Title of Invention

NOVEL COMPOUND, A COMPSITION COMPRISING SUCH NOVEL COMPOUND AND A PROCESS THEREOF"

Abstract The invention relates, as new and useful industrial products, to briaromatic compounds, which are analogues of vitamin D, of general formula (I): Q,A~R 2 R4 R ~ R 4T~B OH(I) HO and to their method of preparation and to their use in pharmaceutical compositions intended for use in human or veterinary medicine, or alternatively in cosmetic compositions.
Full Text The invention relates,, as new and useful industrial products, to biaromatic compounds which are analogues of vitamin D.
The invention also relates to the process for their preparation and their us'e in pharmaceutical compositions intended for use in human or veterinary medicine, or alternatively in cosmetic compositions.
The new family of compounds according to the invention includes compounds which have a marked activity in the fields of cell differentiation and proliferation and find applications more particularly in the topical and systemic treatment of dermatological conditions (and the like) linked to a keratinization disorder, of conditions with an inflammatory and/or immunoallergic components and of hyperproliferation of tissues of ectodermal origin (skin, epithelium and the like), whether benign or malignant. These compounds may, in addition, be used to combat skin ageing, whether photoinduced or chronologic, and to treat cicatrization disorders.
It is also possible to use the compounds according to the invention in cosmetic compositions for body and hair hygiene.
Vitamin D is an essential vitamin for the prevention and treatment of defects in the mineralization of cartilage (rickets), and of bone (osteomalacia), and even of certain forms of
osteoporosis in the elderly subject. However, it is now accepted that its functions extend well beyond the regulation of bone metabolism and of calcium homeostasis. Among these, there may be mentioned its actions on cell proliferation and differentiation and the control of the immune defences. Their discovery has opened the way for new therapeutic approaches in dermatology, cancerology as well as in the field of autoimmune diseases and that of organ and tissue transplants.
An effective therapeutic application has for long been hampered by the toxicity of this vitamin (hypercalcaemia which is sometimes fatal). Currently, structural analogues of vitamin D are synthesized, some of which conserve only the differentiating properties and have no action on calcium metabolism.
Patent application WO 00/10958 describes vitamin D3-mimetic nonsecosteroidal biaromatic compounds, which are ligands for the VDR receptor. These compounds find applications in the treatment of pathologies linked to the deregulation of calcium metabolism. However, the general structure of these compounds is substantially different from that of the compounds of our invention; indeed, the two aromatic rings of the compounds described in the document ' WO 00/10958 are linked to each other by a carbon atom whereas for the compounds of our invention, the two
aromatic rings are linked by a chain comprising three atoms.
Likewise, patent applications 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 analogues of vitamin D. These three families of compounds exhibit, here again, chemical structures which are quite different from that of the compounds of the present invention.
The Applicant has therefore identified a new family of compounds which are analogues of vitamin D, exhibiting a marked biological activity, in particular in tests for activity on the differentiation of HL60 cells and for proliferation of human keratinocytes, and on the test for VDR agonist activity.
Thus, the present invention relates to
compounds of the following general formula (I);
(Formula Removed)
in which:
- A-Q represents an unsubstituted alkyne or alkene
bond, a -CH2-0-, a -CH2-S- or -CH2-CH2- bond;
- B-T represents an unsubstituted alkyne or alkene
bond, a -CH2-S-, -CH2-0-, -CH2-CH2- or -CH2-NR6- bond;
Re having the meanings given below,
- RI and R2, which are identical or different,
represent a hydrogen atom, a linear or branche.d alkyl
radical having 1 to 5 carbon atoms or -the radical
-CF2R5;
- R3 represents a linear or branched alkyl radical
having 1 to 5 carbon atoms or the radical CF2R5;
R5 having the meanings given below,
- the radicals R4 are identical and represent a
hydrogen atom, a linear or branched alkyl radical
having 1 to 6 carbon atoms, the radical -CF2R5, the two
radicals may also form a saturated ring having 4 to 7
carbon atoms, a saturated heterocycle such as furan,
pyran, pyrrolidine substituted on the nitrogen with a
radical R7 or piperidine substituted on the nitrogen
with a radical R7;
R-7 having the meanings given below,
- R5 represents a fluorine atom, a hydrogen atom
or a radical -CF3;
- RS represents a hydrogen atom, a linear or
branched alkyl radical having 1 to 6. carbon atoms or
the radical -C(O)R8;
R8 having the meanings given below,
- R7 and R8, which are identical or different, represent a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms; and their optical and geometric isoruers, and their salts.
The invention embraces mixtures of optical isomers and geometrical isomers, including racemic mixtures.
In the case of the compounds described above comprising a nitrogen atom, the present invention also relates to these compounds when they are in the form of cosmetically or pharmaceutically acceptable salts, as salts of an inorganic or organic acid, in particular hydrochloric, sulphuric, acetic, fumaric, hemisuccinic, maleic and mandelic acid.
The expression linear or branched alkyl radical having 1 to 5 carbon atoms is understood to mean preferably a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, 1-methylbutyl, 3-methylbutyl or 2,2-dimethylbutyl radical.
The expression linear or branched alkyl radical having 1 to 6 carbon atoms is understood to mean preferably a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, 1-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 4-methylpentyl or 3,3-dimethylbutyl radical.
The expression saturated ring having 4 to 7 carbon atoms is understood to mean a cyclobutyl, a cyclopentyl, a cyclohexyl or a cycloheptyl.
Among the compounds of formula (I) falling within the scope of the present invention, the following may be mentioned in particular:
1- l-{4-[3-(3,4-Bis-hydroxymethyl-phenyl)-propyl]-2-
ethyl-phenoxy}-3,3-dimethyl-butan-2-ol;
2- l-{4-[3-(3,4-Bis-hydroxymethyl-phenyl)-propyl]-2-
methyl-phenoxy}-3,3-dimethyl-butan-2-ol; •

3- (4-{3-[3-ethyl-4-(2-ethyl-2-hydroxy-butoxy)-phenyl]-
propyl}-2-hydroxymethyl-phenyl)-methanol;
4- (4-{3-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-
phenyl]-propyl}-2-hydroxymethyl-phenyl)-methanol;
5- (2-hydroxymethyl-4-{3-[4-(2-hydroxy-3-methyl-
butoxy)-3-methyl-phenyl]-propyl}-phenyl)-methanol;
6- (4-{3-[3-ethyl-4-(2-hydroxy-3-methyl-butoxy)-
phenyl]-propyl}-2-hydroxymethyl-phenyl)-methanol;
7- (2-hydroxymethyl-4-{3-[4-(2-hydroxy-3-methyl-
butylsulphanyl)-3-methyl-phenyl]-propyl}-phenyl)-
methanol;

8- (4-{3-[3-ethyl-4-(2-hydroxy-3-methyl-
butylsulphanyl)-phenyl]-propyl}-2-hydroxymethyl-
phenyl) -methanol;
9- (2-hydroxymethyl-4-{3-[4-(3-hydroxy-4-methyl-
pentyl)-3-methyl-phenyl]-propyl}-phenyl)-methanol;

10- (4-{3-[3-ethyl-4-(3-hydroxy-4-methyl-pentyl)-
phenyl]-propyl}-2-hydroxymethyl-phenyl)-methanol;
11- (E)-1-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-propyl]
2-methyl-phenyl}-4-methyl-pent-l-en-3-ol;
12- (E)-l-{4- [3-(3,4-bis-hydroxymethyl-phenyl)-propyl]-
2-ethyl-phenyl}-4-methyl-pent-l-en-3-ol;
13- (4-{3-[4-(2-hydroxy-3,3-dimethyl-butylsulphanyl)-3-
methyl-phenyl]-propyl}-2-hydroxymethyl-phenyl)-
methanol;
14- (4-{3-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-
butylsulphanyl) -phenyl]-propyl}-2-hydroxymethyl-
phenyl)-methanol;
15- (4-{3- [4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-
pheny1]-propyl}-2-hydroxymethyl-phenyl)-methanol;

16- (4-{3-[3-ethyl-4-(3-hydroxy-4,4-dimethyl-pentyl)-
phenyl]-propyl}-2-hydroxymethyl-phenyl)-methanol;
17- (E) -l-{.4- [3- (3, 4-bis-hydroxymethyl-phenyl) -propyl] -
2-methyl-phenyl}-4,4-dimethyl-pent-l-en-3-ol;
18- (E)-l-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-propyl]-
2-ethyl-phenyl}-4,4-dimethyl-pent-l-en-3-ol;
19- (2-hydroxymethyl-4-{3-[3-methyl-4-(3,3,3-trifluoro-
2-hydroxy-propoxy)-phenyl]-propyl}-phenyl)-methanol;
20- (4-{3-[3-ethyl-4-(3,3,3-trifluoro-2-hydroxy-
propoxy)-phenyl]-propyl}-2-hydroxymethyl-phenyl)-
methanol;

21- (2-hydroxymethyl-4-{3-[3-methyl-4-(3,3,3-trifluoro-
2-hydroxy-propylsulphanyl)-phenyl]-propyl}-phenyl)-
methanol;
22- (4-{3-[3-ethyl-4-(3,3,3-trifluoro-2-hydroxy-
propylsulphanyl)-phenyl]-propyl}-2-hydroxymethyl-
phenyl) -methanol;
23- (2-hydroxymethyl-4-{3-[3-methyl-4-(4, 4,4-trifluoro-
3-hydroxy-butyl)-phenyl]-propy1}-phenyl)-methanol;
24- (4-{3-[3-ethyl-4-(4,4,4-trifluoro-3-hydroxy-butyl)-
phenyl]-propyl}-2-hydroxymethyl-phenyl)-methanol;
25- (2-hydroxymethyl-4-{3-[3-methyl-4-((E)-4,4,4-
trifluoro-3-hydroxy-but-l-enyl)-phenyl]-propyl}-
phenyl)-methanol;
26- (4-{3-[3-ethyl-4-((E)-4,4,4-trifluoro-3-hydroxy-
but-1-enyl)-phenyl]-propyl}-2-hydroxymethyl-phenyl)-
methanol;

27- (2-hydroxymethyl-4-{3-[3-methyl-4-(4,4,4-trifluoro-
2-hydroxy-3-trifluoromethyl-butoxy)-phenyl]-propyl}-
phenyl)-methanol;
28- (4-{3-[3-ethyl-4~(4,4,4-trifluoro-2-hydroxy-3-
trifluoromethyl-butoxy)-phenyl]-propyl}-2-
hydroxymethyl-phenyl)-methanol;
29- (2-hydroxymethyl-4-{3-[3-methyl-4-(4,4,4-trifluoro-
2-hydroxy-3-trifluoromethyl-butylsulphanyl)-phenyl] -
propyl}-phenyl)-methanol;
30- (4-{3-[3-ethyl-4-(4,4,4-trifluoro-2-hydroxy-3-
trifluoromethyl-butylsulphanyl)-phenyl]-propyl}-2-
hydroxymethyl-phenyl)-methanol;

31- (2-hydroxymethyl-4-{3- [methyl-(5,5,5-trifluoro-3-
hydroxy-4-trifluoromethyl-pentyl)-phenyl]-propyl}-
phenyl)-methanol;
32- (4-{3-[ethyl-(5,5,5-trifluoro-3-hydroxy-4-
trifluoromethyl-pentyl)-phenyl]-propyl}-2-'
hydroxymethyl-phenyl)-methanol;
33- (E)-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-propyl]-2-
methyl-phenyl}-5,5,5-trifluoro-4-trifluoromethyl-pent-
l-en-3-ol;
34- (E)-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-propyl]-2-
ethyl-phenyl}-5f 5,5-trifluoro-4-trifluoromethyl-pent-1-
en-3-ol;
35- (2-hydroxymethyl-4-{3-[4-(2-hydroxy-3-methyl-
butoxy)-3-methyl-phenyl]-3-raethyl-butyl}-phenyl)-
methanol;

36- (4-{3-[3-ethyl-4-(2-hydroxy-3-methyl-butoxy)-
phenyl]-3-methyl-butyl}-2-hydroxymethyl-phenyl)-
methanol;
37- (2-hydroxymethyl-4-{3-[4-(2-hydroxy-3-methyl-
butylsulphanyl)-3-methyl-phenyl]-3-methyl-butyl}-
phenyl)-methanol;
38- (4-{3-[3-ethyl-4- (2-hydroxy-3-methyl-
butylsulphanyl)-phenyl]-3-methyl-butyl}-2-
hydroxymethyl-phenyl)-methanol;

39- (2-hydroxymethyl-4-{3-[4-(3-hydroxy-4-methyl-
pentyl)-3-methyl-phenyl]-3-methyl-butyl}-phenyl)-
methanol;
40- (4-{3-[3-ethyl-4- (3-hydroxy-4-methyl-pentyl)-
phenyl]-3-methyl-butyl}-2-hydroxymethyl-phenyl)-
methanol;
41- (E)-l-{4-[3-(3,4-bis-hydroxymethyl~phenyl)-I,I-
dimethyl-propyl]-2-methyl-phenyl}-4-methyl-pent-l-en-3-
ol;
42- (E)-l-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-1,1-
dimethyl-propyl]-2-ethyl-phenyl}-4-methyl-pent-l-en-3-
ol;
43- (4-{3-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-
phenyl]-3-methyl-butyl}-2-hydroxymethyl-phenyl)-
methanol;
44- (4-{3-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-butoxy)-
phenyl]-3-methyl-butyl}-2-hydroxymethyl-phenyl)-
methanol;
45- (4-{3-[4-(2-hydroxy-3,3-dimethyl-butylsulphanyl)-3-
methyl-phenyl]-3-methyl-butyl}-2-hydroxymethyl-phenyl)-
methanol;

46- (4-(3-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-
butylsulphanyl) -phenyl]-3-methyl-butyl}-2-
hydroxymethyl-phenyl)-methanol;
47- (4-{3-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-
phenyl]-3-methyl-butyl}-2-hydroxymethyl-phenyl) -
methanol;
48- (4-{3-[3-ethyl-4-(3-hydroxy-4,4-dimethyl-pentyl)-
phenyl]-3-methyl-butyl}-2-hydroxymethyl-phenyl)-
methanol;
49- (E)-l-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-1,1-
dimethyl-propyl]-2-methyl-phenyl}-4,4-dimethyl-pent-l-
en-3-ol;
50- (E)-l-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-1,1-
dimethyl-propyl]-2-ethyl-phenyl}-4,4-dimethyl-pent-1-
en-3-ol;
51- (4-{3-ethyl-3-[4-(2-hydroxy-3-me.thyl-butoxy) -3-
methyl-phenyl]-pentyl}-2-hydroxymethyl-phenyl)-
methanol;
52- (4-{3-ethyl-3-[3-ethyl-4-(2-hydroxy-3-methyl-
butoxy)-phenyl]-pentyl}-2-hydroxymethyl-phenyl)-
methanol;
53- (4-{3-ethyl-3-[4-(2-hydroxy-3-methyl-
butylsulphanyl)-3-methyl-phenyl]-pentyl}-2-
hydroxymethyl-phenyl)-methanol;

