ZA200504263B - Compounds which modulate pparytype receptors, and use thereof in cosmetic or pharmaceutical. - Google Patents

Compounds which modulate pparytype receptors, and use thereof in cosmetic or pharmaceutical. Download PDF

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ZA200504263B
ZA200504263B ZA200504263A ZA200504263A ZA200504263B ZA 200504263 B ZA200504263 B ZA 200504263B ZA 200504263 A ZA200504263 A ZA 200504263A ZA 200504263 A ZA200504263 A ZA 200504263A ZA 200504263 B ZA200504263 B ZA 200504263B
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South Africa
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methyl
radical
biphenyl
ylamino
carbon atoms
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ZA200504263A
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Laurence Glary
Pascal Collette
Michel Rivier
Andre Jomard
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Galderma Res & Dev
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/66—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems and singly-bound oxygen atoms, bound to the same carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/40—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids

Description

COMPOUNDS WHICH MODULATE PPAR-GAMMA TYPE RECEPTORS, AND USE THEREOF IN COSMETIC
OR PHARMACEUTICAL COMPOSITIONS
The invention relates to, as novel and useful industrial products, a novel class of compounds which are modulators of receptors of Peroxisome Proliferator-
Activated Receptor type of subtype y (PPAR-y). The invention also relates to a process for preparing them and to their use in pharmaceutical compositions intended for use in human or veterinary medicine, or alternatively in cosmetic compositions.
The activity of receptors of PPAR type has been the subject of many studies. Mention may be made, as a guide, of 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, pp. 1116-1121, in which is listed a large number of bibliographic references relating to receptors of PPAR type. Mention may also be made, as a guide, of the report 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, pp. 527-550.
PPAR receptors activate transcription by binding to elements of DNA sequences, known as :
peroxisome proliferator response elements (PPRE), in the form of a heterodimer with retinoid X receptors (known as RXRs).
Three subtypes of human PPARs have been identified and described: PPARaq, PPARY and PPARS (or
NUC1) .
PPARa is mainly expressed in the liver, while
PPARO is ubiquitous.
PPARy is the most extensively studied of the three subtypes. All the references suggest a critical role of PPARy in regulating the differentiation of adipocytes, where it is greatly expressed. It also has a key role in systemic lipid homeostasis.
It has been described in particular in patent application WO 96/33724 that PPARy-selective compounds, such as a prostaglandin-J2 or -D2, are potential active agents for treating obesity and diabetes.
Moreover, the Applicant has already described
PPARy compounds and/or the use thereof in the following patent applications. Patent application FR 98/02894 describes the use of PPARy activator compounds in the preparation of a pharmaceutical composition, the composition being intended to treat skin disorders associated with an anomaly of epidermal cell differentiation. Patent application WO 01/02543 describes a novel class of PPARy-modulating compounds.
One of the aims of the present invention is to propose a novel class of PPARy-modulating compounds that show very good specific affinity for PPARy.
Thus, the present invention relates to compounds corresponding to the general formula (I) below:
R13 R1 oC ra" {1) in which: - Ri; represents a radical of the following formulae: (a) (b) (€)
N—~——N 0 Spy
PS BN A R5 V-w oO R4 :
Re, Rs, V, W and Y having the meanings given below, ~ Rz; represents a hydrogen atom, a halogen atom, an alkyl radical containing from 1 to 12 carbon atoms, a hydroxyl radical, an alkoxy radical containing from 1 to 7 carbon atoms, a polyether radical, a nitro radical, or an amino radical that may optionally be substituted with one or more alkyl radicals containing from 1 to 12 carbon atoms, an aryl radical, an aralkyl radical, a heteroaryl radical or a heterocyclic radical; - R3 represents:
— a radical -(CHz)¢= (N=Ris)u= (C(O, N)) Ry, —- an alkyl radical containing from 1 to 12 carbon atoms, an aryl radical, an aralkyl radical, a hetercaryl radical, a helerocyclic radical or a 9-fluorenylmethyl radical; t, u, z, Ris and Ris having the meanings given below, - Rq represents a hydrogen atom, an alkyl radical containing from 1 to 12 carbon atoms, an aryl radical, an aralkyl radical, a heteroaryl radical or a heterocyclic radical; - Rs represents - a radical O-(CH:),—Rsg - a radical NR’ = (CHz)n—Riqs - a hydroxyl radical, an alkoxy radical containing from 1 to 7 carbon atoms, an aryl radical, an aralkyl radical, a heteroaryl radical or a heterocyclic radical, ~- a radical
NR
R”
Re, Ria, R’, R” and n having the meanings below, - R’ represents a hydrogen atom, an alkyl radical containing from 1 to 12 carbon atoms, a hydroxyl radical, an aryl radical, an aralkyl radical, a heteroaryl radical or a heterocyclic radical;
- R” represents a hydrogen atom, an alkyl radical ’ containing from 1 to 12 carbon atoms, an aryl radical, p an aralkyl radical, a heteroaryl radical, a heterocyclic radical or a radical ~ (CH2) n—Rg; 5 R¢ and n having the meanings below, — Re represents an aryl radical, an aralkyl radical, a heteroaryl radical; a heterocyclic radical, a radical
NH-CO-Ry, a radical NH-CO-O-R; or a radical N-R+Rg;
R; and Rg having the meanings below, - n may take the values 1, 2 or 3; — Ry represents a hydrogen atom, an alkyl radical containing from 1 to 12 carbon atoms, an aryl radical, an aralkyl radical, a heteroaryl radical or a heterocyclic radical; - Rg represents a hydrogen atom or an alkyl radical containing from 1 to 3 carbon atoms; ~- X represents an oxygen or sulphur atom, or a methylene (CH,) or NRg radical; - Rg represents a hydrogen atom, an alkyl radical containing from 1 to 12 carbon atoms or an aralkyl radical; —- A represents a bond having the following structure: a) ~(CHz)n= (N-R1p) p~ (CO) q= (D) r= ’ b) = (CHz) m= (N-Rio) p= (CS) g= (D) 1 ¢ 25 D, r, gq, p and m having the meanings given below,
Ris having the meaning given below,
- D represents an oxygen or sulphur atom, a radical NRj1 . or a CH: radical;
Ri: having the meaning given below, ¢ - m, Pp, q and r, which may be identical or different, may take the values 0 or 1; - Rio and Ry; may be identical or different and represent a hydrogen atom or an alkyl radical containing from 1 to 12 carbon atoms; - V represents an oxygen, sulphur or nitrogen atom, nitrogen atom being linked to a hydrogen atom or an alkyl radical containing from 1 to 6 carbon atoms; - W represents a nitrogen atom or a radical C-Ri2;
Ri2 having the meanings given below, - Y represents a nitrogen atom or a carbon atom; - Rj; represents a hydrogen atom, an alkyl radical containing from 1 to 12 carbon atoms, an aryl radical, an aralkyl radical, a heteroaryl radical or a heterocyclic radical; - Riz represents a hydrogen or halogen atom; - Ruy represents a heterocyclic radical; - Ris represents a hydrogen atom, an alkyl radical seen. SORGAInIng from 1 to 12 carbon atoms, an aryl radical, . an aralkyl radical, a heteroaryl radical or a “ heterocyclic radical; . 25 t, u and z, which may be identical or different, may take the values from 0 to 4; i
= Rye represents a hydrogen atom, an alkyl radical ‘ containing from 1 to 12 carbon atoms, an aryl radical, « an aralkyl radical, a heteroaryl radical, a heterocyclic radical, a radical NHCOR,;, a radical
NHCOOR; or a radical NRyRg;
R7 and Rg having the meanings given above, and when m represents 0, then gq represents 1 and Rig represents an alkyl radical containing from 1 to 12 carbon atoms; and the optical and geometrical isomers of the said compounds of formula (I), and also the salts thereof.
In particular, when the compounds according to the invention are in the form of salts, they are salts of an alkali metal or alkaline-earth metal, zinc salts or salts of an organic amine.
According to the present invention, the term “hydroxyl radical” means an -OH radical.
According to the present invention, the expression “alkyl radical containing from 1 to 3 carbon atoms” means a methyl, ethyl or propyl radical.
According to the present invention, the expression “alkyl radical containing from 1 to 12 carbon atoms” means a linear or cyclic, optionally ) branched, hydrogen-containing or fluorine-containing v 25 radical containing 1 to 12 carbon atoms, which may be interrupted with a hetero atom, and the alkyl radicals containing from 1 to 12 carbon atoms are preferably methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, ’ octyl, decyl or cyclohexyl radicals. . The term “polyether radical” means a polyether radical containing from 1 to 6 carbon atoms interrupted with at least one oxygen atom, such as methoxymethoxy, ethoxymethoxy or methoxyethoxymethoxy radicals.
The term “halogen atom” means a fluorine, chlorine or bromine atom.
The term “alkoxy radical containing from 1 to 7 carbon atoms” means a radical containing from one to seven carbon atoms, such as methoxy, ethoxy, isopropyloxy, tert-butoxy, hexyloxy, benzyloxy or phenoxy radicals, which may optionally be substituted with an alkyl radical containing from 1 to 12 carbon atoms.
The term “aryl radical” means a phenyl, biphenyl, cinnamyl or naphthyl radical, which may be mono- or disubstituted with a halogen atom, a CF; radical, an alkyl radical containing from 1 to 12 carbon atoms, an alkoxy radical containing from 1 to 7 carbon atoms, a nitro function, a polyether radical, an aryl radical, a benzoyl radical, an alkyl ester group, ) a carboxylic acid, a hydroxyl radical optionally v 25 protected with an acetyl or benzoyl group or an amino function optionally protected with an acetyl or benzoyl group or optionally substituted with at least one alkyl ’ containing from 1 to 12 carbon atoms. ; The term “aralkyl radical” means a benzyl, phenethyl or 2-naphthylmethyl radical, which may be 5S mono- or disubstituted with a halogen atom, a CF; radical, an alkyl radical containing from 1 to 12 carbon atoms, an alkoxy radical containing from 1 to 7 carbon atoms, a nitro function, a polyether radical, an aryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl radical optionally protected with an acetyl or benzoyl group or an amino function optionally protected with an acetyl or benzoyl group or optionally substituted with at least one alkyl containing from 1 to 12 carbon atoms.
The term “heteroaryl radical” means an aryl radical interrupted with one or more hetero atoms, such as a pyridyl, furyl, thienyl, isoxazolyl, oxadiazolyl, oxazolyl, isothiazolyl, quinazolinyl, benzothiadiazolyl, benzimidazolyl, indolyl or benzofuryl radical, optionally substituted with at least one halogen, an alkyl containing from 1 to 12 carbon atoms, an alkoxy containing from 1 to 7 carbon atoms, an aryl radical, a nitro function, a polyether ) radical, a heteroaryl radical, a benzoyl radical, an v 25 alkyl ester group, a carboxylic acid, a hydroxyl optionally protected with an acetyl or benzoyl group or an amino function optionally protected with an acetyl or benzoyl group or optionally substituted with at ’ least one alkyl containing from 1 to 12 carbon atoms. . The term “heterocyclic radical” preferably means a morpholino, piperidino, piperazino, 2-oxo-1- piperidyl or 2-oxo-1l-pyrrolidinyl radical, optionally substituted with at least one alkyl containing from 1 to 12 carbon atoms, an alkoxy containing from 1 to 7 carbon atoms, an aryl radical, a nitro function, a polyether radical, a heteroaryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl optionally protected with an acetyl or benzoyl group or an amino function optionally protected with an acetyl or benzoyl group or optionally substituted with at least one alkyl containing from 1 to 12 carbon atoms.
