amine (for example triethylamine or pyridine) in an anhydrous solvent, preferably THF, it being possible for the derivatives (2) and (4) to be obtained respectively from the compounds (1) and (3) by deprotection of the amine functional group in the presence of trifluoroacetic anhydride or hydrochloric acid in a solvent such as THF or dichloromethane.
The derivatives of formula (Ic) may be obtained (Figure 1) from the derivatives (4) by reaction with an isocyanate of formula O=C=N-Rs in a solvent such as dichloromethane in the presence of a base such-as triethylamine.
The derivatives of formula (Id) may be obtained (Figure 1) from the derivatives (4) by reaction with an alpha-bromoketone (Br-CH,-CO-Rs) in a solvent such as acetone or methyl ethyl ketone in the presence of a base such as potassium carbonate.
The derivatives (la) and (3a) may be obtained (Figure 2) from the compounds (10) either by hydrogenation in the presence of palladium on carbon or
Raney nickel in a solvent such as ethyl acetate, dioxane, DMF or ethyl alcohol or by reduction in the presence of lithium borohydride and pyridine in THF.
The compounds (10) may be obtained from the compounds (8) by reaction with 2,4-thiazolidinedione (9) in the presence of piperidine acetate in an alcoholic solvent such as ethanol or in toluene. The compounds (8) may be obtained from halogenated derivatives (6), preferably from iodinated or brominated derivatives, by a Suzuki type coupling reaction with a boronic acid (7). This reaction is carried out in the presence of a palladium catalyst, for example tetrakis(triphenylphosphine)- palladium according to the conditions described by
N. Miyaura et al. Synthetic Communications (1981) 11(7), 513-519. The boronic derivatives (7) may be obtained from the corresponding halogenated (preferably iodinated or brominated) derivatives first of all by protection of the aldehyde functional group in acetal oo form-and then conversion to a lithium compound,. . . : : oo reaction with trimethyl or triisopropyl borate and hydrolysis in acidic medium (hydrochloric acid).
The halogenated derivatives (6) are obtained from the corresponding primary amines. The latter are protected by coupling with di-tert-butyl carbonate in a solvent such as dichloromethane. The resulting carbamate is alkylated via the use of a base such as sodium hydride and an alkyl halide in order to give the derivative (6). The derivatives (lb) and (3b) may be obtained (Figure 2) from the derivatives (8) by a succession of reactions according to the conditions described by B. Hulin et al. J. Med. Chem. (1996) 39, 3897-3907.
When R; contains an acid functional group, the compounds are prepared by protecting R; with a protecting group of the alkyl, allyl, benzyl or tert- butyl type. The passage to the free form may be carried out: - in the case of an alkyl protective group, by means of sodium hydroxide or lithium hydroxide in an alcoholic solvent such as methanol or in THF; - in the case of an allyl protective group, by means of a catalyst such as some transition metal complexes in the presence of a secondary amine such as , morpholine; : - - in the case of -a benzyl protective group, . Co : by debenzylation in the presence of hydrogen by means of catalyst such as palladium on carbon; - in the case of a tert-butyl type protective group by means of trimethylsilane iodide.
The compounds according to the invention have }
PPARy type receptor activating properties.
The expression activator of PPARy type receptors is understood to mean according to the invention any compound which exhibits a percentage activation of the PPARy receptors of at least 20%, at the concentration of 1 pM, in a transactivation test as described in Example 35.
The preferred compounds of the present invention have a percentage activation of the PPARy receptors greater than or equal to 40% and advantageously greater than or equal to 70%.
Preferably, the activator of the PPARy type receptors is specific, that is to say that it has a ~ ratio of the percentage activation of the PPARy receptors to the percentage activation of the PPARa receptors (calculated relative to a reference compound,
Wy 14643, activating the PPARa receptors by 100%) greater than or equal to 3. Preferably, this ratio is greater than or equal to 5 and more advantageously ] greater than or equal to 10.
Co - “The affinity -of the PPAR derivatives for the coe human PPARy receptor was also determined in a binding - 5 test as described in Example 36. The expression ligand for the PPARy receptors is understood to mean any compound according to the invention having a Kd value of less than 10 000 nM. Preferably, the compounds according to the invention have a Kd value of less than 1000 nM and advantageously less than 100 nM.
The subject of the present invention is also the compounds of formula (I) as described above, as a medicament.
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 ichtyosis, ichtyosiform states, Darrier's disease, keratosis palmaris et
£. 2200473797 plantaris, leukoplasia and leukoplasiform states, cutaneous or mucosal (buccal) lichen;
Ts ~~ 3) for treating other dermatological conditions.with an CL oo 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 ultraviclet 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 chronologic or actinic
Lo ce . ageing, -such-as—xerosis; - - Se ee A SL Cee ee 8) for combating sebaceous function disorders such as acne hyperseborrhoear or simple seborrhoea; 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 or non-insulin- dependent diabetes; 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 arterosclerosis or hypertension.
The subject of the present invention is also a pharmaceutical composition comprising, in a mo ~physiologically-acceptable medium, at.least one. . . compound of formula (I) as defined above.
The subject of the present invention is also the use of the compounds of formula (I) for manufacturing a composition intended for the treatment of the abovementioned conditions, in particular for regulating and/or restoring skin lipid metabolism.
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.
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, solutions, gels, sprays, lotions or suspensions.
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 cosmetic field, and more particularly for regulating and/or restoring skin lipid metabolism, in particular for preventing and/or treating the cutaneous signs of ageing and/or of dry skin.
The subject of the invention is therefore also a composition comprising, in a cosmetically "acceptable—carrier;—at least--one-of--the compounds -of.. . ) formula (I).
The subject of the invention is also the cosmetic use of the compounds of formula (I) for body or hair hygiene.
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, a soap or a shampoo.
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; | | oo oo —=-_stabilizers;.. - moisture regulators; =- pH regulators; - osmotic pressure modifiers; - emulsifiers; - UV-A and UV-B screening agents; - antioxidants, such as a-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) ; oo . . — nonsteroidal _anti-inflammatory_agents;. - —- carotenoids and, in particular, P-carotene; ) - antipsoriatic agents such as anthralin and its - derivatives; - 5,8,11,14-eicosatetraynoic and 5,8,1l-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; - a-hydroxy acids and a-keto acids or their derivatives, such as lactic, malic, citric, glycolic, mandelic, tartaric, glyceric and ascorbic acids, and their salts, amides or esters, or B-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, N results of biological activity and various concrete formulations based on such compounds, will now be given by way of illustration and without being limiting in any manner.
EXAMPLE 1: methyl 7-{[4'-(2,4-dioxothiazolidin-5- vlmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}heptanoate (a) tert-butyl (3-bromobenzyl)carbamate 40.7 g (183 mmol) of 3-bromobenzylamine hydrochloride, 26 ml of triethylamine (183 mmol) and 450 ml of dichloromethane are introduced into a round- bottomed flask and under a nitrogen stream. 40 g (183 mmol) of di-tert-butyl dicarbonate are added in : small quantities at room temperature and the mixture is stirred overnight. The reaction medium is poured into ice-cold water, extracted with dichloromethane, the organic phase decanted off, dried over magnesium sulphate and evaporated off. 46 g (88%) of the expected product are recovered. (b) tert-butyl (3-bromobenzyl)-N-methylcarbamate 128 g (447 mmol) of tert-butyl (3-bromobenzyl) carbamate and 800 ml of DMF are introduced into a round-bottomed flask and under a nitrogen stream. 19 g (475 mmol) of sodium hydride (60% in oil) are added in small quantities and the mixture is_stirred until _the_gas_emission _ceases._29.3_ml (470 mmol) of methyl iodide are then added and the mixture is stirred overnight.
The reaction medium is poured into ice-cold water, extracted with ethyl acetate, the organic phase decanted off, dried over magnesium sulphate and evaporated off. 152.5 g (92%) of the expected product are recovered.
(c¢) tert-butyl (4'-formylbiphenyl-3- ylmethyl)methylcarbamate
61.5 g (205 mmol) of tert-butyl
(3-bromobenzyl) -N-methylcarbamate, 40 g (260 mmol) of 4-formylbenzeneboronic acid and 800 ml of toluenc are introduced into a three-necked flask and under argon. 205 ml of an aqueous potassium carbonate solution (2 M) are added dropwise, the reaction medium is degassed with argon and 7 g of tetrakis(triphenylphosphine) - palladium (0) chloride are added and the mixture is heated at 90°C for 24 hours.
The reaction medium is poured into water, extracted with dichloromethane, the organic phase decanted off, dried over magnesium sulphate and evaporated off.
The residue obtained is purified by chromatography on a silica column eluted with a heptane and ethyl acetate (70-30) mixture.
After evaporation of the solvents, 38 g (57%) of the expected product are recovered.
(d) tert-butyl [4'-(2,4-dioxothiazolidin-5- ylidenemethyl)biphenyl-3-ylmethyl]methylcarbamate 75.4 g (232 mmol) of tert-butyl (4'- formylbiphenyl-3-ylmethyl)methylcarbamate, 32.5 g (278 mmol) of 2,4-thiazolidenedione, 7.3 g (50 mmol) of piperidine acetate and 1 1 of toluene are introduced into a round-bottomed flask and under a nitrogen stream.
The mixture is heated under reflux for five hours and the water formed is separated with the aid of a Dean-Stark.
The reaction medium is cooled, and the precipitate formed is filtered off. 84 g (86%) of the expected product are recovered. (e) tert-butyl [4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]methylcarbamate 30 g (70.7 mmol) of tert-butyl [4'-(2,4- dioxothiazolidin-5-ylidenemethyl)biphenyl-3- ylmethyl]methylcarbamate in 500 ml of dioxane are introduced into a three-necked flask.
The reaction medium is degassed, 30 g of palladium on carbon (10%) are added and the mixture is hydrogenated at a pressure of 3 bar at 60°C.
The reaction medium is filtered, evaporated off and the residue obtained is purified by chromatography on a silica column eluted with a dichloromethane and methanol (99-1) mixture. 18 g (60%) of the expected product are recovered after evaporation of the solvents.
