Ligand activators of the RAR receptors and pharmaceutical/cosmetic applications thereof

1. A compound having the following structural formula:

in which:

Ar is a radical selected from among the radicals of formulae (a) to (c) below:

wherein R 1 is a radical —OR 3 or —NR 4 R 5 and R 3 , R 4 and R 5 are as defined below,

wherein R 2 is a hydrogen, fluorine or chlorine atom, a methyl radical or a radical OR 6 and R 6 is as defined below;

R 3 is a hydrogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, a mono- or polyhydroxyalkyl radical having from 1 to 20 carbon atoms, a monoaminoalkyl radical having from 1 to 20 carbon atoms, or a sugar residue;

R 4 and R 5 , which may be identical or different, are each a hydrogen atom, a hydroxyl radical, a linear or branched alkyl radical having from 1 to 6 carbon atoms, a mono- or polyhydroxyalkyl radical having from 1 to 20 carbon atoms, or R 4 and R 5 together form, with the nitrogen atom from which they depend, an amino acid residue or a peptide residue, or, alternatively, R 4 and R 5 together form with said nitrogen atom a heterocycle;

R 6 is a hydrogen atom, a methyl radical or an acetyl radical;

R 7 is CF 3 or a methyl radical;

r′ and r″, which may be identical or different, are each a hydrogen atom, a linear, branched or cyclic alkyl radical having from 1 to 4 carbon atoms, or a radical (C═O)R 7 , or, alternatively, r′ and r″ with the nitrogen atom from which they depend, together form a pyrrolidine or piperidine;

A is an oxygen atom or a sulfur atom;

n is an integer ranging from 1 and 4;

W is a —CH 2 — radical;

Y is an oxygen atom or a sulfur atom;

or a salt of the compound of formula (I) when R 1 ═OH, or an optical or geometrical isomer of the compound of formula (I).

2. The compound as defined by claim 1 , wherein formula (I), Ar is a radical a).

3. The compound as defined by claim 1 , wherein formula (I), Ar is a radical b).

4. The compound as defined by claim 1 , wherein formula (I), Ar is a radical c).

5. The compound as defined by claim 1 , wherein formula (I), A is oxygen.

6. An alkali metal or alkaline-earth metal, zinc or organic amine salt of the compound as defined by claim 1 .

7. The compound as defined by claim 1 , wherein at least one of R 4 and R 5 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, i-butyl, t-butyl, n-pentyl and n-hexyl radicals.

8. The compound as defined by claim 1 , wherein R 3 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals.

9. The compound as defined by claim 1 , bearing at least one substituent selected from the group consisting of 2-hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl radicals.

10. The compound as defined by claim 1 , bearing at least one substituent selected from the group consisting of 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl and 2,3,4,5-tetrahydroxypentyl radicals, or a pentaerythritol residue.

11. The compound as defined by claim 1 , bearing at least one substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, i-butyl and t-butyl radicals.

12. The compound as defined by claim 1 , bearing at least one substituent selected from the group consisting of residues derived from glucose, galactose, mannose and glucuronic acid.

13. The compound as defined by claim 1 , bearing at least one substituent selected from the group consisting of residues derived from lysine, glycine and aspartic acid.

14. The compound as defined by claim 1 , bearing at least one substituent selected from the group consisting of dipeptide and tripeptide residues resulting from the combination of amino acids.

15. The compound as defined by claim 1 , wherein at least one of the following conditions is satisfied:

Ar is a radical (a),

A is an oxygen atom,

R 1 is a radical OR 3 .