Among the compounds of formula (I) above that fall within the context of the present invention, mention may be made especially of the following compounds (alone or as a mixture): 1. 2-[3"-({[6-(2-Methoxyethoxymethoxy) naphthalene-2- carbonyl]methylamino}methyl)biphenyl-4- ylamino]methyl benzoate 2. Acide 2-[3'-({[6-(2- ’ Methoxyethoxymethoxy)naphthalene-2- . 25 carbonyl]methylamino}methyl)biphenyl-4- yvlamino]benzoic acid
3. N-{4'-[2-(2,5- . Difluorobenzylcarbamoyl)phenylaminolbiphenyl-3- ylmethyl}-N-methyl-6~ (2- methoxyethoxymethoxy)naphthalene-2-carboxylamide 4. N-{4'-[2(Benzylmethylcarbamoy)phenylamino]biphenyl- 3-ylmethyl}-N-methyl-6- (2- methoxyethoxymethoxy)naphthalene-2-carboxylamide 5. 2-{3’-[(Methyloctanoylamino)methyl]biphenyl-4- ylamino}methyl benzoate 6. Acide 2-{3"-[(methyloctanoylamino)methyl]biphenyl- d-ylamino}benzoic acid 7. 2-(Methyl-{3'- [ (methyloctanoylamino) methyl ]biphenyl-4- yl}amino)methyl benzoate 8. 2~(methyl-{3’~[ (methyloctanoylamino) - methyl]lbiphenyl-4-yl}amino)benzoic acid 9. N-(3-Methylbutyl)-2-{3’- [ (methyloctanoylamino)methyl]biphenyl-4- ylamino}benzamide 10. N-Methyl-N-{4’~-[2-(5-propyl-[1,3,4]oxadiazol-2-yl)~ phenylamino]biphenyl-3-ylmethyl)octanoylamide 11. N-Methyl-N-{4’'-[2-(lH-tetrazol-5- vl) phenylamino]biphenyl-3-ylmethyl}octanoylamide ) 12. 3-3" ({ (6-(2-Methoxyethoxymethoxy)naphthalene-2- . 25 carbonyl ]methylamino}methyl)biphenyl-4- ylamino]ethyl benzoate
13. Acide 3-[3"-({[6-(2- : methoxyethoxymethoxy)naphthalene-2- carbonyl]methylamino}methyl)biphenyl-4- ylaminolbenzoic acid 14. 3-(3'~{[(6-Hydroxynaphthalene-2- carbonyl)methylamino]methyl }biphenyl-4- ylamino) ethyl benzoate 15. 3-(3"-{[(6-hydroxynaphthalene~-2- carbonyl)methylamino]methyl }biphenyl-4- ylamino) benzoic acid i6. N-methyl-N-{4’-[3-(4-methylpiperidine-l-carbonyl) - phenylamino]biphenyl-3-ylmethyl}6-(2- methoxyethoxymethoxy)naphthalene-2-carboxylamide 17. N-methyl-N-{4’ [3- (morpholine-4-carbonyl) - phenylamino]biphenyl-3-ylmethyl}-6-(2- methoxyethoxymethoxy)naphthalene-2-carboxylamide 18. N-methyl-N-{4’-[3-(4-methylpiperidine-1- carbonyl)phenylamino]bipheny-3-ylmethyl}-6- hydroxynaphthalene-2-carboxylamide 19. N-methyl-N-{4’ [3~ (morpholine-4- carbonyl) phenylamino]biphenyl-3-ylmethyl}-6- hydroxynaphtalene-2-carboxylamide 20. 3-{3’-[(methyloctanoylamino) methyl]biphenyl-4- ) ylamino}benzoic acid . 25 21. 2-{3"-[(methyloctanoylamino)methyl]biphenyl-4- yloxylethyl benzoate
22. 2-{3’'-[(methyloctanoylamino)methyl]biphenyl-4- : yloxylbenzoic acid 23. 2-[3’-(1l-methyl-3-naphthalene-2-ylureido)biphenyl- 4-ylamino]benzoic acid 24. 2={[3’-(3-heptyl-1-methylureido)biphenyl-4- yl]lmethylamino}benzoic acid 25. 2-(3’-{ [methyl (quinoxaline-6- carbonyl) amino]lmethyl}biphenyl-4-ylamino) benzoic acid 26. 2-(3"-{[(2-1H-benzoimidazol-2- ylacetyl)methylamino]lmethyl}biphenyl-4- ylamino) benzoic acid 27. 2~[3’-(l-methyl-3-thiophene-3-ylureido)biphenyl-4- ylamino]lbenzoic acid 28. 2-[3"-(3-benzo[l,2,5]thiadiazol-5-yl-1- methylureidobiphenyl-4-ylamino]lbenzoic acid 29. 1-Methyl-1-{4’'-[3- (morpholine-4- carbonyl) phenylamino]bipheny-3-yl}-3-naphth-2-yl1- urea 30. N-Methyl-3-{3’-(l-methyl-3-naphth-2- ylureido)biphenyl-4-ylamino] -N-phenethylbenzamide 31. 3-{methyl-[3’'-(l-methyl-3-naphth-2- vlureido)biphenyl-4-yl]amino }benzoic acid ’ 32. 3-(3"-{ [Methyl (quinoxaline-6-carbonyl) - . 25 amino]methyl}biphenyl-4-ylamino) isobutyl benzoate
33. 3-[3"-({[6~(2-methoxyethoxymethoxy)naphthalene-2~ ’ carbonyl]methylamino}methyl)biphenyl-4- ylmethyl]lbenzoic acid 34. 2-{3’ [3- (4-dimethylaminophenyl)-1~ methylureido]biphenyl-4-ylsulphanyl}benzoic acid 35. 2-[3"-(3-benzo[1,2,5]thiadiazol-5-yl-1- methylureido)biphenyl-4-yloxylbenzoic acid 36. 2-Morpholin-4-ylethyl 3-(3" ~{ [methyl (quinoxaline-6- carbonyl) amino]methyl}biphenyl-4-yloxy)benzoate 37. N-{4’[3-(2-
Dimethylaminoethylcarbamoyl)phenoxy]biphenyl-3- ylmethyl}-N-methyl-6-(2-methoxyethoxy)naphthalene- 2-carboxylamide 38. 3-[3"-({[6-(2-methoxyethoxymethoxy) naphthalene-2- carbonyl]amino}methyl)biphenyl-4-ylamino]benzoic acid 39. 3-{3’-[6-(2-methoxyethoxymethoxy)naphth-2- yloxycarbonylmethyl]biphenyl-4-ylamino}benzoic acid 40. 2-[3"-(3-Heptyl-l-methylureido)biphenyl-4- ylamino]benzoic acid 41. 3-Heptyl-l-methyl-1-{4’-[2- (morpholine-4- carbonyl) phenylamino]biphenyl-3-yl}-urea 42. 3-Heptyl-l-methyl-1-(4’~{methyl-[2- (morpholine-4- ) carbonyl) phenyl]amino}biphenyl-3-yl)urea . 25 43. 3-Heptyl-l-methyl-1-(4’-{methyl-[2- (4- methylpiperidine-l-carbonyl)phenyl]amino}biphenyl- 3-yl) urea
44, 3~Heptyl-l-methyl-1-{4’-[2- (4-methylpiperidine-1- : carbonyl)phenylamino]biphenyl-3-yl}urea 45. 2-[3"~(3-Heptyl-l-methylureido)biphenyl-4-~ ylsulphanyl]lbenzoic acid de. 2-[3"-(3-Heptyl-l-methylureido)biphenyl-4- ylmethyl]benzoic acid 47. 2-[3’-(1-Methyl-3-pentylureido)biphenyl~4- ylamino]benzoic acid 48. 1-Methyl-1-{4’-[2-(morpholine-4- carbonyi)phenylamino]lbiphenyl-3-yl}-3-pentylurea 49. 2-[3"-(3~Heptyl-l-methylthioureido)biphenyl-4- ylamino]benzoic acid 50. 3-Hepty-l-methyl-1-{4'-[2~(5-propyl- [1,3,4]oxadiazol-2-yl)phenylamino]biphenyl-3- yvl})urea 51. 3-Heptyl-l-methyl-1-{4’-[2-(1H-tetrazol-5- yl)phenylamino]biphenyl-3-yl }urea 52. 2-{3"-[ (Hexanoylmethylamino)methyl]biphenyl-4- ylamino}benzoic acid 53. N-methyl-N-{4’-[2-(morpholine-4- carbonyl) phenylamino]biphenyl-3- ylmethyl}hexanoylamide 54. 2-(3"~{[Methyl-(5-oxohexanoy) amino]methyl }biphenyl- : 4-ylamino)benzoic acid . 25 55. 2-(3’-{[Methyl-(4- methylaminobutyryl)aminolmethyl }biphenyl-4- ylamino)benzoic acid
56. 2-{3"~({[3-(N’,N’-Dimethyl- - hydrazinocarbonyl)propionyl]lmethylamino}methyl) - biphenyl-4-ylamino]lbenzoic acid 57. 2-[3’ (3-Heptyl-l-methylureido)biphenyl-4-ylamino]-
N-hydroxybenzamide 58. 2-[3-Fluoro-3’-(3~-heptyl-l-methylureido)biphenyl-4- ylamino]benzoic acid 59. 2-[3-Fluoro-3’'-(l-methyl-3-pentylureido)biphenyl-4- yvlaminolbenzoic acid 60. 2-[2-Fluoro-3'-(l-methyl-3-pentylureido)biphenyl-4- ylamino]lbenzoic acid + 61. 2-[2-Fluoro-3’~(3-heptyl-l-methylureido)biphenyl-4- ylamino]benzoic acid 62. N-methyl-N-{4’'~-[3-(2-piperidin-1- ylethylcarbamoyl)phenylamino]biphenyl-3-ylmethyl}- 6- (2-methoxyethoxymethoxy)naphthalene-2- carboxylamide 63. N-Methyl-N-{4’-[3-(2-morpholin-4-ylethylcarbamoyl) - phenylamino]biphenyl-3-ylmethyl}-6-(2- methoxyethoxymethoxy)naphthalene-2-carboxylic acid amide 64. N-Methyl-N-{4’-[2- (morpholine-4- carbonyl) phenylamino]lbiphenyl-3-ylmethyl}-6-(2- methoxyethoxymethoxy)naphthalene-2-carboxylic acid < 25 amide
65. N-Methyl-N-{4’-[2-(4-methylpiperidine-1- ’ carbonyl) phenylamino]biphenyl-3-ylmethyl}-6-(2- methoxyethoxymethoxy)naphthalene-2-carboxylamide 66. 2-(3’-{[(6-Hydroxynaphthalene-2- carbonyl)methylamino]methyl }biphenyl-4- ylamino)benzoic acid 67. 2-[3'-(3-Hexyl-1-methylthioureido)biphenyl-4- ylaminolbenzoic acid 68. 2-{3’-[(Methyloctanethioylamino)methyl]biphenyl-4- ylamino}benzoic acid 69. 2-{4’-Fluoro-3’- ( (methyloctanoylamino)methyl]biphenyl-4- ylamino}benzoic acid 70. 2~{2’-Fluoro-5’- [ (methyloctanoylamino)methyl]biphenyl-4- ylamino}benzoic acid 71. 3-Heptyl-l-methyl-1-{4'-[2- (pyrazole-1- carbonyl) phenylamino]biphenyl-3-yl}urea 72. 2-(3"-{[Methyl-(1,4,5,6-
tetrahydrocyclopentapyrazole-3- carbonyl) amino]methyl}biphenyl-4-ylamino)benzoic acid
73. 2-(3"-{[Methyl-(2-methylthiazolidine-4- carbonyl)methyl}biphenyl-4-ylamino) benzoic acid « 25 74. 2-[3"-({[Methyl-[2-(3- methylbenzoylamino)acetyl]amino}methyl)biphenyl-4- ylamino]benzoic acid
75. 2-(3’-{[Methyl- (3- : phenylpropionyl) amino]methyl }biphenyl-4- ylamino)benzoic acid 76. 2-{3’ ~[ (Methyloctanoylamino)methyl]biphenyl-4- ylamino}-N-(2-morpholin-4-ylethyl)benzamide 77. 2-(3"~{[(9H~-Fluoren-9- ylmethoxycarbonyl)methylamino]methyl}biphenyl-4- ylamino)benzoic acid 78. N-Methyl-N-{4’'-[2-(4-methylimidazole-1- carbonyl) phenylamino]lbiphenyl-3- ylmethyl}octanoylcarboxylamide 79. 1-[4"-(2-Benzoylphenylamino)biphenyl-3-y1]-3- heptyl-l-methylurea 80. 2-[3’-(3-Heptyl-l-methylureido)biphenyl-4-ylamino]-
N-methyl-N-piperidin~1l-ylbenzamide 81. 2-[3"~(3-Heptyl-l-methylureido)biphenyl-4-ylamino]-
N-methyl-N-phenyl-benzamide
According to the present invention, the compounds of formula (I) that are more particularly preferred are those having at least one of the following characteristics: - R; represents a radical of formula (b), in which Rs is preferably a hydroxyl group, a heterocyclic radical or NR’R”; . 25 - A represents a bond of structure -CH:N (Rpg) -
CO~ or -N(Ryp)-CO-(D)r. with r = 0 or 1;
- R; represents an alkyl, aryl or heteroaryl ‘ radical; - X represents an oxygen atom or a radical NRg in which Re is preferably a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms.
According to one particular embodiment of the invention, the compounds of formula (I) are such that: - Ry represents a radical of formula (b) in which Rs is a hydroxyl group; - A represents a bond of structure —N (R30) =CO- (D) — with r = 1 and D = NRjq; - R3 represents an alkyl radical containing from 1 to 12 carbon atoms; - X represents a radical NRs.
According to another particular embodiment of the invention, the compounds of formula (I) are such that: - Ri; represents a radical of formula (b) in which Rg 1s a heterocyclic radical or NR’R”; - A represents a bond of structure —=N (R30) ~CO-(D) r—- with r = 1 and D = NRj;; - R3 represents an alkyl radical containing from 1 to 12 carbon atoms; . 25 - X represents a radical NRg.
A general description of the preparation of : the compounds of general formulae 7 to 12, 20 to 24 and 30 to 34 of Figures 1, 2 and 3 is given below.
The reaction scheme described in Figure 1 is a general scheme for obtaining derivatives in which X corresponds to NRg.
The intermediate 2 is obtained via a Suzuki coupling between the boronic acid 1 (obtained according to the standard method for obtaining boronic acids from optionally protected N-alkyl-3-bromoaniline or from 3-bromobenzaldehyde) and 4-iodobromobenzene, catalysed, for example, with tetrakis (triphenylphosphino)- palladium.
When R’ = CHO, compound 2 gives compound 4 via an aminative reduction reaction with an amine HNR;gq.
Compounds 85 and 6 are obtained after deprotecting the amine (if necessary) via addition to an isocyanate R3-N=C=0 or condensation with an acid or an acid halide.
The intermediates 7 are prepared via a
Buchwald reaction, in the presence of a palladium-based catalyst (for example palladium (II) acetate or tris (dibenzylideneacetone)dipalladium(0)) of a ligand molecule (for example rac-2,2'-bis (diphenylphosphino)- } 25 1,1’ -binaphthyl:BINAP) and a base (sodium tert-butoxide or caesium carbonate) in toluene at 100°C, followed by a saponification reaction.
The heterocyclic compounds 9 and 10 are : synthesized via standard methods for synthesizing heterocycles, with, in the case of compound 10 (with Rs = n-propyl), for example, condensation of butyric hydrazide and cyclization with heating to 105°C in the presence of phosphorus oxychloride.
The esters 11 may be prepared, for example, via esterification with alcohols HO (CH3) Rs.
The compounds 12 are obtained via an amidation reaction with an amine of aliphatic or cyclic
HNR’R” type.
For the preparation of the compounds corresponding to the general formula with X = O, the reaction scheme, is described in Figure 2.