(f) 5-(3'-methylaminomethylbiphenyl-4- ylmethyl)thiazolidine-2,4-dione 18 g (42 mmol) of tert-butyl [4'-(2,4- dioxothiazolidin-5-ylmethyl)biphenyl-3-
ylmethyl]methylcarbamate in 250 ml of dichloromethane are introduced into a round-bottomed flask and under a nitrogen stream, and 16 ml (208 mmol) of trifluoroacetic acid are added.
The mixture is stirred at room temperature overnight and the reaction medium is hydrolysed with a saturated potassium carbonate solution.
The mixture is extracted with dichloromethane, the organic phase decanted off, washed with water, dried over magnesium sulphate and evaporated off.
The residue obtained is triturated in ethyl acetate and 14.4 g (78%) of the expected product are obtained.
(g) methyl 7-{[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl ]methylcarbamoyl }heptanoate 600 mg (1.36 mmol) of 5-(3'-
methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4- dione, 10 ml of THF and 600 pl (4.3 mmol) of triethylamine are introduced into a round-bottomed flask and under a nitrogen stream. 220 pl (1.55 mmol) of methyl 8-chloro-8-oxooctanoate are added dropwise and the mixture is stirred for one hour.
The reaction medium is poured into water, extracted with dichloromethane, the organic phase decanted off, washed
Bo 200473797 with water, dried over magnesium sulphate and evaporated off. The residue obtained is purified by chromatography on a silica column eluted with a dichloromethane and ethyl acetate (80-20) mixture.
After evaporation of the solvents, 350 mg (50%) of methyl 7-{[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}heptanocate are recovered in the form of an oil. 'H NMR (CDCl3): 0.88-1.40 (m, 4H); 1.62-1.70 (m, 4H); 2.31 (¢, J = 7.4 Hz, 2H); 2.40 (t, J = 7.3 Hz, 2H); 2.96-2.99 (m, 3H); 3.15 (m, 1H); 3.58 (m, 1H); 3.66 (s, 3H); 4.57 (m, 1H); 4.60-4.66 (m, 2H); 7.23-7.55 (m, 8H); 9.15 (m, 1H).
EXAMPLE 2: methyl 9-{[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}nonanocate
In a manner similar to Example 1(g), by reacting 600 mg (1.36 mmol) of 5-(3'- methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2, 4- dione obtained in 1(f) with 340 pl (1.52 mmol) of methyl 10-chloro-10-oxodecanoate, 500 mg (70%) of methyl 9-{[4'-(2,4-dioxothiazolidin-5- yvlmethyl)biphenyl-3-ylmethyl]lmethylcarbamoyl}nonanoate are obtained in the form of an oil after purification by chromatography on a silica column eluted with a dichloromethane and ethyl acetate (80/20) mixture. 'H NMR (CDCls): 1.26-1.32 (m, 8H); 1.59-1.65 (m, 4H); 2.20-2.43 (m, 4H); 2.95-2.99 (m, 3H); 3.16 (m, 1H);
3.55 (m, 1H); 3.85 (s, 3H); 4.54 (m, 1H); 4.60-4.65 (m, 2H); 7.19-7.54 (m, 8H); 9.75 (m, 1H).
EXAMPLE 3: methyl N-[4'-(2,4-dioxothiazolidin-5- vlmethyl)biphenyl-3-ylmethyl] -N-methylterephthalamate
In a manner similar to Example 1(g), by reacting 600 mg (1.36 mmol) of 5-(3'- methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4- dione obtained in 1(f) with 310 mg (1.54 mmol) of methyl 4-chlorocarbonylbenzoate, 370 mg (60%) of methyl
N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methylterephthalamate are obtained in the form of a white solid having a melting point of 186°C after purification by chromatography on a silica column eluted with a dichloromethane and ethyl acetate (90/10) mixture.
EXAMPLE 4: 3-cyclopentyl-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylpropionamide
In a manner similar to Example 1l(g), by reacting 500 mg (1.13 mmol) of 5-(3'- methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2, 4- dione obtained in 1(f) with 200 mg (1.30 mmol) of 3-cyclopentylpropionyl chloride, 170 mg (25%) of 3-cyclopentyl-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylpropionamide are obtained in the form of a solid after purification by chromatography on a silica column eluted with a dichloromethane and methanol (99/1) mixture.
'H NMR (CDCl3): 1.10-1.14 (m, 2H); 1.26 (t, J = 7.1 Hz, 3H); 1.50-1.79 (m, 6H); 2.42 (t, J = 7.6 Hz, 2H); 2.97 (m, 3H); 3.15 (m, 1H); 3.58 {(m, 1H); 4.52 (m, 1H): 4.61-4.66 (m, 2H); 7.20-7.55 (m, 8H); 9.48 (s, 1H).
EXAMPLE 5: N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-1- carboxamide
In a manner similar to Example 1(g), by reacting 1 g (2.3 mmol) of 5-(3'- methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2, 4- dione obtained in 1(f} with 380 pl (2.5 mmol) of l-naphthoyl chloride, 460 mg (41%) of N-{4'-(2,4- dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N- methylnaphthalene-l1-carboxamide are obtained in the form of a white solid having a melting point of 120°C after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (80/20) mixture.
EXAMPLE 6: N-[4'~-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- carboxamide
In 2 manner similar to Example 1l{(g), by reacting 1 g (2.3 mmol) of 5-(3'-methylaminomethylbi- phenyl-4-ylmethyl)thiazolidine-2,4~dione obtained in 1(f) with 480 mg (2.5 mmol) of 2-naphthoyl chloride, 400 mg (40%) of N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-
carboxamide are obtained in the form of a solid having a melting point of 218°C after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (70/30) mixture.
EXAMPLE 7: N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methyl-2-
Phenoxyacetamide
In a manner similar to Example 1(g), by reacting 500 mg (1.53 mmol) of 5-(3'-methylamino- methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione obtained in 1(f) with 210 pl (1.52 mmol) of phenoxyacetyl chloride, 640 mg (91%) of N-[4'-(2,4- dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N- methyl-2-phenoxyacetamide are obtained in the form of a white solid having a melting point of 140°C after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (60/40) mixture.
EXAMPLE 8: N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methyl-1-methyl-1H- pyrrole-2-carboxamide (a) I1-Methyl-1H-pyrrole-2-carboxylic acid chloride 500 mg (4 mmol) of l-methyl-2- pyrrolecarboxylic acid in 5 ml of dichloromethane are introduced into a round-bottomed flask and under a nitrogen stream. There are added, dropwise, 790 nl (4 mmol) of dicyclohexylamine and, 30 minutes later,
290 pl (4 mmol) of thionyl chloride. The medium is stirred for 1 hour at room temperature and then heated for 2 hours at 50°C. The mixture is then diluted with ether and the precipitate is filtered off. The filtrate 1s evaporated off and a brown oil is obtained. (b) N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-1l-methyl-1H-pyrrole-2-carboxamide
In a manner similar to Example 1l(g), by reacting 500 mg (1.53 mmol) of 5-(3'- methylaminomethylbipheényl-4-ylmethyl)thiazolidine-2,4- dione obtained in 1(f) with 220 mg (1.53 mmol) of l-methyl-1H-pyrrole-2-carboxylic acid chloride, 316 mg (47%) of N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methyl-l-methyl-1H- pyrrole-2-carboxamide are obtained in the form of a white solid having a melting point of 184°C after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (60/40) mixture.
EXAMPLE 9: N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methyladamantane-1- carboxamide
In a manner similar to Example 1(g), by reacting 500 mg (1.53 mmol) of 5-(3'- methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4- dione obtained in 1(f) with 310 mg (1.56 mmol) of adamantane-l-carboxylic acid chloride, 390 mg of N-[4'-
(2,4-dioxothiazolidin-5~ylmethyl)biphenyl-3~-ylmethyl]-
N-methyladamantane-l-carboxamide are obtained in the form of a white powder having a melting point of 77°C after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (70/30) mixture.
EXAMPLE 10: N~-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylbiphenyl-4- carboxamide
In a manner similar to Example 1(g), by reacting 500 mg (1.53 mmol) of 5-(3'- methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4- dione obtained in 1(f) with 330 mg (1.52 mmol) of 4-biphenylcarboxylic acid chloride, 681 mg (88%) of
N-[4'-(2,4-dioxothiazolidin-5~-ylmethyl)biphenyl-3- ylmethyl] -N-methylbiphenyl-4-carboxamide are obtained in the form of a white powder having a melting point of 204°C after trituration in ether.
EXAMPLE 11: N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylbenzo[b]thio- phene-2-carboxamide
In a manner similar to Example 1(g), by reacting 500 mg (1.53 mmol) of 5-(3'- methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2, 4- dione obtained in 1(f) with 300 mg (1.52 mmol) of benzo [blthiophene-2-carboxylic acid chloride, 509 mg (68%) of N-[4'-(2,4~-dioxothiazolidin-5-
p.-20047/3797 ylmethyl)biphenyl-3-ylmethyl]-N-methylbenzo[b]thio- phene-2-carboxamide are obtained in the form of a white powder having a melting point of 187°C after trituration in dichloromethane.
5S EXAMPLE 12: N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methyl-6-oxo-6- phenylhexanamide
320 mg (1.55 mmol) of 5-benzoylpentanoic acid in 5 ml of dichloromethane are introduced into a round-
bottomed flask and under a nitrogen stream. 230 mg (1.7 mmol) of l-hydroxybenzotriazole hydrate, 230 ul (1.7 mmol) of triethylamine and 500 mg (1.53 mmol) of 5-(3'-methylaminomethylbiphenyl-4- ylmethyl)thiazolidine-2,4-dione obtained in 1(f) are added.
Next, at 0°C, 320 mg (1.7 mmol) of 1-(3- dimethylaminopropyl)~-3-ethylcarbodiimide hydrochloride are added.
The medium is stirred for 3 hours at room temperature.
It is diluted with dichloromethane and washed with a saturated aqueous sodium hydrogen carbonate solution.
The organic phase is dried over magnesium sulphate, filtered and evaporated off.
