Pharmaceutical/cosmetic compositions comprising novel ligands that activate RAR receptors

1. A compound having the following structural formula (I):

in which:

R1 is an —OH radical, a radical OR7 or a radical —NR8R9, wherein R7, R8 and R9 are as defined below;

R2 is a hydrogen atom, a fluorine atom, a chlorine atom, an alkyl radical having 1 to 3 carbon atoms, an —OH radical or a radical —OR10, wherein R10 is as defined below;

R3 is a hydrogen atom, a methyl radical, an ethyl radical, an isopropyl radical, a tert-butyl radical or a —CF3 radical;

R4 is a hydrogen atom, a fluorine atom, a chlorine atom, a radical —OR11, a methyl radical, an ethyl radical, an isopropyl radical, a tert-butyl radical or a —CF3 radical, wherein R11 is as defined below;

R5 and R6, which may be identical or different, are each a hydrogen atom, a methyl radical, an ethyl radical, an n-propyl radical, an isopropyl radical, a tert-butyl radical, a radical —COR12 or may together form, with the nitrogen atom from which they depend, a piperidine, pyrrolidine, morpholine, pyrrolidin-2-one or piperid-2-one heterocycle, which may be unsubstituted or substituted with one or more methyl, ethyl, fluorine or chlorine groups, wherein R12 is as defined below;

Q is an —OH radical, a radical —OR13, a radical —NR14R15 or a radical —SO2R16, wherein R13, R14, R15 and R16 are as defined below;

is a divalent radical having the following structure:

wherein R17 is as defined below;

R7 is a linear or branched alkyl radical having from 1 to 20 carbon atoms, an alkenyl radical, a monohydroxyalkyl radical, a polyhydroxyalkyl radical, an aryl radical, an optionally substituted aralkyl radical or a sugar residue;

R8 and R9, which may be identical or different, are each a hydrogen atom, an —OH radical, an alkyl radical having 1 to 6 carbon atoms, a monohydroxyalkyl radical, a polyhydroxyalkyl radical, an optionally substituted aryl radical, or form with the nitrogen atom from which they depend, an amino acid residue or a peptide residue, or alternatively R8 and R9 may together form, a piperidine, pyrrolidine, morpholine, pyrrolidin-2-one or piperid-2-one heterocycle;

R10 is an alkyl radical having from 1 to 6 carbon atoms;

R11 is an alkyl radical having from 1 to 6 carbon atoms or a mono- or polyether radical;

R12 is an alkyl radical having from 1 to 6 carbon atoms or a radical —OR18, wherein R18 is as defined below;

R13 is a linear or branched alkyl radical having from 1 to 15 carbon atoms;

R14 and R15, which may be identical or different, are each a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms or a radical —COR19, wherein R19 is as defined below;

R16 is an alkyl radical having from 1 to 6 carbon atoms;

R17 is a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms or a —CF3 radical;

R18 is an alkyl radical having from 1 to 6 carbon atoms;

R19 is an alkyl radical having from 1 to 6 carbon atoms; or salt thereof when R 1 is an OH function, or isomer thereof.

2. An alkali or alkaline earth metal, or zinc or organic amine salt of a compound as defined by claim 1 .

3. A compound as defined by claim 1 , comprising at least one alkyl radical substituent having from 1 to 6 carbon atoms and selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, cyclopropyl, isopropyl, n-butyl, i-butyl, t-butyl, n-pentyl and n-hexyl radicals.

4. A compound as defined by claim 1 , comprising at least one alkyl radical substituent having from 1 to 15 carbon atoms and selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, 2-ethylhexyl, octyl and dodecyl radicals.

5. A compound as defined by claim 1 , comprising at least one alkyl radical substituent having from 1 to 20 carbon atoms and selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals.

6. A compound as defined by claim 1 , comprising at least one monohydroxyalkyl radical selected from the group consisting of hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl radicals.

7. A compound as defined by claim 1 , comprising at least one polyhydroxyalkyl radical selected from the group consisting of 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl and 2,3,4,5-tetrahydroxypentyl radicals, or a pentaerythritol residue.