The intermediate 18 may be obtained according to two routes: - via a Suzuki reaction between compound 15 and 4-hydroxybenzeneboronic acid prepared beforehand.
As described in Figure 1, compound 15 is obtained from compounds 13 and 14 via addition to an isocyanate R3-N=C=0 or condensation with an acid or an acid halide, or - via a deprotection reaction of compound 17, obtained beforehand via a Suzuki reaction between . 25 the boronic acid 1 and protected 4-bromophenol, followed by condensation with an acid or an acid halide or addition to an isocyanate R3-N=C=0. i
Compound 18 gives compound 20 via a coupling . reaction with the fluoro derivative 19 in the presence of a base (for example potassium carbonate) in a polar solvent (dimethylacetamide), followed by a
S saponification reaction.
Compounds 21 to 24 are obtained according to the standard methods used for obtaining derivatives 9 to 12.
The preparation of the compounds for which
X = Ss or CH, in the general formula is described by
Figure 3.
The intermediate 25 is obtained via a coupling reaction between the derivative 5 or 6 (their synthesis is described in Figure 1) and a commercial methyl mercaptobenzoate, in the presence of a reducing agent (for example sodium borohydride) and a nickel- based catalyst (NiBrobipy) .
Compound 26 is obtained via a Suzuki coupling between compound 15(described in Figure 2) and 4-formylbenzeneboronic acid.
Via reduction of the aldehyde function to an alcohol with sodium tetraborohydride in methanol, the intermediate 27 is obtained. ’ The derivative 28 is prepared via bromination ] 25 of compound 27 with carbon tetrabromide, for example, in the presence of triphenylphosphine.
A Suzuki reaction between the derivative 28 : and a commercial methoxycarbonylphenolboronic acid, catalysed with tetrakis (triphenylphosphino) palladium, in ethylene glycol dimethyl ether gives compound 29.
The saponification of compounds 25 and 29 allows the production of the derivative of general formula 30. The production of compounds 31 to 34 is performed according to the standard methods described for derivatives 9 to 12.
The compounds according to the invention show modulatory properties on receptors of PPAR type. This activity on the PPARa, & and Y receptors is measured in a transactivation test and quantified via the dissociation constant Kdapp (apparent), as described in
Example 23.
The preferred compounds of the present invention have a dissociation constant Kdapp of less than or equal to 1000 nM and advantageously less than or equal to 500 nM.
Preferably, the compounds are modulators of receptors of specific PPARy type, i.e. they have a ratio between the Kdapp for the PPAR and PPARS receptors, and the Kdapp for the PPARy receptors, of ’ greater than or equal to 10. Preferably, this ratio . 25 PPARY/PPARa or PPARy/PPARS is greater than or equal to 50 and more advantageously greater than or equal to
A subject of the present invention is also, ’ as medicinal products, the compounds of formula (I) as described above.
A subject of the present invention is the use of the compounds of formula (I) to manufacture a composition for regulating and/or restoring the metabolism of skin lipids.
The compounds according to the invention are particularly suitable in the following fields of treatment: 1) for treating dermatological complaints associated with a keratinization disorder relating to differentiation and to proliferation, in particular for treating common acne, comedones, polymorphs, rosacea, nodulocystic acne, acne conglobata, senile acne and secondary acne such as solar, medicinal or occupational acne, 2) for treating other types of keratinization disorder, in particular ichthyosis, ichthyosiform conditions, Darrier’s disease, palmoplantar keratoderma, leukoplakia and leukoplakiform conditions, and cutaneous or mucous (oral) lichen, 3) for treating other dermatological complaints with an inflammatory immuno-allergic component, with or . 25 without a cellular proliferation disorder, and in particular all forms of psoriasis, whether cutaneous, mucous or ungual psoriasis, and even psoriatic arthritis, or alternatively cutaneous atopy such as ’ eczema, or respiratory atopy or gingival hypertrophy,
4) for treating all dermal or epidermal proliferations, whether benign or malignant, whether or not of viral origin, such as common warts, flat warts and epidermodysplasia verruciformis, oral or florid papillomatoses, T lymphoma and proliferations which may be induced by ultraviolet light, in particular in the case of basal cell and spinocellular epithelioma, and also any precancerous skin lesion such as keratoacanthomas,
5) for treating other dermatological disorders such as immune dermatitides, such as lupus erythematosus, bullous immune diseases and collagen diseases, such as scleroderma,
6) in the treatment of dermatological or systemic complaints with an immunological component,
7) in the treatment of skin disorders due to exposure to UV radiation, and also for repairing or combating ageing of the skin, whether light-induced or chronological ageing, or for reducing actinic keratoses and pigmentations, or any pathology associated with chronological or actinic ageing, such as xerosis,
8) for combating sebaceous function disorders such . 25 as the hyperseborrhoea of acne or simple seborrhoea or seborrhoeic dermatitis,
9) for preventing or treating cicatrization : disorders or for preventing or repairing stretch marks, 10) in the treatment of pigmentation disorders, such as hyperpigmentation, melasma, hypopigmentation or vitiligo, 11) in the treatment of lipid metabolism complaints, such as obesity, hyperlipidaemia, non- insulin-dependent diabetes or syndrome X, 12) in the treatment of inflammatory complaints such as arthritis, 13) in the treatment or prevention of cancerous or precancerous conditions, 14) in the prevention or treatment of alopecia of various origins, in particular alopecia caused by chemotherapy or radiation, 15) in the treatment of immune system disorders, such as asthma, type I sugar diabetes, multiple sclerosis or other selective dysfunctions of the immune system, or 16) in the treatment of complaints of the cardiovascular system, such as arteriosclerosis or hypertension.
A subject of the present invention is also a pharmaceutical or cosmetic composition comprising, in a physiologically acceptable medium, at least one compound of formula (I) as defined above.
The composition according to the invention . may be administered orally, enterally, parenterally, topically or ocularly. The pharmaceutical composition is preferably packaged in a form which is suitable for topical application.
Via the oral route, the composition, more particularly the pharmaceutical composition, may be in the form of tablets, gel capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions or lipid or polymer vesicles or nanospheres or microspheres to allow controlled release. Via the parenteral route, the composition may be in the form of solutions or suspensions for infusion or for injection.
The compounds according to the invention are generally administered at a daily dose of about 0.001 mg/kg to 100 mg/kg of body weight in 1 to 3 dosage intakes.
The compounds are used systemically at a concentration generally of between 0.001% and 10% by weight and preferably between 0.01% and 1% by weight relative to the weight of the composition.
Via the topical route, the pharmaceutical composition according to the invention is more } 25 particularly intended for treating the skin and mucous membranes and may be in the form of ointments, creams, milks, salves, powders, impregnated pads, syndets,
solutions, gels, sprays, foams, suspensions, stick : lotions, shampoos or washing bases. It may also be in the form of suspensions of lipid or polymer vesicles or nanospheres or microspheres or polymer patches and hydrogels to allow controlled release. This topical- route composition may be in anhydrous form, in aqueous form or in the form of an emulsion.
The compounds are used topically at a concentration generally of between 0.001% and 10% by weight, preferably between 0.01% and 1% by weight relative to the total weight of the composition.
The compounds of formula (I) according to the invention also find an application in the cosmetic field, in particular in body and hair hygiene and more particularly for regulating and/or restoring skin lipid metabolism.
A subject of the invention is therefore also the cosmetic use of a composition comprising, in a physiologically acceptable support, at least one of the compounds of formula (I) for body or hair hygiene.
The cosmetic composition according to the invention containing, in a cosmetically acceptable support, at least one compound of formula (I) or an optical or geometrical isomer thereof or a salt . 25 thereof, may usually be in the form of a cream, a milk, a lotion, a gel, suspensions of lipid or polymer vesicles or nanospheres or microspheres, impregnated pads, solutions, sprays, foams, sticks, soaps, shampoos ‘ or washing bases.
The concentration of compound of formula (I) in the cosmetic composition is between 0.001% and 3% by weight relative to the total weight of the composition.
The pharmaceutical and cosmetic compositions as described above may also contain inert or even pharmacodynamically active additives as regards the pharmaceutical compositions, or combinations of these additives, and especially: - wetting agents; - flavour enhancers; ~ preserving agents such as para-hydroxybenzoic acid esters; - stabilizers; - humidity regulators; - pH regulators; - osmotic pressure modifiers; - emulsifiers; - UV-A and UV-B screening agents; - antioxidants, such as a-tocopherol, butylhydroxyanisole or butylhydroxytoluene, superoxide dismutase, ubiquinol or certain metal-chelating agents; - depigmenting agents such as hydroquinone, azelaic . 25 acid, caffeic acid or kojic acid; - emollients;
- moisturizers, for instance glycerol, PEG 400, . thiamorpholinone and derivatives thereof, or urea; ~ antiseborrhoeic or antiacne agents, such as
S-carboxymethylcysteine, S-benzylcysteamine, salts
S thereof or derivatives thereof, or benzoyl peroxide; —- antibiotics, for instance erythromycin and its esters, neomycin, clindamycin and its esters, and tetracyclines; - antifungal agents such as ketoconazole or polymethylene-4, 5-isothiazolidones-3; - agents for promoting regrowth of the hair, for instance 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) ; - non-steroidal anti-inflammatory agents; - carotenoids, and especially B-carotene; - antipsoriatic agents such as anthraline and its derivatives; - eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11- triynoic acid, and esters and amides thereof; - retinoids, i.e. RAR or RXR receptor ligands, which may be natural or synthetic; - corticosteroids or oestrogens; ] 25 - a-hydroxy acids and a-keto acids or derivatives thereof, such as lactic acid, malic acid, citric acid, glycolic acid, mandelic acid, tartaric acid, glyceric acid or ascorbic acid, and also the salts, amides or ’ esters thereof, or P-hydroxy acids or derivatives . thereof, such as salicylic acid and the salts, amides or esters thereof; =- ion-channel blockers such as potassium-channel blockers; — or alternatively, more particularly for the pharmaceutical compositions, in combination with medicinal products known to interfere with the immune system (for example cyclosporin, FK 506, glucocorticoids, monoclonal antibodies, cytokines or growth factors, etc.).
Needless to say, a person skilled in the art will take care to select the optional compound(s) to be added to these compositions such that the advantageous properties intrinsically associated with the present invention are not, or are not substantially, adversely affected by the envisaged addition.
Several examples of the production of active compounds of formula (I) according to the invention, and also biological activity results for such compounds and various concrete formulations based on its compounds will now be given, by way of illustration and with no limiting nature.
EXAMPLE 1: Methyl 2-[3'-({[6-(2- . methoxyethoxymethoxy) naphthalene-2-carbonyllmethyl- amino}methyl)biphenyl-~4-ylaminolbenzoate (a) 4’ ~Bromobiphenyl-3-carbaldehyde 89 ml (180 mmol) of a 2M solution of potassium carbonate are added to a solution containing 20 g (71 mmol) of p-iodobromobenzene and 14 g (92 mmol) of 3-formylbenzeneboronic acid in toluene, followed by addition of 4.1 g (3.5 mmol) of tetrakis (triphenyl-
phosphino)palladium.
The reaction medium is refluxed for 16 hours.
After cooling to room temperature, water is added and the organic products are extracted with ethyl acetate.
The solvents are evaporated off and the residue obtained is purified by chromatography on silica with a 99/1 heptane/ethyl acetate mixture. 6.2 g (23.6 mmol) of the expected aldehyde, an orange solid, are isolated in a yield of 33%.
(b) (4’ -Bromobiphenyl-3-ylmethyl) methylamine hydrochloride
4.5 g (66.2 mmol) of methylamine hydrochloride are introduced into a solution containing 6.2 g (23.6 mmol) of 4” -bromobiphenyl-3-carbaldehyde in 95 ml of methanol.
After stirring for 10 minutes at
) room temperature, 2.3 g (37 mmol) of sodium cyanoboro-
} 25 hydride are added portionwise.
The reaction medium is stirred for 16 hours and water is added.
The organic products are extracted with ethyl acetate.
After evaporating off the solvents, the crude product is . purified by chromatography on a column of silica eluted with a 95/5 heptane/ethyl acetate mixture. 1.3 g of a white solid corresponding to the desired amine are isolated. The amine hydrochloride is obtained by precipitation after dissolving in diethyl ether, ~ followed by addition of a solution of hydrogen chloride in isopropanol. By filtration, 1.0 g (3.3 mmol) of hydrochloride is obtained in a yield of 14%. (oo) 6- (2-Methoxyethoxymethoxy) -2-naphthoic acid = Methyl 6-hydroxynaphthalene-2-carboxylate
A solution of 15.7 g (83.4 mmol) of 6-hydroxy-2-naphthoic acid is refluxed for 8 hours in a mixture of 160 ml of methanol and 8 ml of concentrated sulphuric acid. After cooling, the product precipitates out. After filtration and washing with isopropyl ether, 14.1 g of methyl 6-hydroxynaphthalene-2-carboxylate are obtained in the form of a beige-coloured solid in a yield of 84%. ~- Methyl 6-(2-methoxyethoxymethoxy)napthalene-2- carboxylate 3.3 g (83 mmol) of 60% sodium hydride in oil are added portionwise to a solution of 14 g (69 mmol) ) of methyl 6-hydroxynaphthalene-2-carboxylate in 180 ml } 25 of an equivolume mixture of tetrahydrofuran and dimethylformamide. After the evolution of gas has ceased, 8.7 ml (76 mmol) of methoxyethoxymethyl chloride are added dropwise.
The reaction medium is : stirred at room temperature for 3 hours, immersed into ice-cold water and extracted with ethyl ether.
The organic phase is dried over sodium sulphate, filtered and concentrated under vacuum.