54- (4-{3-ethyl-3-[3-ethyl-4-(2-hydroxy-3-methyl-
butylsulphanyl)-phenyl]-pentyl}-2-hydroxymethyl-
phenyl) -methanol;
55- (4-{3-ethyl-3-[4-(3-hydroxy-4-methyl-pentyl)-3-
methyl-phenyl]-pentyl}-2-hydroxymethyl-phenyl)-
methanol;
56- (4-{3-ethyl-3-[3-ethyl-4-(3-hydroxy-4-methyl-
pentyl)-phenyl]-pentyl}-2-hydroxymethyl-phenyl)-
methanol;

57- (E)-l-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-1,1-
diethyl-propyl]-2-methyl-phenyl}-4-methyl-pent-l-en-3-
ol;
58- (E)-l-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-1,1-
diethyl-propyl] -2-ethyl-phenyl }-4-methyl-pent-l-e'n-3-
ol;
59- (4-{3~ethyl-3-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-
methyl-phenyl]-pentyl}-2-hydroxymethyl-phenyl)-
methanol;
60- (4-{3-ethyl-3-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-
butoxy)-phenyl]-pentyl}-2-hydroxymethyl-phenyl)-
methanol;
61- (4-{3-ethyl-3-[4-(2-hydroxy-3,3-dimethyl~
butylsulphanyl)-3-methyl-phenyl]-pentyl}-2-
hydroxymethyl-phenyl)-methanol;
62- (4-{3-ethyl-3-[3-ethyl-4-{2-hydroxy-3,3-dimethyl-
butylsulphanyl)-phenyl]-pentyl}-2-hydroxymethyl-
phenyl )-methanol ;
63- (4-{3-ethyl-3-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-
methyl-phenyl]-pentyl}-2-hydroxymethyl-phenyl)-
methanol;

64- (4-{3-ethyl-3-[3-ethyl-4-(3-hydroxy-4,4-dimethyl-
pentyl)-phenyl]-pentyl}-2-hydroxymethyl-phenyl)-
methanol;
65- (E)-l-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-l,l-
diethyl-propyl]-2-methyl-phenyl}-4,4-dimethyl-pent-l-
en-3-ol;
66- (E)-l-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-l,l-
diethyl-propyl]-2-ethyl-phenyl}-4,4-dimethyl-pent-l-en-
3-ol;
67- [2-hydroxymethyl-4-(2-{l-[4-(2-hydroxy-3-methyl-
butoxy)-3-methyl-phenyl]-cyclopentyl}-ethyl)-phenyl]-
methanol;
68- [4-(2-{1-[3-ethyl-4-(2-hydroxy-3-methyl-butoxy)-
phenyl]-cyclopentyl}-ethyl)-2-hydroxymethyl-phenyl]-
methanol;
69- [2-hydroxymethyl-4-(2-{l-[4-(2-hydroxy-3-methyl-
butylsulphanyl)-3-methyl-phenyl]-cyclopentyl}-ethyl)-
phenyl]-methanol;
70- [4-(2-{l-[3-ethyl-4-(2-hydroxy-3-methyl-
butylsulphanyl)-phenyl]-cyclopentyl}-ethyl)-2-
hydroxymethyl-phenyl]-methanol;
71- [2-hydroxymethyl-4-(2-{l-[4-(3-hydroxy-4-methyl-
pentyl)-3-methyl-phenyl]-cyclopentyl}-ethyl)-phenyl]-
methanol;
72- [4-(2-{l-[3-ethyl-4-(3-hydroxy-4-methyl-pentyl)-
phenyl]-cyclopentyl}-ethyl)-2-hydroxymethyl-phenyl]-
methanol;

73- (E)-1-(4-{1-[2-(3,4-bis-hydroxymethyl-phenyl)-
ethyl]-cyclopentyl}-2-methyl-phenyl)-4-methyl-pent-1-
en-3-ol;
74- (E)-l-(4-{1-[2-(3,4-bis-hydroxymethyl-phenyl) -
ethyl]-cyclopentyl}-2-ethyl-phenyl}-4-methyl-pent-1-en-
3-ol;
75- [4-(2-{l-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-
methyl-phenyl]-cyclopentyl}-ethyl)-2-hydroxymethyl-
phenyl] -methanol;
76- [4-(2-{l-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-
butoxy)-phenyl]-cyclopentyl}-ethyl)-2-hydroxymethyl-
phenyl ] -methanol ;
77- [4-(2-{l-[4-(2-hydroxy-3,3-dimethyl-butylsulphanyl-
3-methyl-phenyl]-cyclopentyl}-ethyl)-2-hydroxymethyl-
phenyl ]-methanol;
78- [4-(2-{l-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-
butylsulphanyl)-phenyl]-cyclopentyl}-ethyl)-2-
hydroxymethyl-phenyl]-methanol;
79- [4-(2-{l-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-
methyl-phenyl]-cyclopentyl}-ethyl)-2-hydroxymethyl-
phenyl]-methanol;
80- [4-(2-{l-[3-ethyl-4-(3-hydroxy-4, 4-dimethyl-
pentyl)-phenyl]-cyclopentyl}-ethyl)-2-hydroxymethyl-
phenyl]-methanol;
81- (E)-1- (4-{l-[2-(3,4-bis-hydroxymethyl-phenyl)-
ethyl]-cyclopentyl}-2-methyl-phenyl)-4, 4-dimethyl-pent-
l-en-3-ol;

82- (E)-I-(4-{1-[2-(3,4-bis-hydroxymethyl-phenyl)-
ethyl]-cyclopentyl}-2-ethyl-phenyl)-4, 4-dimethyl-pent-
l-en-3-ol;
83- [2-hydroxymethyl-4-(2-{1-[4-(2-hydroxy-3-methyl-
butoxy)-3-methyl-phenyl]-cyclohexyl}-ethyl)-phenyl]-
methanol;
84- [4-(2-{l-[3-ethyl-4-(2-hydroxy-3-methyl-butoxy)-
phenyl]-cyclohexyl}-ethyl)-2-hydroxymethyl-phenyl]-
methanol;
85- [2-hydroxymethyl-4-(2-{1-[4-(2-hydroxy-3-methyl-
butylsulphanyl)-3-methyl-phenyl]-cyclohexyl}-ethyl)-
phenyl]-methanol;
86- [4-(2-{l-[3-ethyl-4-(2-hydroxy-3-methyl-
butylsulphanyl) -phenyl] -cyclohexyl} -ethyl) -2-
hydroxymethyl-phenyl] -methanol;
87- [2-hydroxymethyl-4-(2-{l-[4-(3-hydroxy-4-methyl-
pentyl)-3-methyl-phenyl]-cyclohexyl}-ethyl)-phenyl] -
methanol;
88- [4-(2-{1-[3-ethyl-4-(3-hydroxy-4-methyl-pentyl)-
phenyl]-cyclohexyl}-ethyl)-2-hydroxymethyl-phenyl]-
•methanol;
89- (E)-l-(4-{l-[2-(3,4-bis-hydroxymethyl-phenyl)-
ethyl]-cyclohexyl}-2-methyl-phenyl)-4-methyl-pent-1-en-
3-ol;

90- (E)-1-(4-{l-[2-(3,4-bis-hydroxymethyl-phenyl) -
ethyl]-cyclohexyl}-2-ethyl-phenyl)-4-methyl-pent-l-en-
3-ol;
91- [4-(2-{l-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-
methyl-phenyl]-cyclohexyl}-ethyl)-2-hydroxymethyl-
phenyl ]-methanol;
92- [4-(2-{l-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-
butoxy)-phenyl]-cyclohexyl}-ethyl)-2-hydroxymethyl-
phenyl] -methanol;
93- [4-(2-{l-[4-(2-hydroxy-3,3-dimethyl-
butylsulphanyl)-3-methyl-phenyl]-cyclohexyl}-ethyl)-2-
hydroxymethyl-phenyl]-methanol;

94- [4-(2-{1-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-
butylsulphanyl)-phenyl]-cyclohexyl}-ethyl)-2-
hydroxymethyl-phenyl]-methanol;
95- [4-(2-{l-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-
methyl-phenyl]-cyclohexyl}-ethyl)-2-hydroxymethyl-
phenyl] -methanol;
96- [4-(2-{l-[3-ethyl-4-(3-hydroxy-4,4-dimethyl-
pentyl)-phenyl]-cyclohexyl}-ethyl)-2-hydroxymethyl-
phenyl]-methanol;
97- (E)-1-(4-{1-[2-(3,4-bis-hydroxymethyl-phenyl)-
ethyl]-cyclohexyl}-2-methyl-phenyl)-4,4-dimethyl-pent-
l-en-3-ol;
98- (E)-1-(4-{1-[2- (3,4-bis-hydroxymethyl-phenyl)-
ethyl]-cyclohexyl}-2-ethyl-phenyl)-4,4-dimethyl-pent-l-
en-3-ol;
99- (4-{2-ethyl-2-[4-(2-hydroxy-3-methyl-butoxy)-3-
methyl-phenyl]-butoxy}-2-hydroxymethyl-phenyl)-
methanol;

100- (4-{2-ethyl-2-[3-ethyl-4-(2-hydroxy-3-methyl-
butoxy) -phenyl] -but oxy}-2-rhydroxymethyl-phenyl) -
methanol;
101- (4-{2-ethyl-2-[4-(2-hydroxy-3-methyl-
butylsulphanyl)-3-methyl-phenyl]-butoxy}-2-
hydroxymethyl-phenyl)-methanol;
102- (4-{2-ethyl-2-[3-ethyl-4-(2-hydroxy-3-methyl-
butylsulphanyl)-phenyl]-butoxy}-2-hydroxymethyl-
phenyl)-methanol;
103- (4-{2-ethyl-2- [4- (3-hydroxy-4-methyl-pentyl)-3-
methyl-phenyl]-butoxy}-2-hydroxymethyl-phenyl)-
methanol;
104- (4-{2-ethyl-2- [3-ethyl-4-(3-hydroxy-4-methyl-
pentyl) -phenyl]-butoxy}-2-hydroxymethyl-phenyl)-
methanol;
105- (E)-l-{4-[1- (3, 4-bis-hydroxymethyl-phenoxymethyl)-
l-ethyl-propyl]-2-methyl-phenyl}-4-methyl-pent-l-en-3-
ol;
106- (E)-l-{4-[1-(3, 4-bis-hydroxymethyl-phenoxymethyl)-
l-ethyl-propyl]-2-ethyl-phenyl}-4-methyl-pent-l-en-3-
ol;
107- (4-{2-ethyl-2-[4-(2-hydroxy-3,3-dimethyl-butoxy)-
3-methyl-phenyl]-butoxy}-2-hydroxymethyl-phenyl)-
methanol;
108- (4-{2-ethyl-2-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-
butoxy)-phenyl]-butoxy}-2-hydroxymethyl-phenyl)-
methanol;
109- (4-{2-ethyl-2-[4-(2-hydroxy-3,3-dimethyl-
butylsulphanyl)-3-methyl-phenyl]-butoxy}-2-
hydroxymethyl-phenyl)-methanol;
110- (4-{2-ethyl-2-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-
butylsulphanyl)-phenyl]-butoxy}-2-hydroxymethyl-
phenyl)-methanol;
111- (4-{2-ethyl-2-[4-(3-hydroxy-4,4-dimethyl-pentyl)-
3-methyl-phenyl]-butoxy}-2-hydroxymethyl-phenyl)-
methanol;

112- (4-{2-ethyl-2-[3-ethyl-4-(3-hydroxy-4,4-dimethyl-
pentyl)-phenyl]-butoxy}-2-hydroxymethyl-phenyl)-
methanol;
113- (E)-l-{4-[1-(3,4-bis-hydroxymethyl-phenoxymethyl) -
l-ethyl-propyl]-2-methyl-phenyl}-4,4-dimethyl-pent-l-
en-3-ol;
114- (E)-l-{4-[l-(3,4-bis-hydroxymethyl-phenoxymethyl)-
1-ethyl-propyl]-2-ethyl-phenyl}-4,4-dimethyl-pent-l-en-
3-ol;
115- (4-{(E)-3-ethyl-3-[4-2-hydroxy-3-methyl-butoxy)-3-
methyl-phenyl]-pent-l-enyl}-2-hydroxymethyl-phenyl)-
methanol;
116- (4-{(E)-3-ethyl-3-[3-ethyl-4-(2-hydroxy-3-methyl-
butoxy)-phenyl]-pent-l-enyl}-2-hydroxymethyl-phenyl)-
methanol;
117- (4-{(E)-3-ethyl-3-[4-(2-hydroxy-3-methyl-
butylsulphanyl)-3-methyl-phenyl]-pent-l-enyl}-2-
hydroxymethyl-phenyl)-methanol;

118- (4-{(E)-3-ethyl-3-[3-ethyl-4-(2-hydroxy-3-methyl-
butylsulphanyl)-phenyl]-pent-l-enyl}-2-hydroxymethyl-
pheny1)-methanol;
119- (4-{(E)-3-ethyl-3-[4-(3-hydroxy-4-methyl-pentyl)-
3-raethyl-phenyl]-pent-l-enyl}-2-hydroxymethyl-phenyl)-
methanol;
120- (4-{(E)-3-ethyl-3-[3-ethyl-4-(3-hydroxy-4-methyl~
pentyl)-phenyl]-pent-1-enyl}-2-hydroxymethyl-phenyl)-
methanol;
121- (E)-l-{4-[(E)-3-(3,4-bis-hydroxymethyl-phenyl)-
1, l-di-ethyl-allyl]-2-methyl-phenyl}-4-methyl-pent-l-en-3-ol;
122- (E)-l-{4-[(E)-3-(3,4-bis-hydroxymethyl-phenyl)-
1,1-diethyl-allyl]-2-ethyl-phenyl}-4-methyl-pent-l-en-3-ol;
123- (4-{(E)-3-ethyl-3-[4-(2-hydroxy-3,3-dimethyl-
butoxy)-3-methyl-phenyl]-pent-1-enyl}-2-hydroxymethyl-
phenyl)-methanol;
124- (4-{ (E)-3-ethyl-3-[3-ethyl-4-(2-hydroxy-3,3-
dimethyl-butoxy)-phenyl]-pent-1-enyl}-2-hydroxymethyl-
phenyl)-methanol;
125- (4-{(E)-3-ethyl-3-[4-(2-hydroxy-3,3-dimethyl-
butylsulphanyl)-3-methyl-phenyl]-pent-1-enyl}-2-
hydroxymethyl-phenyl)-methanol;