16. The compound as defined by claim 1 , selected from the group consisting of:

1. 4′-(4-Isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

2. 4′-(4-Ethylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

3. 4′-(4-Propylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

4. 4′-[4-(Isopropylmethylamino)butoxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

5. 4′-(4-Diethylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

6. 4′-(4-Acetylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

7. 4′-[4-(Acetylethylamino)butoxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

8. 4′-[4-(Acetylisopropylamino)butoxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

9. 4′-(4-Acetylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

10. 4′-(4-Pyrrolidin-1-ylbutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

11. 4′-(4-Isopropylaminobutylsulfanyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

12. 4′-(2-Isopropylaminoethoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

13. 4′-(3-Isopropylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

14. 4′-(5-Isopropylaminopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

15. 4′-(5-Ethylaminopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

16. Ethyl 4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

17. Propyl 4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

18. Isopropyl 4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

19. 2,3-Dihydroxypropyl 4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

20. 3-Aminopropyl 4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

21. 6-Glucosyl 4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

22. 6-Mannosyl 4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

23. Ethyl 4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxamide;

24. Diethyl 4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxamide;

25. [4′-(4-Isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-yl]pyrrolidin-1-ylmethanone;

26. {[4′-(4-Isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carbonyl]amino}acetic acid;

27. 3-Hydroxy-2-{[4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carbonyl]amino}propionic acid;

28. 3-Fluoro-4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

29. 3-Chloro-4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

30. 3-Chloro-4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

31. 3-Hydroxy-4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

32. 4′-(4-Isopropylaminobutoxy)-3-methoxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

33. 3-Acetoxy-4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

34. 2-Fluoro-4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

35. 2-Chloro-4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

36. 2-Hydroxy-4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

37. 6-[4-(4-Isopropylaminobutoxy)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)phenyl]nicotinic acid;

38. 5-[4-(4-Isopropylaminobutoxy)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)phenyl]pyridine-2-carboxylic acid;

39. 5-[4-(4-Isopropylaminobutoxy)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)phenyl]thiophene-2-carboxylic acid;

40. 5-[4-(4-Isopropylaminobutoxy)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)phenyl]furan-2-carboxylic acid;

41. 4-[4-(4-isopropylaminobutoxy)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)phenyl]furan-2-carboxylic acid;

42. 4-[4-(4-Isopropylaminobutoxy)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)phenyl]thiophene-2-carboxylic acid;

43. 5-[4-(4-Isopropylaminobutoxy)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)phenyl]thiophene-3-carboxylic acid;

44. 5-[4-(4-Isopropylaminobutoxy)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)phenyl]furan-3-carboxylic acid;

45. 4′-(4-Ethylaminobutoxy)-3-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

46. 3-Hydroxy-4′-(4-propylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

47. 3-Hydroxy-4′-(3-propylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

48. 4′-(4-Piperidin-1-ylbutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

49. Ethyl 4′-(3-isopropylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

50. Ethyl 4′-(3-cyclopropylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

51. 4′-(3-Cyclopropylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

52. Ethyl 4′-(3-butylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

53. 4′-(3-Butylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

54. Ethyl 4′-(3-dimethylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

55. 4′-(3-Dimethylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

56. Ethyl 4′-(3-propylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

57. 4′-(3-Propylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

58. Ethyl 4′-(4-cyclopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

59. 4′-(4-Cyclopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

60. Ethyl 4′-(3-methylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

61. 4′-(3-Methylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

62. Ethyl 4′-(3-ethylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

63. 4′-(3-Ethylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

64. Ethyl 4′-(3-aminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

65. 4′-(3-Aminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

66. Ethyl 4′-(2-cyclopropylaminoethoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

67. 4′-(2-Cyclopropylaminoethoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

68. Ethyl 4′-(5-cyclopropylaminopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

69. 4′-(5-Cyclopropylaminopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

70. Ethyl 4′-(2-isopropylaminoethoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

71. Ethyl 4′-(5-ethylaminopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

72. Ethyl 4′-(5-aminopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate;

73. 4′-(5-Aminopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid;

74. Ethyl 4′-(4-aminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate; and

75. 4′-(4-Aminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid.

17. A pharmaceutical composition useful for activating RAR receptors, comprising a thus effective amount of at least one ligand compound as defined by claim 1 , formulated into a physiologically acceptable medium therefor.

18. The pharmaceutical composition as defined by claim 17 , said at least one ligand compound comprising from 0.001% to 10% by weight thereof.

19. The pharmaceutical composition as defined by claim 17 , said at least one ligand compound comprising from 0.01% to 1% by weight thereof.

20. A compound having a structure 4′-(4-Isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid.