PL209011B1 - Analogues of vitamin d - Google Patents

Abstract

Vitamin D analogs (I), their optical and geometric isomers and salts are new. Vitamin D analogs of formula (I), their optical and geometric isomers and salts are new. A-Q = unsubstituted alkyne or alkene bond, -CH2-O- bond, -CH2-S- bond or -CH2-CH2- bond; B-T = A-Q or -CH2-NR6- bond; R3 = E or -CF2R5; E = linear or branched 1-5C alkyl; R1 and R2 = H or R3; R5 = F, H or CF3; R7 and R8 = H or G; G = linear or branched 1-6C alkyl; R4 = R7 or -CF2R5; R4+R4 = J, or a saturated heterocycle (preferably pyrrolidine, piperidine (both substituted on N by R7) furan or pyran); j = a saturated 4-7C ring; and R6 = R7 or -C(O)R8. Independent claims are included for the following: (1) a pharmaceutical composition comprising at least one (I) (0.001 - 5) wt.% and a carrier; and (2) a cosmetic composition comprising at least one (I) (0.001 - 3) wt.% and a carrier.

Description

Description of the invention

The present invention relates to novel bio-aromatic compounds which are vitamin D analogues, their use in medicine, pharmaceutical and cosmetic compositions containing these compounds and their cosmetic use.

The invention also discloses a method of their preparation and their use in pharmaceutical compositions intended for use in human and veterinary medicine or, optionally, in cosmetic compositions.

The novel family of compounds according to the invention comprises compounds which have significant activity in the field of cell differentiation and proliferation and find application more particularly in the local and systemic treatment of dermatological (or similar) diseases associated with keratinization disorders, diseases with an inflammatory and / or immunoallergic factor, and excessive tissue hyperplasia. of ectodermal origin (skin, epidermis, and the like) which is benign or malignant. The compounds can also be used to combat skin aging induced by light or the passage of time and for the treatment of scarring disorders.

The compounds according to the invention can also be used in cosmetic compositions for body and hair hygiene.

Vitamin D is an essential vitamin in the prevention and treatment of a lack of cartilage (rickets) and bone mineralization (osteomalacia) and even in some forms of osteoporosis in elderly patients. However, its functions are now believed to extend far beyond the regulation of bone metabolism and calcium homeostasis. These include its action on cell proliferation and differentiation, and the control of immune defense. Their discovery opened the way to a new therapeutic approach in dermatology, oncology, as well as in the field of autoimmune diseases and the field of organ and tissue transplantation.

The toxicity of this vitamin (hypercalcemia, sometimes fatal) has long hindered its effective treatment. Structural analogues of vitamin D are currently being synthesized, some of which retain only the differentiation properties and have no effect on calcium metabolism.

Patent application WO 00/10958 describes non-secosteroid biaromatic compounds mimicking vitamin D3, which are ligands for the VDR receptor. These compounds find use in the treatment of diseases related to dysregulated calcium metabolism. However, the overall structure of these compounds is substantially different from that of the compounds of our invention; in fact, the two aromatic rings of the compounds described in WO 00/10958 are linked to each other via a carbon atom, while in the compounds of our invention two aromatic rings are linked by a chain containing three atoms.

Similarly, patent application WO 00/26167 and WO 01/38320 propose bicyclic compounds which are analogues of vitamin D and patent application WO 01/38303 describes triaromatic compounds which are also analogs of vitamin D. These three families of compounds show, here also, chemical structures completely different from the structure of the compounds of the present invention.

The Applicant has therefore identified a new family of vitamin D analog compounds that exhibit remarkable biological activity, particularly in assays for HL60 cell differentiation activity and for human keratinocyte proliferation and assays for VDR agonist activity.

The invention relates to bi-aromatic vitamin D analog compounds selected singly or in admixture from the group consisting of:

1- {4- [3- (3,4-Bis-hydroxymethyl-phenyl) propyl] -2-ethyl-phenoxy} -3,3-dimethyl-butan-2-ol;

1- {4- [3- (3,4-Bis-hydroxymethyl-phenyl) propyl] -2-methyl-phenoxy} -3,3-dimethyl-butan-2-ol;

(4- {3- [3-ethyl-4- (2-ethyl-2-hydroxybutoxy) phenyl] propyl} -2-hydroxymethylphenyl) methanol;

(4- {3- [4- (2-ethyl-2-hydroxy-butoxy) -3-methyl-phenyl] propyl} -2-hydroxymethyl-phenyl) methanol.

The invention also relates to the above compounds for use as a medicament, and the use of one or more of these compounds for the preparation of a pharmaceutical composition for the treatment of:

- dermatological diseases related to disorders of the differentiation or proliferation of keratinocytes or sebaceous cells;

- keratinization disorders;

- dermatological diseases related to keratinization disorders with an inflammatory and / or immunoallergic component;

- inflammatory diseases, showing no disorders of keratinization;

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- skin or epidermal proliferation;

- dermatological disorders such as follicular dermatoses and collagen diseases;

- signs of skin aging, whether caused by light or time, or to reduce pigmentation and radiation-induced hyperkeratosis, or any skin pathology associated with aging due to elapsed time or radiation;

- scarring and stretch marks disorders;

- disorders of the vaginal function such as excessive acne epithelial pain, vaginal epithelial or epithelial eczema;

- dermatological diseases with an immunological component.

Preferably, the use of these compounds for the preparation of a pharmaceutical composition relates to the treatment of dermatological diseases associated with disorders of the differentiation or proliferation of keratinocytes or sebaceous cells, including acne vulgaris, acne of the comedone type, polymorphic acne, rosacea, nodular cystic acne, concentrated acne, acne secondary acne, acne secondary acne. solar, drug or occupational, or preferably alternatively relate to keratinization disorders including ichthyosis, ichthyosis, Darier's disease, palmar plantar keratosis, white keratosis and white keratosis-like conditions, skin or mucosa (oral) lichen, or preferably alternatively, they relate to dermatological conditions associated with keratinization disorders with an inflammatory and / or immunoallergic component, including all forms of skin, mucosa or nail psoriasis, psoriatic rheumatism and skin atopy such as eczema or respiratory atopy , or else gingival hyperplasia, or preferably relates to skin or epidermal proliferation, which can be benign or malignant, and is of viral or non-viral origin, such as common warts, flat warts and wart-like epidermal dysplasia, oral or red papillomatosis, or proliferation which they can be caused by ultraviolet rays, especially in the case of basal and squamous cell epithelioma.

The invention also relates to a pharmaceutical composition, characterized in that it comprises on a pharmaceutically acceptable support at least one of the compounds defined above, preferably the composition comprises a concentration of the above compound (s) of 0.001-5% by weight relative to the total weight of the composition.

The invention also relates to a cosmetic composition, characterized in that it comprises on a cosmetically acceptable base at least one of the compounds defined above, preferably such composition comprises a concentration of the above compound (s) of 0.001-3% by weight relative to the total weight of the composition.

A further object of the invention relates to the cosmetic use of a composition as defined above for body or hair hygiene, and the cosmetic use of the above cosmetic composition to prevent and / or combat skin aging induced by light or time.

The compounds of the invention belong to a wider group of compounds of the following general formula (I):

wherein:

- A-Q is an unsubstituted alkyne or alkene bond, a -CH2-O-, -CH2-S- or -CH2-CH2 bond;

- B-T is an unsubstituted alkyne or alkene bond, a -CH2-S-, -CH2-O-, CH2-CH2- or -CH2-NR5- bond;

PL 209 011 B1 wherein R6 is as defined below,

- R1 and R2, which may be identical or different, represent a hydrogen atom, a linear or branched alkyl group containing 1-5 carbon atoms or the group -CF2R5;

R3 represents a linear or branched alkyl group containing 1-5 carbon atoms or a CF2R5 group; where R5 has the meaning given below,

- the R4 groups, identical or different, represent a hydrogen atom, a linear or branched alkyl group containing 1-6 carbon atoms, a -CF2R5 group, both groups may also form a saturated ring containing 4-7 carbon atoms, a saturated heterocyclic ring, such as furan, pyran, pyrrolidine substituted on the nitrogen atom with R7 or piperidine substituted on the nitrogen atom with R7;

where R7 has the meaning given below,

- R5 represents a fluoro atom, a hydrogen atom or a α-CF3 group;

- R6 represents a hydrogen atom, a linear or branched alkyl group containing 1-6 carbon atoms or a group -C (O) R8; with the meanings given below,

- R7 and R8, which may be identical or different, represent a hydrogen atom or a linear or branched alkyl group containing 1-6 carbon atoms and their optical and geometric isomers, and their salts.

In the case of the nitrogen-containing compounds described above, the compounds may take the form of cosmetically or pharmaceutically acceptable salts, such as salts of inorganic and organic acids, in particular hydrochloric, sulfuric, acetic, fumaric, hemisuccinic, maleic and mandelic acids.

The expression, linear or branched alkyl group containing 1-5 carbon atoms is preferably understood to mean methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 1-methylbutyl, 3- methylbutyl or 2,2-dimethylbutyl.

The expression, linear or branched alkyl group having 1-6 carbon atoms is preferably understood to mean methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 1-methylbutyl, 3- methylbutyl, 2,2-dimethylpropyl, n-hexyl, 4-methylpentyl or 3,3-methylbutyl.