The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 17 g of methyl 6-(2-methoxyethoxymethoxy)naphthalene-2- carboxylate are obtained in the form of a colourless oil, in a yield of 85%. - 6-(2-Methoxyethoxymethoxy)-2-naphthoic acid 12.9 g (325 mmol) of sodium hydroxide pellets are added to a solution of 16.9 g (58 mmol) of methyl 6- (2-methoxyethoxymethoxy)naphthalene-2-carboxylate in 200 ml of tetrahydrofuran, 20 ml of methanol and a few drops of water, and the reaction medium is stirred at room temperature for 4 hours.
Next, aqueous 1N hydrochloric acid solution is added until pH = 2 is obtained, and the reaction medium is extracted with ethyl acetate, dried over sodium sulphate, filtered and concentrated under vacuum.
The residue obtained is washed with heptane and filtered. 14.9 g of 6-(2- methoxyethoxymethoxy)-2-naphthoic acid are obtained in the form of a white solid, in a yield of 92%. . 25 Melting point: 110°C. (d) N-(4’-bromobiphenyl-3-ylmethyl)-N-methyl-6-(2- methoxyethoxymethoxy)naphthalene-2-carboxylamide
1.1 ml (8.0 mmol) of triethylamine and 540 mg - (4.0 mmol) of l-hydroxybenzotriazole are added to a solution containing 1 g (3.6 mmol) of (4" -bromobiphenyl-3-ylmethyl)methylamine hydrochloride in 10 ml of dichloromethane.
After stirring for 30 minutes at room temperature, 1 g (3.6 mmol) of 6-(2- methoxyethoxymethoxy)naphthoic acid are introduced, followed by 760 mg (4.0 mmol) of 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI). The reaction medium is stirred at room temperature for 3 hours and then washed with saturated sodium chloride solution.
After evaporating off the solvents, the crude product is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 1.72 g (3.6 mmol) of the expected amide are isolated in a yield of 99%. (e) Methyl 2-13" = ({[6=(2-methoxyethoxymethoxy) - naphthalene-2-carbonyl]methylamino}methyl)biphenyl-4- ylamino] benzoate 1.7 g (3.2 mmol) of N= (4’ -bromobiphenyl-3- ylmethyl) -N-methyl-6- (2-methoxyethoxymethoxy) - naphthalene-2-carboxylamide, 22 mg (9.80 mmol) of palladium acetate, 0.6 ml (4.45 mmol) of methyl anthranilate and 1.45 g (4.45 mmol) of caesium ) 25 carbonate are successively introduced into a solution containing 79 mg (0.13 mmol) of 2,2’ -bis(diphenyl- phosphino)-1, 1’ -binaphthyl (BINAP) in 20 ml of toluene.
The reaction mixture is heated at 100°C for 8 hours and } then cooled, extracted with ethyl acetate and washed with saturated sodium chloride solution. The organic bhase is separated out after settling of the phases, 5S dried over sodium sulphate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (60/40). After evaporating off the solvents, 1.6 of methyl 2-[3’- ({16-(2-methoxyethoxymethoxy) naphthalene-2-carbonyl]- methylamino}methyl)biphenyl-4-ylamino]benzoate are obtained in the form of a pale yellow powder, in a yield of 83%.
Melting point: 80°C.
EXAMPLE 2: 2-[3" = ({[6- (2-Methoxyethoxymethoxy) - haphthalene-2-carbonylmethylamino}methyl)biphenyl-4-
Ylaminolbenzoic acid 80 mg (2 mmol) of sodium hydroxide are added to a solution of 0.8 g (1.3 mmol) of methyl 2-[3"-({[6- (2-methoxyethoxymethoxy) naphthalene-2-carbonyl methyl - amino}methyl)biphenyl-4-ylamino]benzoate in 8 ml of tetrahydrofuran, 0.8 ml of methanol and a few drops of water. After stirring at room temperature for 8 hours, ’ the reaction medium is diluted with ethyl acetate, washed with aqueous 1N hydrochloric acid solution, extracted with ethyl acetate, dried over sodium sulphate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a . column of silica eluted with a 70/30 heptane/ethyl acetate mixture and then triturated from heptane. 390 mg (50%) of 2-[3"-({[6- (2-methoxyethoxymethoxy) - naphthalene-2-carbonyl]methylamino}methyl)biphenyl-4- ylaminolbenzoic acid are obtained in the form of a yellow powder.
Melting point: 72°C.
EXAMPLE 3: N-{4'-[2-(2,5-Difluorobenzylcarbamoyl) - phenylamino]biphenyl-3-ylmethyl}-N-methyl-6-(2- methoxyethoxymethoxy) naphthalene-2-carboxylamide 19 mg (50.0 pmol) of O-(7-azabenzotriazol-1- yl)-N,N,N’,N’ -tetramethyluronium hexafluorophosphate (HATU) , 49 mg (68.0 pmol) of PS-carbodiimide resin and 0.4 ml (31 pmol) of a solution of 44.3 mg of 2,5~difluorobenzylamine in 4 ml of dichloromethane are successively added to a solution containing 20 mg (33.8 pmol) of 2-[3"-({[6-(2-methoxyethoxymethoxy) ~ naphthalene-2-carbonyl]lmethylamino}methyl)biphenyl-4- ylaminolbenzoic acid (Example 2) in 0.4 ml of dimethylformamide. After stirring for 3 hours 30 minutes, the reaction medium is filtered and the solvents are evaporated off. The crude reaction product ’ is dissolved in 1.5 ml of dichloromethane and 0.4 ml of dimethylformamide, and 100 mg (274 pmol) of
MP-carbonate resin are added. After stirring for 5 hours, the resin is filtered off and the solvents are evaporated off. The residue obtained is purified by : chromatography on a column of silica eluted with a 1/1 heptane/ethyl acetate mixture, followed by increasing the polarity to 2/3. 15.2 mg (63%) of N-{4'-[2-(2,5- difluorobenzylcarbamoyl)phenylamino]biphenyl-3- ylmethyl}-N-methyl-6-(2- methoxyethoxymethoxy)naphthalene-2-carboxylamide are obtained.
HPLC Hypersil Thermoquest, Hypurity Elite C18, 5 microns, 2.1x150 mm, mobile phase: A (CHiCN/0.1 v/v
HCOxH) ; B (H,0/0.1 v/v HCO;H), flow rate: 0.5 ml/min, gradient: 0 min: 35% B, 25 min: 5% B, 30 min. 5% B, flow rate: 0.5 ml/min, retention time: 19.6 min, purity: 97%, MS (ESI) m/z 716.3 (M+H) *.
EXAMPLE 4: N-{4'-[2-Benzylmethylcarbamoyl)phenyl- amino]biphenyl-3-ylmethyl}-N-methyl-6-(2- methoxyethoxymethoxy) naphthalene-2-carboxylamide
In a manner similar to that of Example 3, starting with 20 mg (33.8 pmol) of 2=-[3"=-({[6-(2- methoxyethoxymethoxy)naphthalene-2-carbonyl]methyl- amino}methyl)biphenyl-4-ylamino]benzoic acid (Example 2) and 0.4 ml (31 pmol) of a solution of 37.5 mg of N-methylbenzylamine in 4 ml of DCM, 13.1 mg ) (56%) of N-{4'-[2-benzylmethylcarbamoyl)phenyl- ) 25 amino}biphenyl-3-ylmethyl}-N-methyl-6- (2-methoxy- ethoxymethoxy)naphthalene-2-carboxylamide are obtained.
HPLC Hypersil Thermoquest Hypurity Elite C18, - 5 microns, 2.1x150 mm, mobile phase: A (CHsCN/0.1 v/v
HCO:H) ; B (H,0/0.1 v/v HCO;H), flow rate: 0.5 ml/min, gradient: 0 min: 35% B, 25 min: 5% B, 30 min, 5% B, flow rate: 0.5 ml/min, retention time: 19.0 min, purity: 97.6%, MS (ESI) m/z 694.3 (M+H)*
EXAMPLE 5: Methyl 2-{3~] (methyloctanoylamino) - methyl ]biphenyl-4-ylamino}benzoate (a) N- (47 Bromobiphenyl-3-ylmethyl)-N-methyloctanoyl- amide 1.2 ml (7.0 mmol) of octanoyl chloride are added dropwise at room temperature to a solution of 2 g (6.4 mmol) of (4 -bromobiphenyl-3-ylmethyl)methylamine hydrochloride, obtained as described in Example 1b), in 25 ml of tetrahydrofuran and 2.7 ml (19.2 mmol) of triethylamine. After stirring for 2 hours at room temperature, the reaction medium is immersed into water and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and evaporated.
The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 1.7 g (66%) of N-(4' -bromobiphenyl-3- ylmethyl)-N-methyloctanoylamide are obtained. : (b) Methyl 2-{3’-[(methyloctanoylamino)methyl]- } 25 biphenyl-4-ylamino}benzoate 19 mg (8.4 mmol) of palladium acetate are introduced into a solution containing 78 mg (0.13 mmol)
of BINAP in 2 ml of toluene, followed by successive . addition of 1.7 g (4.2 mmol) of N-(4’-bromobiphenyl-3- ylmethyl) -N-methyloctanoylamide, 25 ml of toluene, 0.65 ml (5 mmol) of methyl anthranilate and 0.56 lof (5.9 mmol) of sodium tert-butoxide. The reaction mixture is heated at 90°C for 24 hours. 78 mg (8.4 mmol) of tris(dibenzylideneacetone)dipalladium (0) (Pdydbas), 78 mg (0.13 mmol) of BINAP and 1.9 g (5.9 mmol) of caesium carbonate are added and the reaction medium is then heated for a further 24 hours.
After cooling to room temperature, the reaction medium is extracted with ethyl acetate, washed with water and acidified to pH 6-7 with aqueous 1N hydrochloric acid solution. The organic phase is separated out after settling of the phases, dried over magnesium sulphate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (80/20). After evaporating off the solvents, 1.0 g of methyl 2-{3"-[(methyloctanoylamino)methyl]biphenyl-4- ylamino}benzoate is obtained in the form of a yellow oil, in a yield of 50%. 'H NMR (8 CDCl3): 0.6 (m, 3H); 1.25-1.35 (m, 8H); 1.68 ’ (m, 2H); 2.95 and 2.99 (2s, 3H); 3.91 (s, 3H); 4.60 and . 25 4.66 (2s, 2H); 6.75 (m, 1H); 7.15-7.60 (m, 9H); 7.98 (d, J = 9 Hz, 1H); 9.54 (m, 1H).
EXAMPLE 6: 2-{3'~[ (Methyloctanoylamino)methyl]biphenyl- . 4-ylamino}benzoic acid
X 320 mg (0.7 mmol) of methyl 2-{3’[(methyl- octanoylamino)methyl]biphenyl-4-ylamino}benzoate obtained as described in Example 5, are placed in 5 ml of tetrahydrofuran, 1 ml of methanol and a few drops of water. 135 mg (3.4 mmol) of sodium hydroxide are added and the reaction medium is stirred at room temperature for 4 hours. The reaction medium is then extracted with ethyl acetate, acidified to pH 6 with aqueous 1N hydrochloric acid solution and washed with water. The organic phase is dried over magnesium sulphate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica, eluted with a 70/30 heptane/ethyl acetate mixture. 200 mg of 2-{3'-[(methyloctanoylamino)methyl]biphenyl- 4-ylamino}benzoic acid are obtained in a yield of 65%, in the form of a yellow solid. "MH NMR (8 CDCl3): 0.79 (m, 3H); 1.17-1.27 (m, 8H); 1.66 (gq, J = 14 Hz, 2H); 2.36 (t, J = 16 Hz, 2H); 2.90 and 2.94 (2s, 3H); 4.45-4.61 (2s, 2H); 6.7 (m, 1H); 7.18- 7.50 (m, 10H); 7.99 (dd, J = 8 Hz and J = 1.5 Hz, 1H); 9.42 (s, 1H).
Melting point: 45°C. . 25 EXAMPLE 7: Methyl 2-(methyl-{3’-[ (methyloctanoylamino) - methyl lbiphenyl-4-yl}amino) benzoate
52 mg (1.3 mmol) of sodium hydride are added . to a solution of 270 mg (0.6 mmol) of 2={3"-[ (methyl- octanoylamino)methyl]biphenyl-4-ylamino}benzoic acid (prepared as described in Example 6) in 5 ml of dimethylformamide, followed by addition of 2.5 ml of iodomethane. After heating at 100°C for 12 hours, the medium is cooled, immersed into water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 210 mg of methyl 2-(methyl-{3’-[(methyloctanoylamino)methyl]biphenyl-4- ! yl}amino)benzoate are obtained in the form of a yellow oil, in a yield of 72%.
HPLC Hypersil Thermoquest Hypurity Elite C18,
S microns, 2.1x150 mm, mobile phase: A (CH3CN/0.1 v/v
HCOH) ; B (H20/0.1 v/v HCOzH), flow rate: 0.5 ml/min, gradient: 0 min: 35% B, 25 min: 5% B, 30 min. 5% B, flow rate: 0.5 ml/min, retention time: 21.8 min, purity: 96%, MS (ESI) m/z 487.2 (M+H)*
EXAMPLE 8: 2- (Methyl-{3’ -[ (methyloctanoylamino) - methyl ]biphenyl-4-yl}amino)benzoic acid ) 190 mg (0.4 mmol) of methyl 2-(methyl-{3’- . 25 [ (methyloctanoylamino)methyl]biphenyl-4-y1}amino) - benzoate are placed in 2 ml of tetrahydrofuran, 0.2 ml of methanol and a few drops of water. 24 mg (0.6 mmol)
of sodium hydroxide are added and the reaction medium . is stirred at room temperature for 18 hours. The reaction medium is then extracted with ethyl acetate, acidified to pH 5 with aqueous 1N hydrochloric acid 5S solution and washed with water. The organic phase is dried over magnesium sulphate, filtered and evaporated.
The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 155 mg of 2- (methyl-{3’~-[ (methyloctanoyl- amino) methyl]biphenyl-4-yl}amino)benzoic acid are obtained in the form of a yellow oil in a yield of 84%.
HPLC Hypersil Thermoquest Hypurity Elite C18, '
S microns, 2.1x150 mm, mobile phase: A (CHiCN/0.1 v/v
HCO:H); B (H,0/0.1 v/v HCO,H), flow rate: 0.5 ml/min, gradient: 0 min: 35% B, 25 min: 5% B, 30 min. 5% B, flow rate: 0.5 ml/min, retention time: 18.8 min, purity: 97%, MS (ESI) m/z 473.4 (M+H)*
EXAMPLE 9: N- (3-Methylbutyl) -2-{3' ~[ (methyloctanoyl- amino)methyl]biphenyl-4-ylamino}benzamide 95 mg (1.1 mmol) of 3-methylbutylamine and 160 mg (1.2 mmol) of l-hydroxybenzotriazole are successively added to a solution of 500 mg (1.1 mmol) ’ of 2-{3"-[(methyloctanoylamino)methyl]biphenyl-4- . 25 ylamino}benzoic acid (Example 6) in 15 ml of dichloromethane. The reaction medium is cooled to 0°C and 230 mg (1.2 mmol) of EDCI are added portionwise.
The reaction medium is stirred from 0°C to room . temperature over 6 hours, diluted with ethyl acetate, washed with water and extracted with ethyl acetate. The ) organic phase is dried over sodium sulphate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 530 mg of N-(3- methylbutyl)-2-{3’-[ (methyloctanoylamino) methyl] - biphenyl-4-ylamino}benzamide are obtained in the form of a yellow oil, in a yield of 93%.
HPLC Hypersil Thermoquest Hypurity Elite C18, 5 microns, 2.1x150 mm, mobile phase: A (CH3CN/0.1 v/v
HCOzH) ; B (H20/0.1 v/v HCO,H), flow rate: 0.5 ml/min, ! gradient: 0 min: 35% B, 25 min: 5% B, 30 min. 5% B, flow rate: 0.5 ml/min, retention time: 22.8 min, purity: 99%, MS (ESI) m/z 526.3 (M+H)*
EXAMPLE 10: N-Methyl-N-{4’'-[2-(5-propyl-[1,3,4]oxa- diazol-2-yl)phenylamino]biphenyl-3-ylmethyl}octanoyl- amide (a) N-Methyl-N-[4’-(2-hydrazinocarbonylphenyl- amino) biphenyl-3-yimethyl]octanoylamide 0.16 m1 (1.4 mmol) of 4-methylmorpholine and 0.2 ml (1.5 mmol) of isobutyl chloroformate are ’ successively added to a solution of 500 mg (1.1 mmol) . 25 of 2-{3'-[(methyloctanoylamino)methyl]biphenyl-4- ylamino}benzoic acid (Example 6) in 15 ml of tetrahydrofuran, cooled to 0°C. The reaction medium is stirred at room temperature for 1 hour. The precipitate 1 is filtered off and the filtrate is collected into . 5.5 ml of a 1M solution of hydrazine in tetrahydro- furan, cooled to 0°C. After stirring from 0°C to room temperature over 1 hour, the reaction medium is diluted with ethyl acetate and washed with saturated ammonium chloride solution and then with sodium chloride. The organic phase is dried over sodium sulphate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 60/40 heptane/ethyl acetate mixture. 390 mg of
N-methyl-N-[4’-(2-hydrazinocarbonylphenylamino)- biphenyl-3-ylmethyl)octanoylamide are obtained in a ! yield of 52%. (b) N-Methyl-N-{4’-[2-(5-propyl-[1,3,4]oxadiazol-2- yl)phenylamino]biphenyl=-3-ylmethyl}octanoylamide 0.36 ml (2.2 mmol) of trimethyl orthobutyrate and 9.6 pl (0.15 mmol) of methanesulphonic acid are added to a solution of 350 mg (0.74 mmol) of N-methyl-
N-[4”-(2-hydrazinocarbonylphenylamino)biphenyl-3- ylmethylloctanoylamide in 10 ml of dioxane, and the mixture is then heated at 105°C for 1 hour. After cooling, the medium is diluted with ethyl acetate and ’ then washed with saturated sodium hydrogen carbonate . 25 solution and then with sodium chloride solution. The organic phase is dried over sodium sulphate, filtered and concentrated. The residue obtained is purified by chromatography on a column of silica eluted with a § 70/30 heptane/ethyl acetate mixture. 270 mg of
N-methyl-N-{4’-[2-(5-propyl-[1, 3,4]oxadiazol-2- ¢ yl)phenylaminolbiphenyl-3-ylmethyl}octanoylamide are
S obtained in the form of an orange-coloured oil, in a yield of 70%.
HPLC Hypersil Thermoquest Hypurity Elite C18, microns, 2.1x150 mm, mobile phase: A (CH5CN/0.1 v/v
HCOzH) ; B (H20/0.1 v/v HCO,H), flow rate: 0.5 ml/min, gradient: 0 min: 35% B, 25 min: 5% B, 30 min. 5% B, flow rate: 0.5 ml/min, retention time: 23.9 min, i purity: 97%, MS (ESI) m/z 525.4 (M+H)* .
EXAMPLE 11: N-Methyl-N-{4’-[2-(1lH-tetrazol-5- yl)phenylamino]biphenyl-3-ylmethyl}octanoylamide (a) N-Methyl-N-[4'~(2-cyanophenylamino)biphenyl-3- ylmethyljoctanoylamide
In a manner similar to that of Example 1(e), starting with 1.0 g (2.5 mmol) of N-(4' -bromobiphenyl- 3-ylmethyl) -N-methyloctanoylamide, obtained as in
Example 5(a), and 0.4 g (3.5 mmol) of anthranilo- nitrile, 1.0 g of N-methyl-N-[4'-(2-cyanophenylamino) — biphenyl-3-ylmethyl]octanoylamide is obtained in a yield of 96%. “4 (b) N-Methyl-N-{4"-[2-(I1H-tetrazol-5-yl)phenylamino]- . 25 biphenyl-3-ylmethyl)octanoylamide 230 mg (1.7 mmol) of triethylamine hydrochloride and 220 mg (3.4 mmol) of sodium azide are added to a solution of 500 mg (1.14 mmol) of N-methyl-
PY N~[4"-(2-cyanophenylamino)biphenyl-ylmethyl]octanoyl- amide in 5 ml of l-methyl-2-pyrrolidinone. The reaction v medium is heated at 150°C for 4 hours. After cooling, > aqueous IN hydrochloric acid solution is added to the reaction medium to pH 4, followed by extraction with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated. The residue obtained is purified by chromatography on a column of silica eluted with a 95/5 dichloromethane/methanol mixture. 369 mg of N-methyl-N-{4'-[2-(1H-tetrazol-5- ’ yl)phenylaminolbiphenyl-3-ylmethyl}octanoylamide are y obtained in the form of a yellow oil, in a yield of 68%.
HPLC Hypersil Thermoquest Hypurity Elite C18, > microns, 2.1x150 mm, mobile phase: A (CHiCN/0.1 v/v
HCOzH); B (H;0/0.1 v/v HCO,H), flow rate: 0.5 ml/min, gradient: 0 min: 35% B, 25 min: 5% B, 30 min. 5% B, flow rate: 0.5 ml/min, retention time: 15.6 min, purity: 96%, MS (ESI) m/z 483.3 (M+H)"
EXAMPLE 12: Ethyl 3-13’ - ({[6- (2-methoxyethoxymethoxy) - naphthalene-2-carbonyl]methylamino}methyl)biphenyl-4- ylaminolbenzoate bh In a manner similar to that of Example 1 (e), . 25 starting with 5.9 g (11 mmol) of N-(4’ ~bromobiphenyl-3~- ylmethyl)~N-methyl-6-(2-methoxyethoxymethoxy) - naphthalene-2-carboxylamide, prepared as described in
Example 1(d), and 2.5 g (15.4 mmol) of ethyl 3-amino- n benzoate, 6.8 g of ethyl 3-[3"7 ({[6~(2-methoxyethoxy~- methoxy) naphthalene-2~carbonyl Jmethylamino}methyl)- v biphenyl-4-ylamino]benzoate are obtained in the form of a beige-coloured solid, in a yield of 90%.
Melting point: 85-86°C.
EXAMPLE 13: 3-[3'-({[6-(2- methoxyethoxymethoxy) naphthalene-2-carbonyl methyl - amino }methyl)biphenyl-4-ylamino]benzoic acid 1.2 ml (1.2 mmol) of aqueous 1M lithium hydroxide solution are added to a solution of 500 mg ) (0.8 mmol) of ethyl 3-[3"-({ [6~ (2-methoxyethoxy~- . methoxy) naphthalene-2-carbonyl]methylamino}methyl) - biphenyl-4-ylaminolbenzoate in 10 ml of tetrahydrofuran and 1 ml of methanol. After heating at 50°C for 18 hours, the reaction medium is diluted with ethyl acetate, washed with aqueous IN hydrochloric acid solution, extracted with ethyl acetate, dried over magnesium sulphate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 60/40 heptane/ethyl acetate mixture. 480 mg of 3-[3'- ({[6- (2-methoxyethoxymethoxy)naphthalene-2-carbonyl] - * methylamino}methyl)biphenyl-4-ylamino]benzoic acid are . 25 obtained in the form of a yellow foam, in a yield of 60%.
Melting point: 60°C.
EXAMPLE 14: Ethyl 3-(3’ -{[ (6-hydroxynaphthalene-2- ~ carbonyl)methylamino]methyl}biphenyl-4-ylaminobenzoate 1 ml of concentrated sulphuric acid is added ‘ to a solution of 1.2 g (1.9 mmol) of ethyl 3-[3’-({[6- (2-methoxyethoxymethoxy)naphthalene-2-carbonyl]methyl- amino}methyl)biphenyl-4-ylamino]benzoate in 10 ml of methanol and 10 ml of tetrahydrofuran. The reaction medium is stirred at room temperature for 6 hours, diluted with ethyl acetate and washed with water. After extraction, the organic phase is dried over magnesium sulphate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 60/40 heptane/ethyl acetate mixture. 1 g of ethyl 3-(3"~{[ (6-hydroxy- naphthalene-2-carbonyl)methylamino]methyl}biphenyl-4- ylamino)benzoate is obtained in the form of a beige- coloured foam, in a yield of 80%.
Melting point: 90°C.
EXAMPLE 15: 3-(3’-{[(6-Hydroxynaphthalene-2- carbonyl) methylamino]methyl}biphenyl-4~ylamino)benzoic acid
In a manner similar to that of Example 13, starting with 820 mg (1.5 mmol) of ethyl 3-(3’-{[(6- : hydroxynaphthalene-2-carbonyl)methylamino]methyl}- . 25 biphenyl-4-ylamino)benzoate and 4.3 ml (4.3 mmol) of aqueous 1M lithium hydroxide solution, 770 mg of 3-(3’- { [ (6-hydroxynaphthalene-2-carbonyl)methylamino]methyl}-
biphenyl-4-ylamino)benzoic acid are obtained in the o form of a yellow foam, in a yield of 78%.
Melting point: 105°C. * > EXAMPLE 16: N-Methyl-N-{4'-[3-(4-methylpiperidine—1- carbonyl) phenylamino]biphenyl-3-ylmethyl}-6-(2- methoxyethoxymethoxy) naphthalene-2-carboxylamide 0.18 ml (1.3 mmol) of triethylamine, 170 mg (1.3 mmol) of l-hydroxybenzotriazole and 0.14 ml (1.2 mmol) of 4-methylpiperidine are successively added to a solution of 700 mg (1.2 mmol) of 3-[3"-({[6-(2- methoxyethoxymethoxy)naphthalene-2-carbonyl]methyl- amino}methyl)biphenyl-4-ylamino]benzoic acid in 15 ml of dichloromethane. The reaction medium is cooled to 0°C and 250 mg (1.3 mmol) of EDCI are then added. After stirring from 0°C to room temperature over 6 hours, the reaction medium is washed with water and extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 50/50 heptane/ethyl acetate mixture. 810 mg of
N-methyl-N-{4’-[3-(4-methylpiperidine-l-carbonyl)- ' phenylamino]biphenyl-3~ylmethyl} 6- (2-methoxyethoxy- . 25 methoxy) naphthalene-2-carboxylamide are obtained in the form of a yellow solid, in a yield of 62%.
Melting point: 60°C.
EXAMPLE 17: N-Methyl-N-{4'~[3- (morpholine-3-carbonyl)- a phenylamino]biphenyl-3-ylmethyl}-6- (2-methoxyethoxy- methoxy) naphthalene-2-carboxylamide } In a manner similar to that of Example 16, starting with 650 mg (1.1 mmol) of 3-[3'-({[6-(2- methoxyethoxymethoxy) naphthalene-2-carbonylImethyl- amino}methyl)biphenyl-4-ylamino]benzoic acid and 0.1 ml (1.1 mmol) of morpholine, 720 mg of N-methyl-N-{4’'-[3- (morpholine-4-carbonyl)phenylamino]biphenyl-3- ylmethyl}-6-(2-methoxyethoxymethoxy) naphthalene-2- carboxylamide are obtained in the form of a white foam, in a yield of 69%.
Melting point: 68-70°C.