126- (4-{ (E)-3-ethyl-3-[3-ethyl-4-(2-hydroxy-3,3-
dimethyl-butylsulphanyl)-phenyl]-pent-1-enyl}-2-
hydroxymethyl-phenyl)-methanol;
127- (4-{(E)-3-ethyl-3-[4-(3-hydroxy-4,4-dimethyl-
pentyl)-3-methyl-phenyl]-pent-1-enyl}-2-hydroxymethyl-
phenyl)-methanol;
128- (4-{ -(E) -3-ethyl-3- [3-ethyl-4- (3-hydroxy-4, 4-
dimethyl-pentyl)-phenyl]-pent-1-enyl}-2-hydroxymethyl-
phenyl)-methanol;
129- (E)-l-{4-[(E)-3-(3,4-bis-hydroxymethyl-phenyl)-
1,1-diethyl-allyl]-2-methyl-phenyl}-4,4-dimethyl-pent-l-en-3-ol;
130- (E)-l-{4-[(E)-3-(3,4-bis-hydroxymethyl-phenyl)-
1,1-diethyl-allyl]-2-ethyl-phenyl}-4,4-dimethyl-pent-l-en-3-ol;
131- (4-{3-[3-ethyl-4-(3,3,3-trifluoro-2-hydroxy-
propoxy)-phenyl]-3-methyl-butyl}-2-hydroxymethyl-
phenyl)-methanol;
132- (4-{3-[3-ethyl-4-(3, 3, 3-trifluoro-2-hydroxy-
propylsulphanyl)-phenyl]-3-methyl-butyl}-2-
hydroxymethyl-phenyl)-methanol;
133- (4-{3-[3-ethyl-4-(4,4,4-trifluoro-3-hydroxy-
butyl)-phenyl]-3-methyl-butyl}-2-hydroxymethyl-phenyl)
methanol;
134- (4-{3-[3-ethyl-4-((E)-4,4,4-trifluoro-3-hydroxy-
but-1-enyl)-phenyl]-3-methyl-butyl}-2-hydroxymethyl-
phenyl) -methanol;

135- (4-{3-[3-ethyl-4-(4,4,4-trifluoro-2-hydroxy-3-
trifluoromethyl-butoxy)-phenyl]-3-methyl-butyl}-2-
hydroxymethyl-phenyl)-methanol;
136- (4-{3-[3-ethyl-4-(4,4,4-trifluoro-2-hydroxy-3-
trifluoromethyl-butylsulphanyl)-phenyl]-3-methyl-
butyl }-2-hydroxymethyl-phenyl)-methanol;
137- (4-{[ethyl-(5,5,5-trifluoro-3-hydroxy-4-
trifluoromethyl-pentyl)-phenyl]-methyl-butyl}-2-hydroxymethyl-phenyl)-methanol;
138- (E)-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-1,1-
dimethyl-propyl]-2-ethyl-phenyl}-5,5,5-trifluoro-4-
trifluoromethyl-pent-l-en-3-ol;
139- (4-{3-ethyl-3-[3-ethyl-4-(3,3,3-trifluoro-2-
hydroxy-propoxy)-phenyl]-pentyl}-2-hydroxymethyl-
phenyl } -methanol;
140- (4-{3-ethyl-3-[3-ethyl-4- (3,3,3-trifluoro-2-
hydroxy-propylsulphanyl)-phenyl]-pentyl}-2-
' hydroxymethyl-phenyl)-methanol;
141- (4-{3-ethyl-3-[3-ethyl-4-(4,4,4-trifluoro-3-
hydroxy-butyl)-phenyl]-pentyl}-2-hydroxymethyl-phenyl)
methanol;
142- (4-{3-ethyl-3-[3-ethyl-4-((E)-4,4,4-trifluoro-3-
hydroxy-but-1-enyl)-phenyl]-pentyl}-2-hydroxymethyl-
phenyl) -methanol';
143- (4-{3-ethyl-3-[3-ethyl-4-(4,4,4-trifluoro-2-
hydroxy-3-trifluoromethyl-butoxy)-phenyl]-pentyl}-2-
hydroxymethyl-phenyl)-methanol ;
144- (4-{3-ethyl-3-[3-ethyl-4-(4,4,4-trifluoro-2-
hydroxy-3-trifluoromethyl-butylsulphanyl)-phenyl]-
pentyl}-2-hydroxymethyl-phenyl) -methanol;

145- (4-{ethyl-[ethyl-(5,5,5-trifluoro-3-hydroxy-4-
trifluoromethyl-pentyl)-phenyl]-pentyl}-2-
hydroxymethyl-phenyl)-methanol;
146- (E)-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-1,1-
diethyl-propyl]-2-ethyl-phenyl}-5,5,5-trifluoro-4-
trifluoromethyl-pent-l-en-3-ol;
147- [4-(2-{1-[3-ethyl-4-(3,3, 3-trifluoro-2-hydroxy-
propoxy)-phenyl]-cyclohexyl}-ethyl)-2-hydroxymethyl-
phenyl ]-methanol;
148- [4-(2-{l-[3-eth'yl-4-(3f 3,3-trifluoro-2-hydroxy-
propylsulphanyl)-phenyl]-cyclohexyl}-ethyl)-2-
hydroxymethyl-phenyl]-methanol ;
149- [4-(2-{l-[3-ethyl-4-(4,4,4-trifluoro-3-hydroxy-
butyl)-phenyl]-cyclohexyl}-ethyl)-2-hydroxymethyl-
phenyl] -methanol;
150- [4-(2-{l-[3-ethyl-4-((E)-4,4,4-trifluoro-3-
hydroxy-but-1-enyl)-phenyl]-cyclohexyl}-ethyl)-2-
hydroxymethyl-phenyl]-methanol;
151- [4- (2-{,l- [3-ethyl-4- (4, 4, 4-trifluoro-2-hydroxy-3-
trifluoromethyl-butoxy)-phenyl]-cyclohexyl}-ethyl)-2-
hydroxymethyl-phenyl]-methanol;
152- [4-(2-{1-[3-ethyl-4-(4,4 r 4-trifluoro-2-hydroxy-3-
trifluoromethyl-butylsulphanyl)-phenyl]-cyclohexyl}-
ethyl)-2-hydroxymethyl-phenyl]-methanol;

153- [4-(2-{l-[ethyl-(5,5,5-trifluoro-3-hydroxy-4-
trifluoromethyl-pentyl)-phenyl]-cyclohexyl}-ethyl)-2-
hydroxymethyl-pheny1]-methanol;
154- (E)-(4-{1-[2-(3,4-bis-hydroxymethyl-phenyl)-
ethyl]-cyclohexyl}-2-ethyl-phenyl)-5,5,5-trifluoro-4-
trifluoromethyl-pent-l-en-3-ol;
155- (4-{2-ethyl-2-[3-ethyl-4-(3,3,3-trifluoro-2-
hydroxy-propoxy)-phenyl]-butoxy}-2-hydroxymethyl-
phenyl)-methanol;
156- (4-{2-ethyl-2-[3-ethyl-4-(3,3,3-trifluoro-2-
hydroxy-propylsulphanyl)-phenyl]-butoxy}-2-
hydroxymethyl-phenyl)-methanol;

157- (4-{2-ethyl-2-[3-ethyl-4-(4,4,4-trifluoro-3-
hydroxy-butyl)-phenyl]-butoxy}-2-hydroxymethyl-phenyl)
methanol;
158- (4-{2-ethyl-2-[3-ethyl-4-((E)-4,4,4-trifluoro-3-
hydroxy-but-1-enyl)-phenyl]-butoxy}-2-hydroxymethyl-
phenyl) -methanol;
159- (4-{2-ethyl-2-[3-ethyl-4-(4, 4,4-trifluoro-2-
hydroxy-3-trifluoromethyl-butoxy)-phenyl]-butoxy}-2-
hydroxymethyl-pheny1)-methanol; •
160- (4-{2-ethyl-2-[3-ethyl-4-(4, 4, 4-trifluoro-2-
hydroxy-3-trifluoromethyl-butylsulphanyl)-phenyl]-
butoxy}-2-hydroxymethyl-phenyl)-methanol;
161- (4-{ethyl-[ethyl-(5,5,5-trifluoro-3-hydroxy-4-
trifluoromethyl-pentyl)-phenyl]-butoxy}-2-
hydroxymethyl-phenyl)-methanol;
162- (E)-{4-[l-(3,4-bis-hydroxymethyl-phenoxymethyl)-1-
ethyl-propyl]-2-ethyl-phenyl}-5,5, 5-trifluoro-4-
trifluoromethyl-pent-l-en-3-ol.
The above compounds may also be used in the form of a mixture.
The compounds of general formula (I) may be prepared from the following synthesis scheme relating to Figure 1:
The compound 2 may be prepared from the compound 1 by selective bromination, followed by protection (P)of the phenol functional group. The compounds having the structure 3 may be obtained from the compounds 2 by Stille type coupling with an appropriate organotin partner, for example an allyltributyltin or a cyanomethyltributyltin.
The compounds having the structure 4 may be obtained from 3a:
- in the case where B-T = CH2-CH2, by hydroboration of the olefin functional group, followed by Suzuki type
coupling with a triflate partner of the dimethyl 4-trifluoromethanesulphonyloxyphthalate type,
- in the case where B-T = CH=CHr after ozonolysis .of
the olefin, followed by a Wittig or Horner-Eramons type
reaction with for example a phosphorus-containing
partner of the dimethyl 4-
(diethoxyphosphorylmethyl)phthalate type,
- in the case where B-T = CH2-O, CH2-S or CH2-NH-, after
reductive ozonolysis of the olefin functional group,
followed by a Mitsunobu type reaction with a phenol or
thiophenol or aniline partner of the dimethyl 4-hydroxy
(or mercapto or amino)phthalate type, followed by deprotection of the phenol functional group.
The compounds having the structure 5 may then be obtained in the following manner: the phenol functional group may be substituted with an a-bromoketone. Next, the compounds obtained may be reduced to the final compounds 5 (R2 = H) by addition of hydrides, such as lithium aluminium hydride for example, or alternatively the ketones may be alkylated with selective reagents such as organozinc reagents, and then the ester functional groups may be reduced with hydrides, in order to obtain the final compounds 5 (R2 different from H).
The compounds having the structure 6 may be obtained from the compounds of the 3b type, by double alkylation of the benzyl position, for example in the presence of an alkyl halide R4-X and of lithium
diisopropylamide, followed by reduction of the nitrile functional group to an aldehyde.
The compounds having the structure 7 may then be obtained from 6:
- in the case where B-T = CH=CH, after a Wittig or
Horner-Eiranons type reaction with for example a
phosphorus-containing partner of the dimethyl 4-
(diethoxyphosphorylmethyl)phthalate type,
- in the case where B-T = CH2-CH2, by hydrogenation of
the olefin functional group obtained from B-T = CH=CH,
- and finally in the case where B-T = CH2-O, CH2-S or
CH2-NH, after reduction of the aldehyde functional
group to an alcohol followed by a Mitsunobu type
reaction with a phenol or thiophenol or aniline partner
of the dimethyl 4-hydroxy(or mercapto or
amino)phthalate type, followed by deprotection of the phenol functional group.
The compounds having the structure 8 may then be obtained in the following manner: the phenol functional group may be substituted with an a-bromoketone. Next, the compounds obtained may be reduced to the final compounds 8 (R2 = H) by addition of hydrides, such as lithium aluminium hydride for example, or alternatively the ketones may be alkylated with selective reagents such as organozinc reagents, and then the ester functional groups may be reduced with hydrides, in order to obtain the final compounds 8 (R2 different from H).
The compounds having the structure 9 may be obtained after conversion to a
trifluoromethanesulphonate of the phenol functional group of the compounds of type 7:
- when Q-A = CH-CH, the intermediate thus obtained may
be converted after a Heck type reaction with a
corresponding vinyl ketone of the CH2=CHC(O)R1 type,
- when Q-A = CH2-CH2, the compounds may then be obtained
after hydrogenation of the olefin functional group of
the compounds 9 with Q-A = CH=CH,
- when Q-A = ethynyl, the compounds are obtained after
a Sonogashira type coupling between a true alkyne
functional group and the trifluoromethanesulphonate
derived from 7 described above.
The compounds 9 obtained may be reduced to the final compounds 10 (R2 = H) by addition of hydrides, such as lithium aluminium hydride for example, or alternatively the ketones may be alkylated with selective reagents such as organozinc reagents, and then the ester functional groups may be reduced with hydrides, in order to obtain the final compounds 10 (R2 different from H).
The compounds of general formula (I) exhibit biological properties similar to those of vitamin D, in particular the vitamin D response element (VDRE) transactivating properties, such as an agonist or antagonist activity towards receptors for vitamin D or its derivatives. Vitamins D or their derivatives are
understood to mean, for example, the derivatives of vitamin D2 or DS and in particular 1,25-dihydroxy vitamin D3 (calcitriol).
This agonist activity towards receptors for vitamin D or its derivatives may be demonstrated in vitro by methods recognized in the field of the study of gene transcription (Hansen et al., The Society for Investigative Dermatology, vol. 1, No. 1, April 1996).
The biological properties analogous to vitamin D may also be measured by the capacity of the product to induce differentiation of promyelocytic leukaemia cells HL60. The protocol and the results obtained with the compounds according to the invention are described in Example 6 of the present application.
By way of example, the VDR agonist activity may be tested on the HeLa cell line, by cotransfecting a human VDR receptor expression vector and the reporter plasmid p240Hase-CAT. The agonist activity may also be characterized in this cotransfection system by the determination of the dose necessary to reach 50% of the maximum activity of the product (AC50). The detail of the protocol for this test and the results obtained with the compounds according to the invention are described in Example 7 of the present application.
The biological properties which are similar
to vitamin D may also be measured by the capacity of the product to inhibit the proliferation of normal human keratinocytes (NHK in culture). The product is
added to NHKs cultured under conditions promoting the proliferative state. The product is left in contact with the cells for 5 days. The number of proliferative cells is measured by incorporation of bromodeoxyuridine (BRdU) into DNA. The protocol for this test and the results obtained with the compounds according to the invention are described in Example 8 of the present application.
The subject of the present invention is also, as a medicament, the compounds described above.
The compounds according to the invention are particularly suitable in the following fields of treatment:
1) for treating dermatological conditions linked to a
keratinocyte or sebocyte differentiation or
proliferation disorder, in particular for treating acne
vulgaris, comedo-type acne, polymorphic acne, acne
rosacea, nodulocystic acne, acne conglobata, senile
acne, secondary acne such as solar acne, acne
medicamentosa or occupational acne;
2) for treating other types of keratinization
disorders, in particular ichthyosis, ichthyosiform
states, Darier's disease, keratosis palmaris et
plantaris, leukoplasia, leukoplasiform states,
cutaneous or mucosal (buccal) lichen;
3) for treating other dermatological conditions
linked to a keratinization disorder with an
inflammatory and/or immunoallergic component, and in
particular all the forms of psoriasis, whether cutaneous, mucosal or ungual, and even psoriatic rheumatism or cutaneous atopy, such as eczema or respiratory atopy or gingival hypertrophy;
4) for treating certain cutaneous inflammatory
conditions which do not exhibit keratinization
disorders, such as atopic eczema and contact allergies;
5) for treating any dermal or epidermal
proliferations whether benign or malignant, whether of
viral origin or not, such as verruca vulgaris, verruca
plana and epidermodysplasia verruciformis, oral or
florid papillomatoses and proliferations which may be
induced by ultraviolet radiation in particular in the
case of baso- and spinocellular epithelioma;