The expression, a saturated ring containing 4-7 carbon atoms is understood to mean cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Among the compounds of formula (I), the following compounds may also be mentioned:

1. (2-Hydroxymethyl-4- {3- [4- (2-hydroxy-3-methylbutoxy) -3-methylphenyl] propyl) phenyl) methanol;

2. (4- {3- [3-ethyl-4- (2-hydroxy-3-methylbutoxy) phenyl] propyl} -2-hydroxymethylphenyl) methanol;

3. (2-Hydroxymethyl-4- {3- [4- (2-hydroxy-3-methylbutylsulfanyl) -3-methylphenyl] propyl} phenyl) methanol;

4. (4- {3- [3-Ethyl-4- (2-hydroxy-3-methylbutylsulfanyl) phenyl] propyl} -2-hydroxymethylphenyl) methanol;

5. (2-Hydroxymethyl-4- {3- [4- (3-hydroxy-4-methylpentyl) -3-methylphenyl] propyl} phenyl) methanol;

6. (4- {3- [3-Ethyl-4- (3-hydroxy-4-methylpentyl) phenyl] propyl} -2-hydroxymethylphenyl) methanol;

7. (E) -1- {4- [3- (3,4-Bishydroxymethylphenyl) propyl] -2-methylphenyl} -4-methylpent-1-en-3-ol;

8. (E) -1- {4- [3- (3,4-Bishydroxymethylphenyl) propyl] -2-ethylphenyl} -4-methylpent-1-en-3-ol;

9. (4- {3- [4- (2-Hydroxy-3,3-dimethylbutylsulfanyl) -3-methylphenyl] propyl} -2-hydroxymethylphenyl) methanol;

10. (4- (3- [3-Ethyl-4- (2-hydroxy-3,3-dimethylbutylsulfanyl) phenyl] propyl} -2-hydroxymethylphenyl) methanol;

11. (4- {3- [4- (3-Hydroxy-4,4-dimethylpentyl) -3-methylphenyl] propyl) -2-hydroxymethylphenyl) methanol;

12. (4- {3- [3-Ethyl-4- (3-hydroxy-4,4-dimethylpentyl) phenyl] propyl) -2-hydroxymethylphenyl) methanol;

13. (E) -1- {4- [3- (3,4-Bishydroxymethylphenyl) propyl] -2-methylphenyl} -4,4-dimethylpent-1-en-3-ol;

14. (E) -1- {4- (3- (3,4-Bishydroxymethylphenyl) propyl] -2-ethylphenyl} -4,4-dimethylpent-1-en-3-ol;

15. (2-Hydroxymethyl-4- {3- [3-methyl-4- (3,3,3-trifluoro-2-hydroxypropoxy) phenyl] propyl} phenyl) methanol;

16. (4- {3- [3-Ethyl-4- (3,3,3-trifluoro-2-hydroxypropoxy) phenyl] propyl} -2-hydroxymethylphenyl) methanol;

17. (2-Hydroxymethyl-4- {3- [3-methyl-4- (3,3,3-trifluoro-2-hydroxypropylsulfanyl) phenyl] propyl} phenyl) methanol;

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18. (4- {3- [3-Ethyl-4- (3,3,3-trifluoro-2-hydroxypropylsulfanyl) phenyl] propyl) -2-hydroxymethylphenyl) methanol;

19. (2-Hydroxymethyl-4- {3- [3-methyl-4- (4,4,4-trifluoro-3-hydroxybutyl) phenyl] propyl} phenyl) methanol;

20. (4- {3- [3-ethyl-4- (4,4,4-trifluoro-3-hydroxybutyl) phenyl] propyl} -2-hydroxymethylphenyl) methanol;

21. (2-Hydroxymethyl-4- {3- [3-methyl-4 - ((E) -4,4,4-trifluoro-3-hydroxybut-1-enyl) phenyl] propyl} phenyl) methanol;

22. (4- {3- [3-ethyl-4 - ((E) -4,4,4-trifluoro-3-hydroxybut-1-enyl) phenyl] propyl} -2-hydroxymethylphenyl) methanol;

23. (2-Hydroxymethyl-4- {3- [3-methyl-4- (4,4,4-trifluoro-2-hydroxy-3-trifluoromethylbutoxy) phenyl] propyl} phenyl) methanol;

24. (4- {3- [3-ethyl-4- (4,4,4-trifluoro-2-hydroxy-3-trifluoromethylbutoxy) phenyl] propyl} -2-hydroxymethylphenyl) methanol;

25. (2-Hydroxymethyl-4- (3- [3-methyl-4- (4,4,4-trifluoro-2-hydroxy-3-trifluoromethylbutylsulfanyl) phenyl] propyl} phenyl) methanol;

26. (4- {3- [3-ethyl-4- (4,4,4-trifluoro-2-hydroxy-3-trifluoromethylbutylsulfanyl) phenyl] propyl} -2-hydroxymethylphenyl) methanol;

27. (2-Hydroxymethyl-4- {3- [methyl- (5,5,5-trifluoro-3-hydroxy-4-trifluoromethylpentyl) phenyl] propyl} phenyl) methanol;

28. (4- {3- [Ethyl- (5,5,5-trifluoro-3-hydroxy-4-trifluoromethylpentyl) phenyl] propyl} -2-hydroxymethylphenyl) methanol;

29. (E) - {4- [3- (3,4-Bishydroxymethylphenyl) propyl] -2-methylphenyl} -5,5,5-trifluoro-4-trifluoromethylpent-1-en-3-ol;

30. (E) - {4- [3- (3,4-Bishydroxymethylphenyl) propyl] -2-ethylphenyl} -5,5,5-trifluoro-4-trifluoromethylpent-1-en-3-ol;

31. (2-Hydroxymethyl-4- {3- [4- (2-hydroxy-3-methylbutoxy) -3-methylphenyl] -3-methylbutyl} phenyl) methanol;

32. (4- {3- [3-ethyl-4- (2-hydroxy-3-methylbutoxy) phenyl] -3-methylbutyl} -2-hydroxymethylphenyl) methanol;

33. (2-Hydroxymethyl-4- {3- [4- (2-hydroxy-3-methylbutylsulfanyl) -3-methylphenyl] -3-methylbutyl} phenyl) methanol;

34. (4- {3- [3-Ethyl-4- (2-hydroxy-3-methylbutylsulfanyl) phenyl] -3-methylbutyl} -2-hydroxymethylphenyl) methanol;

35. (2-Hydroxymethyl-4- {3- [4- (3-hydroxy-4-methylpentyl) -3-methylphenyl] -3-methylbutyl} phenyl) methanol;

36. (4- {3- [3-Ethyl-4- (3-hydroxy-4-methylpentyl) phenyl] -3-methylbutyl} -2-hydroxymethylphenyl) methanol;

37. (E) -1- {4- [3- (3,4-Bishydroxymethylphenyl) -1,1-dimethylpropyl] -2-methylphenyl} -4-methylpent-1-en-3-ol;

38. (E) -1- {4- [3- (3,4-Bishydroxymethylphenyl) -1,1-dimethylpropyl] -2-ethylphenyl} -4-methylpent-1-en-3-ol;

39. (4- {3- [4- (2-Hydroxy-3,3-dimethylbutoxy) -3-methylphenyl] -3-methylbutyl} -2-hydroxymethylphenyl) methanol

40. (4- {3- (3-ethyl-4- (2-hydroxy-3,3-dimethylbutoxy) phenyl] -3-methylbutyl} -2-hydroxymethylphenyl) methanol;

41. (4- {3- [4- (2-Hydroxy-3,3-dimethylbutylsulfanyl) -3-methylphenyl] -3-methylbutyl} -2-hydroxymethylphenyl) methanol

42. (4- {3- [3-Ethyl-4- (2-hydroxy-3,3-dimethylbutylsulfanyl) phenyl] -3-methylbutyl) -2-hydroxymethylphenyl) methanol;

43. (4- {3- [4- (3-Hydroxy-4,4-dimethylpentyl) -3-methylphenyl] -3-methylbutyl} -2-hydroxymethylphenyl) methanol;

44. (4- {3- [3-ethyl-4- (3-hydroxy-4,4-dimethylpentyl) phenyl] -3-methylbutyl} -2-hydroxymethylphenyl) methanol;

45. (E) -1- {4- [3- (3,4-Bishydroxymethylphenyl) -1,1-dimethylpropyl] -2-methylphenyl} -4,4-dimethylpent-1-en-3-ol;

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46. (E) -1- {4- [3- (3,4-Bishydroxymethylphenyl) -1,1-dimethylpropyl] -2-ethylphenyl} -4,4-dimethylpent-1-en-3-ol;

47. (4- {3-ethyl-3- [4- (2-hydroxy-3-methylbutoxy) -3-methylphenyl] pentyl} -2-hydroxymethylphenyl) methanol;

48. (4- {3-ethyl-3- [3-ethyl-4- (2-hydroxy-3-methylbutoxy) phenyl] pentyl} -2-hydroxymethylphenyl) methanol;

49. (4- {3-ethyl-3- [4- (2-hydroxy-3-methylbutylsulfanyl) -3-methylphenyl] pentyl} -2-hydroxymethylphenyl) methanol;

50. (4- {3-ethyl-3- [3-ethyl-4- (2-hydroxy-3-methylbutylsulfanyl) phenyl] pentyl} -2-hydroxymethylphenyl) methanol;

51. (4- {3-ethyl-3- [4- (3-hydroxy-4-methylpentyl) -3-methylphenyl] pentyl} -2-hydroxymethylphenyl) methanol;

52. (4- {3-ethyl-3- [3-ethyl-4- (3-hydroxy-4-methylpentyl) phenyl] pentyl} -2-hydroxymethylphenyl) methanol;

53. (E) -1- {4- [3- (3,4-Bishydroxymethylphenyl) -1,1-diethylpropyl] -2-methylphenyl} -4-methylpent-1-en-3-ol;

54. (E) -1- {4- [3- (3,4-Bishydroxymethylphenyl) -1,1-diethylpropyl] -2-ethylphenyl} -4-methylpent-1-en-3-ol;

55. (4- {3-ethyl-3- [4- (2-hydroxy-3,3-dimethylbutoxy) methylphenyl] pentyl) -2-hydroxymethylphenyl) methanol;

56. (4- {3-ethyl-3- [3-ethyl-4- (2-hydroxy-3,3-dimethylbutoxy) phenyl] pentyl} -2-hydroxymethylphenyl) methanol;

57. (4- {3-ethyl-3- [4- (2-hydroxy-3,3-dimethylbutylsulfanyl) -3-methylphenyl] pentyl} -2-hydroxymethylphenyl) methanol;

58. (4- {3-ethyl-3- [3-ethyl-4- (2-hydroxy-3,3-dimethylbutylsulfanyl) phenyl] pentyl} -2-hydroxymethylphenyl) methanol;

59. (4- {3-ethyl-3- [4- (3-hydroxy-4,4-dimethylpentyl) -3-methylphenyl] pentyl} -2-hydroxymethylphenyl) methanol;

60. (4- {3-ethyl-3- [3-ethyl-4- (3-hydroxy-4,4-dimethylpentyl) phenyl] pentyl} -2-hydroxymethylphenyl) methanol;

61. (E) -1- {4- (3- (3,4-Bishydroxymethylphenyl) -1,1-diethylpropyl] -2-methylphenyl} -4,4-dimethylpent-1-en-3-ol;

62. (E) -1- {4- [3- (3,4-Bishydroxymethylphenyl) -1,1-diethylphenyl] -2-ethylphenyl} -4,4-dimethylpent-1-en-3-ol;

63. [2-Hydroxymethyl-4- (2- {1- [4- (2-hydroxy-3-methylbutoxy) -3-methylphenyl] cyclopentyl} ethyl) phenyl] methanol;

64. [4- (2- {1- [3-Ethyl-4- (2-hydroxy-3-methylbutoxy) phenyl] cyclopentyl} ethyl) -2-hydroxymethylphenyl] methanol;

65. [2-Hydroxymethyl-4- (2- {1- [4- (2-hydroxy-3-methylbutylsulfanyl) -3-methylphenyl] cyclopentyl} ethyl) phenyl] methanol;

66. [4- (2- {1- [3-Ethyl-4- (2-hydroxy-3-methylbutylsulfanyl) phenyl] cyclopentyl} ethyl) -2-hydroxymethylphenyl] methanol;