EXAMPLE 18: N-Methyl-N-{4’-[3- (4-methylpiperidine-1- carbonyl) phenylamino]biphenyl-3-ylmethyl}-6-hydroxy- naphthalene-2-carboxylamide
In a manner similar to that of Example 14, starting with 150 mg (0.22 mmol) of N-methyl-N-~{4'-[3- (4-methylpiperidine-1l-carbonyl)phenylamino]biphenyl-3— ylmethyl}-6-(2-methoxyethoxymethoxy)naphthalene-2- carboxylamide, 130 mg of N-methyl-N-{4’'-[3-(4- methylpiperidine-1l-carbonyl)phenylamino]biphenyl-3- ylmethyl}-6-hydroxynaphthalene-2-carboxylamide are ’ obtained in the form of a white solid, in a yield of . 25 100%.
Melting point: 90°C.
EXAMPLE 19: N-Methyl-N-{4’-[3-morpholine-4-carbonyl) - , phenylamino]biphenyl-3-ylmethyl }-6-hydroxynaphthalene- 2-carboxylamide i} In a manner similar to that of Example 14, starting with 160 mg (0.24 mmol) of N-methyl-N-{4’-[3- (morpholine-4-carbonyl)phenylamino]biphenyl-3-yl- methyl }~6-(2-methoxyethoxymethoxy)naphthalene-2- carboxylamide, 120 mg of N-methyl-N-{4’-[3-morpholine- 4-carbonyl)phenylamino]biphenyl-3-ylmethyl}-6- hydroxynaphthalene-2-carboxylamide are obtained in the form of a white solid, in a yield of 86%.
Melting point: 92°C.
EXAMPLE 20: 3-{3' -[ (Methyloctanoylamino)methyl] - biphenyl~4-ylamino}benzoic acid (a) Ethyl 3-{3’-[(methyloctanoylamino)methyl]biphenyl- 4-ylamino)benzoate
In a manner similar to that of Example 1(e), starting with 500 mg (1.24 mmol) of N-(4'- bromobiphenyl-3-ylmethyl)-N-methyloctanoylamide, prepared as described in Example 5(a) and 0.26 ml (1.74 mmol) of ethyl 3-aminobenzoate, 570 mg of ethyl 3-{3’-[(methyloctanoylamino)methyl]biphenyl-4- ylamino}benzoate are obtained in the form of a yellow ’ oil, in a yield of 95%. . 25 (b) 3-{3"=[ (Methyloctanoylamino)methyl}biphenyl-4- ylaminoj}benzoic acid
In a manner similar to that of Example 2, ’ starting with 500 mg (1 mmol) of ethyl 3-{3’-[ (methyl- octanoylamino)methyl]biphenyl-4-ylaminolbenzoate, 390 mg of 3-{3'~[(methyloctanoylamino)methyl]biphenyl- 4-ylamino}benzoic acid are obtained in the form of a yellow foam, in a yield of 83%.
Melting point: 58°C.
EXAMPLE 21: Ethyl 2-{3’-[ (Methyloctanoylamino)methyl]- biphenyl-4-yloxy}benzoate (a) tert-Butyl (3-bromobenzyl)carbamate 40 g (183 mmol) of di-tert-butyl dicarbonate are added portionwise, at room temperature, to a mixture of 40.7 g (183 mmol) of 3-bromobenzylamine hydrochloride, 26 ml of triethylamine (183 mmol) and 450 ml of dichloromethane. After stirring for 18 hours, the reaction medium is poured into ice-cold water and extracted with dichloromethane. The organic phase is separated out after settling of the phases, dried over magnesium sulphate and evaporated. 46 g of tert-butyl (3-bromobenzyl)carbamate are obtained in a yield of 88%. (b) tert-Butyl (3-bromobenzyl)-N-methylcarbamate ’ 19 g (475 mmol) of sodium hydride (60% in . 25 o0il) are added portionwise to a solution of 128 g (447 mmol) of tert-butyl (3-bromobenzyl)carbamate in 800 ml of DMF, and the reaction medium is stirred until the evolution of gas has ceased. 29.3 ml (470 mmol) of ‘ methyl iodide are added dropwise and stirring is continued for 18 hours. The reaction medium is poured ) into ice-cold water and extracted with ethyl acetate.
The organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 152.5 g of tert-butyl (3-bromobenzyl)-N- methylcarbamate are obtained in a yield of 92%. (c) tert-Butyl (4"' -hydroxybiphenyl-3-ylmethyl)methyl- carbamate 41.6 ml (83.2 mmol) of aqueous 2M potassium carbonate solution are added dropwise to a solution of 10 g (33 mmol) of tert-butyl (3-bromobenzyl) -N- methylcarbamate and 8.3 g (60 mmol) of 4-hydroxy- benzeneboronic acid in 100 ml of ethylene glycol dimethyl ether. The reaction medium is degassed and 1.9 g (1.7 mmol) of tetrakis(triphenylphosphino)- palladium are added. After heating for 12 hours at 80°C, the reaction medium is cooled, diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 7 g of tert-butyl . 25 (4'-hydroxybiphenyl-3-ylmethyl)methylcarbamate are obtained in the form of a beige-coloured solid, in a yield of 68%.
Melting point: 174°C. , (d) Ethyl 2-{3’-[ (tert-butoxycarbonylmethylamino) - methyl]biphenyl-4-yloxy}benzoate ) 2.15 g (12.8 mmol) of ethyl 2-fluorobenzoate 5S and 1.9 g (14 mmol) of potassium carbonate are
Successively added to a solution of 4 g (12.8 mmol) of tert-butyl (4’-hydroxybiphenyl-3-ylmethyl)methyl- carbamate in 45 ml of dimethylacetamide. The reaction medium is refluxed for 48 hours, cooled, diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 3.1 g of ethyl 2-{3’-[(tert-butoxycarbonylmethylamino)methyl]- biphenyl-4-yloxy}benzoate are obtained in the form of a colourless oil, in a yield of 53%. (e) Ethyl 2-(3'-methylaminomethylbiphenyl-4- yloxy)benzoate 3.1 g (6.7 mmol) of ethyl 2-{3'-[(tert- butoxycarbonylmethylamino)methyl]lbiphenyl-4-yl- oxylbenzoate are placed in 50 ml of dichloromethane and 2.6 ml of trifluoroacetic acid. After stirring at room temperature for 8 hours, the reaction medium is . 25 concentrated, placed in water, brought to pH 8 with aqueous 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated under vacuum. 2.3 g . of ethyl 2-(3'-methylaminomethylbiphenyl-4-yloxy) - benzoate are obtained in the form of an Orange-coloured oil, in a yield of 95%. (f) Ethyl 2-{3"~[ (methyloctanoylamino)methyl]biphenyl- 4-yloxy}benzoate
In a manner similar to that of Example 5 (a), starting with 2.3 g (6.4 mmol) of ethyl 2-(3"-methyl- aminomethylbiphenyl-4-yloxy)benzoate and 1.1 ml (6.4 mmol) of octanoyl chloride, 2.9 g of ethyl 2-{3’- [ (methyloctanoylamino)methyllbiphenyl-4-yloxy}benzoate are obtained in the form of a colourless oil, in a yield of 92%.
HPLC Hypersil Thermoquest Hypurity Elite C18, 5 microns, 2.1x150 mm, mobile phase: A (CHsCN/0.1 v/v
HCOH); B (H0/0.1 v/v HCO,H), flow rate: 0.5 ml/min, gradient: 0 min: 35% B, 25 min: 5% B, 30 min. 5% B, flow rate: 0.5 ml/min, retention time: 21.5 min, purity: 99%, MS (ESI) m/z 488.3 (M+H)*
EXAMPLE 22: 2-{3’ - [Methyloctanoylamino) methyl]biphenyl- 4-yloxyl}benzoic acid
In a manner similar to that of Example 8, starting with 1 g (2 mmol) of ethyl 2-{3’~[(methyl- ’ octanoylamino)methyl]biphenyl-4-yloxy}benzoate, 800 mg . 25 of 2-{3'-[methyloctanoylamino)methyl]biphenyl-4- yloxyl}benzoic acid are obtained in the form of a white solid, in a yield of 85%. ry
Melting point: 115°C. ' EXAMPLE 23 - CROSSOVER-CURVE PPAR TRANSACTIVATION TEST
The activation of receptors with an agonist (activator) in HeLN cells leads to the expression of a reporter gene, luciferase, which, in the presence of a substrate, generates light. The modulation of the receptors is measured by quantifying the luminescence produced after incubating the cells in the presence of a reference agonist. The ligands displace the agonist from its site. The measurement of the activity is performed by quantifying the light produced. This measurement makes it possible to determine the modulatory activity of the compounds according to the invention by determining the constant that represents the affinity of the molecule for the receptor. Since this value can fluctuate depending on the basal activity and the expression of the receptor, it is referred to as Kd apparent (KdApp in nM).
To determine this constant, "crossover curves" of the test product against a reference agonist are performed in a 96-well plate: 10 concentrations of the test product plus a concentration 0 are arranged in a line, and 7 concentrations of the agonist plus a concentration 0 are arranged in a column. This . 25 represents 88 measurement points for 1 product and 1 receptor. The remaining 8 wells are used for repeatability controls.
In each well, the cells are in contact with a ’ concentration of the test product and a concentration of the reference agonist, 2-(4-{2~[3-(2,4-difluoro- phenyl) -l-heptylureido]ethyl)phenylsulphanyl)-2-methyl- 5S propionic acid for PPARa, {2-methyl-4-[4-methyl-2- (4- trifluoromethylphenyl)thiazol-5-ylmethylsulphanyl]- phenoxylacetic acid for PPARS and 5-{4-[2-(methylpyrid- 2-ylamino)ethoxylbenzyl}thiazolidine-2, 4~dione for
PPARy. Measurements are also taken for total agonist controls with the same products.
The HeLN cell lines used are stable transfectants containing the plasmids ERE-BGlob-Luc-SvV-
Neo (reporter gene) and PPAR (a, 8, y) Gal-hPPAR. These cells are inoculated into 96-well plates at a rate of 10 000 cells per well in 100 pl of DMEM medium without phenol red and supplemented with 10% of defatted calf serum. The plates are then incubated at 37°C and 7% CO, for 16 hours.
The various dilutions of the test products and of the reference ligand are added at a rate of 5 ul per well. The plates are then incubated for 18 hours at 37°C and 7% CO;. The culture medium is removed by turning over and 100 pl of a 1:1 PBS/luciferine mixture are added to each well. After 5 minutes, the plates are . 25 read by the luminescence detector.
These crossed curves make it possible to determine the
AC50 values (concentration at which 50% activation is observed) of the reference ligand at various ’ concentrations of test product. These AC50 values are used to calculate the Schild regression by plotting a straight line corresponding to the Schild equation ("quantitation in receptor pharmacology" Terry P.
Kenakin, Receptors and Channels, 2001, 7, 371-385) which allows the Kd app values (in nM) to be obtained.
Transactivation results:
Compounds PPAR PPARS PPARY
Kd app Kd app Kd app (nM) (in nM) (in nM)
Reference 1: 2-(4-{2-[3-(2,4- 200 n.a. n.a. difluorophenyl)-l-heptylureido]- ethyl }phenylsulphanyl)-2-methyl- propionic acid
Reference 2: {2-methyl-4-[4- n.a. 10 n.a. methyl-2-(4- trifluoromethylphenyl)thiazol-5- ylmethylsulphanyllphenoxylacetic acid
Reference 3: 5-{4-[2-(methylpyrid- n.a. n.a. 30 2-ylamino)ethoxylbenzyl}thi- ’ azolidine-2, 4-dione n.a. means not active : These results show the affinity of the compounds for PPAR-y and more particularly the specificity of the affinity of the compounds of the invention for the PPARy subtype, compared with the affinity of the compounds for the PPARa subtype or for the PPARS subtype.
EXAMPLE 24 - COMPOSITIONS
Various concrete formulations based on the compounds according to the invention are illustrated in this example.