The residne is purified by chromatography on a silica column eluted with a heptane and ethyl acetate (50/50) mixture. 590 mg (75%) of N-[4'-(2,4-dioxothiazolidin-5-
vylmethyl)biphenyl-3-ylmethyl]-N-methyl-6-oxo-6- phenylhexanamide are obtained in the form of a white powder having a melting point of 48°C.
EXAMPLE 13: 4-dimethylamino-N-[4'-(2,4- dioxothiazolidin~5-ylmethyl)biphenyl-3-ylmethyl] -N- methylnaphthalene-1l-carboxamide
In a manner similar to Example 12, by reacting 500 mg (1.53 mmol) of 5-(3'- methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4- dione obtained in 1(f) with 330 mg (1.53 mmol) of 4- dimethylaminonaphthalene-l-carboxylic acid, 520 mg (65%) of 4-dimethylamino-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-1- carboxamide are obtained in the form of a yellowish foam having a melting point of 67°C after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (50/50) mixture.
EXAMPLE 14: N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -4-methanesulphonyl-N- methylbenzamide
In a manner similar to Example 12, by reacting 500 mg (1.53 mmol) of 5-(3'- methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2, 4- dione obtained in 1 (f) with 310 mg (1.55 mmol) of 4- (methylsulphonyl)benzoic acid, 540 mg (69%) of N-[4'- (2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3~ylmethyl]- 4-methanesulphonyl-N-methylbenzamide are obtained in the form of a white solid having a melting point of 172°C after purification by chromatography on a silica column eluted with a dichloromethane and methanol (98/2) mixture.
EXAMPLE 15: N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methyl-4-~ (1- phenylmethanoyl)benzamide (a) 4-(l-phenylmethanoyl)benzoyl chloride
In a manner similar to Example 9(a), starting with 500 mg (2.2 mmol) of 4-benzoylbenzoic acid, 490 mg (91%) of the expected product are obtained in the form of a white solid. (b) N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4-(l-phenylmethanoyl)benzamide
In a manner similar to Example 1(g), by reacting 500 mg (1.53 mmol) of 5-(3'-methylaminomethyl- biphenyl-4-ylmethyl)thiazolidine-2,4-dione obtained in 1(f) with 380 mg (1.55 mmol) of 4-(l-phenylmethanoyl) benzoyl chloride, 660 mg (81%) of
N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4- (1l-phenylmethanoyl)benzamide are obtained in the form of a white powder having a melting point of 94°C after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (50/50) mixture.
EXAMPLE 16: 6-(2-methoxyethoxymethoxy)-N-[4'-(2,4- dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N- methylnapthalene-2-carboxamide (a) methyl 6-hydroxynaphthalene-2-carboxylate
£20047 3797
15.7 g (83 mmol) of 6-hydroxy-2-naphthoic acid in 160 ml of methanol are introduced into a round- bottomed flask. 8 ml of concentrated sulphuric acid are added and the mixture is heated under reflux for 8 hours.
At room temperature, a precipitate forms.
It is filtered off, rinsed with ether and dried. 14.1 g (84%) of the expected product are obtained in the form of a beige powder. (b) methyl 6-(2-methoxyethoxymethoxy)naphthalene-2- carboxylate 14 g (69 mmol) of methyl 6-hydroxynaph- thalene-2-carboxylate in 90 ml of dimethylformamide and 90 ml of tetrahydrofuran are introduced into a round- bottomed flask and under a nitrogen stream. 3.3 g (82 mmol) of sodium hydride at 60% are added in small portions.
When the gas emission has ceased, 8.7 ml (76 mmol) of 2-methoxyethoxymethyl chloride are added and the reaction medium is stirred for 3 hours at room temperature.
It is then poured into ice-cold water and extracted with ether.
The organic phase is dried over magnesium sulphate, filtered and evaporated off.
The residue obtained is purified by chromatography on a silica column eluted with a heptane and ethyl acetate (80/20) mixture and 17 g (85%) of the expected product are obtained in the form of a colourless oil. (c) 6-(2-methoxyethoxymethoxy)naphthale-2-carboxylic acid
16.9 g (58 mmol) of methyl 6-(2- methoxyethoxymethoxy)naphthalene-2-carboxylate in 200 ml of tetrahydrofuran and 20 ml of methanol are introduced into a round-bottomed flask. 1 ml of water and 12.9 g (322 mmol) of sodium hydroxide pellets are added. The reaction medium is stirred for 4 hours at room temperature. 1N hydrochloric acid is slowly added in the cold state up to pH 2-3. The mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and then evaporated off. The residue is triturated in heptane, filtered and dried. 14.9 g (92%) of the expected product are obtained in the form of a white powder having a melting point of 110°C. (d) 6-(2-methoxyethoxymethoxy)-N-[4'-(2,4- dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N- methylnaphthalene-2-carboxamide
In a manner similar to Example 12, by reacting 1.5 g (4.6 mmol) of 5-(3'- methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2, 4- dione obtained in 1(f) with 1.27 g (4.6 mmol) of 6- (2-methoxyethoxymethoxy) naphthalene-2-carboxylic acid, 1.97 g (62%) of 6-(2-methoxyethoxymethoxy)-N-[4'- (2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-
N-methylnaphthalene-2-carboxamide are obtained in the form of a white powder having a melting point of 68°C after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (50/50) mixture.
EXAMPLE 17: 6-hydroxy-N-[4'-(2,4-dioxothiazolidin-5-~ vlmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide 1.5 g (2.5 mmol) of 6-(2- methoxyethoxymethoxy) -N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- carboxamide (obtained in Example 16) in 10 ml of tetrahydrofuran and 10 ml of methanol are introduced into a round-bottomed flask. 500 pl of concentrated sulphuric acid are added and the medium is stirred for 2 hours at room temperature. Water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and then evaporated off. The residue is purified by chromatography on a silica column eluted with a heptane and ethyl acetate (30/70) mixture. 1.26 g (99%) of 6-hydroxy~-N-[4'-(2,4-dioxothiazolidin-5- vylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- carboxamide are obtained in the form of a white powder having a melting point of 218°C.
EXAMPLE 18: N-[4'-(2,4-dioxothiazolidine-5- ylmethyl)biphenyl-3-ylmethyl] -N-methyl-4- methylsulphanylbenzamide (a) 4-methylsulphanylbenzoyl chloride
In a manner similar to Example 9(a), starting with 400 mg (2.4 mmol) of 4-(methylthio)benzoic acid, 440 mg (99%) of the expected product are obtained in the form of a yellowish solid. (b) N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- methyl] -N-methyl-4-methylsulphanylbenzamide
In a manner similar to Example 1(g), by reacting 500 mg (1.53 mmol) of 5-(3'- methylaminomethylbiphenyl-4~ylmethyl)thiazolidine-2, 4- dione obtained in 1(f) with 290 mg (1.55 mmol) of 4-methylsulphanylbenzoyl chloride, 470 mg (64%) of
N-{4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4-methylsulphanylbenzamide are obtained in the form of a white powder having a melting point of 203-7°C after recrystallization from methanol.
EXAMPLE 19: (S)-3-(3'-{[(1-biphenyl-4- ylmethanoyl)methylamino]methyl}biphenyl-4-yl)-2- ethoxypropionic acid (a) ethoxyacetyl chloride g (240 mmol) of ethoxyacetic acid in 300 ml of dichloromethane are introduced into a round- bottomed flask and under a nitrogen stream. 47.6 ml (239 mmol) of dicyclohexylamine are added. The medium is stirred for 1 hour at room temperature. 19.2 ml 25 (265 mmol) of thionyl chloride are added and the mixture is stirred for 3 hours. Ethyl ether is added to the reaction medium, the precipitate formed is filtered off and rinsed with ether.
After evaporation of the filtrate, 29 g (100%) of the expected product are obtained in the form of a brown liquid. (b) 3-(2-ethoxyethanoyl)-4-benzyloxazolidin-2-one 5) 36.7 g (207 mmol) of (S)-4-benzyloxazolidin- 2-one in 800 ml of THF are introduced into a round- bottomed flask and under a nitrogen stream.
The reaction medium is cooled to -78°C and 83 ml (207 mmol) of n-butyllithium (2.5 M/hexane) are added dropwise.
30 minutes later, 25.4 g (207 mmol) of ethoxyacetyl chloride are added at -78°C.
The reaction medium is stirred for 24 hours and then poured into a saturated aqueous sodium chloride solution and extracted with ethyl acetate.
The organic phase is dried over magnesium sulphate, filtered and evaporated off. 30.6 g (56%) of the expected product are obtained in the form of an orange-coloured oil after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (60/40) mixture.