6) for treating other dermatological disorders such
as bullous dermatoses and collagen diseases;
7) for preventing or treating skin ageing, whether
photoinduced or chronologic, or for reducing
pigmentations and actinic keratoses, or any cutaneous
pathologies associated with chronologic or actinic
ageing;
8) for preventing or treating cicatrization disorders
or for preventing or repairing stretch marks;
9) for combating disorders of the sebaceous function,
such as hyperseborrhoea of acne or simple seborrhoea or
seborrhoeic eczema;
10) for treating certain ophthalmological disorders,
in particular corneopathies;
11) in the treatment or prevention of cancerous or
precancerous states of cutaneous or non-cutaneous
cancers exhibiting or capable of being induced so as. to
exhibit vitamin D receptors, such as, but without
limitation, breast cancer, leukaemia, myelodysplasic
syndromes and lymphomas, carcinomas of the cells of the
Malpighian epithelium and gastrointestinal cancers,
melanomas and osteosarcoma;
12) in the treatment of inflammatory conditions such
as arthritis or rheumatoid arthritis;

13) in the treatment of any condition of viral origin
at the cutaneous level or in general;
14) in the prevention or treatment of alopecia of
various origins, in particular alopecia due to
chemotherapy or to radiation;
15) in the treatment of dermatological or general
conditions with an immunological component;
16) in the treatment of immunological conditions such
as autoimmune diseases (such as, but without
limitation, type 1 diabetes mellitus, multiple
sclerosis, lupus and lupus-type conditions, asthma,
glomerulonephritis and the like), selective
dysfunctions of the immune system (for example AIDS)
and the prevention of immune rejection such as the
rejection of grafts (for example the kidney, heart,
bone marrow, liver, pancreatic islets or the whole
pancreas, the skin and the like) or the prevention of
graft-versus-host disease;
17) in the treatment of endocrinal conditions which
can be treated with vitamin D analogues such as those
advantageously modulating hormonal secretion such as by
increasing the secretion of insulin or selectively
suppressing the secretion of the parathyroid hormone
(for example in chronic renal insufficiency and
secondary hyperparathyroidism);
18) in the treatment of conditions characterized by an
abnormal management of intracellular calcium; and
19) in the treatment and/or prevention of vitamin D
deficiencies and of other conditions of the homeostasis
of the minerals in the plasma and the bones, such as
rickets, osteomalacia, osteoporosis, in particular in
the case of menopausal women, renal osteodystrophy,
parathyroid function disorders;
The' subject of the present invention is also a pharmaceutical composition comprising at least one compound as defined above in a pharmaceutically acceptable carrier.
The administration of the compounds according to the invention may be carried out by the enteral, parenteral, topical or ocular route.
By the enteral route, the pharmaceutical compositions may be provided in the form of tablets, gelatin capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, lipid or polymeric microspheres or nanospheres or vesicles which allow a controlled release.
By the parenteral route, the compositions may be provided in the form of solutions or suspensions for infusion or for injection.
The compounds according to the invention are generally administered at a daily dose of about 0.001 µg/kg to 1000 µg/kg and preferably about 0.01 µg/kg to 100 µg/kg as bodyweight, in 1 to 3 doses.
By the topical route, the pharmaceutical compositions based on compounds according to the invention are intended for the treatment of the skin, the scalp and the mucous membranes and are provided in the form of salves, creams, milks, ointments, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They may also be provided in the form of lipid-or polymeric microspheres or nanospheres or vesicles or of polymeric patches and hydrogels allowing a controlled release. These compositions for the topical route may be provided either in anhydrous form or in an aqueous form, depending on the clinical indication.
By the ocular route, they are mainly collyria.
These compositions for the topical or ocular route contain at least one compound according to the invention at a concentration preferably of between 0.0001 and 5% and preferably between 0.001 to 1% relative to the total weight of the composition.
The compounds according to the invention also find application in the cosmetics field, in particular in body and hair care and in particular for the treatment of skins with a tendency towards acne, for hair regrowth, against hair loss, for combating the greasy appearance of the skin or the hair, in protecting against the harmful effects of the sun and in the treatment of dry skins, for preventing and/or for treating photoinduced or chronologic ageing.
The present invention therefore also targets a cosmetic composition containing, in a cosmetically acceptable carrier, at least one compound as defined above.
This cosmetic composition may be provided in particular in the form of a cream, a milk, a lotion, a gel, a suspension of lipid or polymeric microspheres or nanospheres or vesicles, a soap or a shampoo.
The concentration of compound of general formula (I) in the cosmetic composition according to the invention may be between 0.001 and 3% by weight relative to the total weight of the composition.
In the pharmaceutical and cosmetic fields, the compounds according to the invention may be advantageously used in combination with inert or even pharmacodynamically or cosmetically active additives or combinations of these additives and in particular:
- wetting agents;
- taste-enhancing agents;
preservatives such as para-hydroxybenzoic acid
esters;
stabilizing agents/moisture-regulating agents;
pH-regulating agents;
osmotic pressure-modifying agents;
emulsifying agents;
UV-A and UV-B screening agents;
antioxidants such as a-tocopherol, butylated
hydroxyanisole, butylated hydroxytoluene, Super Oxide Dismutase, Ubiquinol or some metal chelators; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients;
moisturizing agents such as glycerol, PEG 400, thiamorpholinone and its derivatives, or urea; antiseborrhoeic or anti-acne agents, such as S-carboxymethylcysteine, S-benzylcysteamine, their salts and their derivatives, or benzoyl peroxide; antibiotics such as erythromycin and its esters, neomycin, clindamycin and its esters., tetracyclins; antifungal agents such as ketoconazole or 4,5-polymethylene-3-isothiazolinones;
agents which limit hair loss, such as Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and its derivatives, Diazoxide (7-chloro-3-methyl-l,2,4-benzothiadiazine 1,1-dioxide) and Phenytoin (5,4-diphenyl-2,4-imidazolidinedione);
- nonsteroidal anti-inflammatory agents;
- carotenoides,and in particular p-carotene;
- antipsoriatic agents such as anthralin and its-
derivatives;
- 5, 8,11,14-eicosatetraynoic and 5,8,11-eicosatrynoic
acids, their esters and amides;
- retinoids, that is to say ligands for the RA.R or RXR
receptors, which may be natural or synthetic;
- corticosteroids or oestrogens;
- α-hydroxy acids and a-keto acids or their
derivatives, such as lactic, malic, citric, glycolic,
mandelic, tartaric, glyceric and ascorbic acids, and
their salts, amides or esters, or ß-hydroxy acids or
their derivatives, such as salicylic acid and its
salts, amides or esters;