A- ORAL ROUTE (a) 0.2 g tablet —- Compound of Example 2 0.001 g - Starch 0.114 g¢ — Dicalcium phosphate 0.020 g¢ - Silica 0.020 g —- Lactose 0.030 g - Talc 0.010 ¢ - Magnesium stearate 0.005 g (b) Drinkable suspension in 5 ml ampules —- Compound of Example 7 0.001 g - Glycerol 0.500 ¢ . - 70% Sorbitol 0.500 g - Sodium saccharinate 0.010 g - Methyl para-hydroxybenzoate 0.040 g
6l - Flavouring gas ’ - Purified water gs 5 ml (c) 0.8 g tablet - Compound of Example 1 0.500 g - Pregelatinized starch 0.100 g - Microcrystalline cellulose 0.115 g¢ - Lactose 0.075 g —- Magnesium stearate 0.010 g¢ (d) Drinkable suspension in 10 ml ampules - Compound of Example 1 0.200 g - Glycerol 1.000 g¢g - 70% Sorbitol 1.000 g¢g ~ Sodium saccharinate 0.010 g - Methyl para-hydroxybenzoate 0.080 g - Flavouring gs - Purified water gs 10 ml
B- TOPICAL ROUTE (a) Ointment - Compound of Example 1 0.020 g - Isopropyl myristate 81.700 g - Liquid petroleum jelly fluid 9.100 g - Silica (“Aerosil 200” sold by 9.180 g
Degussa)
(b) Ointment ) ~ Compound of Example 2 0.300 g ~ White petroleum jelly codex 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 gs 100 g (d) Lotion — Compound of Example 9 0.100 g ~ Polyethylene glycol (PEG 400) 69.900 g - 95% Ethanol 30.000 g (e) Hydrophobic ointment —- Compound of Example 13 0.300 g - Isopropyl myristate 36.400 ¢g ~ Silicone oil (“Rhodorsil 47 V 300” sold by Rhone-Poulenc) 36.400 g ~ Beeswax 13.600 g : - Silicone oil (“Abil 300,000 cst” sold by Goldschmidt) das 100 g
(f) Nonionic oil-in-water cream . — Compound of Example 17 1.000 g — Cetyl alcohol 4.000 g — Glyceryl monostearate 2.500 g —- PEG-50 stearate 2.500 g —- Karite butter 9.200 g — Propylene glycol 2.000 g — Methyl para-hydroxybenzoate 0.075 g — Propyl para-hydroxybenzoate 0.075 g —- Sterile demineralized water gs 100 g

Claims (11)

  1. ’ 1. Compounds characterized in that they correspond to formula (I) below: 13 X R1 Ra A IAN od Ra" U) in which: ~- R; represents a radical of the following formulae: (a) (b) (€) NT 0 a pS A ; oO R4 R5 V—-W Rs, Rs, V, W and Y¥ having the meanings given below, - R, represents a hydrogen atom, a halogen atom, an alkyl radical containing from 1 to 12 carbon atoms, a hydroxyl radical, an alkoxy radical containing from 1 to 7 carbon atoms, a polyether radical, a nitro radical, or an amino radical that may optionally be substituted with one or more alkyl radicals containing from 1 to 12 carbon atoms, an aryl radical, an aralkyl radical, a heteroaryl radical or a heterocyclic radical; - Ry represents: - a radical -(CHz)e¢=(N-Ris)u— (C(O, N)) Ris,
    — an alkyl radical containing from 1 to 12 carbon . atoms, an aryl radical, an aralkyl radical, a heteroaryl radical, a heterocyclic radical or a ] 9-fluorenylmethyl radical; t, u, z, Ris and Ryg having the meanings given below, ~ Rg represents a hydrogen atom, an alkyl radical containing from 1 to 12 carbon atoms, an aryl radical, an aralkyl radical, a heteroaryl radical or a heterocyclic radical; - Rs represents — a radical O-(CH,),-Rg — a radical NR’~-(CH;),~Ri, —- a hydroxyl radical, an alkoxy radical containing from 1 to 7 carbon atoms, an aryl radical, an aralkyl radical, a heteroaryl radical or a heterocyclic radical, — a radical NR des Re, Rig, R’, R” and n having the meanings below, - R’ represents a hydrogen atom, an alkyl radical containing from 1 to 12 carbon atoms, a hydroxyl radical, an aryl radical, an aralkyl radical, a . heteroaryl radical or a heterocyclic radical; - R” represents a hydrogen atom, an alkyl radical containing from 1 to 12 carbon atoms, an aryl radical, r an aralkyl radical, a heteroaryl radical, a ’ heterocyclic radical or a radical -(CHs),—Rg; R¢ and n having the meanings below, - R¢ represents an aryl radical, an aralkyl radical, a heteroaryl radical; a heterocyclic radical, a radical NH-CO-Ry, a radical NH-CO-0-R; or a radical N-R4Rg; R; and Rg having the meanings below, - n may take the values 1, 2 or 3; - Ry represents a hydrogen atom, an alkyl radical containing from 1 to 12 carbon atoms, an aryl radical, an aralkyl radical, a heteroaryl radical or a heterocyclic radical; - Rg represents a hydrogen atom or an alkyl radical containing from 1 to 3 carbon atoms; =~ X represents an oxygen or sulphur atom, or a methylene (CH;) or NRg radical; - Rg represents a hydrogen atom, an alkyl radical containing from 1 to 12 carbon atoms or an aralkyl radical; - A represents a bond having the following structure: a) ~ (CHa) n= (N-Ryp) p= (CO) q— (D) — b) -(CHz2) n= (N=-Rig) p= (CS) q— (D) r~ D, r, q, p and m having the meanings given below, Rjp having the meaning given below, . 25 - D represents an oxygen or sulphur atom, a radical NRp or a CH, radical; Ri: having the meaning given below,
    - mm BP, gq and r, which may be identical or different, . may take the values 0 or 1; - Rio and Ry; may be identical or different and represent i a hydrogen atom or an alkyl radical containing from 1 to 12 carbon atoms;
    - V represents an oxygen, sulphur or nitrogen atom, nitrogen atom being linked to a hydrogen atom or an alkyl radical containing from 1 to 6 carbon atoms; - W represents a nitrogen atom or a radical C-R;,;
    Riz having the meanings given below, ~- Y represents a nitrogen atom or a carbon atom; - Riz; represents a hydrogen atom, an alkyl radical containing from 1 to 12 carbon atoms, an aryl radical, an aralkyl radical, a heteroaryl radical or a heterocyclic radical; —- Ri3 represents a hydrogen or halogen atom; - Rig represents a heterocyclic radical; - Ris represents a hydrogen atom, an alkyl radical containing from 1 to 12 carbon atoms, an aryl radical,
    an aralkyl radical, a heteroaryl radical or a heterocyclic radical; t, u and z, which may be identical or different, may take the values from 0 to 4;
    ' ~ Ris represents a hydrogen atom, an alkyl radical containing from 1 to 12 carbon atoms, an aryl radical, an aralkyl radical, a heteroaryl radical, a heterocyclic radical, a radical NHCOR;, a radical iy NHCOOR; or a radical NR4Rg; R; and Rg having the meanings given above, and when m represents 0, then g represents 1 and Rj, represents an alkyl radical containing from 1 to 12 carbon atoms; and the optical and geometrical isomers of the said compounds of formula (I), and also the salts thereof.
  2. 2. Compounds according to Claim 1, characterized in that they are in the form of salts of an alkali metal or alkaline-earth metal, zinc salts or salts of an organic amine.
  3. 3. Compounds according to Claim 1 or 2, characterized in that the alkyl radicals containing from 1 to 3 carbon atoms are chosen from methyl, ethyl and propyl radicals.
  4. 4. Compounds according to any one of the preceding claims, characterized in that the alkyl radicals containing from 1 to 12 carbon atoms are chosen from a linear or cyclic, optionally branched, hydrogen-containing or fluorine-containing radical containing 1 to 12 carbon atoms, which may be interrupted with a hetero atom, and the alkyl radicals containing from 1 to 12 carbon atoms are preferably . 25 methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, octyl, decyl or cyclohexyl radicals.
  5. 5. Compounds according to any one of the . breceding claims, characterized in that the polyether radicals are chosen from polyether radicals containing ’ from 1 to 6 carbon atoms interrupted with at least one oxygen atom, such as methoxymethoxy, ethoxymethoxy or methoxyethoxymethoxy radicals.
  6. 6. Compounds according to any one of the preceding claims, characterized in that the halogen atom is chosen from the group consisting of a fluorine, chlorine or bromine atom.
  7. 7. Compounds according to any one of the preceding claims, characterized in that the alkoxy radical containing from 1 to 7 carbon atoms is chosen from the group consisting of methoxy, ethoxy, isopropyloxy, tert-butoxy, hexyloxy, benzyloxy or phenoxy radicals, which may optionally be substituted with an alkyl radical containing from 1 to 12 carbon atoms.
  8. 8. Compounds according to any one of the preceding claims, characterized in that the aryl radical is chosen from a phenyl, biphenyl, cinnamyl or naphthyl radical, which may be mono- or disubstituted with a halogen atom, a CF; radical, an alkyl radical containing from 1 to 12 carbon atoms, an alkoxy radical containing from 1 to 7 carbon atoms, a nitro function, a polyether radical, an aryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl radical optionally protected with an acetyl or ’ benzoyl group or an amino function optionally protected with an acetyl or benzoyl group or optionally if substituted with at least one alkyl containing from 1 to 12 carbon atoms.
  9. 9. Compounds according to any one of the preceding claims, characterized in that the aralkyl radical is chosen from a benzyl, phenethyl or 2-naphthylmethyl radical, which may be mono- or disubstituted with. a halogen atom, a CFs radical, an alkyl radical containing from 1 to 12 carbon atoms, an alkoxy radical containing from 1 to 7 carbon atoms, a nitro function, a polyether radical, an aryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl radical optionally protected with an acetyl or benzoyl group or an amino function optionally protected with an acetyl or benzoyl group or optionally substituted with at least one alkyl containing from 1 to 12 carbon atoms.
  10. 10. Compounds according to any one of the preceding claims, characterized in that the heteroaryl radical is chosen from the group consisting of an aryl radical interrupted with one or more hetero atoms, such ' as a pyridyl, furyl, thienyl, isoxazolyl, oxadiazolyl,
    . 25 oxazolyl, isothiazolyl, guinazolinyl, benzothiadiazolyl, benzimidazolyl, indolyl or benzofuryl radical, optionally substituted with at least one halogen, an alkyl containing from 1 to 12 ‘ carbon atoms, an alkoxy containing from 1 to 7 carbon atoms, an aryl radical, a nitro function, a polyether radical, a heteroaryl radical, a benzoyl radical, an 5S alkyl ester group, a carboxylic acid, a hydroxyl optionally protected with an acetyl or benzoyl group or an amino function optionally protected with an acetyl or benzoyl group or optionally substituted with at least one alkyl containing from 1 to 12 carbon atoms.
  11. 11. Compounds according to any one of the preceding claims, characterized in that the heterocyclic radical is chosen from the group consisting of a morpholino, piperidino, piperazino, 2-oxo-l-piperidyl and 2-oxo-l-pyrrolidinyl radical, optionally substituted with at least one alkyl containing from 1 to 12 carbon atoms, an alkoxy containing from 1 to 7 carbon atoms, an aryl radical, a nitro function, a polyether radical, a heteroaryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl optionally protected with an acetyl or benzoyl group or an amino function optionally protected with an acetyl or benzoyl group or optionally substituted with at least one alkyl containing from 1 to 12 carbon atoms.
    . 25 12. Compounds according to Claim 1, characterized in that they are taken, alone or as mixtures, from the group consisting of:
    l. methyl 2=[3"-({[6~(2-methoxyethoxymethoxy) — : naphthalene-2-carbonyllmethylamino}methyl)biphenyl- 4-ylaminolbenzoate
    ) 2. 2=[3"~({ [6- (2-methoxyethoxymethoxy)naphthalene-2- carbonyl]methylamino}methyl)biphenyl-4-ylamino]- benzoic acid
    3. N-{4’-[2-(2,5-difluorobenzylcarbamoyl)phenylamino] - biphenyl-3-ylmethyl}-N-methyl-6- (2-methoxy—- ethoxymethoxy) naphthalene-2-carboxylamide 4, N-{4’-[2- (benzylmethylcarbamoyl)phenylamino] - biphenyl-3-ylmethyl)}-N-methyl-6-(2-methoxy— ethoxymethoxy)naphthalene-2-carboxylamide
    5. methyl 2={3"~[ (methyloctanoylamino)methyl}- biphenyl-4-ylamino}benzoate
    6. 2={3’-[(methyloctanoylamino)methyl]biphenyl-4- ylamino}benzoic acid
    7. methyl 2=(methyl-{3’-[ (methyloctanoylamino)- methyllbiphenyl-4-yl}amino)benzoate
    8. 2-(methyl-{3’~[ (methyloctanoylamino)methyl]- biphenyl-4-yl}amino)benzoic acid
    9. N= (3-methylbutyl)-2-{3’~[ (methyloctanoylamino) - methyl]biphenyl-4-ylamino}benzamide
    10. N-methyl-N-{4’~[2-(5-propyl[1, 3, 4]oxadiazol-2-yl)- phenylamino]biphenyl-3-ylmethyl}octanoylamide } 25 11. N-methyl-N-{4’~[2- (1H-tetrazol-5-yl)phenylamino]- biphenyl-3-ylmethyl}octanoylamide