(c) methyl (25,3R)-3-{3'-[(tert- butoxycarbonylmethylamino)methyl ]biphenyl-4-yl}-2- ethoxy-3-hydroxypropionate
21.9 g (83 mmol) of 3-(2-ethoxyethanol)-4- benzyloxazolidin-2-one and 100 ml of dichloromethane are introduced into a round-bottomed flask and under argon. 103 ml (103 mmol) of dibutylborane trifluoromethanesulphonate and 18 ml (104 mmol) of
2 2004/3797
N-ethyldiisopropylamine are successively added, at 0°C, dropwise, and the mixture is stirred for one hour. At -78°C, a solution of 23.5 g (69 mmol) of tert-butyl (4'-formylbiphenyl-3-ylmethyl)methylcarbamate obtained in 1(c) in 100 ml of dichloromethane is added and the mixture is stirred overnight. It is treated with a buffer solution pH = 7 (170 ml) in 500 ml of methanol and then with a solution of hydrogen peroxide (170 ml) in 500 ml of methanol and the mixture is stirred for 1 hour 30 minutes at 0°C. The reaction medium is poured into water, and extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated off. The residue obtained is purified by chromatography on a silica column eluted with a heptane and ethyl acetate (70/30) mixture and 21 g (51%) of the expected product are obtained. (d) methyl (2S,3R)-2-ethoxy-3-hydroxy-3-(3'- methylaminomethylbiphenyl-4-yl)propionate 21 g (47.3 mmol) of methyl (2S,3R)-3-{3'- [(tert-butoxycarbonylmethylamino)methyl]biphenyl-4-yl}- 2-ethoxy-3-hydroxypropionate, 8.76 ml (54.9 mmol) of triethvlsilane in 300 ml of trifluoroacetic acid are introduced into a round-bottomed flask and under a nitrogen stream. The reaction medium is stirred for 4 hours at room temperature. Ethyl acetate is then added and the mixture is neutralized with sodium hydroxide. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated off. 19.6 g (100%) of the expected crude product are obtained. (e) methyl (S)-2-ethoxy-3-(3'- methylaminomethylbiphenyl-4-yl)propionate 19.6 g of the crude product methyl (2S,3R)-2- ethoxy-3-hydroxy-3-(3'-methylaminomethylbiphenyl-4- yl)propionate are dissolved in 200 ml of trifluoroacetic acid and 41.7 ml (297 mmol) of triethylamine are added. The reaction medium is stirred at room temperature for 48 hours and then extracted with ethyl acetate. The organic phase is decanted off, washed with a sodium hydroxide solution and then with a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated off. The residue obtained is purified by chromatography on a silica column eluted with a dichloromethane and methanol (95/5) mixture. 1.6 g (10%) of the expected product are obtained. (f) methyl (S)-3-(3'-{[(l1-biphenyl-4- ylmethanoyl)methylamino]jmethyl}biphenyl-4-yl)-2- ethoxypropionate
In a manner similar to Example 1 (gq), by reacting 500 mg (1.5 mmol) of methyl (S)-2-ethoxy-3- (3'-methylaminomethylbiphenyl-4-yl)propionate with 680 mg (3.1 mmol) of 4-biphenylcarboxylic acid chloride, 360 mg (47%) of the expected product are obtained after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (70/30) mixture. (g) (§)-3-(3'-{[(1-biphenyl-4-
ylmethanoyl)methylamino]methyl}biphenyl-4-yl)-2-
ethoxypropionic acid
360 mg (0.7 mmol) of methyl (S)-3-(3'-{[(1- biphenyl-4-ylmethanoyl)methylaminolmethyl}biphenyl-4- yl) -2-ethoxypropionate in 10 ml of THF are introduced into a round-bottomed flask. 60 mg (1.4 mmol) of lithium hydroxide monohydrate, 1 ml of water and 1 ml of methanol are added and the mixture is stirred for 4 hours.
The reaction medium is poured into water, acidified to pH 1, extracted with ethyl acetate, the organic phase decanted off, dried over magnesium sulphate and evaporated off.
The residue obtained is purified by chromatography on a silica column eluted with a heptane and ethyl acetate (50/50) mixture and 280 mg (80%) of (S)-3-(3'-{[(l-biphenyl-4-
vylmethanoyl)methylaminolmethyl}biphenyl-4-yl)-2- ethoxypropionic acid are obtained in the form of an amorphous white solid.
'H NMR (CDCl3): 1.19 (t, J = 8 Hz, 3H); 2.96-3.09 (m, 3H); 3.05 (dd, J = 14.1 Hz and J = 7.8 Hz, 1H); 3.17
(dd, J = 14.1 Hz and J = 4 Hz, 1H); 3.45-3.61 (m, 2H);
4.12 (m, 1H); 4.64-4.84 (m, 2H); 7.25-7.56 (m, 17H).
EXAMPLE 20: (S)-2-ethoxy-3-(3'-{[methyl (6-oxo-6- phenylhexanoyl) amino]methyl }biphenyl-4-yl)propionic acid (a) methyl (S)-2-ethoxy-3-(3'-{[methyl (6-o0x0-6- phenylhexanoyl)amino]methyl}biphenyl-4-yl)propionate
In a manner similar to Example 12, by reacting 660 mg (2 mmol) of methyl (S)-2-ethoxy-3-(3'- methylaminomethylbiphenyl-4-yl) propionate obtained in 19(e) with 346 mg (1.68 mmol) of S5-benzoylpentanoic acid, 330 mg (33%) of the expected product are obtained after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (50/50) mixture. (b) (S)-2-ethoxy-3-(3'~{ [methyl (6-0x0-6- phenylhexanoyl)amino]methyl}biphenyl-4-yl)propionic acid
In a manner similar to Example 18(g), starting with 330 mg (0.64 mmol) of methyl (S8)-2- ethoxy-3-(3'~{ [methyl (6-ox0-6- phenylhexanoyl)amino]methyl}biphenyl-4-yl)propionate, 230 mg (72%) of (S)-2-ethoxy-3-(3'-{ [methyl (6-oxo-6- phenylhexanoyl)amino])methyl}biphenyl-4~-yl)propionic acid are obtained in the form of a yellow oil after purification by chromatography on a silica column.
H NMR (CDCls3): 1.20 (m, 3H); 1.77-1.85 (m, 4H); 2.44 (m, 2H); 2.95-2.98 (m, 3H); 3.01 (m, 2H); 3.05 (m, 1H);
3.15 (m, 1H); 3.46-3.61 (m, 2H); 4.10 (2s, 1H); 4.59- 4.64 (m, 2H); 7.18-7.55 (m, 11H); 7.90-7.96 (m, 2H).
EXAMPLE 21: 1-[4'-(2,4-dioxothiazolidin-~5- ylmethyl)biphenyl-3-yl]-1-methyl-3-naphthalen-2-ylurea (a) (3-bromophenyl) methylamine g (58 mmol) of 3-bromoaniline and 34 ml (204 mmol) of triethylorthoformate are introduced into a round-bottomed flask and under a nitrogen stream. The reaction medium is heated under reflux for 7 hours. The 10 triethylorthoformate is then evaporated off. The residue is dissolved in ethanol and 4.9 g (12.8 mmol) of sodium borohydride are added at 0°C. The medium is stirred overnight at room temperature. It is then poured into water and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and then evaporated off. The residue obtained is purified by chromatography on a silica column eluted with a heptane and ethyl acetate (90/10) mixture and 5 g (46%) of the expected product are obtained in the form of a light oil. (b) 3'-methylaminobiphenyl-4-carbaldehyde
In a manner similar to Example l(c), by reacting 4.3 g (23.2 mmol) of (3-bromophenyl)methylamine with 5.2 g (34.8 mmol) of 4-formylbenzeneboronic acid, 2.2 g (59%) of the expected product are obtained in the form of a yellow solid after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (90/10) mixture. (c) b5-(3'-methylaminobiphenyl-4- ylmethylene)thiazolidine-2,4-dione
In a manner similar to Example 1(d), by reacting 2.9 g (13.7 mmol) of 3'-methylaminobiphenyl-4- carbaldehyde with 1.6 g (13.7 mmol) of 2,4-thiazolidinedione, 3.9 g (91%) of the expected product are obtained after trituration in dichloromethane and ether. (d) 1-[4'-(2,4-dioxothiazolidin-5- ylidenemethyl)biphenyl-3-yl]-l1-methyl-3-naphthalen-2- ylurea 500 mg (1.6 mmol) of 5-(3'- methylaminobiphenyl-4-ylmethylene)thiazolidine-2, 4- dione in 10 ml of dichloromethane and 540 mg (3.2 mmol) of naphthyl isocyanate are introduced into a round- bottomed flask and under a nitrogen stream. The mixture is stirred at 35°C for 4 hours. The reaction medium is filtered and the solid is rinsed with dichloromethane.
The filtrate is evaporated off and 660 mg (86%) of the expected product are obtained in the form of a yellow powder. (e) 1-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- yl]-1-methyl-3-naphthalen-2-ylurea
In a manner Similar to Example le), Starting
With 660 mg (1.38 mmol) of 17142, 4-dioxothiazel 1g; enh bBo 1-3 11) parts ss
Ylurea, 320 mg (48%) of 1714-2, 4-dioxothiazol qi ps. a TE are obtained in the form of 3 white powder having a melting point of 196°C after Purification by
Chromatography On a silica column eluted with a heptane and ethyl acetate (70/30) Mixture.
EXAMPLE 22: 7" (4-dinethylaninophany 1) 1-14. (5 ,.
Lin lm btthany1 31 1 een (a) TT (4rdine thy lami nopheny 1) 1-14. (5 eOthaOLidin Sy enema) biphenyg. methylurea
In a manner Similar tg Example 22 (d), by reacting 500 mg (1.6 Mol) of 5- (37.
Smo heny) Aydt dene) hsazot sana... dione Obtained in 21 (c) with 520 mg (3.2 mmol) of 4 (dimethylamino) pheny: isocyanate, 760 mg (100%) of - the expected Product are obtained in the form of a yellow powder. {b) 7 (4-dinethylominopheny 1) 1-141 5 ,.
OR nS tnt bona apy
In a Manner Similar to Example 1(e), Starting with 760 mg (1.6 mmol) of 37 (4-dimethylaminopheny1) 1.
Oh an01 i045) enema pose go
Yll-l-methylurea, 330 mg (43%) of 3~(4-
dimethylaminophenyl)-1-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-yl]-l-methylurea are obtained in the form of a white powder having a melting point of 102°C after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (60/40) mixture.
EXAMPLE 23: (S)-2-ethoxy-3-{3'-[({1-[6-(2- methoxyethoxymethoxy) naphthalen-2- yl]lmethanoyl}methylamino)methyl]biphenyl-4-yl}propionic acid (a) (S)-2-ethoxy-3-({3'-[({1-[6-(2- methoxyethoxymethoxy)naphthalen-2- yl]methanoyl }methylamino)methyl]biphenyl-4-yl}propionic acid
In a manner similar to Example 13, by reacting 380 mg (1.16 mmol) of methyl (S)-2-ethoxy-3- (3'-methylaminomethylbiphenyl-4-yl) propionate obtained in 19(e) with 350 mg (1.27 mmol) of 6-{(2-methoxy- ethoxymethoxy) naphthalene-2-carboxylic acid (prepared in 16(c)), 110 mg (16%) of the expected product are obtained after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (50/50) mixture. (b) (S)-2-ethoxy-3-{3'-[({1-[6-(2~ methoxyethoxymethoxy)naphthalen-2-yl]methanoyl}- methylamino)methyl]biphenyl-4-yl}propionic acid
In a manner similar to Example 19(g), by reacting 110 mg (0.18 mmol) of methyl (S)-2-ethoxy-3- {3'-[({1-[6-(2-methoxyethoxymethoxy)naphthalen-2- yllmethanoyl}methylamino)methyl]biphenyl-4- vyllpropionate with 16 mg (0.38 mmol) of lithium hydroxide monohydrate, 30 mg (42%) of (S)-2-ethoxy-3- {3'-[({1-[6- (2-methoxyethoxymethoxy)naphthalen-2- yllmethanoyl}methylamino)methyl]biphenyl-4-yl}propionic acid are obtained~’in the form of a yellow oil after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (50/50) mixture then with pure ethyl acetate. 'H NMR (CDCl;3): 1.18 (t, J = 6.9 Hz, 3H); 2.90-3.17 (m, 5H); 3.37 (s, 3H); 3.44-3.64 (m, 4H); 3.86 (m, 2H); 4.11 (m, 1H); 4.70 (m, 2H); 5.39 (s, 2H); 7.23-7.54 (m, 11H); 7.75 (m, 2H); 7.91 (s, 1H).