- ion channel, such as potassium channel, blockers;
- or alternatively, more particularly for
pharmaceutical compositions, in combination with
medicaments known to interfere with the immune system
(for example cyclosporin, FK 506, glucocorticoids, monoclonal antibodies, cytokines or growth factors, and the like).
Of course, persons skilled in the art will be careful to choose the possible compound(s) to be added to these compositions such that the advantageous properties of the compounds of the present invention are not or not substantially impaired by the addition envisaged.
The subject of the present invention finally relates to the cosmetic use of a cosmetic composition as defined above for body or hair hygiene.
It also relates to the cosmetic use of a cosmetic composition as defined for preventing and/or treating photoinduced or chronologic skin ageing.
There will now be given, by way of illustration and with no limitation, examples of producing the active compounds of general formula (I) according to the invention, and various concrete formulations based on such compounds and-tests for evaluating the biological activity of the compounds according to the invention.
EXAMPLE 1: l-{4- [3- (3,4-Bis-hydro3cymethyl-phenyl) -propyl]-2-ethyl-phenoxy}-3,3-dimethyl-butan-2-ol
a. 4-Bromo-2-ethylphenol
15 g (123 mmol) of 2-ethylphenol are
dissolved in 150 ml of chloroform. 59 g (123 mmol) of tetrabutylammonium tribromide are added in portions of 10 g, and the reaction medium is stirred for 20 minutes. The medium is then poured into a saturated sodium thiosulphate solution, and then the pH is adjusted to 7. The mixture is 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, y = 99%).
b. 4-Bromo-l-ethoxymethoxy-2-ethylbenzene
24.5 g (121 ramol) of 4-bromo-2-ethylphenol are dissolved in 150 ml of DMF, and this solution is slowly added to a suspension of 5.3 g (133 iranol) of sodium hydride in 50 ml of DMF. The medium is stirred for 30 minutes, and then 12.4 ml (133 mmol) of ethoxymethyl chloride are added. The reaction medium is stirred for 4 hours at room temperature, and 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, y = 80%).
c. 4-Allyl-l-ethoxymethoxy-2-ethylbenzene
15 g (58 mmol) of 4-bromo-l-ethoxymethoxy-2-ethylbenzene are dissolved in 150 ml of DMF. 26.9 ml (87 mmol) of allyltributyltin are added, and then the mixture is degassed with a nitrogen stream. 1.2 g (1.8 mmol) of dichlorobis(triphenylphosphino)palladium are added, and the medium is heated at 120°C for 10 hours. The reaction medium is poured into water, and then extracted 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, y = 100%).
d. Dimethyl 4-trifluoromethanesulphonyloxyphthalate
21 g (100 inmol) 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' triflic anhydride are slowly added, and the reaction medium is slowly brought to room temperature, and is then treated with water, and extracted with dichloromethane. The organic phases are washed with a dilute sodium bicarbonate solution, and then dried and concentrated. The residue is purified by chromatography on a silica column (eluent ethyl acetate 30/heptane 70}. A yellow oil is obtained (m = 27 g, y = 79%) .
e. Dimethyl 4-[3-(4-ethoxymethoxy~3-e thylph enyl) propyl ]ph t ha late
5 g (22.7 mmol) of 4-allyl-l-ethoxymethoxy-2-ethylbenzene are dissolved in 100 ml of anhydrous THF, and the medium is cooled to 0°C. 6.6 g (27 mmol) of 9-BBN are added, and 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-
• trifluoromethanesulphonyloxyphthalate in 100 ml of DMF is added, as well as '6.2 g (44.8 mmol) of potassium carbonate. The reaction medium is degassed with a
nitrogen stream, and then 930 mg (1.1 mmol) of dichloropalladium diphosphinoferrocene are added. The medium is heated at 50°C for 3 hours, and then poured into an 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, and then heptane 85/ethyl acetate 15). A yellow oil is obtained (m = 6.9 g, y = 73%).
f. Dimethyl 4-[3-(3-ethyl-4-hydroxyphenyl) propyl]phthalate
6.9 g (16.6 mmol)' of dimethyl 4-[3-(4-ethoxymethoxy-3-ethylphenyl)propyl]phthalate are dissolved in 100 ml of methanol. 3 ml of concentrated sulphuric acid are added dropwise, and the medium is stirred for 1 hour, and then poured into water, and extracted with dichloromethane. The organic phases are dried and concentrated. The residue obtained is purified by chromatography on a silica column (eluent heptane 80/ethyl acetate 20). A colourless oil is obtained (m = 5 g; y = 84%).
g. Dimethyl 4-{3-[4-(3,3~dimethyl-2-oxobutoxy)-3-e t hylph enyl ] propyl} ph t ha late
800 mg (2.2 mmol) of dimethyl 4-[3-(3-ethyl-4-hydroxyphenyl)propyl]phthalate are dissolved in 40 ml of 2-butanone. 340 mg (2.5 mmol) of potassium carbonate
and 330 jj.1 (2.5 irunol) of 1-bromopinacolone are added. The reaction medium is heated under reflux for 8 hours, and is then filtered on celite. The residue obtained is purified by chromatography on a silica column (eluent ethyl acetate 20/heptane 80). A colourless oil is obtained (m = 920 mg; y = 90%) .
h. l-{4-[3-(3,4 -Bi s -hydroxym e thy I -ph enyl) -propyl ]-2-ethyl-phenoxy}-3,3-dimethyl-but an-2-ol
900 mg (2 mmol) of dimethyl 4-{3- [4- (3,3-dimethyl-2-oxobutoxy)-3-ethylphenyl]propyl}phthalate are dissolved in 20 ml of THF, and slowly added to a suspension of 375 mg (10 mmol) of lithium aluminium hydride. The reaction medium is stirred for 30 minutes at room temperature, and is then sequentially treated by slow addition of 400 JJ.1 of water, 400 \ii of 15% sodium hydroxide and 1 ml of water. The reaction medium is poured into a 1% hydrochloric acid solution, and then extracted with ethyl ether. The residue obtained after drying and concentrating is purified by chromatography on a silica column. A thick colourless oil is obtained (m = 760 mg, y = 95%) .
1H NMR (CDC13) : 1.01 (s, 9H); 1.19 (t, J = 7.4 Hz, 3H) ; 1.92 (m, 2H); 2.0 (bs, 3H); 2.56-2.66 (m, 6H) ; 3.71 (dd, Jl = 2.5 Hz, J2 = 8.7 Hz, 1H); 3.86 (t, 1H, J = 8.7 Hz); 4.09 (dd, Jl = 8.7 H, J2 = 2.5 Hz, 1H); 4.73 (s, 4H), 6.75 (d, J - 8 Hz, 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: l-{4-[3-(3,4-Bis-hydroxymethyl-phenyl)-propyl] -2 -methyl -phenoxy} -3,3-d line thyl-butan-2-ol
a. 4-Bromo-2-methylphenol
In a manner similar to Example la, by reacting 10 g (91 mmol) of 2-methylphenol with 44 g (91 mmol) of tetrabutylammonium tribromide. A yellow oil is obtained (m = 16.3 g, y = 95%).
b. 4-Bromo-l-methoxymethoxy-2-ethylbenzene
In a manner similar to Example Ib, 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 is obtained (m = 16.4 g, y = 84%).
c. 4-Allyl-l-ethoxymethoxy-2-methylbenzene
In a manner similar to Example Ic, by reacting 16 g (65 mmol) of 4-bromo-l-ethoxymethoxy-2-methylbenzene with 30 ml (97 mmol) of allyltributyltin and 1.35 g (2 mmol) of
dichlorobis(triphenylphosphino)palladium. A yellow oil is obtained (m = 12'.1 g, y = 89%).
d. Dimethyl 4-13-(4-methoxymethoxy-3-
methylphenyl) propyl] phthalate
In a manner similar to Example le, by
reacting 4.5 g (21.6 mmol) of 4-allyl-l-ethoxymethoxy-2-methylbenzene with 6.3 g (25.7 mmol) of 9-BBNr 7.4 g {21.6 mmol) of dimethyl 4-
trifluoromethanesulphonyloxyphthalate, 5.9 g (42.6 mmol} of potassium carbonate and 880 mg (1.05 mmol} 'of dichloropalladium diphosphinoferrocene. A yellow oil is obtained (m = 7 g, y = 80%).
e. Dimethyl 4-[3-(3-methyl-4~
hydroxypheriyl) propyl ]ph tha late
In a manner similar to Example If, 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 sulphuric acid. A colourless oil is obtained (m = 5.2 g; y = 88%).
f. Dimethyl 4-{3-[4-(3,3-dimethyl-2-oxobutoxy)-3-
methylphenyl ] propyl }ph thala te
In a manner similar to Example Ig, 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 µl (2.9 mmol) of 1-bromopinacolone. A colourless oil is obtained (m = 910 mg; y = 79%).
g. l-{ 4-[3- (3,4-Bis-hydroxymethyl-phenyl) -propyl] -2-
methyl-phenoxy} -3,3-dimethyl-butan-2-ol
In a manner similar to Example Ih, by reacting 900 mg (2.1 mmol) of dimethyl 4-{3-[4- (3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]propyl}phthalate with 375 mg (10 mmol) of lithium aluminium hydride. A thick colourless oil is obtained (m = 780 mg, y = 96%). 1H 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, IH); 3.61 (dd, IH, Jl = 8.4 Hz, J2 = 2.3 Hz); 3.86 (dd, Jl = 8.4 H, J2 = 2.3 Hz, IH); 4.36 (t, J = 6Hz, 4H), 4.64 (d, J = 5.3 Hz, IH); 4.82-4.91 (m, 2H); 6.68 (d, J = 8 Hz, IH); 6.78-6.91 (m, 3H) ; 7.06-7.14 (m, 2H) .
EXAMPLE 3: (4-{3-[3-Ethyl-4-(2-ethyl-2-hydroxy-butoxy)-phenyl] -propyl}-2-hydroxymethyl'-phenyl) -methanol
a. 4-[3- (3,4-Bis-hydroxymethyl-phenyl) -propyl] -2-ethyl-phenol
1.7 g (4.8 mmol) of dimethyl 4-[3-(3-ethyl-4-hydroxyphenyl)propyl]phthalate (Example If) are dissolved in 50 ml of ethyl ether, and this solution is slowly added to a suspension of 435 mg (11.4 mmol) of lithium aluminium hydride. The medium is stirred for 30 minutes and is then sequentially treated with 450 µl of water, 450 µ1 of 15% sodium hydroxide and 1.5 ml of water. The reaction medium is poured into a IN hydrochloric acid solution, and extracted wi.th ethyl ether. A white solid is obtained (m = 1.2 g, m.p. = 82°C, y = 84%)'.
b. Ethyl (4-[3-(3,4-bis-hydroxymethyl-phenyl)-propyl]-2-ethyl-phenoxy} -acetate
In a manner similar to Example Ig, by reacting 1.1 g (3.7 mmol) of 4-[3-(3,4-bis-hydroxymethyl-phenyl)-propyl]-2-ethyl-phenol with 560 mg (4 mmol) of potassium carbonate and 450 jj.1 of ethyl bromoacetate. A colourless oil is obtained (m = 680 mg, y = 48%).
c. (4-{3-[3-Ethyl-4-(2-ethyl-2-hydroxy-butoxy) -phenyl]-propyl}-2-hydroxymethyl-phenyl)-methanol
640 mg (1.65 mmol) of ethyl {4-[3-(3,4-bis-hydroxymethyl-phenyl)-propyl]-2-ethyl-phenoxy}-acetate are dissolved in 30 ml of THF. 2.2 ml (6.6 mmol) of a 3M ethylmagnesium bromide solution are added dropwise. The reaction medium is stirred for 30 minutes, and is then treated with a saturated ammonium chloride solution. The residue obtained after extraction and concentration is purified by chromatography on a silica column. A colourless oil is obtained (m = 510 mg, y = 77%).
1H NMR (CDC13) : 0.94 (t, J = 7.6 Hz, 6H); 1.19 (t, J = 7.4 Hz, 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 = 8 Hz, 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-hydroxy-butoxy)-3-methyl-phenyl] -propyl}-2-hydroxymethyl-phenyl) -methanol
a . 4- [3- (3, 4-Bis-hydroxymethyl-phenyi; -propyl] -2-methyl-phenol
In a manner similar to Example 3a, by
reacting 1 g (2.9 mmol) of dimethyl 4-[3-(3-methyl-4-hydroxyphenyl) propyl jphthalate (Example 2'e) with 260 mg (7 mmol) of lithium aluminium hydride. A white solid is obtained (m = 740 mg, m.p. = 92°C, y = 89%).
b. Ethyl {4-[3- (3, 4-bis-hydroxymethyl-phenyl) -propyl] -
2-methyl-phenoxy}-acetate
In a manner similar to Example 3b, by reacting 720 mg (2.5 mmol) with 380 mg (2.7 mmol) of potassium carbonate and 310 p.1 (2.7 mmol) of ethyl bromoacetate. A colourless oil is obtained (m = 540 mg, y = 58%).
c. (4-{3-[4- (2-Ethyl-2-hydrox.y-butoxy)-3-methyl-
phenyl] -propyl} -2-hydroxymethyl-phenyl) -methanol
In a manner similar to Example 3c, by reacting 530 mg (1.42 mmol) of ethyl {4-[3-(3,4-bis-hydroxymethyl-phenyl) -propyl] -2-methyl-phenoxy} -acetate with 2.4 ml (7 mmol) of a 3M ethylmagnesium bromide solution. A colourless oil is obtained (m = 410 mg, y = 75%).
1H 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: Formulations
1) ORAL ROUTE
(a) The following composition is prepared in the form of a 0.2-g tablet
Compound of Example 2 0.005 g
Pregelatinized starch 0.065 g
Macrocrystalline cellulose 0.075 g
Lactose 0.050 g
Magnesium stearate 0.005 g
For the treatment of ichthyosis, 1 to 3 tablets are administered to an adult individual per day for 1 to 12 months depending on the seriousness of the case treated.
(b) An oral suspension intended to toe packaged in 5-ml vials is prepared
Compound of Example 3 0.050 mg
Glycerin 0.500 g
Sorbitol at 70% 0.500 g
Sodium saccharinate 0.010 g
Methyl para-hydroxybenzoate 0.040 g
Flavouring qs
Purified water qs 5 ml
For the treatment of acne, 1 vial is administered to an adult individual per day for 1 to 12 months depending on the seriousness of the case treated.
(c) The following formulation intended to be packaged in gelatin capsules is prepared:
Compound of Example 4 0.0001 mg
Maize starch 0.060 g
Lactose qs 0.300 g
The gelatin capsules used consist of gelatin, titanium oxide and a preservative.
In the treatment of psoriasis, 1 gelatin capsule is administered to an adult individual per day for 1 to 12 months.
(d) The following formulation intended to be packaged in gelatin capsules is prepared:
Compound of Example 1 0.01 mg
Compound of Example 3 0.01 mg
Cyclosporin 0.050 g
Maize starch 0.060 g
Lactose qs 0.300 g
The gelatin capsules used consist of gelatin, titanium oxide and a preservative.
In the treatment of psoriasis, 1 gelatin capsule is administered to an adult individual per day for 1 to 12 months.
2) TOPICAL ROUTE
(a) The following nonionic Water-in-Oil cream is prepared:
Compound of Example 3 0.100 g
Mixture of emulsive lanolin alcohols,
of waxes and of refined oils, sold
by the company Beiersdorf under the name
"Eucerine anhydre" 39. 900 g
Methyl para-hydroxybenzoate 0.075 g
Propyl para-hydroxybenzoate 0.075 g
Sterile demineralized water qs 100.000 g
This cream is applied to a psoriatic skin once or twice per day for 1 to 12 months.
(b) A gel is prepared by producing the following formulation:
Compound of Example 2 0.001 g
Erythromycin base 4.000 g
Butylated hydroxytoluene 0.050 g
Hydroxypropylcellulose sold by the company Hercules under the name
"KLUCEL HF" 2.000 g
Ethanol (at 95%) qs 100.000 g
This gel is applied to a skin affected by dermatosis or a skin with acne 1 to 3 times per day for 6 to 12 weeks depending on the seriousness of the case
treated.
(c) An antiseborrhoeic lotion is prepared by mixing the following ingredients:
Compound of Example 1 0.030 g
Propylene glycol 5.000 g
Butylated hydroxytoluene 0.100 g
Ethanol (at 95%) qs 100.000 g
This lotion is applied twice per day to a seborrhoeic scalp and a significant improvement is observed within a period of between 2 and 6 weeks.
(d) A cosmetic composition against the harmful effects of the sun is prepared by mixing the following ingredients:
Compound of Example 3 0.500 g
Compound of Example 4 0.500 g
Benzylidene camphor 4 .000 g
Fatty acid triglycerides 31.000 g
Glycerol monostearate 6.000 g
Stearic acid 2.000 g
Cetyl alcohol 1.200 g
Lanolin 4 .000 g
Preservatives 0.300 g
Propylene glycol 2.000 g
Triethanolamine 0.500 g
Perfume 0.400 g
Demineralized water qs 100.000 g
This composition is applied daily; it makes it possible to combat photoinduced ageing.
(e) The following Oil-in-Water cream is prepared:
• Compound of Example 4 0.500 g
Retinoic acid 0.020 g
Cetyl alcohol 4.000 g
Glycerol monostearate 2.500 g
PEG 50 stearate 2.500 g
Shea butter 9.200 g
Propylene glycol 2.000 g
Methyl para-hydroxybenzoate 0.075 g
Propyl para-hydroxybenzoate 0.075 g
Sterile demineralized water gs 100.000 g
This cream is applied to a psoriatic skin once or twice per day for 30 days for intensive treatment and indefinitely for maintenance.
(f) A topical gel is 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 the company
"Goodrich" 0.500 g
Triethanolamine in aqueous solution
at 20% by weight 3.800 g
Water 9.300 g
Propylene glycol qs 100.000 g
This gel is applied in the treatment of acne 1 to 3 times per day for 6 to 12 weeks depending on the seriousness of the case treated.
(g) A hair lotion against hair loss and for regrowth is prepared by mixing the following ingredients:
Compound of Example 4 0.05 g
Compound sold under the name
"Minoxidil" 1.00 g
Propylene glycol 20.00 g
Ethanol 34.92 g
Polyethylene glycol (molecular
mass = 400) 40.00 g
Butylated hydroxyanisole 0.01 g
Butylated hydroxytoluene 0.02 g
Water qs 100.00 g
This lotion is applied once or twice per day for 3 months to a scalp having suffered a loss of hair and indefinitely for maintenance treatment.
(h) An antiacne cream is prepared by mixing the following ingredients:
Compound of Example 1 0.050 g
Retinoic acid 0.010 g
Mixture of glycerol stearates and polyethylene glycol (75 mol) sold under the name "Gelot 64" by the company
"GATTEFOSSE" . 15.000 g
Polyoxyethylenated stone oil containing 6 mol of ethylene oxide sold under the name "Labrafil M2130 CS" by the company "GATTEFOSSE" ... 8.000 g
Perhydrosgualene 10.000 g
Preservatives qs
Polyethylene glycol (molecular
mass = 400) 8.000 g
Disodium salt of ethylenediamine-
tetraacetic acid 0.050 g
Purified water qs 100.000 g
This cream is applied to a skin affected by dermatosis or a skin with acne 1 to 3 times per day for 6 to 12 weeks.
(i) An oil-in-water cream is prepared by producing the following formulation:
Compound of Example 2 0.020 g
Betamethasone 17-valerate 0.050 g
S-carboxymethylcysteine 3.000 g
Polyoxyethylene stearate (40 mol of ethylene oxide) sold under the name "Myrj 52" by the company
"ATLAS" 4.000 g
Sorbitan monolaurate, polyoxyethylene containing 20 mol of ethylene oxide sold under the name "Tween 20" by
the company "ATLAS" 1.800 g
Mixture of glycerol mono- and distearate sold under the name "Geleol" by the company "GATTEFOSSE" ... 4.200 g
Propylene glycol 10.000 g
Butylated hydroxyanisole 0.010 g
Buytlated hydroxytoluene 0.020 g
Cetylstearyl alcohol 6.200 g
Preservatives qs
Perhydrosqualene 18.000 g
Mixture of caprylic-capric triglycerides sold under the name "Miglyol 812" by the company
"DYNAMIT NOBEL" 4 .000 g
Triethanolamine (99% by weight) 2.500 g
Water qs 100.000 g
This cream is applied twice per day to a skin affected by inflammatory dermatosis for 30 days.
(j) The following cream of oil-in-water type is prepared:
Lactic acid 5.000 g
Compound of Example 1 0.020 g
S-carboxymethylcysteine 3.000 g
Polyoxyethylene stearate (40 mol of ethylene oxide) sold under the name "Myrj 52" by the company
"ATLAS" , 4.000 g
Polyoxyethylenated sorbitan monolaurate containing 20 mol of ethylene oxide sold under the name "Tween 20" by
the company "ATLAS" 1.800 g
Mixture of glycerol mono- and
distearate sold under the name "Geleol"
by the company "GATTEFOSSE" ... 4.200 g
Propylene glycol 10.000 g
Butylated hydroxyanisole 0.010 g
Buytlated hydroxytoluene 0.020 g
Cetylstearyl alcohol 6.200 g
Preservatives qs
Perhydrosqualene 18.000 g
Mixture of caprylic-capric triglycerides sold under the name "Miglyol 812" by the company
"DYNAMIT NOBEL" 4.000 g
Water qs 100.000 g
This cream is applied once 'per day; it helps to combat ageing whether photoinduced or chronologic.
(k) The following anhydrous salve is prepared:
Compound of Example 3 5.000 g
Liquid paraffin 50.00 g
Butylated hydroxytoluene 0.050 g
Petroleum jelly qs 100 g
This salve is applied twice per day to a skin affected by squamose dermatosis for 30 days.
3) INTRALESION ROUTE
(a) The following composition is prepared:
Compound of Example 1 0.002 g
Ethyl oleate qs 10 g
In the treatment of malignant melanoma, the composition is injected into an adult individual at a frequency of 1 to 7 times per week for 1 to 12 months.
(b) The following composition is prepared:
Compound of Example 2 0.050 g
Olive oil qs 2 g
In the treatment of basocellular carcinoma, the composition is injected into an adult individual at a frequency of 1 to 7 times per week for 1 to 12 months.
(c) The following composition is prepared:
Compound of Example 3 0.1 mg
Sesame oil qs 2 g
In the treatment of spinocellular carcinoma, the composition is injected into an adult individual at a frequency of 1 to 7 times per week for 1 to 12 months.
(d) The following composition is prepared:
Compound of Example 4 0.001 mg
Methyl benzoate qs 10 g
In the treatment of colon carcinoma, the composition is injected into an adult individual at a frequency of 1 to 7 times per week for 1 to 12 months,
(e) The following composition is prepared:
Compound of Example 2 0.001 g
Compound of Example 4 0.001 g
Ethyl oleate qs 10 g
In the treatment of malignant melanoma, the composition is injected into an adult individual at a frequency of 1 to 7 times per week for 1 to 12 months.
4) INTRAVENOUS ROUTE
(a) The following injectable lipid emulsion is
prepared:
Compound of Example 1 0.001 mg
Soya bean oil 10.000 g
Egg phospholipid 1.200 g
Glycerin 2.500 g
Water for injection qs 100.000 g
In the treatment of psoriasis, the composition is injected into an adult individual at a frequency of 1 to 7 times per week for 1 to 12 months.
(b) The following injectable lipid emulsion is
prepared:
Compound of Example 3 0.010 g
Cottonseed oil 10.000 g
Soya bean lecithin 0.750 g
Sorbitol 5.000 g
(DL)-a-Tocopherol 0.100 g
Water for injection qs 100.000 g
In the treatment of ichthyosis, the composition is injected into an adult individual at a frequency of 1 to 7 times per week for 1 to 12 months.
(c) The following injectable lipid emulsion is prepared:
Compound of Example 1 0.001 g
Soya bean oil 15.000 g
Acetylated monoglycerides .... 10.000 g
Pluronic F-108 1.000 g
Glycerol 2.500 g
Water for injection qs 100.000 g
In the treatment of leukaemia, the composition is injected into an adult individual at a frequency of 1 to 7 times per week for 1 to 12 months.
(d) The following mixed micell composition is prepared:
Compound of Example 2 0.001 g
Lecithin 16.930 g
Glycocholic acid 8.850 g
Water for injection qs 100.000 g
In the treatment of malignant melanoma, the composition is injected into an adult individual at a frequency of 1 to 7 times per week for 1 to 12 months.
(e) The following cyclodextrin composition is prepared:
Compound of Example 1 0.05 mg
Compound' of Example 2 0. 05 mg
p-Cyclodextrin 0.100 g
Water for injection qs 10.000 g
In the treatment of graft rejection, the composition is injected into an adult individual at a frequency of'l to 7 times per week for 1 to 12 months.
(f) The following cyclodextrin composition is prepared:
Compound of Example 3 0.010 g
2-Hydroxypropyl-p-cyclodextrin 0.100 g
Water for injection qs 10.000 g
In the treatment of kidney cancer, the composition is injected into an adult individual at a frequency of 1 to 7 times per week for 1 to 12 months.
EXAMPLE 6: Test for evaluating the biological activity of the compounds of the invention - activity on the differentiation of HL60 cells
Calcitriol induces the differentiation of promyelocytic leukaemia cells (HL60) into monocytes/macrophages. This differentiation-inducing effect is a well characterized marker for cellular vitamin D. One of the most important antimicrobial products of macrophages is hydrogen peroxide, which may be analysed experimentally by the reduction of NET (Nitroblue Tetrazolium).
The method used is the following: the HL60 cells are inoculated into 6-well plates and then treated immediately with a test compound.. After 4 days of culture, the cells are incubated with phorbol TPA ester and NET for a short period and the differentiated cells, that is to say which are positive to NET are counted.
The differentiation inducing effect on HL60 cells of the compounds according to the invention, and that of the reference compound calcitriol, are presented in Table I.
The results show that the compounds of Examples 1 and 2 have a differentiation-inducing activity on the HL60 cells which is weaker than that of calcitriol; these AC50 values are nevertheless significant and show the marked activity, in particular of the compound of Example 1, of the compounds according to the invention on the differentiation of HL60 cells.
(Table Removed)
Table I
EXAMPLE 7: Tests for evaluating the biological activity of the compounds of the invention — measurement of the VDR agonist activity (AC50 hVDR)
The VDR agonist activity of the compounds of the invention may be tested on the HeLa cell line by cotransfection of the human VDR receptor expression vector and of the reporter plasrnid p240Hase-CAT which contains the -1399 to +76 region of the rat 24-hydroxylase promoter, cloned upstream of the coding frame of the chloramphenicolacetyl transferase (CAT) gene. 18 hours after cotransfection, the compound to be tested is added to the medium. After 18 hours of treatment, the assay of the CAT activity of the cellular lysates is carried out by an ELISA test (Enzyme Linked Immuno Sorbent Assay, marketed by Roche Molecular Biochemicals). The agonist activity may be characterized in this cotransfection system by determining the dose required to reach 50% of the maximum activity of the compound tested (AC50).
The measurement of the VDR agonist activity of the compounds according to the invention and that of
the reference compound, calcitriol, are presented in Table II.
As in Example 6, these results show that the compounds according to the present invention have activities which are weaker than that of calcitriol but nevertheless significant.