8. A compound as defined by claim 1 , comprising at least one polyether radical selected from the group consisting of methoxymethoxy, methoxyethoxy and methoxyethoxymethoxy radicals.

9. A compound as defined by claim 1 , comprising at least one aryl radical selected from the group consisting of a phenyl radical optionally substituted with at least one halogen, an (a lower) alkyl radical having from 1 to 6 carbon atoms, a hydroxyl, a C 1 -C 3 alkoxy radical, a nitro function, a polyether radical or an amino function optionally protected with an acetyl group or optionally substituted with at least one alkyl radical having from 1 to 6 carbon atoms or an alkoxy radical having from 1 to 6 carbon atoms.

10. A compound as defined by claim 1 , comprising at least one aralkyl radical selected from the group consisting of a benzyl or phenethyl radical optionally substituted with at least one halogen, an alkyl radical having from 1 to 6 carbon atoms, a hydroxyl, an alkoxy radical having from 1 to 3 carbon atoms, a nitro function, a polyether radical or an amino function optionally protected with an acetyl group or optionally substituted with at least one alkyl radical having from 1 to 6 carbon atoms or an alkoxy radical having from 1 to 6 carbon atoms.

11. A compound as defined by claim 1 , comprising at least one alkenyl radical having from 2 to 5 carbon atoms and having one or more sites of ethylenic unsaturation.

12. A compound as defined by claim 1 , comprising at least one sugar residue selected from the group consisting of the residue derived from glucose, galactose or mannose, or from glucuronic acid.

13. A compound as defined by claim 1 , comprising at least one amino acid residue selected from the group consisting of a residue derived from lysine, from glycine or from aspartic acid.

14. A compound as defined by claim 1 , comprising at least one amino acid residue selected from the group consisting of a dipeptide or tripeptide residue resulting from the combination of amino acids.

15. A compound as defined by claim 1 , selected from the group consisting of:

1. 4-[2-(3-tert-Butyl-4-diethylaminophenyl)-2-hydroxyiminoethoxy]benzoic acid;

2. 4-[2-(3-tert-Butyl-4-diethylaminophenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoic acid;

3. 4-[2-(3-tert-Butyl-4-pyrrolidin-1-ylphenyl)-2-hydroxyiminoethoxy]benzoic acid;

4. 4-[2-(3-tert-Butyl-4-pyrrolidin-1-ylphenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoic acid;

5. 4-{2-[4-(Acetylethylamino)-3-tert-butylphenyl]-2-hydroxyiminoethoxy}benzoic acid;

6. 4-{2-[4-(Acetylethylamino)-3-tert-butylphenyl]-2-hydroxyiminoethoxy}-2-hydroxybenzoic acid;

7. Ethyl 4-[2-(3-tert-butyl-4-diethylaminophenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoate;

8. Isopropyl 4-[2-(3-tert-butyl-4-diethylaminophenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoate;

9. Isobutyl 4-[2-(3-tert-butyl-4-diethylaminophenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoate;

10. Octyl 4-[2-(3-tert-butyl-4-diethylaminophenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoate;

11. Dodecyl 4-[2-(3-tert-butyl-4-diethylaminophenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoate;

12. 4-[2-(3-tert-Butyl-4-diethylaminophenyl)-2-hydroxyiminoethoxy]-N-ethyl -2-hydroxy-N-methylbenzamide;

13. 4-[2-(3-tert-Butyl-4-diethylaminophenyl)-2-methoxyiminoethoxy]-2-hydroxybenzonic acid;

14. 4-[2-(3-tert-Butyl-4-diethylaminophenyl)-2-methylhydrazono)ethoxy]-2-hydroxybenzoic acid;

15. 4-[2-(3-tert-Butyl-4-diethylaminophenyl)-2-pentylhydrazono)ethoxy]-2-hydroxybenzoic acid;

16. 4-[2-(3-tert-Butyl-4-diethylaminophenyl)-2-2-methanesulfonyliminoethoxy]-2-hydroxybenzoic acid;

17. 4-[2-(3-tert-Butyl-4-diethylaminophenyl)-2-(pentane-1-sulfonylimino)ethoxy]-2-hydroxybenzoic acid;