EXAMPLE 24: 6- (methoxymethoxy)-N-[4'-(2,4- dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N- methylnaphthalene-2-carboxamide
In a manner similar to Example 12, by . reacting 500 mg (1.53 mmol) of 5-(3'-methylamino- methylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione obtained in 1(f) with 371 mg (1.6 mmol) of 6-methoxymethoxynaphthalene-2-carboxylic acid, 648 mg (75%) of 6-(methoxymethoxy)-N-[4'-(2,4- dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N- methylnaphthalene-2-carboxamide are obtained in the form of a white powder having a melting point of 160°C after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (50/50) mixture. 'H NMR (DMSO d6; 400 MHz): 2.96 (broad s, 3H); 3.19 (dd, J = 9.2 Hz and J = 14.1 Hz, 1H); 3.41 (s, 3H); 3.44 (dd, J = 4.2 Hz and J = 14.1 Hz, 1H); 4.58-4.82 (m, 2H); 4.97 (dd, J = 4.3 Hz and J = 9.1 Hz, 1H): 7.25-8.03 (m, 14H); 12.10 (broad s, 1H)
EXAMPLE 25: 6- (methoxycarbonyl)-N-[4'-(2,4- dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl] -N- methylnaphthalene-2-carboxamide
In a manner similar to Example 12, by reacting 500 mg (1.53 mmol) of 5-(3'-methylamino- methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione obtained in 1(f) with 370 mg (1.6 mmol) of 6-methoxycarbonylnaphthalene-2-carboxylic acid, 580 mg (67%) of 6-(methoxycarbonyl)-N-[4'-(2,4- dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl}-N- methylnaphthalene-2-carboxamide are obtained in the _ form of a white powder having a melting point of 125- 127°C after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (50/50) mixture. 'H NMR (DMSO d6; 400 MHz): 2.92-3.01 (m, 3H); 3.18 (m, 1H); 3.44 (m, 1H); 3.93 (s, 3H); 4.59-4.80 (m, 2H);
4.97 (m, 1H); 7.20-7.70 (m, SH); 8.00-8.20 (m, 3H); 8.23 (m, 1H); 8.69 (m, 1H); 12.10 (broad s, 1H).
EXAMPLE 26: 6- (propyloxy)-N-[4'-(2,4-dioxothiazolidin~ 5-ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide
In a manner similar to Example 12, by reacting 500 mg (1.53 mmol) of 5-(3'-methylamino- methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione obtained in 1(f) with 370 mg (1.6 mmol) of 6- propyloxynaphthalene-2-carboxylic acid, 530 mg (61%) of 6- (propyloxy) -N-[4'-(2,4-dioxothiazolidin-5- yimethyl)biphenyl-3~-ylmethyl] -N-methylnaphthalene-2- carboxamide are obtained in the form of a white powder having a melting point of 108-110°C after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (50/50) mixture. 'H NMR (DMSO d6; 400 MHz): 1.00 (t, J = 7.4 Hz, 3H); 1.80 (m, 2H); 2.96 (broad s, 3H); 3.17 (dd, J = 9.2 Hz and J = 14.1 Hz, 1H); 3.44 (dd, J = 4.2 Hz and J = 14.1 Hz, 1H); 4.06 (t, J = 6.5 Hz, 2H); 4.63-4.77 (m, 2H); 4.96 (dd, J = 4.3 Hz and J = 9.1 Hz, 1H); 7.19- 7.98 (m, 14H); 12.10 (broad s, 1H).
EXAMPLE 27: 6- (hexyloxy)-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide
In a manner similar to Example 12, by reacting 500 mg (1.53 mmol) of 5-(3'-methylamino-
methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione obtained in 1(f) with 436 mg (1.6 mmol) of 6-hexyloxynaphthalene-2-carboxylic acid, 520 mg (56%) of 6-(hexyloxy)-N-[4'-(2,4-dioxothiazolidin~-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- carboxamide are obtained in the form of a white powder having a melting point of 117°C after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (60/40) mixture. 'H NMR (DMSO dé; 400 MHz): 0.88 (m, 3H); 1.32 (m, 4H); 1.44 (m, 2H); 1.79 (m, 2H); 2.96 (broad s, 3H); 3.17 (dd, J = 9.2 Hz and J = 14.1 Hz, 1H); 3.44 (dd, J = 4.2 Hz and J = 14.1 Hz, 1H); 4.09 (t, J = 6.5 Hz, 2H): 4.63-4.77 (m, 2H); 4.96 (dd, J = 4.3 Hz and J = 9.1 Hz, 1H); 7.19-7.98 (m, 14H); 12.10 (broad s, 1H).
EXAMPLE 28: 6- (nonyloxy)-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide
In a manner similar to Example 12, by reacting 500 mg (1.53 mmol) of 5-(3'-methylamino- - methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione obtained in 1(f) with 503 mg (1.6 mmol) of 6-nonyloxynaphthalene-2-carboxylic acid, 590 mg (59%) of 6-(nonyloxy)-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- carboxamide are obtained in the form of a white powder having a melting point of 117°C after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (60/40) mixture. 'H NMR (DMSO dé; 400 MHz): 0.85 (m, 3H); 1.20-1.40 (m, 10H); 1.45 (m, 2H); 1.78 (m, 2H); 2.96 (broad s, 3H); 3.17 (dd, J = 9.2 Hz and J = 14.1 Hz, 1H); 3.44 (dd,
J = 4.2 Hz and J = 14.1 Hz, 1H); 4.09 (t, J = 6.5 Hz, 2H); 4.63-4.77 (m, 2H); 4.96 (dd, J = 4.3 Hz and J = 9.1 Hz, 1H); 7.19-7.98 (m, 14H); 12.10 (broad s, 1H).
EXAMPLE 29: N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4"'- propylbiphenyl-2-carboxamide
In a manner similar to Example 12, by reacting 500 mg (1.53 mmol) of 5-(3'-methylamino- methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione obtained in 1(f) with 384 mg (1.6 mmol) of 4- (4'-propylphenyl)benzoic acid, 602 mg (68%) of
N-[4'-(2,4-dioxothiazolidin~-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4'-propylbiphenyl-2-carboxamide are obtained in the form of a white powder after purification by chromatography on a silica column . eluted with a heptane and ethyl acetate (60/40) mixture. 'H NMR (DMSO d6; 400 MHz): 0.91 (t, J = 7.3 Hz, 3H); 1.72 (m, 2H); 2.58 {(m, 2H); 2.93 (broad s, 3H); 3.19 (dd, J = 9.2 Hz and J = 14.1 Hz, 1H); 3.43 (dd, J = 4.2 Hz and J = 14.1 Hz, 1H); 4.58-4.78 (m, 2H); 4.96
(dd, J = 4.3 Hz and J = 9.1 Hz, 1H); 7.20-7.75 (m, 16H); 12.10 (broad s, 1H).
EXAMPLE 30: N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methyl-4- phenoxybenzamide
In a manner similar to Example 12, by reacting 500 mg (1.53 mmol) of 5-(3'-methylamino- methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione obtained in 1(f) with 343 mg (1.6 mmol) of 4-phenoxybenzoic acid, 545 mg (68%) of N-[4'-(2,4- dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N- methyl-4-phenoxybenzamide are obtained in the form of a white powder having a melting point of 95°C after purification by chromatography on a silica column eluted with a heptane and ethyl acetate mixture in a polarity gradient from (80/20) to (60/40).
EXAMPLE 31: N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methyl-7-oxo0-7- phenylheptanamide
In a manner similar to Example 12, by - reacting 500 mg (1.53 mmol) of 5-(3'-methylamino- methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione obtained in 1(f) with 352 mg (1.6 mmol) of 6-benzoylhexanoic acid, 610 mg (75%) of N-[{4'-(2,4- dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N- methyl-7-oxo-7-phenylheptanamide are obtained in the form of a white powder having a melting point of 55-
56°C after purification by chromatography on a silica column eluted with a heptane and ethyl acetate mixture in a polarity gradient from (70/30) to (50/50).
EXAMPLE 32: 4'-(2-methoxyethoxymethoxy)-N-[4'-(2,4~- dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N- methylbiphenyl-4-carboxamide fa) methyl 4'-(2-methoxyethoxymethoxy)biphenyl-4- carboxylate g (43.8 mmol) of 4'-hydroxybiphenyl-4- 10 carboxylic acid methyl ester, 100 ml of THF and 150 ml of DMF are introduced in order and under a nitrogen stream into a 500 ml three-necked flask. 1.93 g (48.2 mmol) of NaH at 60% in oil are added in small portions and the mixture is stirred at room temperature for 15 hours. 5.75 ml of l-chloromethoxy-2- methoxyethane are added dropwise, and the mixture is stirred at room temperature for 30 minutes. The reaction medium is poured over a 1N HCl solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulphate. :
After filtration and evaporation 12 g of 4'-(2- methoxvethoxymethoxv)biphenvl-4-carboxylic acid methyl ester are obtained in the form of a beige powder after filtration and evaporation (yield = 87%). (b) 4'-(2-methoxyethoxymethoxy)biphenyl-4-carboxylic acid
10 g (31.6 mmol) of 4'-(2- methoxyethoxymethoxy)biphenyl-4-carboxylic acid methyl ester, 100 ml of methanol and 31 ml of a 10 M NaOH solution are introduced, in order, into a 250 ml three- necked flask. The mixture is stirred at 80°C for 30 minutes. After returning to room temperature, the reaction medium is poured over water and acidified with a 1 N HCl solution. The precipitate is filtered off. It is taken up in heptane. After filtering and drying, 9 g of 4'-(2-methoxyethoxymethoxy)biphenyl-4-carboxylic acid are obtained in the form of a beige powder (yield = 98%). (c) 4'-(2-methoxyethoxymethoxy)-N-[4'~(2,4~ dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N- methylbiphenyl-4-carboxamide
In a manner similar to Example 12, by reacting 4 g (12.3 mmol) of 5-(3'- methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4- dione obtained in 1(f) with 3.58 g (12.3 mmol) of 4'-(2-methoxyethoxymethoxy)biphenyl-4-carboxylic acid, - 2.9 g (38%) of 4'-(2-methoxyethoxymethoxy)-N-[4'-(2,4- dioxothiazolidin-5-ylmethyl)biphenyl-3~ylmethyl]-N- methylbiphenyl-4-carboxamide are obtained in the form of a white powder having a melting point of 126-128°C after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (50/50) mixture, followed by recrystallization from methanol.