(Table Removed)
Table II
EXAMPLE 8: Tests for evaluating- the biological activity of the compounds of the invention - activity on the proliferation of human keratinocytes
It is known that 1,25-dihydroxyvitamin D3, called calcitriol and corresponding to natural vitamin D, inhibits the proliferation of human keratinocytes in culture.
The method used is the following: normal human keratinocytes are inoculated at low density into a 24-well plate. After 4 hours, the compounds to be tested are added to the culture medium. After 5 days of culture, the proliferation of the keratinocytes is determined by incorporating 5-bromo-2'-deoxyuridine
(BrdU) into the DNA. The quantity of BrdU incorporated is then measured using the ELISA test (Enzyme 'Linked Immuno Sorbent Assay, marketed by Roche Molecular Biochemicals).
The inhibitory effect, on the proliferation of keratinocytes, of the compounds according to the invention and of calcitriol used as reference compound is summarized in Table III.
The IC50 value indicates the concentration of the compound tested for which the compound inhibits by 50% the proliferation of the keratinocytes.
These results show that the compounds of the invention have an inhibitory activity on the proliferation of keratinocytes which is lower than that of calcitriol; these compounds remain nevertheless of interest compared with the state of the art compounds.

(Table Removed)
Table III





WE CLAIM:
1. Compounds, characterized in that they correspond to the following general formula (I):
(Formula Removed)
in which:
- A-Q represents an unsubstituted alkyne or alkene bond, a -CH2-
O-, a -CH2-S- or -CH2-CH2- bond;
- B-T represents an unsubstituted alkyne or alkene bond,
a -CH2-S-, -CH2-O-, -CH2-CH2- or -CH2-NR6- bond;
R6 having the meanings given below,
- R1 and Ra, which are identical or different, represent a hydrogen
atom, a linear or branched alkyl radical having 1 to 5 carbon atoms or
the radical
-CF2R5;
- R3 represents a linear or branched alkyl radical having 1 to 5
carbon atoms or the radical CF2R5;
R5 having the meanings given below,
- the radicals R4 are identical and represent a hydrogen atom, a
linear or branched alkyl radical having 1 to 6 carbon atoms, the radical
-CF2R5, the two radicals may also form a saturated ring having 4 to 7 carbon atoms, a saturated heterocycle such as furan, pyran, pyrrolidine substituted on the nitrogen with a radical Ry or piperidine substituted on the nitrogen with a radical Ry;
Ry having the meanings given below,
- R5 represents a fluorine atom, a hydrogen atom or a radical -CF3 ;
- R6 represents a hydrogen atom, a linear or branched alkyl radical
having 1 to 6 carbon atoms or the radical -C (O)R8;
R8 having the meanings given below,
- R7 and R8, which are identical or different, represent a hydrogen
atom or a linear or branched alkyl radical having 1 to 6 carbon atoms;
and the optical and geometric isomers of the said compounds of formula (I) and their salts.
2. Compounds as claimed in claim 1, wherein those comprising a nitrogen atom exist in the form of salts of an inorganic or organic acid, in particular hydrochloric, sulphuric, acetic, fumaric, hemisuccinic, maleic and mandelic acid.
3. Compounds as claimed in claim 1 or 2, wherein the linear or branched alkyl radical having 1 to 5 carbon atoms is a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl,l-methylbutyl, 3-methylbutyl or 2, 2-dimethylbutyl radical.
4. Compounds as claimed in any one of the preceding claims, wherein
the linear or branched alkyl radical having 1 to 6 carbon atoms is a
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, 1-
methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, n-hexyl, 4-
methylpentyl or 3,3-dimethylbutyl radical.
5. Compounds as claimed in any one of the preceding claims, wherein
the saturated ring having 4 to 7 carbon atoms is a cyclobutyl, a
cyclopentyl, a cyclohexyl or a cycloheptyl.
6. Compounds as claimed in claim 1, wherein they are chosen, alone
or as mixtures, from the group consisting of:

1- l-{4-[3-(3,4-Bis-hydroxymethyl-phenyl) -propyl] - 2 -ethyl-phenoxy}-
3,3-dimethyl-butan-2-ol;
2- l-{4-[3-(3,4-Bis-hydroxymethyl-phenyl)-propyl]-2-methyl-phenoxy}-
3,3-dimethyl-butan-2-ol;
3- (4-{3-[3-ethyl-4-(2-ethyl-2-hydroxy-butoxy)-phenyl]-propyl}-2-
hydroxymethyl-phenyl) -methanol;
4- (4-{3-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}-2-
hydroxymethyl-phenyl) -methanol;
5- (2-hydroxymethyl-4-{3-[4-(2-hydroxy-3-methyl-butoxy)-3-methyl-
phenyl] -propyl}-phenyl) -methanol;
6- (4-{3-[3-ethyl-4-(2-hydrosy-3-methyl-butoxy)-phenyl-propyl}-2-
hydroxymethyl-phenyl-methanol;
7- (2-hydroxymethyl-4-{3-[4-(2-hydroxy-3-methyl-
butylsulphanyl)-3-methyl-phenyl]-propyl}-phenyl)-
methanol;
8- (4-{3-[3-ethyl-4-(2-hydroxy-3-methyl-
butylsulphanyl)-phenyl]-propyl}-2-hydroxymethyl-
phenyl)-methanol;
9- (2-hydroxymethyl-4-{3-[4~(3-hydroxy-4-methyl-
pentyl)-3-methyl-phenyl]-propyl}-phenyl)-methanol;