67. [2-Hydroxymethyl-4- (2- {1- [4- (3-hydroxy-4-methylpentyl) -3-methylphenyl] cyclopentyl} ethyl) phenyl] methanol;

68. [4- (2- {1- [3-Ethyl-4- (3-hydroxy-4-methylpentyl) phenyl] cyclopentyl} ethyl) -2-hydroxymethylphenyl] methanol;

69. (E) -1- (4- {1- [2- (3,4-Bishydroxymethylphenyl) ethyl] cyclopentyl} -2-methylphenyl) -4-methylpent-1-en-3-ol;

70. (E) -1- (4- {1- [2- (3,4-Bishydroxymethylphenyl) ethyl] cyclopentyl} -2-ethylphenyl) -4-methylpent-1-en-3-ol;

71. [4- (2- {1- [4- (2-Hydroxy-3,3-dimethylbutoxy) -3-methylphenyl] cyclopentyl} ethyl) -2-hydroxy-methylphenyl] methanol;

72. [4- (2- {1- [3-Ethyl-4- (2-hydroxy-3,3-dimethylbutoxy) phenyl] cyclopentyl} ethyl) -2-hydroxymethylphenyl] methanol;

73. [4- (2- (1- [4- (2-Hydroxy-3,3-dimethylbutylsulfanyl-3-methylphenyl] cyclopentyl} ethyl) -2-hydroxymethylphenyl] methanol;

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74. [4- (2- {1- [3-Ethyl-4- (2-hydroxy-3,3-dimethylbutylsulfanyl) phenyl] cyclopentyl} ethyl) -2-hydroxymethylphenyl] methanol;

75. [4- (2- (1- [4- (3-Hydroxy-4,4-dimethylpentyl) -3-methylphenyl] cyclopentyl} ethyl) -2-hydroxymethylphenyl] methanol;

76. [4- (2- {1- [3-Ethyl-4- (3-hydroxy-4,4-dimethylpentyl) phenyl] cyclopentyl) ethyl) -2-hydroxymethylphenyl] methanol;

77. (E) -1- (4- {1- [2- (3,4-Bishydroxymethylphenyl) ethyl] cyclopentyl} -2-methylphenyl) -4,4-dimethylpent-1-en-3-ol;

78. (E) -1- (4- {1- [2- (3,4-Bishydroxymethylphenyl) ethyl] cyclopentyl} -2-ethylphenyl) -4,4-dimethylpent-1-en-3-ol;

79. [2-Hydroxymethyl-4- (2- {1- [4- (2-hydroxy-3-methylbutoxy) -3-methylphenyl] cyclohexyl} ethyl) phenyl] methanol;

80. [4- (2- {1- [3-Ethyl-4- (2-hydroxy-3-methylbutoxy) phenyl] cyclohexyl} ethyl) -2-hydroxymethylphenyl] methanol;

81. [2-Hydroxymethyl-4- (2- {1- [4- (2-hydroxy-3-methylbutylsulfanyl) -3-methylphenyl] cyclohexyl} ethyl) phenyl] methanol;

82. [4- (2- {1- [3-Ethyl-4- (2-hydroxy-3-methylbutylsulfanyl) phenyl] cyclohexyl} ethyl) -2-hydroxymethylphenyl] methanol;

83. [2-Hydroxymethyl-4- (2- {1- [4- (3-hydroxy-4-methylpentyl) -3-methylphenyl] cyclohexyl} ethyl) phenyl] methanol;

84. [4- (2- {1- [3-Ethyl-4- (3-hydroxy-4-methylpentyl) phenyl] cyclohexyl} ethyl) -2-hydroxymethylphenyl] methanol;

85. (E) -1- (4- {1- [2- (3,4-Bishydroxymethylphenyl) ethyl] cyclohexyl} -2-methylphenyl) -4-methylpent-1-en-3-ol;

86. (E) -1- (4- {1- [2- (3,4-Bishydroxymethylphenyl) ethyl] cyclohexyl} -2-ethylphenyl) -4-methylpent-1-en-3-ol;

87. [4- (2- {1- [4- (2-Hydroxy-3,3-dimethylbutoxy) -3-methylphenyl] cyclohexyl} ethyl) -2-hydroxymethylphenyl] methanol;

88. [4- (2- {1- [3-Ethyl-4- (2-hydroxy-3,3-dimethylbutoxy) phenyl] cyclohexyl} ethyl) -2-hydroxymethylphenyl] methanol;

89. [4- (2- (1- [4- (2-Hydroxy-3,3-dimethylbutylsulfanyl) -3-methylphenyl] cyclohexyl} ethyl) -2-hydroxymethylphenyl] methanol;

90. [4- (2- {1- [3-Ethyl-4- (2-hydroxy-3,3-dimethylbutylsulfanyl) phenyl] cyclohexyl} ethyl) -2-hydroxymethylphenyl] methanol;

91. [4- (2- {1- [4- (3-Hydroxy-4,4-dimethylpentyl) -3-methylphenyl] cyclohexyl} ethyl) -2-hydroxymethylphenyl] methanol;

92. [4- (2- {1- [3-Ethyl-4- (3-hydroxy-4,4-dimethylpentyl) phenyl] cyclohexyl} ethyl) -2-hydroxymethylphenyl] methanol;

93. (E) -1- (4- {1- [2- (3,4-Bishydroxymethylphenyl) ethyl] cyclohexyl} -2-methylphenyl) -4,4-dimethyl-1-pent-1-en-3- ol;

94. (E) -1- (4- {1- [2- (3,4-Bishydroxymethylphenyl) ethyl] cyclohexyl} -2-ethylphenyl) -4,4-dimethyl-1-pent-1-en-3- ol;

95. (4- {2-ethyl-2- [4- (2-hydroxy-3-methylbutoxy) -3-methylphenyl] butoxy} -2-hydroxymethylphenyl) methanol;

96. (4- {2-ethyl-2- [3-ethyl-4- (2-hydroxy-3-methylbutoxy) phenyl] butoxy} -2-hydroxymethylphenyl) methanol;

97. (4- {2-ethyl-2- [4- (2-hydroxy-3-methylbutylsulfanyl) -3-methylphenyl] butoxy} -2-hydroxymethylphenyl) methanol;

98. (4- {2-ethyl-2- [3-ethyl-4- (2-hydroxy-3-methylbutylsulfanyl) phenyl] butoxy} -2-hydroxymethylphenyl) methanol;

99. (4- {2-ethyl-2- [4- (3-hydroxy-4-methylpentyl) -3-methylphenyl] butoxy} -2-hydroxymethylphenyl) methanol;

100. (4- {2-ethyl-2- [3-ethyl-4- (3-hydroxy-4-methylpentyl) phenyl] butoxy} -2-hydroxymethylphenyl) methanol

101. (E) -1- {4- [1- (3,4-Bishydroxymethylphenoxymethyl) -1-ethylpropyl] -2-methylphenyl} -4-methylpent-1-en-3-ol;

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102. (E) -1- {4- [1- (3,4-Bishydroxymethylphenoxymethyl) -1-ethylpropyl] -2-ethylphenyl} -4-methylpent-1-en-3-ol;

103. (4- {2-ethyl-2- [4- (2-hydroxy-3,3-dimethylbutoxy) -3-methylphenyl] butoxy} -2-hydroxymethylphenyl) methanol;

104. (4- {2-ethyl-2- [3-ethyl-4- (2-hydroxy-3,3-dimethylbutoxy) phenyl] butoxy} -2-hydroxymethylphenyl) methanol;

105. (4- {2-ethyl-2- [4- (2-hydroxy-3,3-dimethylbutylsulfanyl) -3-methylphenyl] butoxy} -2-hydroxymethylphenyl) methanol;

106. (4- {2-ethyl-2- [3-ethyl-4- (2-hydroxy-3,3-dimethylbutylsulfanyl) phenyl] butoxy} -2-hydroxymethylphenyl) methanol;

107. (4- {2-ethyl-2- [4- (3-hydroxy-4,4-dimethylpentyl) -3-methylphenyl] butoxy} -2-hydroxymethylphenyl) methanol;

108. (4- {2-ethyl-2- [3-ethyl-4- (3-hydroxy-4,4-dimethylpentyl) phenyl] butoxy} -2-hydroxymethylphenyl) methanol;

109. (E) -1- {4- [1- (3,4-Bishydroxymethylphenoxymethyl) -1-ethylpropyl] -2-methylphenyl} -4,4-dimethylpent-1-en-3-ol;

110. (E) -1- {4- [1- (3,4-Bishydroxymethylphenoxymethyl) -1-ethylpropyl] -2-ethylphenyl} -4,4-dimethylpent-1-en-3-ol;

111. (4 - {(E) -3-ethyl-3- [4-2-hydroxy-3-methylbutoxy) -3-methylphenyl] pent-1-enyl} -2-hydroxymethylphenyl) methanol;

112. (4 - {(E) -3-ethyl-3- [3-ethyl-4- (2-hydroxy-3-methylbutoxy) phenyl] pent-1-enyl} -2-hydroxymethylphenyl) methanol;

113. (4 - {(E) -3-ethyl-3- [4- (2-hydroxy-3-methylbutylsulfanyl) -3-methylphenyl] pent-1-enyl} -2-hydroxymethylphenyl) methanol;

114. (4 - {(E) -3-ethyl-3- [3-ethyl-4- (2-hydroxy-3-methylbutylsulfanyl) phenyl] pent-1-enyl} -2-hydroxymethylphenyl) methanol;

115. (4 - {(E) -3-ethyl-3- [4- (3-hydroxy-4-methylpentyl) -3-methylphenyl] pent-1-enyl} -2-hydroxymethylphenyl) methanol;

116. (4 - {(E) -3-ethyl-3- [3-ethyl-4- (3-hydroxy-4-methylpentyl) phenyl] pent-1-enyl} -2-hydroxymethylphenyl) methanol;

117. (E) -1- (4 - [(E) -3- (3,4-Bishydroxymethylphenyl) -1,1-diethylallyl] -2-methylphenyl} -4-methylpent-1-en-3-ol;

118. (E) -1- {4 - [(E) -3- (3,4-Bishydroxymethylphenyl) -1,1-diethylallyl] -2-ethylphenyl} -4-methylpent-1-en-3-ol;

119. (4 - {(E) -3-ethyl-3- [4- (2-hydroxy-3,3-dimethylbutoxy) -3-methylphenyl] pent-1-enyl} -2-hydroxytylphenyl) methanol;

120. (4 - {(E) -3-ethyl-3- [3-ethyl-4- (2-hydroxy-3,3-dimethylbutoxy) phenyl] pent-1-enyl} -2-hydroxymethylphenyl) methanol;

121. (4 - {(E) -3-ethyl-3- [4- (2-hydroxy-3,3-dimethylbutylsulfanyl) -3-methylphenyl] pent-1-enyl} -2-hydroxymethylphenyl) methanol;

122. (4 - {(E) -3-ethyl-3- [3-ethyl-4- (2-hydroxy-3,3-dimethylbutylsulfanyl) phenyl] pent-1-enyl} -2-hydroxymethylphenyl) methanol;

123. (4 - {(E) -3-ethyl-3- [4- (3-hydroxy-4,4-dimethylpentyl) -3-methylphenyl] pent-1-phenyl} -2-hydroxyylphenyl) methanol;

124. (4 - {(E) -3-ethyl-3- [3-ethyl-4- (3-hydroxy-4,4-dimethylpentyl) phenyl] pent-1-enyl} -2-hydroxymethylphenyl) methanol;

125. (E) -1- {4 - [(E) -3- (3,4-Bishydroxymethylphenyl) -1,1-diethylallyl] -2-methylphenyl} -4,4-dimethylpent-1-en-3- ol;

126. (E) -1- {4 - [(E) -3- (3,4-Bishydroxymethylphenyl) -1,1-diethylallyl] -2-ethylphenyl} -4,4-dimethylpent-1-en-3- ol;

127. (4- {3- [3-Ethyl-4- (3,3,3-trifluoro-2-hydroxypropoxy) phenyl] -3-methylbutyl} -2-hydroxymethylphenyl) methanol;

128. (4- {3- [3-ethyl-4- (3,3,3-trifluoro-2-hydroxypropylsulfanyl) phenyl] -3-methylbutyl} -2-hydroxymethylphenyl) methanol;

129. (4- (3- [3-ethyl-4- (4,4,4-trifluoro-3-hydroxybutyl) phenyl] -3-methylbutyl} -2-hydroxymethylphenyl) methanol;

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130. (4- {3- [3-ethyl-4 - ((E) -4,4,4-trifluoro-3-hydroxybut-1-enyl) phenyl] -3-methylbutyl} -2-hydroxymethylphenyl) methanol;

131. (4- {3- [3-ethyl-4- (4,4,4-trifluoro-2-hydroxy-3-trifluoromethylbutoxy) phenyl] -3-methylbutyl} 2-hydroxymethylphenyl) methanol;

132. (4- {3- [3-ethyl-4- (4,4,4-trifluoro-2-hydroxy-3-trifluoromethylbutylsulfanyl) phenyl] -3-methylbutyl} -2-hydroxymethylphenyl) methanol;

133. (4 - {[ethyl- (5,5,5-trifluoro-3-hydroxy-4-trifluoromethylpentyl) phenyl] methylbutyl} -2-hydroxymethylphenyl) methanol;

134. (E) - {4- [3- (3,4-Bishydroxymethylphenyl) -1,1-dimethylpropyl] -2-ethylphenyl} -5,5,5-trifluoro-4-trifluoromethylpent-1-en-3- ol;

135. (4- {3-ethyl-3- [3-ethyl-4- (3,3,3-trifluoro-2-hydroxypropoxy) phenyl] pentyl} -2-hydroxymethylphenyl) methanol;

136. (4- {3-ethyl-3- [3-ethyl-4- (3,3,3-trifluoro-2-hydroxypropylsulfanyl) phenyl] pentyl} -2-hydroxymethylphenyl) methanol;

137. (4- {3-ethyl-3- [3-ethyl-4- (4,4,4-trifluoro-3-hydroxybutyl) phenyl] pentyl} -2-hydroxymethylphenyl) methanol;

138. (4- {3-ethyl-3- [3-ethyl-4 - ((E) -4,4,4-trifluoro-3-hydroxybut-1-enyl) phenyl] pentyl} -2-hydroxymethylphenyl) methanol ;

139. (4- {3-ethyl-3- [3-ethyl-4- (4,4,4-trifluoro-2-hydroxy-3-trifluoromethylbutoxy) phenyl] pentyl} 2-hydroxymethylphenyl) methanol;

140. (4- {3-ethyl-3- [3-ethyl-4- (4,4,4-trifluoro-2-hydroxy-3-trifluoromethylbutylsulfanyl) phenyl] pentyl} -2-hydroxymethylphenyl) methanol;

141. (4- {ethyl [ethyl- (5,5,5-trifluoro-3-hydroxy-4-trifluoromethylpentyl) phenyl] pentyl} -2-hydroxymethylphenyl) methanol;

142. (E) - {4- [3- (3,4-Bishydroxymethylphenyl) -1,1-diethylpropyl] -2-ethylphenyl} -5,5,5-trifluoro-4-trifluoromethylpent-1-en-3- ol;

143. [4- (2- {1- [3-Ethyl-4- (3,3,3-trifluoro-2-hydroxypropoxy) phenyl] cyclohexyl} ethyl) -2-hydroxymethylphenyl] methanol;

144. [4- (2- {1- [3-Ethyl-4- (3,3,3-trifluoro-2-hydroxypropylsulfanyl) phenyl] cyclohexyl} ethyl) -2-hydroxymethylphenyl] methanol;

145. [4- (2- {1- [3-Ethyl-4- (4,4,4-trifluoro-3-hydroxybutyl) phenyl] cyclohexyl} ethyl) -2-hydroxymethylphenyl] methanol;

146. [4- (2- {1- [3-ethyl-4 - ((E) -4,4,4-trifluoro-3-hydroxybut-1-enyl) phenyl] cyclohexyl} ethyl) -2-hydroxymethylphenyl] methanol;

147. [4- (2- {1- [3-Ethyl-4- (4,4,4-trifluoro-2-hydroxy-3-trifluoromethylbutoxy) phenyl] cyclohexyl} ethyl) -2-hydroxymethylphenyl] methanol;

148. [4- (2- {1- [3-Ethyl-4- (4,4,4-trifluoro-2-hydroxy-3-trifluoromethylbutylsulfanyl) phenyl] cyclohexyl} ethyl) -2-hydroxymethylphenyl] methanol;

149. [4- (2- (1- [Ethyl- (5,5,5-trifluoro-3-hydroxy-4-trifluororoethylpentyl) phenyl] cyclohexyl} ethyl) -2-hydroxymethylphenyl] methanol;

150. (E) - (4- {1- [2- (3,4-Bishydroxymethylphenyl) ethyl] cyclohexyl} -2-ethylphenyl) -5,5,5-trifluoro-4-trifluoromethylpent-1-en-3- ol

151. (4- {2-ethyl-2- [3-ethyl-4- (3,3,3-trifluoro-2-hydroxypropoxy) phenyl] butoxy} -2-hydroxymethylphenyl) methanol;

152. (4- {2-ethyl-2- [3-ethyl-4- (3,3,3-trifluoro-2-hydroxypropylsulfanyl) phenyl] butoxy} -2-hydroxymethylphenyl) methanol;

153. (4- {2-ethyl-2- [3-ethyl-4- (4,4,4-trifluoro-3-hydroxybutyl) phenyl] butoxy} -2-hydroxymethylphenyl) methanol;

154. (4- {2-ethyl-2- [3-ethyl-4 - ((E) -4,4,4-trifluoro-3-hydroxybut-1-enyl) phenyl] butoxy} -2-hydroxymethylphenyl) methanol ;

155. (4- {2-ethyl-2- [3-ethyl-4- (4,4,4-trifluoro-2-hydroxy-3-trifluoromethylbutoxy) phenyl] butoxy} 2-hydroxymethylphenyl) methanol;

156. (4- {2-ethyl-2- [3-ethyl-4- (4,4,4-trifluoro-2-hydroxy-3-trifluoromethylbutylsulfanyl) phenyl] butoxy) -2-hydroxymethylphenyl) methanol;

157. (4- {ethyl [ethyl- (5,5,5-trifluoro-3-hydroxy-4-trifluoromethylpentyl) phenyl] butoxy} -2-hydroxymethylphenyl) methanol;

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158. (E) - {4- [1- (3,4-Bishydroxymethylphenoxymethyl) -1-ethylpropyl] -2-ethylphenyl} -5,5,5-trifluoro-4-trifluoromethylpent-1-en-3-ol.

Compounds of general formula (I) can be prepared according to the following synthetic scheme, given in Figure 1:

A compound of formula 2 can be prepared from a compound of formula 1 by selective bromination followed by protection of the (P) phenolic functional group. Compounds of structure 3 can be obtained from compounds of formula 2 by Stille coupling with a suitable organotin partner, e.g. allyltributyltin or cyanomethyltributyltin.

Compounds of structure 4 can be obtained from compounds of formula 3a:

- in the case where B-T = CH2-CH2, by borohydrating the olefin functional group, followed by Suzuki coupling with a triflate partner of the dimethyl 4-trifluoromethanesulfonyloxyphthalate type,

- in the case where B-T = CH = CH, after olefin ozonolysis, followed by a Wittig or Horner-Emmons type reaction, e.g. with a phosphorus partner of the type 4- (diethoxyphosphorylmethyl) phthalate,

- in the case where BT = CH2-O, CH2-S or CH2-NH-, after reductive ozonolysis of the olefin functional group, then by a Mitsunobu type reaction with a partner containing a phenol, thiophenol or aniline group of the 4-hydroxy type (or mercapto or amino ) of dimethyl phthalate followed by removal of the protecting groups of the phenol function.

The compounds of structure 5 can then be obtained as follows: the phenolic functional group can be substituted with an α-bromoketone. The resulting compounds may then be reduced to the final compounds of formula 5 (R2 = H) by the addition of hydrides such as e.g. lithium aluminum hydride, or alternatively the ketones may be alkylated with selective reagents such as organozinc reagents whereafter the ester functional groups may be reduced with hydrides. to give the final compounds of formula 5 (R2 other than H).

The compounds of structure 6 can be obtained from compounds of the compound of formula IIIb by double alkylation at the benzyl position, e.g. in the presence of an alkyl halide R4-X and lithium diisopropylamide, followed by reduction of the nitrile function to an aldehyde.

Compounds of structure 7 can then be obtained from a compound of formula 6:

- in the case where B-T is CH = CH, after a Wittig or Horner-Emmons type reaction, e.g. with a phosphorus partner of the type dimethyl 4- (diethoxyphosphorylmethyl) phthalate

- in the case where B-T = CH2-CH2, by hydrogenation of the olefinic functional group obtained from B-T denoting CH = CH

- and finally in the case where BT = CH2-O, CH2-S or CH2-NH, after reduction of the aldehyde function to an alcohol, then by a Mitsunobu type reaction with a partner containing a phenol, thiophenol or 4-hydroxy aniline group (or mercapto or dimethyl amino) phthalate followed by removal of the protecting groups of the phenol function.