'H NMR (DMSO dé; 400 MHz): 2.93 (m, 3H); 3.15-3.22 (m, 4H); 3.41-3.47 (m, 3H); 3.72 (m, 2H); 4.61-4.75 (m, 2H); 4.96 (dd, J = 4.3 Hz and J = 9.1 Hz, 1H); 5.29 (broad s, 2H); 7.11-7.68 (m, 16H); 12.10 (broad s, 1H).
EXAMPLE 33: 4'-hydroxy-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylbiphenyl-4- carboxamide 1.6 g of 4'-(2-methoxyethoxymethoxy)-N-~[4"'- (2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-
N-methylbiphenyl-4-carboxamide, 100 ml of methanol and 1 ml of 98% sulphuric acid are introduced, in order, into a 250 ml three-necked flask. The mixture is stirred at room temperature for 18 hours. The reaction medium is concentrated. It is taken up in ethyl acetate and it is washed twice with water. The organic phase is dried over magnesium sulphate. After filtration and evaporation, the product obtained is recrystallized from an acetone/dichloromethane mixture. After filtration and drying, 1.34 g (99%) of 4'-hydroxy-N- [4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methylbiphenyl-4-carboxamide are obtained in the form of a white powder having a melting point of 211-213°C. 'H NMR (DMSO d6; 400 MHz): 2.93 (m, 3H); 3.18 (dd, J = 9.6 Hz and J = 14.1 Hz, 1H); 3.43 (dd, J = 4.3 Hz and
J = 14.1 Hz, 1H); 4.61-4.75 (m, 2H); 4.96 (dd, J =
4.3 Hz and J = 9.6 Hz, 1H); 6.85-7.63 (m, 16H); 9.62 {broad s, 1H); 12.10 (broad s, 1H).
EXAMPLE 34: 1-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-yl]-3-(4-hexyloxyphenyl)-1- methylurea (a) tert-butyl (3-bromophenyl)carbamate 667 g (3 mol) of di-tert-butyl dicarbonate are introduced into a 10 litre round-bottomed flask. 4.5 litres of a 2 M sodium hydroxide solution and 453 g (2.58 mol) of 3-bromoaniline are added under nitrogen.
The mixture is heated under reflux for 4.5 hours. The reaction medium is extracted with ethyl acetate, the organic phase is washed with water and then evaporated under vacuum. The solid obtained is taken up, with stirring, in heptane. After filtration and drying, 609 g (86%) of tert-butyl (3-bromophenyl)carbamate are obtained in the form of a white powder. (b) tert-butyl (3-bromophenyl)methylcarbamate 9.33 g (0.22 mol) of NaH at 60% in oil and 250 ml of DMF are introduced under nitrogen into a _ round-bottomed flask. 53 g (0.18 mol) of (3- bromophenyl) carbamic acid tert-butyl ester in solution in 150 ml of DMF are added dropwise. After 10 minutes, 14.5 ml (0.22 mmol) of methyl iodide are added dropwise. The mixture is stirred at room temperature for 30 minutes. After filtration of the Nal and evaporation of the DMF, the medium is solubilized in
350 ml of ethyl acetate and washed with twice 300 ml of water. After drying over sodium sulphate and evaporation of the solvents, 55 g (98%) of tert-butyl (3-bromophenyl)methylcarbamate are obtained in the form of a yellow liquid. (c) tert-butyl (4'-formylbiphenyl-3-yl)methylcarbamate
In a manner similar to Example 1(c), by reacting 55 g (0.19 mol) of tert-butyl (3-bromophenyl)methylcarbamate with 50.5 g (0.30 mol) of 4-formylbenzeneboronic acid, 48 g (80%) of tert- butyl (4'-formylbiphenyl-3-yl)methylcarbamate are obtained after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (90/10) mixture. (d) tert-butyl [4'-(2,4-dioxothiazolidin-5- ylidenemethyl)biphenyl-3-yl]methylcarbamate
In a manner similar to Example 1(d), by reacting 40 g (0.128 mol) of tert-butyl (4'-formylbiphenyl-3-yl)methylcarbamate with 15 g (0.128 mol) of 2,4-thiazolidinedione and 3.7 g - (0.025 mol) of piperidinium acetate and 0.4 1 of toluene, 42.8 g (81.6%) of tert-butyl [4'-(2,4- dioxothiazolidin-5-ylidenemethyl)biphenyl-3- yllmethylcarbamate are obtained. (e) tert-butyl [4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-yl]methylcarbamate
3.69 g (0.009 mol) of tert-butyl {4'-(2,4- dioxothiazolidin-5-ylidenemethyl)biphenyl-3- yllmethylcarbamate, 6 ml of THF and 7.3 ml of pyridine are introduced, in order, into a 50 ml three-necked round-bottomed flask. The mixture is placed under nitrogen and 10 ml of a freshly prepared 2 M LiBH, solution (0.02 mol) in THF are added dropwise. After stirring for 30 minutes at room temperature, the mixture is heated under reflux for 16 hours. The reaction medium is poured over 32 ml of a 1 N HCl solution and the THF is evaporated under vacuum. The precipitate obtained is filtered. After drying, the crude product (2.75 g) is chromatographed on 95 g of silica gel, eluting with a heptane/ethyl acetate = 3/7 mixture. 2.45 g (66%) of tert-butyl [4'-(2,4- dioxothiazolidin~5-ylmethyl)biphenyl-3- yllmethylcarbamate are obtained. (f) 5-(3'-methylaminobiphenyl-4-ylmethyl)thiazolidine- 2,4-dione 2.32 g (5.6 mmol) of ([4'-(2,4~ . dioxothiazolidin-5-ylmethyl)biphenyl-3- vllmethylcarbamic acid tert-butyl ester, 40 ml of dichloromethane and 6.4 g (56 mmol) of trichloroacetic acid are introduced into a 100 ml round-bottomed flask.
After stirring for 24 h at room temperature, the reaction medium is concentrated in a rotary evaporator and taken up in diisopropyl ether. After trituration and stirring, it is filtered, taken up in 50 ml of water and neutralized with 0.53 g (6.2 mmol) of sodium bicarbonate. The precipitate is filtered, washed with ethyl ether and dried under vacuum. 1.43 g (81.7%) of 5-(3'-methylaminobiphenyl-4-ylmethyl)thiazolidine-2,4- dione are obtained in the form of a white powder. (g) 1-({4'-(2,4-dioxothiazolidin~5-ylmethyl)biphenyl-3- yl]-3-(4-hexyloxyphenyl)-l-methylurea 0.67 g (2.14 mmol) of 5-(3'- methylaminobiphenyl-4-ylmethyl)thiazolidine-2,4-dione in 20 ml of dichloromethane is introduced into a 50 ml round-bottomed flask. 1 g (4.3 mmol) of l-hexyloxy-4- isocyanatobenzene is added and the mixture is heated under reflux for 16 hours. The reaction medium is poured at room temperature over a 1 N HCl solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulphate.
After evaporation of the solvents, the product obtained is purified by chromatography on silica gel (eluent: heptane/ethyl acetate = 3/2). 0.78 g (68%) of : 1-[(4'-(2,4-dioxothiazolidin-5~ylmethyl)biphenyl-3-yl]- 3-(4-hexyloxyphenyl)-l-methvlurea is obtained in the form of a white powder having a melting point of 146- 148°C. 'H NMR (DMSO dé; 400 MHz): 0.81 (t, 3H); 1.29 (m, 4H); 1.39 (m, 2H); 1.67 (m, 2H); 3.18 (dd, J = 9.6 Hz and
J = 14.1 Hz, 1H); 3.31 (s, 3H); 3.43 (dd, J = 4.3 Hz and J = 14.1 Hz, 1H); 3.90 (m, 2H); 4.96 (dd, J = 4.3 Hz and J = 9.6 Hz, 1H); 6.80 (m, 2H); 7.28-7.66 (m, 10H); 8.07 (s, 1H); 12.10 (broad s, 1H).
EXAMPLE 35: TRANSACTIVATION TEST
The agonist activity towards the PPARy receptors of the compounds according to the invention may be evaluated by transactivation tests.
The capacity of the molecules to activate and/or inhibit the PPARy receptors is evaluated from
Hela cells stably transfected with the chimeric Gal-
PPARY receptor (LBD). 96-well plates are inoculated at the rate of 10 000 cells/100 pl/well in DMEM 10% SDL medium and then placed for 24 hours at 37°C, 7% CO,.
To determine the PPARy agonist activity, the cells are then treated by addition of 5 pl/well of the molecules to be tested at the final concentration of 1 uM. Cells are also treated in parallel with a reference agonist, (-)-3-{4-[2-(benzooxazol-2- ylmethylamino)ethoxylphenyl}-2-ethoxypropionic acid, 1 nM.
After another incubation of 24 hours at 37°C, 7% CO2, a luciferase assay is carried out with the aid of the "Steady-Glo Luciferase Assay System" kit from
Promega. The luminescence is counted on a Microbeta
Trilux microplate reader (Wallac).