10- (4-{3~[3-ethyl-4-(3-hydroxy-4-methyl-pentyl)-
phenyl]-propyl}-2-hydroxymethyl-phenyl)-methanol;
11- (E)-l-{4-[3-(3, 4-bis-hydroxymethyl-ptienyl) -propyl]-
2-methyl-phenyl}-4-methyl-pent-l-en-3-ol;
12- (E)-l-{4-[3-(3,4-bis-hydroxymethyl-phenyl}-propyl] -
2-ethyl-phenyl}-4-methyl-pent-l-en-3-ol;
13- (4-{3-[4-(2-hydroxy-3,3-dimethyl-butylsulphanyl}-3-
methyl-phenyl]-propyl}-2-hydroxymethyl-phenyl)-
methanol;
14- {4-{3-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-
butylsulphanyl)-phenyl]-propyl}-2-hydroxymethyl-
phenyl)-methanol;
15- (4-{3-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-
phenyl] -propyl}-2-hydroxymethyl-phenyl)-methanol;
16- (4-{3-[3-ethyl-4-(3-hydroxy-4,4-dimethyl-pentyl)-
phenyl]-propyl}-2-hydroxymethyl-phenyl)-methanol;
17- (E)-l-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-propyl ] -
2-methyl-phenyl}-4,4-dimethyl-pent-l-en-3-ol;
18- (E)-l-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-propyl] -
2-ethyl~phenyl}-4,4—dimethyl-pent-l-en-3—ol;
19- (2-hydroxytnethyl-4-{3- [3-methyl-4- (3, 3, 3-trif luoro-
2-hydroxy-propoxy) -phenyl]-propyl}-phenyl) -methanol;
20- (4~{3-[3-ethyl-4-(3,3,3-trifluoro-2-hydroxy-
propoxy) -phenyl] -propyl}-2-hydroxymethyl-phenyl) -
methanol;
21- (2~hydroxymethyl-4- {3- [3-methyl-4-(3,3, 3-trifluoro-
2-hydroxy-propylsulphanyl)-phenyl] -propyl}-phenyl) -
methanol;
22- (4-{3-[3-ethyl-4-(3,3,3-trifluoro-2-hydroxy-
propylsulphanyl) -phenyl] -propyl} -2-hydroxymethyl-
phenyl)-methanol; •
23- (2-hydroxymethyl-4-{3-[3-ruethyl-4-(4, 4,4-trifluoro-
3~hydroxy-butyl)-phenyl]-propyl}-phenyl)-methanol;
24- (4-{3-[3-ethyl-4-(4,4,4-trifluoro-3-hydroxy-butyl)-
phenyl] -propyl}-2-hydroxymethyl-phenyl) -methanol;
25- (2-hydroxymethyl-4-{3-[3-methyl-4-((E)-4,4,4-
trifluoro-3-hydroxy-but-l-enyl) -phenyl] -propyl }-
phenyl)-methanol;
26- (4-(3- [3-ethyl-4-((E) -4, 4, 4-trifluoro-3-hydroxy-
but-1-enyl)-phenyl]-propyl}-2-hydroxymethyl-phenyl)-
methanol;
27- (2-hydroxymethyl-4-{3-[3-methyl-4-(4,4,4-trifluoro-
2-hydroxy-3-trifluoromethyl-butoxy) -phenyl] -propyl}-
phenyl)-methanol;
28- (4-{3-[3-ethyl-4-(4,4,4-trifluoro-2-hydroxy-3-
trif luoromethyl-butoxy) -phenyl] -propyl} -2-
hydroxymethyl-phenyl)-methanol;
29- (2-hydroxymethyl-4-{3-[3-methyl-4-(4,4,4-trifluoro-
2-hydroxy-3-trifluoromethyl-butyl sulphanyl) -phenyl] -
propyl}-phenyl)-methanol;
30- (4-{3-[3-ethyl-4-(4,4,4-trifluoro-2-hydroxy-3-
trifluoromethyl-butylsulphanyl) -phenyl] -propyl}-2-
hydroxymethyl-phenyl)-methanol;
31- {2-hydroxymethyl-4-{3- [methyl-(5,5,5-trifluoro-3-
hydroxy-4-trif luoromethyl-pentyl) -phenyl] -propyl}-
phenyl)-methanol;
32- (4-{3-[ethyl-(5,5,5-trifluoro-3-hydroxy-4-
trifluoromethyl-penty-1) -phenyl] -propyl} -2-
hydroxymethyl-phenyl)-methanol;
33- (E)-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-propyl]-2~
methyl-phenyl}-5,5,5-trifluoro-4-trifluoromethyl-pent-
l-en-3-ol;
34- (E)-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-propyl]-2-
ethyl-phenyl}-5,5,5-trifluoro-4-trifluoromethyl-pent-l-
en-3-ol;
35- (2-hydroxymethyl-4-{3-[4-(2-hydroxy-3-methyl-
butbxy) -3-methyl-phenyl] -3-methyl-butyl}-phenyl) -
methanol;
36- (4-{3-[3-ethyl-4-(2-hydroxy-3-methyl-butoxy)-
phenyl]-3-methyl-butyl}-2-hydroxymethyl-phenyl)-
methanol;
37- (2-hydroxymethyl-4-{3-[4-(2-hydroxy-3-methyl-
butylsulphanyl)-3-methyl-phenyl]-3-methyl-butyl}-
phenyl)-methanol;
38- (4-{3-[3-ethyl-4-(2-hydroxy-3-methyl-
butylsulphanyl)-phenyl]-3-methyl-butyl}-2-
hydroxymethyl-phenyl)-methanol;
39- (2-hydroxymethyl-4-{3-[4-(3-hydroxy-4-methyl-
pentyl)-3-methyl-phenyl]-3-methyl-butyl}-phenyl)-
methanol;
40- (4-{3-[3-ethyl-4-(3-hydroxy-4-methyl-pentyl)-
phenyl]-3-methyl-butyl}-2-hydroxymethyl-phenyl)-
methanol;
. 41- (E)-i-{4-[3-(3,4-bis-hydroxymethyl-phenyl)~l,l-dimethyl-propylj-2-methyl-phenyl}-4-iriethyl-pent-l-en.-3-ol;
42- (E)-l-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-l,l-
dimethyl-propyl ] -2-ethyl-phenyl} -4-methyl-pent-l-e.n—3-
ol;
43- ,(4-{3-[4- (2-hydroxy-3, 3-dimethyl-butoxy)-3-methyl-
phenyl] -3-methyl-butyl}~2-hydroxymethyl-phenyl)-
methanol;
44- (4-{3-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-butoxy)-
phenyl]-3-methyl-butyl}-2-hydroxymethyl-phenyl)-
methanol;
45- (4~{3-[4-(2-hydroxy-3,3-dimethyl-butylsulphanyl)-3-
methyl-phenyl]~3~methyl-butyl}-2-hydroxymethyl-phenyl)-
methanol;
46- (4-{3-[3-ethyl-4-(2'-hydroxy-3,3-dimethyl-
butylsulphanyl)-phenyl]-3-methyl-butyl}-2-
hydroxymethyl-phenyl)-methanol;
47- (4-{3-[4-(3-hydroxy-4, 4-dimethyl-pentyl) -3-methyl-
phenyl] -3-methyl-butyl}-2-hydroxymethyl-phenyl) -
methanol;
48- (4-{3-[3-ethyl-4-(3-hydroxy-4, 4-dimethyl-pentyl)-
phenyl] -3-methyl-butyl} -2-hydroxymethyl-phenyl) - '
methanol;
49- (E)-l-{4-[3-(3, 4-bis-hydroxymethyl-phenyl)-l,l-
dimethyl-propyl] -2-methyl-phenyl} -4, 4-dimethyl-pent-l-
en-3-ol;
50- (E) -1-{4- [3- (3, 4-bis-hydroxymethyl-phenyl) -I, l-
dimethyl-propyl] -2-ethyl-phenyl} -4, 4-dimethy!-pent-1-
en-3-ol;
51- (4-{3-ethyl-3~[4-(2-hydroxy~3-methyl-butoxy)-3-
raethyl-phenyl] -pentyl}-2-hydroxymethyl-phenyl) -
methanol;
52- (4-{3-ethyl-3-[3-ethyl-4-(2-hydroxy-3-methyl-
butoxy) -phenyl]-pentyl}-2-hydroxymethyl-phenyl) -
raethanol;
53- (4-{3-ethyl-3-[4-(2-hydroxy-3-methyl-
butylsulphanyl)-3-methyl-phenyl]-pentyl} -2-
hydroxymethyl-phenyl)-methanol;
54- (4-{3-ethyl-3-[3-ethyl-4-(2-hydroxy-3-methyl-
butylsulphanyl) -phenyl] -pentyl}-2-hydroxymethyl-
phenyl) -methanol ;
55- (4-{3-ethyl-3-[4-(3-hydroxy-4-methyl-pentyl)-3-
methyl-phenyl]-pentyl}-2-hydroxymethyl-phenyl)-
methanol;
56- (4-{3-ethyl-3-[3-ethyl-4-(3-hydroxy-4-methyl-
pentyl) -phenyl] -pentyl }-2-hydroxyme thy 1-phenyl) -
itiethanol;
57- (E)-l-{4-[3-{3,4-bis-hydroxymethyl-phenyl)-1,1-
diethyl-propyl]-2-methyl-phenyl}-4-methyl-pent-l-en-3-
ol;
58- (E) -1-{4-[3-(3, 4-bis-hydroxymethyl-phenyl) -1,1-
diethyl-propyl]-2-methyl-phenyl}-4-methyl-pent-1-en-3-
ol;
59- {4-{3-ethyl-3-[4-(2-hydroxy-3r 3-dimethyl-butoxy)-3-
methyl-phenyl] -pentyl}-2-hydroxymethyl-phenyl) -
raethanol;
60- (4-{3-ethyl-3-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-
butoxy }-phenyl]-penty1}-2-hydroxymethy1-phenyl)-
methanol;
61- (4-{3-ethyl-3-[4-(2-hydroxy-3,3-dimethyl-
butylsulphanyl)-3-methyl-phenyl]-pentyl}-2-
hydroxymethyl-phenyl)-methanol;
62- (4-{3-ethyl-3-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-
butylsu-lphanyl) -phenyl] -pentyl}-2-hydroxymethyl-
phenyl)-methanol;
63- (4-{3-ethyl-3-[4-(3-hydroxy-4, 4-dimethyl-pentyl)-3-
methyl-phenyl]-pentyl}-2-hydroxymethyl-phenyl)-
methanol;
64- (4-{3-ethyl-3-[3-ethyl-4-(3-hydroxy-4,4-dimethyl-
pentyl) -phenyl]-pentyl}-2-hydroxymethyl-phenyl)-
methanol;
65- (E)-l-{4-[3-(3,4-bis-hydroxymethyL-phenyl)-1,1-
diethyl-propyl]-2-methyl-phenyl}-4,4-dimethyl-pent-l-
en-3-ol;
66- (E)-1-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-1,1-
diethyl-propyl]-2-ethyl~phenyl}-4,4-dimethyl-pent-l-en-
3-ol;
67- [2-hydroxymethyl-4-(2-{l-[4-(2-hydroxy-3-methyl-
butoxy)-3-methyl-phenyl]-cyclopentyl}-ethyl)-phenyl]-
methanol;
68- [4-(2-{l-[3-ethyl-4-(2-hydroxy-3-methyl-butoxy)-
phenyl]-cyclopentyl}-ethyl)-2-hydroxymethyl-phenyl]-
methanol; "
69- [2-hydroxymethyl-4-(2-{l-[4-(2-hydroxy-3-methyl-
butylsulphanyl)-3-methyl-phenyl]-cyclopentyl}-ethyl)-
phenyl]-methanol;
70- [4-(2-{l-[3-ethyl-4-(2-hydroxy-3-methyl-
butylsulphanyl) -phenyl] -cyclopentyl }'-ethyl) -2-
hydroxymethyl-phenyl]-methanol;
71- [2-hydroxymethyl-4-(2-{l-[4-(3-hydroxy-4-methyl-
pentyl)-3-methyl-phenyl]-cyclopentyl}-ethyl)-phenyl]-
methanol;
72- [4-(2-{l-[3-ethyl-4-(3-hydroxy-4-methyl-pentyl)-
phenyl]-cyclopentyl}-ethyl)-2-hydroxymethyl-phenyl]-
methanol;
73- (E)-1-(4-{1-[2-(3,4-bis-hydroxymethyl-phenyl)-
ethyl]-cyclopentyl}-2-methyl-phenyl)-4-methyl-pent-1-
en-3-ol;
74- (E) -1- (4-{l- [2- (3,4-bis-hydroxymethyl-phenyl) -
ethyl]-cyclopentyl}-2-ethyl-phenyl)-4-methyl-pent-l~en-
3-ol;
75- [4- (2-{l- [4- (2-hydroxy-3, 3-dimethyl-butoxy) -3-
methyl-phenyl] -cyclopentyl}—ethyl) -2-hydroxymethyl-
phenyl]-methanol;
76- [4- (2-{l-[3-ethyl-4- (2-hydroxy-3, 3-dimethyl-
butoxy ) -phenyl] -cyclopentyl}-ethyl) -2-hydroxymethyl-
phenyl]-methanol; -
77- [4-{2-{l-[4- (2-hydroxy-3,3-dimethyl-butylsulphanyl-
3-methyl-phenyl] -cyclopentyl}-ethyl) -2-hydroxymethyl-
phenyl]-methanol;
78- [4-(2-{l-[3-ethyl-4-(2-hydrox;y-3,3-dimethyl-
butylsulphanyl)-phenyl]-cyclopentyl}-ethyl)-2-
hydroxyraethyl-phenyl]-methanol;
79- [4- (2-{l-[4- (3-hydroxy-4,4-dimethyl-pentyl)-3-
methy1-phenyl]-cyclopentyl}-ethyl)-2-hydroxymethyl-
phenyl]-methanol;
80- [4-(2-{l-[3-ethyl-4-(3-hydroxy-4,4-dimethyl-
pentyl)-phenyl]-cyclopentyl}-ethyl)-2-hydroxymethyl-
•phenyl ] -methanol;
81- (E)-l-(4-{l- [2-(3,4-bis-hydroxymethyl-phenyl)-
ethyl]-cyclopentyl}-2-methyl-phenyl)-4,4-dimethyl-pent-
l-en-3-ol;
82- (E)-1-(4-{l- [2-(3,4-bis-hydroxymethyl-phenyl)-
ethyl] -cyclopentyl}-2-ethyl-phenyl) -4, 4-dimethyl-pent-
l-en-3-ol;
83- [2-hydroxymethyl-4-(2-{l-[4-(2-hydroxy-3-methyl-
butoxy) -3-methyl-phenyl] -cyclohexyl} -ethyl) -phenyl] -
methanol;
84- [4- (2-{ 1- [3-ethyl-4- (2-hydroxy-3-methyl-butoxy) -
phenyl] -cyclohexyl}-ethyl) -2-hydroxymethyl-phenyl] -
methanol;
85- [2-hydroxymethyl-4- (2-{l- [4- (2-hydroxy-3-methyl-
butylsulphanyl) -3-methyl-phenyl] -cyclohexyl}-ethyl) -
phenyl]-methanol;
86- [4- (2-{l-[3-ethyl-4-(2-hydroxy-3-methyl-
butylsulphanyl) -phenyl] -cyclohexyl}-ethyl) -2-
hydroxymethyl-phenyl]-methanol; •
87- [2-hydroxymethyl-4-{2-{l-[4-(3-hydroxy-4-'methyl-
pentyl) -3-methyl-phenyl] -cyclohexyl}-ethyl) -phenyl] -
methanol;
88- [4- (2-{l-[3-ethyl-4-(3-hydroxy-4-methyl-pentyl)-
phenyl] -cyclohexyl}-ethyl) -2-hydroxymethyl-phenyl] -
methanol;
89- (E)-l-(4-{l-[2-(3,4-bis-hydroxymethyl-phenyl)-
ethyl] -cyclohexyl}-2-methyl-phenyl) -4-methyl-pent-l-en-
3-ol;
90- (E) -1- (4-{l- [2- (3, 4-bis-hydroxyniethyl-phenyl) -
ethyl] -cyclohexyl}-2-ethyl-phenyl) -4-methyl-pent-l-en-
3-ol;
91- [4- (2-{l-[4- (2-hydroxy-3, 3-dimethyl-butoxy) -3-