The compounds of structure 8 can then be obtained as follows: The phenolic functional group can be substituted with an α-bromoketone. The resulting compounds may then be reduced to the final compounds of formula 8 (R2 = H) by the addition of hydrides such as e.g. lithium aluminum hydride, or alternatively the ketones may be alkylated with selective reagents such as organozinc reagents, whereafter the ester functional groups may be reduced with hydrides. to give the final compounds of formula 8 (R2 other than H).

Compounds of structure 9 can be obtained after conversion to the triflate of the phenolic functional group in compounds of the type of compounds of formula 7:

- when Q-A is CH = CH, the thus obtained intermediate can be converted after a Heck type reaction with the corresponding vinyl ketone type CH2 = CHC (O) R1;

- when Q-A is CH2-CH2, the compounds can then be obtained after hydrogenation of the olefin function of the compounds of formula 9 with Q-A representing CH = CH;

- when Q-A = ethynyl, the compounds are obtained after Sonogashira coupling between the appropriate alkyne functional group and the triflate derivative of compound 7 described above.

The resulting compounds of formula 9 can be reduced to the final compounds of formula 10 (R2 = H) by the addition of hydrides such as e.g. lithium aluminum hydride, or alternatively ketones can be alkylated with selective reagents such as organozinc reagents, whereafter the ester functional groups can be reduced hydrides to give the final compounds of formula 10 (R2 other than H).

The compounds of general formula (I) show biological properties similar to those of vitamin D, especially vitamin D response elements (VDRE) transactivation, such as

Agonist or antagonistic activity at vitamin D receptors or derivatives thereof. Vitamin D or derivatives thereof are understood to mean, for example, vitamin D2 or D3 derivatives and in particular 1,25-dihydroxyvitamin D3 (calcitriol).

This agonist activity at vitamin D receptors or derivatives thereof can be demonstrated "in vitro by methods known in the art of gene transcription research (Hansen et al., Society For Investigative Dermatology, Vol. 1, No. 1, April 1996).

The biological properties analogous to vitamin D can also be measured by the ability of the product to induce HL60 promyelocytic leukemia cell differentiation. The protocol and the results obtained with the compounds of the invention are described in example 6 of the present application.

For example, VDR agonist activity can be tested in the HeLa cell line by co-transfecting the expression vector of the human VDR receptor and the p240Hase-CAT reporter plasmid. The agonist activity can also be characterized in this co-transfection system by determining the dose required to achieve 50% of the maximum activity of the product (AC50). The details of the test protocol and the results obtained with the compounds of the invention are described in Example 7 of the present application.

Vitamin D-like biological properties can also be determined by the ability of the product to inhibit the proliferation of normal human keratinocytes (NHK in culture). The product is added to NHK grown under conditions favorable to proliferation. The product is left in contact with the cells for 5 days. The amount of proliferating cells is measured by incorporating bromodeoxyuridine (BRdU) into the DNA. The protocol of this test and the results obtained with the compounds of the invention are described in example 8 of the present application.

Administration of the compounds of the invention may be by the enteral, parenteral, topical or ocular route.

Pharmaceutical compositions according to the invention for administration by the enteral route may be in the form of tablets, gelatin capsules, sugar-coated dragées, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres, or lipid or polymer vesicles allowing controlled release.

Compositions for parenteral administration may be in the form of infusion or injection solutions or suspensions.

The compounds of the invention are generally administered in daily doses of from about 0.001 µg / kg to 1000 µg / kg, preferably from about 0.01 µg / kg to 100 µg / kg body weight, in 1-3 administrations.

Topical pharmaceutical compositions based on the compounds according to the invention are intended for the treatment of skin, hairy skin and mucous membranes and are in the form of lotions, creams, lotions, ointments, powders, impregnated tampons, solutions, gels, sprays, lotions or suspensions. They can also be in the form of microspheres or nanospheres, or lipid or polymer vesicles, or polymer patches and hydrogels, allowing controlled release. These topical compositions may be in either anhydrous or hydrated form depending on the clinical indication.

For ocular administration, mainly eye drops are used.

These compositions for topical or ocular administration contain at least one compound according to the invention at a concentration of preferably 0.0001-5%, preferably 0.001-1% based on the total weight of the composition.

The compounds according to the invention are also used in the field of cosmetics, in particular for body and hair care, in particular for the treatment of acne-prone skin, for the regrowth or inhibition of hair loss, for combating the greasy appearance of the skin or hair, for protection against the harmful effects of the sun or for treating dry skin, for preventing and / or treating skin aging caused by light or time.

The cosmetic composition according to the invention may in particular be in the form of a cream, milk, lotion, gel, suspension of microspheres or nanospheres, or lipid or polymer vesicles, soap or shampoo.

The concentration of the compound of general formula (I) in the cosmetic composition according to the invention may be 0.001-3% by weight relative to the total weight of the composition.

In the pharmaceutical and cosmetic fields, the compounds according to the invention can advantageously be used in combination with inert or even pharmacodynamically or cosmetically active additives or with combinations of these additives, in particular with:

- moisturizing agents;

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- taste improvers:

- preservatives, such as esters of p-hydroxybenzoic acid;

- stabilizers;

- humidity regulators;

- pH regulators;

- osmotic pressure modifiers;

- emulsifiers;

- filters of UV-A and UV-B rays;

- antioxidants such as α-tocopherol, butylhydroxyanisole, butylhydroxytoluene, superoxide dismutase, ubiquinol or certain metal chelating agents;

- decolorizing agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid;

- soften with kczaczami;

- rehydrating agents such as glycerol, PEG 400, thiamorpholinone and its derivatives or urea;

anti-seborrheic or anti-acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, their salts and derivatives, or benzoyl peroxide;

- antibiotics such as erythromycin and its esters, neomycin, clindamycin and its esters, tetracyclines;

- antifungal agents such as ketoconazole or 4,5-polymethylene-3-isothiazolinone;

- hair loss reducing agents such as Minoxidil (2,4-diamino-6-piperidinopyrimidine-3-oxide) and its derivatives, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1- dioxide) and Phenytoin (5,4-diphenyl-2,4-imidazolinedione);

- non-steroidal anti-inflammatory agents;

- carotenoids, especially β-carotene;

anti-psoriatic agents such as anthralin and its derivatives;

- 5,8,11,14-eicosatetrainic and 5,8,11-eicosatriic acids, their esters and amides;

- retinoids, i.e. natural or synthetic RAR or RXR receptor ligands;

- corticosteroids or estrogens;

- α-hydroxy acids and α-keto acids or their derivatives, such as lactic acid, malic acid, citric acid, glycolic acid, mandelic acid, tartaric acid, glyceric acid, ascorbic acid, and also their salts, amides or esters, or p-hydroxy acids or their derivatives, such as salicylic acid and its salts, amides or esters;

- blockers of ion channels such as potassium channels;

- or optionally, especially for pharmaceutical compositions, in combination with drugs known to disrupt the immune system (e.g. cyclosporin, FK 506, glucocorticoids, monoclonal antibodies, cytokines or growth factors etc.).

Obviously, one skilled in the art will take care to select the possible compound (s) added to these compositions such that the beneficial properties of the compounds of the present invention are not deteriorated, at least not substantially, by the contemplated addition.

Examples of the preparation of the active compounds of the invention as well as various specific preparations based on such compounds and tests for assessing the biological activity of the compounds of the invention are given below by way of illustration.

Example 1. 1- (4- [3- (3,4-Bishydroxymethylphenyl) propyl] -2-ethylphenoxy} -3,3-dimethylbutan-2-ol

a. 4-Bromo-2-ethylphenol g (123 mmol) of 2-ethylphenol was dissolved in 150 ml of chloroform. 59 g (123 mmol) of tetrabutylammonium tribromide were added in portions of 10 g and the reaction medium was stirred for 20 minutes. The medium was then poured into saturated sodium thiosulfate solution and the pH was adjusted to 7. The mixture was extracted with dichloromethane. After drying and concentration, the residue obtained is purified by chromatography on a silica column (eluent: ethyl acetate 10 / heptane 90). A yellow oil is obtained (m = 24.5 g, yield = 99%).

b. 4-Bromo-1-ethoxymethoxy-2-ethylbenzene

24.5 g (121 mmol) of 4-bromo-2-ethylphenol was dissolved in 150 ml of DMF and this solution was slowly added to a suspension of 5.3 g (133 mmol) of sodium hydride in 50 ml of DMF. The medium was stirred for 30 minutes, then 12.4 ml (133 mmol) of ethoxymethyl chloride were added. The reaction medium is stirred for 4 hours at room temperature, then poured into water and extracted with ethyl acetate. The organic phases are washed with water and the residue obtained after drying and concentration is purified by chromatography on a silica column (eluent: ethyl acetate 10 / heptane 90). A yellow oil is obtained (m = 25 g, yield = 80%).

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c. 4-Allyl-1-ethoxymethoxy-2-ethylbenzene g (58 mmol) of 4-bromo-1-ethoxymethoxy-2-ethylbenzene was dissolved in 150 ml of DMF. 26.9 ml (87 mmol) of allyltributyltin was added and then the mixture was degassed with a stream of nitrogen. 1.2 g (1.8 mmol) of dichlorobis (triphenylphosphine) palladium are added and the medium is heated at 120 ° C for 10 hours. The reaction medium was poured into water, followed by extraction with ethyl acetate. The residue obtained after drying and concentration is purified by chromatography on a silica column (eluent: heptane and then heptane 95 / ethyl acetate 5). A yellow oil is obtained (m = 13.6 g, yield = 100%).

d. Dimethyl 4-trifluoromethanesulfonyloxphthalate 21 g (100 mmol) of dimethyl 4-hydroxyphthalate are dissolved in 500 ml of dichloromethane. The reaction medium is cooled to 0 ° C and 21 ml (155 mmol) of triethylamine are added. 30 g (105 mmol) of trifluoromethanesulfonic anhydride are slowly added, the reaction medium is slowly brought to room temperature, then treated with water and extracted with dichloromethane. The organic phases are washed with dilute sodium bicarbonate solution, then dried and concentrated. The residue was purified by chromatography on a silica column (eluent: ethyl acetate 30 / heptane 70). A yellow oil is obtained (m = 27 g, yield = 79%).

e. Dimethyl 4- [3- (4-Ethoxymethoxy-3-ethylphenyl) propyl] phthalate g (22.7 mmol) 4-allyl-1-ethoxymethoxy-2-ethylbenzene was dissolved in 100 ml of anhydrous THF and the medium was cooled to 0 ° C. 6.6 g (27 mmol) of 9-BBN are added, the medium is brought to room temperature and then stirred for 12 hours. A solution of 7.8 g (22.6 mmol) of dimethyl 4-trifluoromethanesulfonyloxphthalate in 100 ml of DMF and 6.2 g (44.8 mmol) of potassium carbonate were added. The reaction medium was degassed with a stream of nitrogen and then 930 mg (1.1 mmol) of dichloropalladium diphosphinoferrocene were added. The medium was heated at 50 ° C for 3 hours, then poured into ammonium chloride solution and extracted with ethyl acetate. The residue obtained after drying and concentration is purified by chromatography on a silica column (eluent heptane then heptane 85 / ethyl acetate 15). A yellow oil is obtained (m = 6.9 g, yield = 73%).