The agonist activity of the test product will be expressed as a percentage activation relative to the control agonist, the reference agonist at 1 uM.
By applying this same protocol with the chimeric Gal-PPARa receptor, it is possible to measure the agonist activity of the compounds towards the
PPARalpha receptors and thus to compare it with that of the PPARy receptor.
The AC50, expressed in nM, is determined as the concentration which makes it possible to obtain 50% activation of the basal signal relative to the reference agonist.
The results obtained for the compounds according to the invention are grouped together in the following table: (at 1 microM)
Example 2
Compound of 22.3 N.T. >50 000.0 | 13.1
Example 3
Example 4
Example 5
Fol A a la ll
Example 6
Example 7
Example 8
Example 9
Example 10
Example 11
Example 12
Example 13
Example 14
Example 15 i
Compound of 22.9 93.3 >50 000.0 [0.55
Example 16
Example 17
Example 18
Example 19
Example 20
Example 21
Example 22
Eel Ll ll a a
Example 23
N.T. means not tested
These results show the transactivation activity of the compounds according to the invention.
These results show more particularly the specificity of the activation of the compounds of the invention for the PPPR-y subtype compared with the activation of the compounds for the PPAR-a subtype.
EXAMPLE 36 BINDING TEST
The affinity of the compounds of the invention for the human PPARY receptor was determined in a test of binding, by competition for the attachment of a reference agonist, the following tritiated compound 5-{4-[2-(methylpyridin-2- ylamino)ethoxylbenzylithiazolidine-2,4-dione.
The receptors are obtained by infecting SF9 insect cells with a recombinant bacculovirus. They exist in the form of hPPARyY/RXRa heterodimers. The presence of RXRa increases the solubility and the stability of the hPPARy receptor and, consequently, its biological activity, without as a result interfering in the determination of the binding constants.
The technique of adsorption on hydroxyapatite gel was used to separate the ligand bound to the receptor from the free ligand. The results are expressed as Kd value (nM) which represents the dissociation constant at equilibrium obtained for each compound.
The results obtained for the compounds according to the invention are grouped together in the following table:
Tr
Kd (in nM)
Compound of Examples | s0.0
Compound of mxample 10] 0.0
Compound of Example 11 375.0
Compound of Example 12| 0.0
Compound of Bxampte 15| 0.0
Compound of Example 16] 4.0
These results show the very good affinity of the compounds according to the present invention for the PPARY receptor.
EXAMPLE 37
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 16 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 17 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 as - Purified water gs 5 ml
(c) 0.8 g tablet - Compound of Example 19 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 20 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 as - Purified water gs 10 ml
B- TOPICAL ROUTE (a) Salve —- Compound of Example 12 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 15 0.300 g - Petroleum jelly gs 100 g
(c) Nonionic water-in-oil cream - Compound of Example 10 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 gas 100 g
(d) Lotion - Compound of Example 19 0.100 g - Polyethylene glycol (PEG 400) 69.900 ¢g - Ethanol at 95% 30.000 g¢
(e) Hydrophobic salve
- Compound of Example 20 0.300 g - Isopropyl myristate 36.400 g - Silicon oil ("Rhodorsil 47 Vv 300" sold by RHONE-POULENC) 36.400 g - Beeswax 13.600 g - ~ Silicone oil ("Abil 300,000 cst" sold by GOLDSCHMIDT) gs 100 ¢g
(f) Nonionic oil-in-water cream - Compound of Example 16 1.000 ¢g - Cetyl alcohol 4.000 ¢ - 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 gas 100 ¢g

Claims (34)

1. Compounds, characterized in that they correspond to the following formula (I): R, R, 4 - in which: - R; represents a radical of the following formulae (a) or (b): 0 0 S—( 5 (@ Re (0) Rs and Rg having the meanings given below, - R; and Rj, which may be identical or different, represent a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms, an aryl radical, a halogen atom, a radical -OR;, a polyether radical, a nitro radical or an amino radical which may be optionally substituted with alkyl radicals having from 1 to 6 carbon atoms;
R; having the meaning given below,
- X represents the bonds having the following structures:
~CH,-N (Rg) -CO-
-N (Rg) ~CO-N (Rg) —-
-N (Rg) —CO-CH,-
-N (Rg) -CH,-CO-
which may be read from left to right or conversely
Rg and Rg having the meanings given below,
- Ry represents:
- a phenyl, benzyl, phenethyl, thienyl, furyl or pyridyl radical, all these radicals being substituted with a group Rio, Rip having the meanings given below,
- a pyrrolyl, pyrazinyl, naphthyl, biphenyl, indolyl, indenyl, benzothienyl, benzofuryl, benzothiazolyl or quinolyl radical, it being possible for all these radicals to be mono- or disubstituted with a group R;: and/or Rij; Riv and Ri; having the meanings given below,
- a radical -{(CH;),-(CO)q4R13,
n, gq and Rj; having the meanings given below,
- an adamantyl, diphenylmethyl, diphenylethyl, diphenylpropyl, diphenylbutyl, cyclopropylmethyl, cyclopentylethyl, 2-benzimidazolyl- ethyl, cyclohexylmethyl, phenoxyphenyl, 9H-fluorenyl,
5S benzyloxyphenyl, 4-heptyloxyphenyl, or 4-(6-methyl-2-
benzothiazolyl) phenyl radical;
- a radical -(CH;),-O-Ri3,
n and Rj; having the meanings given below,
- Rs represents a hydroxyl radical or an alkoxy ‘radical having from 1 to 9 carbon atoms,
- Rg represents an alkyl radical having from 1 to 6 carbon atoms, a radical OR;; or a radical SRis, R14 having the meanings given below,
- Ry represents a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms, an aryl radical or an aralkyl radical,
- Rg represents a hydrogen atom or an alkyl radical having from 1 to 6 carbon atoms,
- Rg represents a hydrogen atom or an alkyl - radical having from 1 to 6 carbon atoms,
- Ryp represents: a radical -S{0O)nRis a radical - (CHz)p-CORjs a radical -0-Rjy
-m, p, Ris, Rig and Rj; having the meanings given below,
- Ri; and Rj; represent a halogen atom, a radical CF3, an alkyl radical having from 1 to 12 carbon atoms, an alkoxy radical having from 1 to 9 carbon atoms, a polyether radical, a nitro functional group, a hydroxyl radical optionally protected by an acetyl or benzoyl group, an amino functional group optionally substituted with at least one alkyl having from 1 to 12 carbon atoms or with a radical -CONH-Rs, or protected by an acetyl or benzoyl group, a radical -S(0)pR;s, a radical (CH2) p—COR;15 or a radical -OR;7, m, p, Ris, Ris, Ri7 and Ryy having the meanings given below, - n may take the values ranging from 1 to 9, - g may take the values 0 or 1, - Ri3 represents a radical -OR;3, a radical -N (R19) (R20), an aryl radical, an aralkyl radical or a hetercaryl radical, Rig, Ris and Rp having the meanings given below, - m may take the values 0, 1 or 2, - - p may take the values 0, 1 or 2, - Ry4 represents an alkyl radical having from 1 to 12 carbon atoms, a radical CF3, an aryl radical or an aralkyl radical, - Ris represents an alkyl radical having from 1 to 12 carbon atoms, an aryl radical or an aralkyl radical,
- R;¢ represents an alkyl radical having from 1 to 12 carbon atoms, a radical -ORj;, a radical -N(R;;) (Rz3), an aryl radical or an aralkyl radical,
R21, R22 and R;3 having the meanings given below,
~ Ri7 represents an aryl radical or an aralkyl radical,
- Rig represents a hydrogen atom or an alkyl radical having from 1 to 12 carbon atoms,
- Rig and Ryo, which may be identical or different, represent a hydrogen atom, an alkyl radical having from 1 to 12 carbon atoms, or taken together may form a heterocycle,
- Ry; represents a hydrogen atom or an alkyl radical having from 1 to 12 carbon atoms,
- Ry; and Ry3, which may be identical or different, represent a hydrogen atom, an alkyl radical having from 1 to 12 carbon atoms, or taken together may form a heterocycle,
- Ry4 represents a phenyl, diphenylmethyl, - diphenylpropyl, diphenylbutyl, biphenylyl, phenoxyphenyl, 9H-fluorenyl, 4-benzyloxyphenvyl, 4-heptyloxyphenyl, or 4-(6-methyl-2- benzothiazolyl)phenyl radical,
and the salts of the compounds of formula (I) when R; contains a carboxylic acid functional group and the optical and geometric isomers of the said compounds of formula (I).
2. Compounds according to Claim 1, characterized in that they are provided in the form of salts of an alkali or alkaline-earth metal, of zinc salts, or of salts of an organic amine.
3. Compounds according to either of Claims 1 and 2, characterized in that the alkyl radicals having from 1 to 6 carbon atoms are chosen from the methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals.
4. Compounds according to either of Claims 1 and 2, characterized in that the alkyl radicals having from 1 to 12 carbon atoms are chosen from the methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, octyl, decyl and dodecyl radicals.
5. Compounds according to either of Claims 1 and 2, 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 the methoxymethoxy, ethoxymethoxy and methoxyethoxymethoxy radicals.
6. Compounds according to either of Claims 1 and 2, characterized in that the halogen atom is chosen from the group consisting of a fluorine, chlorine and bromine atom.
7. Compounds according to either of Claims 1 and 2, characterized in that the alkoxy radical having from 1 to 9 carbon atoms is chosen from the group consisting of the methoxy, ethoxy, isopropyloxy, tert-butoxy and hexyloxy radicals.
8. Compounds according to either of Claims 1 and 2, characterized in that the aryl radical is chosen from a phenyl 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 6 carbon atoms, a nitro functional group, a polyether radical, 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 either of Claims 1 and 2, characterized in that the aralkyl radical is chosen from a benzyl or phenethyl 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 6 carbon atoms, a nitro functional group, a polyether radical, 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 either of Claims 1 and 2, characterized in that the heteroaryl radical is chosen from the group consisting of a pyridyl, furyl, thienyl and isoxazolyl radical, optionally substituted with at least one halogen atom, an alkyl radical having from 1 to 12 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms, a nitro functional group, a polyether radical, 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 radical having from 1 to 12 carbon atoms.