    12. ethyl 3-13" ({[6-(2-methoxyethoxymethoxy) — : naphthalene-2-carbonyl]methylamino}methyl) — biphenyl-4-ylamino]benzoate
    13. 3-[3"-({[6- (2-methoxyethoxymethoxy) naphthalene-2- carbonyl]methylamino}methyl)biphenyl-4-ylamino] - benzoic acid
    14. ethyl 3-(3"-{[(6-hydroxynaphthalene-2-carbonyl) - methylaminolmethyl}biphenyl-4-ylamino)benzoate
    15. 3-(3"-{[(6-hydroxynaphthalene-2-carbonyl) methyl - amino]methyl}biphenyl-4-ylamino)benzoic acid
    16. N-methyl-N-{4’-[3-(4-methylpiperidine-1- carbonyl) phenylaminolbiphenyl-3-ylmethyl}-6- (2- methoxyethoxymethoxy)naphthalene-2-carboxylamide
    17. N-methyl-N-{4’-[3- (morpholine-4-carbonyl)- phenylamino]biphenyl-3-ylmethyl}-6~(2-methoxy- ethoxymethoxy) naphthalene-2-carboxylamide
    18. N-methyl-N-{4’~[3-(4-methylpiperidine-1l-carbonyl)- phenylamino]-biphenyl-3-ylmethyl}-6-hydroxy- naphthalene-2-carboxylamide
    19. N-methyl-N-{4’-[3- (morpholine-4-carbonyl)- phenylamino]lbiphenyl-3-ylmethyl}-6-hydroxy- naphthalene-2-carboxylamide
    20. 3-{3'-[(methyloctanoylamino)methyl]biphenyl-4- ylaminol}benzoic acid } 25 21. ethyl 2-{3"~[(methyloctanoylamino)methyl]biphenyl- 4-yloxyl}benzoate
    22. 2-{3'~[(methyloctanoylamino)methyl]biphenyl-4~ ’ yloxylbenzoic acid
    23. 2-[3"-(1-methyl-3-naphth-2-ylureido)biphenyl-4- ylaminolbenzoic acid
    24. 2-{[3"-(3-heptyl-1l-methylureido)biphenyl-4-y1]- methylamino}benzoic acid
    25. 2-(3"-{ [methyl (quinoxaline-6-carbonyl) amino] - methyl }biphenyl-4-ylamino)benzoic acid
    26. 2-(3"-{[(2-1H-benzoimidazol-2-ylacetyl)methyl- amino]methyl}biphenyl-4-ylamino)benzoic acid
    27. 2-[3"-(1-methyl-3-thiophen-3-ylureido) biphenyl-4- ylamino]lbenzoic acid
    28. 2-[3"-(3-benzo([1,2,5]thiadiazol-5-yl-1-methyl- ureidobiphenyl-4-ylaminolbenzoic acid
    29. l-methyl-1-{4’-[3- (morpholine-4-carbonyl)- phenylamino]biphenyl-3-yl}-3-naphth-2-ylurea
    30. N-methyl-3-[3’-(1l-methyl-3-naphth-2-ylureido)- biphenyl-4-ylamino}-N-phenethylbenzamide
    31. 3-{methyl-[3’~ (l-methyl-3-naphth-2-ylureido)- biphenyl-4-yl]amino}benzoic acid
    32. isobutyl 3-(3’-{ [methyl (quinoxaline-6- carbonyl) amino]methyl}biphenyl-4-ylamino)benzoate
    33. 3-[3"-({[6-(2-methoxyethoxymethoxy)naphthalene-2- ’ carbonyl]methylamino}methyl)biphenyl-4-ylmethyl]- . 25 benzoic acid
    34. 2-{3’-[3-(4-dimethylaminophenyl) -1-methylureido] - biphenyl-4-ylsulphanyl}benzoic acid
    35. 2-[3"-(3-benzo[1,2,5]thiadiazol-5-yl-1-methyl- ’ ureido)biphenyl-4-yloxylbenzoic acid
    36. 2-morpholin-4-ylethyl 3-(3’ ~{ [methyl (quinoxaline-6- carbonyl) amino]methyl}biphenyl-4-yloxy)benzoate
    37. N-{4'-[3-(2-dimethylaminoethylcarbamoyl) phenoxy] ~ biphenyl-3-ylmethyl)-N-methyl-6- (2-methoxyethoxy- methoxy) naphthalene-2-carboxylamide
    38. 3-[3"-({[6- (2-methoxyethoxymethoxy)naphthalene-2- carbonyl]amino}methyl)biphenyl-4-ylamino]benzoic acid
    39. 3-{3"-[6-(2-methoxyethoxymethoxy) naphth-2- yloxycarbonylmethyl]biphenyl-4-ylamino}benzoic acid
    40. 2-[3"-(3-heptyl-l-methylureido)biphenyl-4-ylamino]- benzoic acid
    41. 3-heptyl-l-methyl-1-{4’-[2- (morpholine-4-carbonyl)- phenylaminolbiphenyl-3-yl}-urea
    42. 3~heptyl-l-methyl-1-(4’-{methyl-[2- (morpholine-4- carbonyl)phenyl]amino}biphenyl-3-yl)urea 43, 3-heptyl-l1-methyl-1-(4’-{methyl-[2-(4-methyl- piperidine-l-carbonyl)phenyl]amino}biphenyl-3-yl1)- urea
    44. 3-heptyl-l-methyl-1-{4'-[2-(4-methylpiperidine-1- carbonyl) phenylamino]biphenyl-3-yl}urea 45, 2-[3"-(3-heptyl-l-methylureido)biphenyl-4-yl- . 25 sulphanyl]benzoic acid
    46. 2-[3"-(3-heptyl-l-methylureido)biphenyl-4-yl— methyl]benzoic acid
    47. 2-[3"~(1l-methyl-3-pentylureido)biphenyl-4-ylamino] - : benzoic acid
    48. 1-methyl-1-{4'-[2-(morpholine-4-carbonyl) - phenylamino]biphenyl-3-yl}-3-pentylurea
    49. 2-[3"-(3-heptyl-l-methylthioureido)biphenyl-4- ylamino]benzoic acid
    50. 3-heptyl-l-methyl-1-{4’-[2~(5-propyl[1,3,4]- oxadiazol-2-yl)phenylamino]biphenyl-3-y1}urea
    51. 3-heptyl-l-methyl-1-{4’-[2-(1H-tetrazol-5-yl)- phenylamino]biphenyl-3-yl}urea
    52. 2-{3’-[ (hexanoylmethylamino) methyl ]biphenyl-4- ylaminol}benzoic acid
    53. N-methyl-N-{4’-[2-(morpholine-4-carbonyl)- phenylamino]biphenyl-3-ylmethyl}hexanoylamide
    54. 2=(3’-{ [methyl- (5-oxohexanoyl) amino]methyl } - biphenyl-4-ylamino)benzoic acid
    55. 2=(3"-{[methyl- (4-methylaminobutyryl) amino]methyl }- biphenyl-4-ylamino)benzoic acid
    56. 2-[3"-({[3-(N",N’ ~dimethylhydrazinocarbonyl) - propionyljmethylamino)methyl)biphenyl-4-ylamino]- benzoic acid
    57. 2-[3"-(3-heptyl-l-methylureido)biphenyl-4-ylamino]- N-hydroxybenzamide ’ 58. 2~[3-fluoro-3’-(3-heptyl-l-methylureido)biphenyl-4- ] 25 ylamino] benzoic acid
    59. 2-[3-fluoro-3’-(l-methyl-3-pentylureido)biphenyl -4-~ ylamino]benzoic acid
    60. 2-[2-fluoro-3'-(l-methyl-3-pentylureido)biphenyl-4- - ylamino]benzoic acid
    61. 2-[2-fluoro-3’- (3-heptyl-l-methylureido)biphenyl-4- i ylaminolbenzoic acid
    62. N-methyl-N-{4’-[3-(2-piperidin-1-ylethyl- carbamoyl)phenylamino]biphenyl-3-ylmethyl}-6- (2 methoxyethoxymethoxy)naphthalene-2-carboxylamide
    63. N-methyl-N-{4’-[3~(2-morpholin-4-ylethyl- carbamoyl)phenylamino]biphenyl-3-ylmethyl}-6- (2—- methoxyethoxymethoxy)naphthalene-2-carboxylic acid amide
    64. N-methyl-N-{4’-[2-(morpholine-4-carbonyl)- phenylamino]biphenyl-3~ylmethyl}-6-(2-methoxy- ethoxymethoxy) naphthalene-2-carboxylic acid amide
    65. N-methyl-N-{4’-[2-(4-methylpiperidine-1-carbonyl) - phenylaminolbiphenyl-3~ylmethyl}-6- (2-methoxy- ethoxymethoxy)naphthalene-2-carboxylamide
    66. 2-(3"-{[(6-hydroxynaphthalene-2-carbonyl)methyl- amino]methyl }biphenyl-4-ylamino)benzoic acid
    67. 2-[3"-(3-hexyl-1-methylthioureido)biphenyl-4- ylamino]benzoic acid
    68. 2-{3'~[(methyloctanethioylamino)methyl]biphenyl-4- ylamino}benzoic acid ’ 69. 2-{4'-fluoro-3’-[ (methyloctanoylamino)methyl]- biphenyl-4-ylamino}benzoic acid
    70. 2-{2’-fluoro-5'-[ (methyloctanoylamino)methyl]- biphenyl-4-ylamino}benzoic acid
    71. 3-heptyl-l-methyl-1-{4’-[2-(pyrazole-l-carbonyl)- : phenylamino]biphenyl-3-yl})urea
    72. 2-(3’-{[methyl-(1,4,5, 6~tetrahydrocyclopenta- pyrazole-3-carbonyl)aminolmethyl }biphenyl-4- ylamino)benzoic acid
    73. 2-(3"-{[methyl-(2-methylthiazolidine-4— carbonyl) amino]lmethyl}biphenyl-4-ylamino)benzoic acid
    74. 2-[3"-({methyl-[2- (3-methylbenzoylamino)acetyl]- aminolmethyl)biphenyl-4-ylaminolbenzoic acid
    75. 2-(3' -{ [methyl- (3-phenylpropionyl) amino]methyl} - biphenyl-4~ylamino)benzoic acid
    76. 2-{3’-[(methyloctanoylamino)methyl]biphenyl-4~- ylamino}-N-(2-morpholin-4-ylethyl)benzamide
    77. 2=(3"-{[(9H-fluoren-9-ylmethoxycarbonyl)methyl- amino]methyl}biphenyl-4-ylamino)benzoic acid
    78. N-methyl-N-{4’-[2-(4-methylimidazole-l-carbonyl)- phenylamino]biphenyl-3-ylmethyl}octanoylcarboxyl- amide
    79. 1-14" -(2-benzoylphenylamino)biphenyl-3-y1]}-3- heptyl-1-methylurea
    80. 2-[3"-(3-heptyl-l-methylureido)biphenyl-4-ylamino]- N-methyl-N-piperidin-1-ylbenzamide
    81. 2-[3’-(3-heptyl-l-methylureido)biphenyl-4~ylamino]- ; 25 N-methyl-N-phenylbenzamide
    13. Compounds according to Claim 1 or 2, g characterized in that they have at least one of the following characteristics: - R; represents a radical of formula (b), in which Rs is preferably a hydroxyl group, a heterocyclic radical or NR’R”; - A represents a bond of structure -CH,N (Rig) - CO- or —-N(Rjp)~CO-(D)r- with r = 0 or 1; - R3 represents an alkyl, aryl or heteroaryl radical; - X represents an oxygen atom or a radical NR, in which Rg is preferably a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms.
    14. Cosmetic composition, characterized in that it comprises, in a physiologically acceptable support, at least one compound as defined in any one of Claims 1 to 13.
    15. Composition according to Claim 14, characterized in that the concentration of compound (s) according to one of Claims 1 to 13 is between 0.001% and 3% by weight relative to the total weight of the composition.
    16. Cosmetic use of a composition as defined ; 25 in either of Claims 14 and 15, for body or hair hygiene.
    17. Compounds according to any one of Claims . 1 to 13, as medicinal products.
    18. Use of a compound according to any one of Claims 1 to 13 in the manufacture of a composition for regulating and/or restoring the metabolism of skin lipids.
    19. Use of a compound according to any one of Claims 1 to 13 in the manufacture of a composition for treating: - dermatological complaints associated with a keratinization disorder relating to differentiation and to proliferation, in particular common acne, comedones, polymorphs, rosacea, nodulocystic acne, acne conglobata, senile acne and secondary acne such as solar, medicinal or occupational acne, - ichthyosis, ichthyosiform conditions, Darier’s disease, palmoplantar keratoderma, leukoplakia and leukoplakiform conditions, and cutaneous Or mucous (oral) lichen, ~ dermatological complaints with an inflammatory immuno-allergic component, with or without a cellular proliferation disorder, and in particular cutaneous, mucous or ungual psoriasis, psoriatic arthritis, or ’ cutaneous atopy such as eczema, respiratory atopy or
    . 25 gingival hypertrophy, - dermal or epidermal proliferations, whether benign or malignant, whether or not of viral origin, in particular common warts, flat warts and
    ‘ epidermodysplasia verruciformis, oral or florid papillomatoses, T lymphoma, - proliferations which may be induced by ultraviolet light, in particular basal cell and spinocellular epithelioma, ~— Pbrecancerous skin lesions, in particular keratoacanthomas, - immune dermatitides, in particular lupus erythematosus,
    - bullous immune diseases, —- collagen diseases, in particular scleroderma, —- dermatological or systemic complaints with an immunological component,
    - skin disorders due to exposure to UV radiation, light-induced or chronological ageing of the skin, actinic pigmentations and keratoses, or any pathology associated with chronological or actinic ageing, in particular xerosis,
    - sebaceous function disorders, in particular the hyperseborrhoea of acne, simple seborrhoea or seborrhoeic dermatitis,
    - cicatrization disorders or stretch marks, g - pigmentation disorders, such as hyperpigmentation, . 25 melasma, hypopigmentation or vitiligo,
    ~ lipid metabolism complaints, such as obesity, y hyperlipidaemia, non-insulin-dependent diabetes or syndrome X, — inflammatory complaints such as arthritis, S - cancerous or precancerous conditions, ~ alopecia of various origins, in particular alopecia caused by chemotherapy or radiation, — immune system disorders, such as asthma, type I sugar diabetes, multiple sclerosis or other selective dysfunctions of the immune system, or — complaints of the cardiovascular system, such as arteriosclerosis or hypertension.
    20. Pharmaceutical composition, characterized in that it comprises, in a physiologically acceptable support, at least one of the compounds as defined in any one of Claims 1 to 13.
    21. Composition according to Claim 20, 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.
    22. Composition according to Claim 20, characterized in that the concentration of compound (s) ’ according to one of Claims 1 to 13 is between 0.01% and . 25 1% by weight relative to the total weight of the composition.
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FR2862870A1 (en) * 2003-12-01 2005-06-03 Galderma Res & Dev USE OF PPAR RECEPTOR ACTIVATORS IN COSMETICS AND DERMATOLOGY.
KR20070047308A (en) * 2004-08-17 2007-05-04 갈데르마 리써어치 앤드 디벨로프먼트 Novel biaromatic compounds that activate ppar type receptors, and use thereof in cosmetic or pharmaceutical compositions
FR2878247B1 (en) * 2004-11-19 2008-10-03 Galderma Res & Dev NOVEL MODULATING COMPOUNDS OF PPARY RECEPTORS AND THEIR USE IN COSMETIC OR PHARMACEUTICAL COMPOSITIONS
CA2587545C (en) * 2004-11-19 2013-10-22 Galderma Research & Development, S.N.C. Novel compounds that modulate ppar.gamma. type receptors, and use thereof in cosmetic or pharmaceutical compositions
CN101330902A (en) * 2005-12-13 2008-12-24 宝洁公司 Personal care compositions comprising PPAR GAMMA antagonists
CN104611645B (en) * 2014-12-29 2018-09-21 芜湖金龙模具锻造有限责任公司 A kind of high-temperature alloy mould steel

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