f. Dimethyl 4- [3- (3-ethyl-4-hydroxyphenyl) propyl] phthalate

6.9 g (16.6 mmol) of dimethyl 4- [3- (4-ethoxymethoxy-3-ethyl-phenyl) propyl] phthalate were dissolved in 100 ml of methanol. 3 ml of concentrated sulfuric acid was added dropwise and the medium was stirred for 1 hour, then poured into water and extracted with dichloromethane. The organic phases were dried and concentrated. The residue obtained is purified by silica column chromatography (eluent heptane 80 / ethyl acetate 20). A colorless oil is obtained (m = 5 g; Y = 84%).

g. 4- {3- [4- (3,3-Dimethyl-2-oxobutoxy) -3-ethylphenyl] propyl} dimethyl phthalate

800 mg (2.2 mmol) of dimethyl 4- [3- (3-ethyl-4-hydroxyphenyl) propyl] phthalate were dissolved in 40 ml of 2-butanone. 340 mg (2.5 mmol) of potassium carbonate and 330 μl (2.5 mmol) of 1-bromopinacolone were added. The reaction medium was heated to reflux for 8 hours, and then filtered through celite. The residue obtained is purified by silica column chromatography (eluent: ethyl acetate 20 / heptane 80). A colorless oil is obtained (m = 920 mg; Y = 90%).

h. 1- {4- [3- (3,4-Bishydroxymethylphenyl) propyl] -2-ethylphenoxy} -3,3-dimethylbutan-2-ol

900 mg (2 mmol) of dimethyl 4- {3- [4- (3,3-dimethyl-2-oxobutoxy) -3-ethylphenyl] propyl} phthalate were dissolved in 20 ml of THF and 375 mg (10 mmol) was slowly added to the suspension. lithium aluminum hydride. The reaction medium was stirred for 30 minutes at room temperature, then 400 μ of water, 400 μΐ of a 15% sodium hydroxide solution and 1 ml of water were slowly added successively. The reaction medium was poured into a 1% hydrochloric acid solution, followed by extraction with diethyl ether.

The residue obtained after drying and concentration was purified by chromatography on a silica column. A thick colorless oil was obtained (m = 760 mg, yield = 95%).

¹ H NMR (CDCl3): 1.01 (s, 9H); 1.19 (t, J = 7.4Hz, 3H); 1.92 (m, 2H); 2.0 (bs, 3H); 2.56-2.66 (m,

6H); 3.71 (dd, J = 2.5 Hz, J2 = 8.7 Hz, 1H); 3.86 (t, 1H, J = 8.7Hz); 4.09 (dd, J = 8.7 Hz, J2 = 2.5 Hz, 1H); 4.73 (s, 4H), 6.75 (d, J = 8Hz, 1H); 6. 94-6.97 (m, 2H); 7.14 (d, J = 7.6 Hz, 1H); 7.19 (s. 1H);

7.28 (s. 1H).

Example: 2. 1- {4- [3- (3,4-Bishydroxymethylphenyl) propyl] -2-methylphenoxy} -3,3-dimethylbutan-2-ol

a. 4-Bromo-2-methylphenol

As in Example 1a, by reacting 10 g (91 mmol) of 2-methylphenol with 44 g (91 mmol) of tetrabutylammonium tribromide, a yellow oil was obtained (m = 16.3 g, yield = 95%).

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b. 4-Bromo-1-methoxymethoxy-2-ethylbenzene

As in Example 1b, by reacting 15 g (79 mmol) of 4-bromo-2-methylphenol with 3.5 g (87 mmol) of sodium hydride and 8.1 ml (87 mmol) of ethoxymethyl chloride, a yellow oil was obtained (m = 16.4 g, yield = 84%).

c. 4-Allyl-1-ethoxymethoxy-2-methylbenzene

As in Example 1c, by reacting 16 g (65 mmol) of 4-bromo-1-ethoxymethoxy-2-methylbenzene with 30 ml (97 mmol) of allyltributyltin and 1.35 g (2 mmol) of dichlorobis (triphenylphosphine) palladium, yellow was obtained. oil (m = 12.1 g, yield = 89%).

d. Dimethyl 4- [3- (4-methoxymethoxy-3-methylphenyl) propyl] phthalate

As in example 1e, by reacting 4.5 g (21.6 mmol) 4-allyl-1-ethoxymethoxy-2-methylbenzene with 6.3 g (25.7 mmol) 9-BBN, 7.4 g (21 6 mmol) dimethyl 4-trifluoromethanesulfonyloxyphthalate, 5.9 g (42.6 mmol) of potassium carbonate and 880 mg (1.05 mmol) of dichloropalladium diphosphinoferrocene give a yellow oil (m = 7 g, yield = 80%).

e. Dimethyl 4- [3- (3-Methyl-4-hydroxyphenyl) propyl] phthalate

As in Example 1f, by reacting 6.9 g (17.2 mmol) of dimethyl 4- [3- (4-ethoxymethoxy-3-methylphenyl) propyl] phthalate in 100 ml of methanol with 3 ml of concentrated sulfuric acid, a colorless oil was obtained. (m = 5.2 g; yield = 88%).

f. 4- {3- [4- (3,3-Dimethyl-2-oxobutoxy) -3-methylphenyl] propyl} dimethyl phthalate

As in example 1g, by reacting 900 mg (2.6 mmol) of dimethyl 4- [3- (3-methyl-4-hydroxyphenyl) propyl] phthalate with 400 mg (2.9 mmol) of potassium carbonate and 390 μΐ (2 , 9 mmol) of 1-bromo-pinacolone, a colorless oil is obtained (m = 910 mg; yield = 79%).

g. 1- {4- [3- (3,4-Bishydroxymethylphenyl) propyl] -2-methylphenoxy} -3,3-dimethylbutan-2-ol

As in example 1h, by reacting 900 mg (2.1 mmol) of 4- {3- [4- (3,3-dimethyl-2-oxobutoxy) -3-methylphenyl] propyl} dimethyl phthalate with 375 mg (10 mmol) ) of lithium aluminum hydride, a thick colorless oil was obtained (m = 780 mg, yield = 96%).

¹ H NMR (DMSO): 0.78 (s, 9H); 1.65-1.72 (m, 2H); 2.0 (s, 3H); 2.32-2. 44 (m, 4H); 3.30 (m, 1H); 3.61 (dd, 1H, J1 = 8.4Hz, J2 = 2.3Hz); 3.86 (dd, J1 = 8.4 Hz, J2 = 2.3 Hz, 1H); 4.36 (t, J = 6 Hz, 4H), 4.64 (d, J = 5.3 Hz, 1H); 4.82-4.91 (m, 2H); 6.68 (d, J = 8 Hz, 1H); 6.78-6.91 (m, 3H); 7.06-7.14 (m, 2H).

Example d 3. (4- {3- [3-Ethyl-4- (2-ethyl-2-hydroxybutoxy) phenyl] propyl} -2-hydroxy methylphenyl) methanol

a. 4- [3- (3,4-Bishydroxymethylphenyl) propyl] -2-ethylphenol

1.7 g (4.8 mmol) of dimethyl 4- [3- (3-ethyl-4-hydroxyphenyl) propyl] phthalate (example 1f) was dissolved in 50 ml of diethyl ether and this solution was slowly added to a suspension of 435 mg (11 4 millimoles) of lithium aluminum hydride. The medium was stirred for 30 minutes and then treated successively with 450 µl of water, 450 µl of 15% sodium hydroxide solution and 1.5 ml of water. The reaction medium is poured into a 1N hydrochloric acid solution and extracted with diethyl ether. A white solid is obtained (m = 1.2 g, mp = 82 ° C, yield = 84%).

b. ethyl (4- [3- (3,4-Bishydroxymethylphenyl) propyl] -2-ethylphenoxy} acetate

As in Example 1g, by reacting 1.1 g (3.7 mmol) of 4- (3- (3,4-bis-hydroxymethylphenyl) propyl] -2-ethylphenol with 560 mg (4 mmol) of potassium carbonate and 450 μl of ethyl bromoacetate , a colorless oil is obtained (m = 680 mg, yield = 48%).

c. (4- (3- [3-Ethyl-4- (2-ethyl-2-hydroxybutoxy) phenyl] propyl} -2-hydroxymethylphenyl) methanol

640 mg (1.65 mmol) of {4- [3- (3,4-bis-hydroxymethylphenyl) propyl] -2-ethylphenoxy} ethyl acetate were dissolved in 30 ml of THF. 2.2 ml (6.6 mmol) of a 3M solution of ethylmagnesium bromide were added dropwise. The reaction medium was stirred for 30 minutes and then treated with a saturated ammonium chloride solution. The residue obtained after extraction and concentration was purified by chromatography on a column of silica. A colorless oil is obtained (m = 510 mg, Y = 77%).

¹ H NMR (CDCl3): 0.94 (t, J = 7.6 Hz, 6H); 1.19 (t, J = 7.4Hz, 3H); 1.67 (q, J = 7.6 Hz, 4H); 1.92 (m, 2H); 2.15 (bs, 3H); 2.56-2.66 (m, 6H); 3.80 (s, 2H); 4.72 (s, 4H), 6.75 (d, J = 8Hz, 1H); 6.94-6.96 (m, 2H); 7.13 (d, J = 7.6 Hz, 1H); 7.18 (s. 1H); 7.27 (s. 1H).

Example 4. (4- {3- [4- (2-Ethyl-2-hydroxybutoxy) -3-methylphenyl] propyl} -2-hydroxymethylphenyl) methanol

a. 4- [3- (3,4-Bishydroxymethylphenyl) propyl] -2-methylphenol

As in example 3a, by reacting 1 g (2.9 mmol) of dimethyl 4- [3- (3-methyl-4-hydroxyphenyl) propyl] phthalate (example 2e) with 260 mg (7 mmol) of lithium aluminum hydride. a white solid is obtained (m = 740 mg, mp = 92 ° C, yield = 89%).

PL 209 011 B1

b. {4- [3- (3,4-Bishydroxymethylphenyl) propyl] -2-methylphenoxy} ethyl acetate

As in Example 3b, by reacting 720 mg (2.5 mmol) with 380 mg (2.7 mmol) of potassium carbonate and 310 μΐ (2.7 mmol) of ethyl bromoacetate, a colorless oil was obtained (m = 540 mg, yield = 58%).

c. (4- {3- [4- (2-ethyl-2-hydroxybutoxy) -3-methylphenyl] propyl} 2-hydroxymethylphenyl) methanol

As in example 3c, by reacting 530 mg (1.42 mmol) of {4- [3- (3,4-bis-hydroxymethylphenyl) propyl] -2-methylphenoxy} ethyl acetate with 2.4 ml (7 mmol) of a 3M bromide solution ethylmagnesium, a colorless oil is obtained (m = 410 mg, yield = 75%).