11. Compounds according to either of Claims 1 and 2, characterized in that the heterocycle is chosen from the group consisting of a piperidino, morpholino, pyrrolidino or piperazino radical optionally substituted with an alkyl radical 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 a mixture, from the group consisting of: 1- methyl 7-{[4'-(2,4-dioxothiazolidin-5-ylmethyl) - biphenyl-3-ylmethyl]methylcarbamoyl}heptanoate;
2- methyl 9-{[4'-(2,4-dioxothiazolidin-5-ylmethyl)- biphenyl-3-ylmethyl]lmethylcarbamoyl}nonanoate; 3- methyl N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)- biphenyl-3-ylmethyl]-N-methylterephthalamate; 4- 3-cyclopentyl-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylpropionamide; 5- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methylnaphthalene-1-carboxamide; o- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methylnaphthalene~2-carboxamide; 7- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-2-phenoxyacetamide; 8- N-{4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-1l-methyl-1H~-pyrrole-2-carboxamide; 9- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyladamantane-1l-carboxamide; 10- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methylbiphenyl-4-carboxamide; 11- N-[4'-(2,4-dioxothiazolidin-S-ylmethyl)biphenyl-3- ylmethyl]-N-methylbenzo[b]thiophene-2-carboxamide; : 12- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-6-oxo-6-phenylhexanamide; 13- 4-dimethylamino-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-1- carboxamide; 14- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-4-methanesulphonyl-N-methylbenzamide;
15- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4-(l-phenylmethanoyl)benzamide; l16- 6-(2-methoxyethoxymethoxy)-N-[4'-(2,4- dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-
methylnaphthalene-2-carboxamide; 17- 6-hydroxy-N-{4'-(2,4-dioxothiazolidin-5-ylmethyl) - biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide; 18- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4-methylsulphanylbenzamide;
19- (S)-3-(3'-{[(l-biphenyl-4-ylmethanoyl)methyl- amino]methyl }biphenyl-4-yl)-2-ethoxypropionic acid;
20- (S)-2-ethoxy-3-(3'-{[methyl- (6-0x0-6- phenylhexanoyl)aminolmethyl}biphenyl-4-yl) propionic acid;
21- 1-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- yl]l-l-methyl-3-naphthalen-2-ylurea;
22- 3-(4-dimethylaminophenyl)-1-(4'-(2,4- dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1- methylurea;
23- (S)-2-ethoxy-3-{3'-[({l-[6-(2-methoxyethoxy- - methoxy) naphthalen-2-yl]lmethanoyl }methylamino)methyl]- biphenyl-4-vyl}propionic acid; 24~ 6- (methoxymethoxy)-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl)-N-methylnaphthalene-2-
carboxamide;
25- 6-(methoxycarbonyl)-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- carboxamide; 26- 6-(propyloxy)-N-[4'-(2,4-dioxothiazolidin-5-
ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- carboxamide; 27- 6-(hexyloxy)-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- carboxamide;
28- 6~(nonyloxy)-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- carboxamide;
29- N-[4'-(2,4-dioxothiazolidin~5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4'-propylbiphenyl-2-carboxamide;
30- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4-phenoxybenzamide;
31- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-7-oxo-7-phenylheptanamide; 32- (6-{[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-
3-ylmethyl)methylcarbamoyl}naphthalen-2-yloxy)acetic - acid;
33- (6-{[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl- 3-ylmethyl]methylcarbamoyl }naphthalen-2-yloxy) acetic acid methyl ester;
34- 6-methoxy-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- carboxamide;
35- 6-acetoxy-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide; 36- 6-amino-N-[4'-(2,4-dioxothiazolidin-5-
ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- carboxamide; 37- 6-acetylamino-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide;
38~ 1-hydroxy-N-[{4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide;
39- 1-methoxy-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-
carboxamide;
40- o6-bromo-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide;
41- 6-carboxyl-N-{4'-(2,4~-dioxothiazolidin-5-
ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- - carboxamide;
42- o6-carboxyl-N-{4'-(2,4~-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide methyl ester;
43- 6-(3-phenylureido)-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- carboxamide;
44- 3-hydroxy-N-{4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl] -N-methylnaphthalene-2- carboxamide; 45~ 3-methoxy-N-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2- carboxamide; 46- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl] -N-methyl-4'-hydroxybiphenyl-4-carboxamide; 47- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4'-methoxybiphenyl-4-carboxamide; 48- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl] -N-methyl-4'-propyloxybiphenyl-4-carboxamide; 49- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl] -N-methyl-4'-hexyloxybiphenyl-4-carboxamide; 50- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4'-acetoxybiphenyl-4-carboxamide; 51- (4'-{[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-ylmethyl]lmethylcarbamoyl}biphenyl- 4-yloxy) acetic acid;
: 20 52- (4'-{[4'~-(2,4-dioxothiazolidin-5- - ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}biphenyl- 4-yloxy)acetic acid methyl ester;
53- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4'-methoxymethoxybiphenyl-4-
carboxamide; 54- N-{4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4'-nonyloxybiphenyl-4-carboxamide;
55- N-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- ylmethyl]-N-methyl-4"'-(2-methoxyethoxy)biphenyl-4- carboxamide; 56- 3-biphenyl-4-yl-1-[4'-(2,4-dioxothiazolidin-5~ vylmethyl)biphenyl-3-yl]-1l-methylurea; 57- 1-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- y1l]-3-(9H-fluoren-2-yl)-l-methylurea; 58- 1-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- y1l]-3-(9H-fluoren-9-yl)-l-methylurea;
59- 3-benzhydryl-1-[4'-(2,4-dioxothiazolidin-5- ylmethyl)biphenyl-3-yl]-1-methylurea;
60- 1-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- yl]-1-methyl-3-(3-phenoxyphenyl)urea; 61- 1-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-
yl]-3-(4-heptyloxyphenyl)-1l-methylurea;
62- 3-(4-benzyloxyphenyl)-1-[4'-(2,4-dioxothiazolidin- S-ylmethyl)biphenyl-3-yl]-l-methylurea;
63- 1-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- yl} -1-methyl-3-[4-(6-methylbenzothiazol-2-
yl)phenyllurea; - 64- 4'-(2-methoxyethoxymethoxy)-N-[4'~(2,4- dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N- methylbiphenyl-4-carboxamide;
65- 4'-hydroxy-N-[4'-(2,4-dioxothiazolidin-5-
ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-
carboxamide;
66- 1-[4'-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3- yl]-3-(4-hexyloxyphenyl)-l-methylurea.
13. Compounds according to Claim 1 or 2, characterized in that they exhibit one of the following characteristics: - R; represents the radical of formula (a) or the radical of formula (b) where Rs represents a hydroxyl radical and R¢ represents the radical OR,4 and/or - X represents the linkage having the structure -CH;-N(Rg) -CO- or -N(Rg)-CO-N(Rg)- read from left to right or conversely.
14. Compounds according to any one of Claims 1 to 13, as a medicament.
15. Use of a compound according to any one of Claims 1 to 13, in the manufacture of a composition intended for regulating and/or restoring skin lipid metabolism.
16. Use of a compound according to any one of Claims 1 to 13, in the manufacture of a composition intended for the treatment: _ —- of dermatological conditions linked to a keratinization disorder related to cell differentiation and proliferation; - of ichtyosis, ichtyosiform 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; - of benign or malignant dermal or epidermal proliferations, of viral or nonviral origin; - of proliferations which may be induced by ultraviolet radiation; - of precancerous skin lesions; - of immune dermatoses; - of bullous immune diseases; - of collagen diseases; - 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; - of pathologies associated with chronological or actinic ageing; - of sebaceous function disorders; - of cicatrization disorders or of stretch marks; or - - of pigmentation disorders.
17. Use according to Claim 16, characterized in that the dermatological conditions linked to a keratinization disorder are 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.
18. Use according to Claim 16, characterized in that the dermatological conditions with an inflammatory immunoallergic component are cutaneous, mucosal or ungual psoriasis, psoriatic rheumatism or cutaneous atopy, such as eczema, respiratory atopy or gingival hypertrophy.
19. Use according to Claim 16, characterized in that the dermal or epidermal proliferations are : verruca vulgaris, verruca plana and epidermodysplasia verruciformis, oral or florid papillomatoses or T lymphoma.
20. Use according to Claim 16, characterized in that the proliferations which may be induced by ultraviolet radiation are baso- and spinocellular epitheliomas.
21. Use according to Claim 16, characterized in that the precancerous skin lesions are keratoacanthomas.
22. Use according to Claim 16, characterized in that the immune dermatoses are lupus erythematosus. -
23. Use according to Claim 16, characterized in that the collagen diseases are scleroderma.
24. Use according to Claim 16, characterized in that the pathologies associated with chronological or actinic ageing are xerosis.
25. Use according to Claim 16, characterized in that the sebaceous function disorders are acne hyperseborrhoea or simple seborrhoea.
26. Use according to Claim 16, characterized in that the pigmentation disorders are hyperpigmentation, melasma, hypopigmentation and vitiligo.
27. 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 13.
28. Composition according to Claim 27, characterized in that the concentration of compound(s) according to one of Claims 1 to 13 is between 0.001% and 10% by weight relative to the total weight of the composition.
29. Composition according to Claim 27, characterized in that the concentration of compound(s) according to one of Claims 1 to 13 is between 0.01% and 1% by weight relative to the total weight of the - composition.
30. Cosmetic composition, characterized in that it comprises, in a cosmetically acceptable carrier, at least one of the compounds as defined in any one of Claims 1 to 13.
31. Composition according to Claim 30, characterized in that the concentration of compound(s)
according to one of Claims 1 to 13 is between 0.001% and by weight relative to the total weight of the composition.
32. Cosmetic use of a composition as defined in either of Claims 30 and 31, for preventing and/or treating the signs of ageing and/or dry skin.
33. Cosmetic use of a composition as defined In either of Claims 30 and 31, for body or hair hygiene.
34. A compound substantially as herein described and as exemplified in any one of Examples 1 to 34. AMENDED SHEET
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