18. 4-[2-(3-tert-Butyl-5-chloro-4-diethylaminophenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoic acid;

19. 4-[2-(3-tert-Butyl-4-diethylamino-5-fluorophenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoic acid;

20. 4-[2-(3-tert-Butyl-4-diethylamino-5-trifluoromethylphenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoic acid;

21. 4-[2-(3-tert-Butyl-4-diethylamino-5-methylphenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoic acid;

22. 4-[2-(3-tert-Butyl-4-diethylamino-5-ethylphenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoic acid;

23. 4-{2-[3-tert-Butyl-4-diethylamino-5-(2-ethoxyethoxy)phenyl]-2-hydroxyiminoethoxy}-2-hydroxybenzoic acid;

24. 4-[2-(3-tert-Butyl-4-diethylamino-5-propoxyphenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoic acid;

25. 4-[2-(4-diethylamino-3-isopropylphenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoic acid;

26. 4-[2-(4-diethylamino-3-trifluoromethylphenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoic acid;

27. 4-[2-(4-diethylaminophenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoic acid;

28. 4-{2-[3-tert-Butyl-4-(ethylmethylamino)phenyl]-2-hydroxyiminoethoxy}-2-hydroxybenzoic acid;

29. 4-[2-(3-tert-Butyl-4-dimethylaminophenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoic acid;

30. 4-{2-[3-tert-Butyl-4-(ethylisobutylamino)phenyl]-2-hydroxyiminoethoxy}-2-hydroxybenzoic acid;

31. 4-[2-(3-tert-Butyl-4-morpholin-4-ylphenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoic acid;

32. 4-[2-(3-tert-Butyl-4-piperid-1-ylphenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoic acid;

33. 4-{2-[3-tert-Butyl-4-(2-oxopiperid-1-yl)phenyl]-2-hydroxyiminoethoxy}benzoic acid;

34. 4-{2-[3-tert-Butyl-4-(2-oxopyrrolidin-1-yl)phenyl]-2-hydroxyiminoethoxy}benzoic acid;

35. 4-[2-(3-tert-Butyl-4-ethylaminophenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoic acid;

36. 4-{2-[4-(Ethylpropionylamino)-3-tert-butylphenyl]-2-hydroxyiminoethoxy}-2-hydroxybenzoic acid;

37. 4-{2-[3-tert-Butyl-4-(ethoxycarbonylethylamino)phenyl]-2-hydroxyiminoethoxy}-2-hydroxybenzoic acid;

38. 4-{2-[3-tert-Butyl-4-(ethylmethoxycarbonylamino)phenyl]-2-hydroxyiminoethoxy}-2-hydroxybenzoic acid;

39. 4-{2-[4-(Ethyltrifluoroacetylamino)-3-tert-butylphenyl]-2-hydroxyiminoethoxy}-2-hydroxybenzoic acid;

40. 4-{2-[4-(Trifluoroacetylamino)-3-tert-butylphenyl]-2-hydroxyiminoethoxy}-2-hydroxybenzoic acid; and

41 .4-{2-[3-tert-Butyl-4-(ethylisopropylamino)phenyl]-2-hydroxyiminoethoxy}-2-hydroxybenzoic acid.

16. A compound as defined by claim 1 , wherein:

R1 is a radical —OR7;

R2 is a hydrogen or —OH;

R5 and R6, which may be identical or different, are each a methyl radical or an ethyl radical, or together form with the nitrogen atom from which they depend, a pyrrolidine heterocycle;

Q is a radical —OR13.

17. A pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound (I) as defined by claim 1 , formulated into a physiologically acceptable support therefor.

18. The pharmaceutical composition as defined by claim 17 , comprising from 0.001% to 10% by weight of said at least one compound (I).

19. The pharmaceutical composition as defined by claim 17 , comprising from 0.01% to 1% by weight of said at least one compound (I).

20. A cosmetic composition comprising a cosmetically effective amount of at least one compound (I) as defined by claim 1 , formulated into a physiologically acceptable support therefor.

21. The cosmetic composition as defined by claim 20 , comprising from 0.001% to 3% by weight of said at least one compound (I).