¹ H NMR (DMSO): 0.64 (t, J = 7.6 Hz, 6H); 1.33 (q, J = 7.4 Hz, 4H); 1.59-1.62 (m, 2H); 1.92 (s, 3H); 2.26-2.37 (m, 4H); 3.30 (m, 1H); 3.46 (s. 2H); 4.08 (s. 1H); 4.27-4. 31 (m, 4H); 4.77 (t, J = 5.3 Hz, 1H); 4.82 (t, J = 5.3 Hz, 1H); 6.58 (d, J = 8 Hz, 1H); 6.72-6. 74 (m, 2H); 6. 82-6.84 (m, 1H); 7.00 (s. 1H); 7.05 (d, J = 7.7 Hz, 1H).

Example 5. Preparations

1. Administered by the oral route (a) The following composition was prepared as a 0.2 g tablet:

Compound of example 2 .......................... 0.005 g

Pre-gelatinized starch ........... 0.065 g

Microcrystalline cellulose ..................... 0.075 g

Lactose ........................................ 0.050 g

Magnesium stearate ............................. 0.005 g

For the treatment of ichthyosis, an adult is given 1-3 tablets daily for 1-12 months depending on the severity of the treated case.

b) A suspension for drinking was prepared, intended for packaging in ampoules of 5 ml:

Compound of Example 3 ......................... 0.050 mg

Glycerin ..................................... 0.500 g

Sorbitol 70% .................................. 0.500 g

Sodium Saccharin .............................. 0.010 g Methyl p-Hydroxybenzoate ............ ........ 0.040 g

Fragrance q.s.

Purified water q.s.ad ...................... 5 ml

For the treatment of acne, an adult is given 1 ampoule daily for 1-12 months depending on the severity of the treated case.

c) The following preparation for the confectioning in gelatine capsules was prepared:

Compound of Example 4 ......................... 0.0001 mg

Corn starch .......................... 0.060 g

Lactose q.s .................................. 0.300 g

The gelatin capsules used consist of gelatin, titanium oxide and a preservative.

For the treatment of psoriasis, an adult is given 1 gelatin capsule daily for 1-12 months.

d) The following preparation was prepared for the packaging in gelatin capsules:

Compound of Example 1 ..................'....... 0.01 mg

Compound of Example 3 ......................... 0.01 mg

Cyclosporin .................................. 0.050 g

Corn starch .......................... 0.060 g

Lactose q.s .................................. 0.300 g

The gelatin capsules used consist of gelatin, titanium oxide and a preservative.

For the treatment of psoriasis, an adult is given 1 gelatin capsule daily for 1-12 months.

2. Applied by local road

a) The following non-ionic water-in-oil cream was prepared:

Compound of Example 3 ......................... 0.100 g

Mixture of emulsifying alcohols from lanolin, waxes and refined oils, sold by the Beiersdorf company under the name "Eucerine anhydre ........................... 39,900 g

PL 209 011 B1 Methyl p-Hydroxybenzoate ............... 0.075 g Propyl p-Hydroxybenzoate ................ ... 0.075 g

Demineralized sterile water q.s.ad ...... 100,000 g

This cream is applied to psoriatic skin once or twice a day for 1-12 months.

b) A gel was prepared with the following preparation:

Compound of Example 2 ......................... 0.001 g

Alkaline erythromycin ......................... 4,000 g

Butylated hydroxytoluene .......................... 0.050 g

Hydroxypropylcellulose marketed by Hercules under the name "Klucel HF .......... 2,000 g

Ethanol (95%) q.s.ad ......................... 100,000 g

This gel is applied to dermatosis or acne-prone skin 1-3 times a day for 6-12 weeks depending on the severity of the treated case.

c) An anti-seborrheic lotion was prepared by mixing the following ingredients:

Compound from Example 1 .......................... 0.030 g

Propylene glycol ............................. 5,000 g

Butylated hydroxytoluene ............................ 0.100 g

Ethanol (95%) q.s.ad .......................... 100,000 g

This lotion was applied twice a day to seborrhoeic skin and showed significant improvement over a period of 2-6 weeks.

d) A sun protection cosmetic composition was prepared by mixing the following ingredients:

Relationship from Example 3 ....................

Relationship from Example 4 ...................

Benzylidenecamphor .......................

Fatty acid triglycerides.

Glycerol Monostearate ................

Stearic acid............................

Cetyl alcohol .............................

Lanolin.......................................

Preservatives...................................

Propylene glycol .........................

Triethanolamine ..............................

Fragrance .........................

Demineralized water q.s.ad ....

0.500 g

0.500 g

4,000 g

31.000 g 6.000 g 2.000 g 1.200 g 4.000 g 0.300 g 2.000 g 0.500 g 0.400 g 100.000 g

This composition is applied daily to combat light-induced aging.

e) The following oil-in-water cream was prepared:

Compound of Example 4 .......................... 0.500 g

Retinoic acid ..................................

Cetyl alcohol ...............................

Glycerol monostearate .......................

PEG 50 stearate ..............................

Shea butter .....................................

Propylene glycol .............................

Methyl p-Hydroxybenzoate ...................

Propyl p-Hydroxybenzoate ..................

Demineralized sterile water q.s.ad.

0.020 g

4,000 g

2,500 g

2,500 g

9,200 g

2,000 g

0.075 g

0.075 g

100,000 g

This cream is applied to the psoriatic skin once or twice a day for 30 days with intensive treatment and unlimited maintenance.

PL 209 011 B1

f) A topical gel was prepared by mixing the following ingredients: Compound of Example 2 .......................... 0.050 g

Ethanol ........................................ 43,000 g α-Tocopherol .... ................................ 0.050 g

Carboxyvinyl polymer sold under the name "Carbopol 941 by Goodrich ............ 0.500 g

Triethanolamine in a 20% (by weight) aqueous solution of 3.800 g

Water ........................................... 9,300 g

Propylene glycol q.s.ad ................... 100,000 g

This gel is applied for the treatment of acne 1-3 times a day for 6-12 weeks depending on the severity of the treated case.

g) Prepare an anti-hair loss and regrowth lotion by mixing the following ingredients:

Compound from Example 4 .......................... 0.05 g

The compound sold under the name "Minoxidil ...... 1.00 g

Propylene glycol ..'.......................... 20.00 g

Ethanol ........................................ 34.92 g

Polyethylene glycol (MW = 400) .. 40.00 g

Butylhydroxyanisole ........................... 0.01 g

Butylhydroxytoluene ........................... 0.02 g

Q.s.ad water .................................. 100.00 g

This lotion is applied once or twice a day for 3 months to the hairy skin affected by hair loss and without restrictions for conservative treatment.

h) An anti-acne cream is made by mixing the following ingredients:

Compound of Example 1 ........................... 0.050 g

Retinoic acid ................................... 0.010 g

A mixture of glycerol stearates and polyethylene glycol (75 moles) sold under the name "Gelot 64 by the company Gattefosse .............. 15,000 g

Seed oil polyoxyethylene with 6 moles of ethylene oxide sold under the name "Labrafil M2130 CS by Gattefosse ...... 8,000 g

Perhydrosqualene ................................ 10,000 g

Preservatives .................................... q.s.

Polyethylene glycol (MW = 400) .... 8,000 g

Disodium salt of ethylenediaminetetraacetic acid 0.050 g Purified water q.s.ad ....................... 100,000 g

This cream is applied to the skin affected by dermatosis or acne prone skin 1-3 times a day for 6-12 weeks.

i) An oil-in-water cream was prepared with the following formulation:

Compound of Example 2 ........................... 0.020 g

Betamethasone 17-valerate ........... 0.050 g

S-carboxymethylcysteine ........................ 3 3,000 g

Polyoxyethylene stearate (40 moles of ethylene oxide) sold under the name "Myrj 52 by the company Atlas ................................. .... 4,000 g

Sorbitan monolaurate, polyoxyethylene with 20 moles of ethylene oxide, sold under the name "Tween 20 by Atlas .............. 1,800 g

A mixture of glycerol mono- and distearate sold under the name "Geleol by the company Gattefosse ...................................." .. 4,200 g

Propylene glycol ............................. 10.00 g

Butylhydroxyanisole ............................ 0.010 g

Butylhydroxytoluene ............................ 0.020 g

Cetyl stearyl alcohol ........................ 6,200 g

Preservatives ..................................... q.s.

Perhydrosqualene ................................ 18,000 g

A mixture of caprylic-capric triglycerides sold under the name "Miglyol 812 by the company."

PL 209 011 B1

Dynamite Nobel ................................... 4,000 g

Triethanolamine (99% by weight) ................... 2.500 g

Q.s.ad water ................................... 100,000 g

This cream is applied twice a day to the skin affected by inflammatory dermatosis for 30 days.

j) The following oil-in-water cream was prepared:

Lactic acid ..................................... 5,000 g

Compound of Example 1 ............................ 0.020 g

S-carboxymethylcysteine ......................... 3,000 g

Polyoxyethylene stearate (40 moles of ethylene oxide) sold under the name "Myrj 52 by the company Atlas ................................. ..... 4,000 g

Sorbitan monolaurate, polyoxyethylene with 20 moles of ethylene oxide, sold under the name "Tween 20 by Atlas ............... 1,800 g

A mixture of glycerol mono- and distearate sold under the name "Geleol by the company" Gattefosse ... " .. 4,200 g

Propylene glycol .............................. 10.00 g

Butylhydroxyanisole ............................. 0.010 g

Butylhydroxytoluene ............................. 0.020 g

Cetyl stearyl alcohol ......................... 6,200 g

Preservatives ...................................... q.s.

Perhydrosqualene ................................. 18,000 g

A mixture of caprylic-capric triglycerides sold under the name "Miglyol 812 by the company."

Dynamite Nobel ................................... 4,000 g

Q.s.ad water ................................... 100,000 g

This cream is applied once a day to help fight aging caused by light and time.

k) The following anhydrous lotion was prepared:

Compound of Example 3 ........................... 5,000 g

Paraffin oil ................................ 50.00 g

Butylhydroxytoluene ............................ 0.050 g

Vaseline .................................. q.s 100 g

This balm is applied 2 times a day to the skin affected by scaly dermatosis for 30 days.

3. Applied to inside disease lesions

a) The following composition was prepared:

Compound of Example 1 ........................... 0.002 g

Ethyl Oleate ............................. q.s.10 g

For the treatment of malignant melanoma, an adult is injected with the composition at a frequency of 1-7 times a week for 1-12 months.

b) The following composition was prepared:

Compound of Example 2 ........................... 0.050 g

Olive oil ............................ q.s ... 2 g

In the treatment of basal cell carcinoma, the composition is injected into an adult at a frequency of 1-7 times a week for 1-12 months.

c). The following composition was made:

Compound of Example 3 ........................... 0.1 mg

Sesame oil ............................. q.s ... 2 g

In the treatment of squamous cell carcinoma, an adult is injected with the composition at a frequency of 1-7 times a week for 1-12 months.

d) The following composition was prepared:

Compound of Example 4 .......................... 0.001 mg

Methyl benzoate ........................ q.s ... 10 g

In the treatment of colon cancer, an adult is injected with the composition at a frequency of 1-7 times a week for 1-12 months.

e) The following composition was prepared:

Compound of Example 2 ......................... 0.001 mg

Compound of Example 4 ......................... 0.001 mg

PL 209 011 B1

Ethyl Oleate ........................... q.s.10 g

In the treatment of malignant melanoma, an adult is injected with the composition at a frequency of 1-7 times a week for 1-12 months.

4. Administration by the intravenous route

a) The following lipid emulsion for injection was prepared:

Compound of Example 1 .......................... 0.001 mg

Soybean Oil ................................... 10,000 g

Egg phospholipid .............................. 1,200 g

Glycerin ...................................... 2,500 g

Water for injections q.s.ad ................... 100,000 g

For the treatment of psoriasis, an adult is injected with the composition at a frequency of 1-7 times a week for 1-12 months.

b) The following lipid emulsion for injection was prepared:

Compound from Example 3 .......................... 0.010 g

Cotton oil ................................ 10,000 g

Soybean lecithin ................................. 0.750 g

Sorbitol ....................................... 5,000 g (DL) -a-Tocopherol. .............................. 0.100 g

Water for injections q.s.ad ................... 100,000 g

In the treatment of ichthyosis, the composition is injected into an adult with a frequency of 1-7 times a week for 1-12 months.

c) The following lipid emulsion for injection was prepared:

Compound of Example 1 .......................... 0.001 g

Soybean Oil ................................... 15,000 g

Acetylated monoglycerides ..................... 10,000 g

Pluronic F-108 ................................. 1,000 g

Glycerol ....................................... 2,500 g

Water for injections q.s.ad ................... 100,000 g

For the treatment of leukemia, an adult is injected with the composition at a frequency of 1-7 times a week for 1-12 months.

d) The following mixed micellar composition was prepared:

Compound of example 2 .......................... 0.001 g

Lecithin ...................................... 16,930 g

Glycocholic acid .............................. 8.850 g

Water for injections q.s.ad ................... 100,000 g

For the treatment of malignant melanoma, an adult is injected with the composition at a frequency of 1-7 times a week for 1-12 months.

e) The following composition was made with cyclodextrin:

Compound of Example 1 .......................... 0.05 mg

Compound of Example 2 .......................... 0.05 mg β-Cyclodextrin ............. .................. 0.100 g

Water for injections q.s.ad ................... 100,000 g

For the treatment of transplant rejection, an adult is injected with a composition at a frequency of 1-7 times a week for 1-12 months.

f) The following composition was made with cyclodextrin:

Compound from Example 3 .......................... 0.010 g

2-Hydroxypropyl-e-cyclodextrin ............. 0.100 g

Water for injections q.s.ad ................... 100,000 g

In the treatment of kidney cancer, an adult is injected with the composition at a frequency of 1-7 times a week for 1-12 months.

P r z k ł a d 6

Assay for Evaluating the Biological Activity of Compounds of the Invention - Activity Against HL60 Cell Differentiation

Calcitriol induces the differentiation of promyelocytic leukemia (HL60) cells into monocytes / macrophages. This differentiation-inducing effect is a well-characterized marker of vitamin D in cells. Jed20

One of the most important macrophage antimicrobial products is hydrogen peroxide, which can be experimentally analyzed by reducing NBT (Nitroblue Tetrazolium).

The method used was as follows: HL60 cells were seeded in 6-well plates, then test compound was immediately added. After 4 days of culture, cells were incubated with phorbol TPA ester and NBT for a short period and differentiated cells, ie NBT positive, were counted.

The HL60 differentiation inducing effect by the compounds of the invention and by the reference compound, calcitriol, is shown in Table I.

The results show that the compounds of Examples 1 and 2 exhibit HL60 cell differentiation induction activity less than that of calcitriol; nevertheless, these AC50 values of the compounds of the invention are significant and show remarkable activity, in particular the compound of Example 1 in the differentiation of HL60 cells.

T a b l i c a I

Test compound AC50-HL60 (in nM) Calcitriol 10.7 The relationship of example 1 312

P r z k ł a d 7

Tests for the evaluation of biological activity of compounds according to the invention - measurement of VDR agonist activity (AC50 hVDR)

The VDR agonist activity of the compounds of the invention was tested in the HeLa cell line by co-transfection of the human VDR receptor expression vector and the p240HaseCAT reporter plasmid, which contains the region -1399 to +76 of the rat 24-hydroxylase promoter, cloned upstream of the phase coding for the chloramphenicol acetyl transferase (CAT) gene. 18 hours after cotransfection, the test compound was added to the medium. After 18 hours of treatment, the CAT activity of the cell lysates was determined by ELISA (Enzyme Linked Immuno Sorbent Essay, sold by Roche Molecular Biochemicals). The agonist activity in this co-transfection system was characterized by determining the dose required to obtain 50% of the maximum activity of the test compound (AC50).

The measurement of the VDR agonist activity of the compounds of the invention and the reference compound, calcitriol, is given in Table II.

As in Example 6, these results show that the compounds of the invention exhibit weaker activity than calcitriol, but nonetheless significant activity.

T a b l i c a II

Test compound AC50-hVDR (in nM) Calcitriol 2.5 The relationship of example 1 40 The relationship of example 2 172 Compound of Example 3 1211 Compound of Example 4 > 3000

P r z k ł a d 8

Assays for Evaluating the Biological Activity of Compounds of the Invention - Activity Against the Proliferation of Human Keratinocytes

1,25-dihydroxyvitamin D3, called calcitriol and corresponding to natural vitamin D, is known to inhibit the proliferation of human keratinocytes in culture.

The method used was as follows: normal human keratinocytes were seeded at low density in a 24-well plate. After 4 hours, test compounds were added to the culture medium. After 5 days of culture, keratinocyte proliferation was determined by introducing 5-bromo-2'-deoxyuridine (BrdU) into DNA. The amount of BrdU incorporated was then measured using an ELISA (Enzyme Linked Immuno Sorbent Essay, sold by Roche Molecular Biochemicals).

The keratinocyte proliferation inhibitory activity of the compounds of the invention and the calcitriol used as reference is given in Table III.

PL 209 011 B1

The IC50 value is the concentration of the test compound at which the compound inhibits 50% of keratinocyte proliferation.

These results show that the compounds of the invention exhibit a keratinocyte proliferation inhibitory activity less than calcitriol, but the compounds remain interesting compared to the state of the art.

T a b l i c a III

Activity measured IC50 - KHN proliferation (in nM) Calcitriol 15.3 The relationship of example 1 150 The relationship of example 2 140

Patent claims

Claims (13)

Patent claims 1.Biaromatic compounds that are vitamin D analogues, selected individually or in a mixture from the group consisting of: 1- {4- [3- (3,4-Bis-hydroxymethyl-phenyl) propyl] -2-ethyl-phenoxy} -3,3-dimethyl-butan-2-ol; 1- {4- [3- (3,4-Bis-hydroxymethyl-phenyl) propyl] -2-methyl-phenoxy} -3,3-dimethyl-butan-2-ol; (4- {3- [3-ethyl-4- (2-ethyl-2-hydroxybutoxy) phenyl] propyl} -2-hydroxymethylphenyl) methanol; (4- {3- [4- (2-ethyl-2-hydroxy-butoxy) -3-methyl-phenyl] -propyl} -2-hydroxymethyl-phenyl) methanol. 2. Compounds as defined in claim 1 for use as a medicament. 3. The use of one or more compounds as defined in claim 1, for the preparation of a pharmaceutical composition intended for the treatment of: - dermatological diseases related to disorders of the differentiation or proliferation of keratinocytes or sebaceous cells; - keratinization disorders; - dermatological diseases related to keratinization disorders with an inflammatory and / or immunoallergic component; - inflammatory diseases, showing no disorders of keratinization; - skin or epidermal proliferation; - dermatological disorders such as follicular dermatoses and collagen diseases; - signs of skin aging, whether caused by light or time, or to reduce pigmentation and radiation-induced hyperkeratosis, or any skin pathology associated with aging due to elapsed time or radiation; - scarring and stretch marks disorders; - disorders of the sebaceous function, such as excessive acne seborrhea, ordinary seborrhea or seborrheic eczema; - dermatological diseases with an immunological component. 4. Use according to claim 1 3. A method according to claim 3, wherein the dermatological conditions associated with disorders of keratinocyte or sebaceous cell differentiation or proliferation include acne vulgaris, acne comedones, polymorphic acne, rosacea, nodular cystic acne, cluster, senile acne, secondary acne, such as acne acne, drug acne, drug acne. . 5. Use according to claim 1 3. The method of claim 3, wherein the keratinization disorders include ichthyosis, ichthyosis-like conditions, Darier's disease, palmar-plantar keratosis, keratosis and keratosis-like conditions, skin or mucosa (oral) lichen. 6. Use according to claim 1 The method of claim 3, wherein the dermatological disorders associated with keratinization disorders with an inflammatory and / or immunoallergic component include all forms of skin, mucosa or nail psoriasis, psoriatic rheumatism and skin atopy such as eczema or respiratory atopy, or gingival hyperplasia. Use according to claim 1 3. wherein the skin or epidermal proliferation can be benign or malignant, viral or non-viral in origin, such as common warts, flat warts and wart-like epidermal dysplasia, oral or red papillomatosis, and wherein the proliferation can be induced by ultraviolet rays, especially in the case of basal and squamous cell epithelioma. PL 209 011 B1 8. A pharmaceutical composition, characterized in that it comprises, on a pharmaceutically acceptable support, at least one of the compounds as defined in claim 1. 9. A composition according to p. The composition of claim 8, characterized in that it comprises a concentration of the compound (s) as defined in claim 1 of 0.001-5% by weight based on the total weight of the composition. 10. A cosmetic composition, characterized in that it comprises, on a cosmetically acceptable base, at least one of the compounds as defined in claim 1. 11. The composition according to p. The composition of claim 10, wherein the concentration of the compound (s) is 0.001-3% by weight based on the total weight of the composition. 12. Cosmetic use of a composition according to any one of claims 1 to 12 10 and 11, for body or hair hygiene. 13. Cosmetic use of a composition according to any one of claims 10 and 11, for preventing and / or combating skin aging induced by light or the passage of time.