methyl-phenyl] -cyclohexyl}-ethyl) -2-hydroxymethyl-
phenyl] -methanol;
92- [4-(2-{l-[3-ethyl-4-(2-rhydroxy-3,3-dimethyl-
butoxy)-phenylj-cyclohexyl}-ethyl)-2-hydroxymethyl-
phenyl]-methanol;
93- [4-(2-{1-[4-(2-hydroxy-3,3-dimethyl-
butylsulphanyl)-3-methyl-phenyl]-cyclohexyl}-ethyl)-2-
hydroxymethyl-phenyl] -methaiiol;
94- [4-{2-{l-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-
butylsulphanyl)-phenyl]-cyclohexyl}-ethyl)-2-
hydroxymethyl-phenyl] -methanol;
95- [4- (2-{l-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-
methyl-phenyl]-cyclohexyl}-ethyl)-2-hydroxymethyl-
phenyl]-methanol;
96- [4-(2-{l-[3~ethyl-4-(3-hydroxy~4,4-dimethyl-
pentyl )-phenyl]-cyclohexyl}-ethyl)-2-hydroxymethyl-
phenyl]-methanol;
97- (E)-1-(4-{l-[2-(3,4-bis-hydroxymethy1-phenyl)-
ethyl]-cyclohexyl}-2-methyl-phenyl)-4,4-dimethyl-pent-
l-en-3-ol;
98- (E)-l-(4-{l-[2-(3,4-bis-hydroxymethyl-phenyl)-
ethyl]-cyclohexyl}—2-ethyl-phenyl)-4,4-dimethyl-pent-1-
en-3-ol;
99- (4-{2-ethyl-2-[4-(2-hydroxy-3-methyl-butoxy)-3-
methyl-phenyl]-butoxy}-2-hydroxymethyl-phenyl) -
methanol;
100- (4-{2-ethyl-2-[3-ethyl-4-(2-hydroxy-3-methyl-
butoxy)-phenyl]-butoxy}-2-hydroxymethyl-phenyl)-
methanol;
101- (4-{2-ethyl-2-[4-(2-hydroxy-3-methyl-
butylsulphanyl)-3-methyl-phenyl]-butoxy}-2-
hydroxymethyl-phenyl)-methanol;
102- (4-{2-ethyl-2--[3-ethyl-4-(2-hydroxy-3-methyl-
butylsulphanyl)-phenyl]-butoxy}-2-hydrpxymethyl-
phenyl)-methanol;
103- (4-{2-ethyl-2-[4-(3-hydroxy-4-methyl-pentyl)-3-
methyl-phenyl] -butoxy}-2-hydroxymethyl-phenyl) -
methanol;
104- (4-{2-ethyl-2-[3-ethyl-4-(3-hydroxy-4-methyl-
pentyl)-phenyl]-butoxy}-2-hydroxymethyl-phenyl}-
methanol;
105- (E)-1-{4-[1- (3,4-bis-hydroxymethyl-phenoxymethyl)-
l~ethyl-propyl]-2-methyl-phenyl}-4-methyl~pent-l-en-3-
ol;
106- (E)-l-{4-[l-(3r4-bis-hydroxymethyl-phenoxymethyl)-
1-ethyl-propyl]-2-ethyl-phenyl}-4-methyl-pent-l-en-3-
ol;
107- (4-{2-ethyl-2- [4-(2-hydroxy-3,3-dimethyl-butoxy)-
3-methyl-phenyl]-butoxy}-2-hydroxymethyl-phenyl)-
methanol;
108- (4-{2-ethyl-2-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-
butoxy) -phenyl]-butoxy}-2-hydroxymethyl-phenyl)-
methanol;
109- (4-{2-ethyl-2-[4-(2-hydroxy-3, 3-dimethyl-
butylsulphanyl)-3-methyl-phenyl]-butoxy}-2-
hydroxymethyl-phenyl) -methanol;
110- (4-{2-ethyl-2-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-
b'utylsulphanyl) -phenyl] -butoxy}-2-hydroxymethyl-
phenyl)-methanol;
111- (4-{2-ethyl-2-[4-(3-hydroxy-4,4-dimethyl-pentyl)-
3-methyl-phenyl] -butoxy}-2-hydroxymethyl-phenyl) -
methanol;
112- (4-{2-ethyl-2-[3-ethyl-4-(3-hydroxy-4,4-dirnethyl-
pentyl) -phenyl] -butoxy} -2-hydroxymethyl-phenyl) -
methanol;
113- (E) -l-{4-[l- (3,4-bis-hydroxymethyl-phenoxymethyl) -
l-ethyl-propyl]-2-iriethyl-phenyl}-4, 4-dimethyl-pent-l- .
en-3-ol;
114- (E) -1- { 4- [1- (3, 4-bis-hydroxymethyl-phenoxymethyl) -
1-ethyl-propyl] -2-ethyl-phenyl}-4, 4-dimethyl-pent-1-en-
3-ol;
115- (4-{ (E)-3-ethyl-3-[4-2-hydroxy-3-methyl-butoxy)-3-
methyl-phenyl] -pent-1-enyl} -2-hydroxymethyl-phenyl) -
methanol;
116- (4-{ (E)-3-ethyl-3-[3-ethyl-4-(2-hydroxy-3-methyl-
butoxy) -phenyl] -pent-1-enyl} -2-hydroxymethyl-phenyl) -
methanol;
117- (4-{ (E)-3-ethyl-3-[4-(2-hydroxy-3-methyl-
butylsulphanyl) -3-methyl-phenyl] -pent-1-enyl }-2-
hydroxymethyl-phenyl) -methanol;
118- (4-{ (E)-3-ethyl-3-[3-ethyl-4-(2-hydroxy-3-methyl-
butylsulphanyl) -phenyl] -pent-1-enyl }-2-hydroxymethyl-
phenyl) -methanol;
119- (4-{(E)-3-ethyl-3-[4-(3-hydroxy-4~methyl-pentyl)-
3-methyl-phenyl]-pent-1-enyl}-2-hydroxymethyl-phenyl)-
methanol;
120- (4-{(E)-3-ethyl-3-[3-ethyl-4-(3-hydroxy-4-methyl-
pentyl)-phenyl]-pent-1-enyl}-2-hydroxymethyl-phenyl)-
methanol;
121- (E)-1-{4-[ (E)-3-(3, 4-bis-hydroxymethyl-phenyl)-
1, -l-diethyl-allyl]-2-methyl-phenyl }-4-inethyl-pent-l-en-3-ol;
122- (E)-l-{4-[(E)-3-(3, 4-bis-hydroxymethyl-phenyl)-
1,1-diethyl-allyl]-2-ethyl-phenyl}-4-methyl-pent-l-en-
3-o 1;
123- (4-{(E)-3-ethyl-3-[4-(2-hydroxy-3,3-dimethyl-
butoxy)-3-methyl-phenyl] -pent-1-enyl}-2-hydroxymethyl-
phenyl) -methanol;
124- (4-{(E)~3-ethyl-3-[3-ethyl-4-(2-hydroxy-3,3-
dimethyl-butoxy)-phenyl] -pent-1-enyl}-2-hydroxymethyl-
phenyl) -methanol;
125- (4-{(E)-3-ethyl-3-[4-(2-hydroxy-3r3-dimethyl-
butylsulphanyl)-3-methyl-phenyl]-pent-1-enyl}-2-
hydroxymethyl-phenyl)-methanol;
126- (4-{(E)-3-ethyl-3-[3-ethyl-4-(2-hydroxy-3,3-
dimethyl-butylsulphanyl)-phenyl] -pent-1-enyl}-2-
hydroxyraethyl-phenyl) -methanol;
127- (4-{ (E)-3-ethyl-3- [4-'(3-hydroxy-4, 4-dimethyl-
pentyl)-3-methyl-phenyl]-pent-1-enyl}-2-hydroxymethyl-
phenyl )-methanol;
128- (4-{ (E)-3-ethyl-3-[3-ethyl-4-(3-hydroxy-4,4-
diraethyl-pentyl) -phenyl] -pent-1-enyl }-2-hydroxymethyl-
phenyl)-methanol;
129- (E)-l-{4-[ (E)-3-(3,4-bis-hydroxymethyl~phenyl)-
1,1-diethyl-allyl] -2-methyl-phenyl}-4, 4-dimethyl-pent-
l-en-3-ol;
130- (E) -l-{4- [ (E) -3- (3, 4-bis-hydroxyraethyl-phenyl) -
.1,1-diethyl-allyl] -2-ethyl-phenyl}-4, 4-dim.ethyl-pent-l-
en-3-ol;
131- (4-{3-[3-ethyl-4-(3,3,'3~trifluoro-2-hydroxy-
propoxy) -phenyl] -3-methyl-butyl}-2-hydroxymethyl-
phenyl)-methanol;
132- (4-{3- [3-ethyl-4- (3, 3, 3-trifluoro-2-hydroxy-
propylsulphanyl)-phenyl] -3-methyl-butyl}-2-
hydroxymethyl-phenyl) -methanol ;
133- (4-{3-[3-ethyl-4- (4, 4, 4-trifluoro-3-hydroxy-
butyl) -phenyl] -3-methyl-butyl} -2-hydroxymethyl-phenyl) -
methanol;
134- (4-{3-[3-ethyl-4-( (E)-4,4, 4-trifluoro-3-hydroxy-
but-1-enyl) -phenyl] -3-methyl-butyl} -2-hydroxymethyl-
phenyl)-methanol;
135- (4-{3-[3-ethyl-4-(4,4,4-trifluoro-2-hydroxy~3-
trifluoromethyl-butoxy) -phenyl] -3-methyl-butyl}-2-
hydroxymethyl-phenyl) -methanol;
136- (4- { 3- [3-ethyl-4- (4r 4, 4-trif luoro-2-hydroxy-3-
trif luoromethyl-butylsulphanyl) -phenyl] -3—methyl-
butyl}-2-hydroxymethyl-phenyl)-methanol;
137- (4-{[ethyl-(5,5,5-trifluoro-3-hydroxy-4-
trifluoromethyl-pentyl)-phenyl]-methyl-butyl}—2-
hydroxymethyl-phenyl)-methanol;
138- (E)-{4-[3-(3,4-bis-hydroxymethyl-phenyl)-1,1-
dimethyl-propyl]-2-ethyl-phenyl}-5,5,5-trifluoro-4-
trifluoromethyl-pent-l-en-3-ol;
139- (4-{3-ethyl-3-[3-ethyl-4-(3,3,3-trifluoro-2-
hydroxy-propoxy)-phenyl]-pentyl}-2-hydroxymethyl-
phenyl)-methanol;
140- (4-{3-ethyl-3-[3-ethyl-4-(3,3,3-trifluoro-2-
hydroxy-propyIsulphanyl)-phenyl]-pentyl}-2-
hydroxymethyl-phenyl)-methanol;
141- (4-{3-ethyl-3-[3-ethyl-4-(4,4,4-trifluoro-3-
hydroxy-butyl)-phenyl]-pentyl}-2-hydroxymethyl-phenyl)
methanol;
142- (4-{3-ethyl-3-.[3-ethyl-4-( (E) -4, 4, 4-trif luoro-3- _
hydroxy-but-1-enyl)-phenyl]-pentyl}-2-hydroxymethyl-
phenyl ) -methanol;
143- (4-{3-ethyl-3-[3-ethyl-4-(4,4,4-trifluoro-2-
hydr-oxy-3-trif luoromethyl-btitoxy) -phenyl] -pentyl} -2-
hydroxymethyl-phenyl)-methanol;
144- (4-{3-ethyl-3-[3-ethyl-4-(4,4,4-trifluoro-2-
hydroxy-3-trifluoromethyl-butylsulphanyl)-phenyl]-
pentyl}-2-hydroxymethyl-phenyl)-methanol;
145- (4-{ethyl-[ethyl-(5,5,5-trifluoro-3-hydroxy-4-
trifluoromethyl-pentyl)-phenyl]-pentyl}-2-
hydroxymethyl-phenyl)-methanol;
146- (E)-{4-[3-(3,4-bis-hydroxymethyl-phenyl) -1,1-
diethyl~propyl]-2-ethyl-phenyl}-5, 5, 5-trifluoro-4-
trifluoromethyl-pent-l-en-3-ol;
147- [4- (2-{ 1- [3-ethyl-4- (3, 3, 3-trif luoro-2-hydroxy-
propoxy) -phenyl] -cyclohexyl} -ethyl) -2-hydroxymethyl~
phenyl]-methanol;
148- [4-(2-{1-[3-ethyl-4-(3,3, 3-trifluoro-2-hydroxy-
propylsulphanyl)-phenyl]-cyclohexyl}-ethyl)-2-
hydroxymethyl-phenyl]-methanol;
149- [4- (2-{l-[3-ethylr4- (4, 4, 4-trifluoro-3-hydroxy-
bxityl) -phenyl]--cyclohexyl}-ethyl) -2-hydroxymethyl-
phenyl]-methanol;
150- [4-(2-{1-[3-ethyl-4-((E) -4, 4,4-trifluoro-3-
hydroxy-but-1-enyl)-phenyl] -cyclohexyl}-ethyl)-2-
hydroxymethyl-phenyl] -methanol;
151- [4-(2-{l-[3-ethyl-4_-(4,41,4-trifluoro-2-hydroxy-3-
trifluoromethyl-butoxy) -phenyl] -cyclohexyl}-ethyl) —2-
hydroxymethyl-phenyl] -methanol;
152- [4- (2- {1- [3-ethyl-4- (4,4, 4-trif luoro-2-hydroxy-3-
trif luoromethyl-butylsulphanyl) -phenyl] -cyclohexyl }-
ethyl)-2-hydroxymethyl-phenyl] -methanol;
153- [4-(2-{l-[ethyl-(5,5,5-trifluoro-3-hydroxy-4-
trif luoromethyl-pentyl) -phenyl] -cyclohexyl}-ethyl) -2-
hydroxyraethyl-phenyl]-methanol;
154- (E)-(4-{1-[2- (3,4-bis-hydroxymethyl-phenyl)-
ethyl] -cyclohexyl }-2-ethyl-phenyl) -5,5, 5-trif luoro-4-
trifluoromethyl-pent-l-en-3-ol;
155- (4-{2-ethyl-2--[3-ethyl-4- (3,3,3-trifluoro-2-
hydroxy-propoxy) -phenyl] -butoxy}-2-hydroxymethyl-
phenyl}-methanol;
156- (4- {2-ethyl-2- [3-ethyl-4- (3,3, 3-trifluoro-2-
hydroxy-propylsulphanyl) -phenyl] -butoxy} -2-
hydroxymethyl-phenyl)-methanol;
157- (4-{2-ethyl-2-[3-ethyl-4-(4,4,4-trifluoro-3-
hydroxy-butyl) -phenyl] -butoxy}-2-hydroxymethyl-phenyl) -
methanol;
158- (4-{2-ethyl-2- [3-ethyl-4- ( (E) -4, 4, 4-trifluoro-3-
hydroxy-but-1-enyl) -phenyl] -butoxy} -2-hydroxymethyl-
phenyl)-methanol;
159- (4-{2-ethyl-2-[3-ethyl-4-(4, 4, 4-trifluord-2-
hydroxy-3-trif luoromethyl-butoxy). -phenyl] -butoxy}-2-
hydroxymethyl-phehyl) -methanol;
160- (4-{2-ethyl-2-[-3-ethyl-4-(4,4,4-trifluoro-2-
hydroxy-3-trif luoromethyl-butylsulphanyl) -phenyl] -
butoxy}-2-hydroxymethyl-phenyl) -methanol;
161- (4-{ethyl- [ethyl- (5,5, 5-trifluoro-3-hydroxy-4-
trif luoro'methyl-pentyl) -phenyl] -butoxy} -2-
hydroxymethyl-phenyl)-methanol;
162- (E) -{4- [1- (3, 4-bis-hydroxymethyl-phenoxymethyl) -1-
ethyl-propyl] -2-ethyl-phenyl}-5, 5, 5-trif luoro-4-
trifluoromethyl-pent-l-en-3-ol.
7. Pharmaceutical composition, wherein it comprises, in a pharmaceutically acceptable carrier of a kind such as herein described at least one of the compounds as claimed in any of claims 1 to 6 in a concentration of between 0.001% and 5% by weight relative to the total weight of the composition.
8. Cosmetic composition, wherein it comprises, in a cosmetically acceptable carrier of a kind such as herein described at least one of the compounds as claimed in any one of claims 1 to 6 in a connection of between 0.001% and 3% by weight relative to the total weight of the composition.

Documents:

865-delnp-2005-abstract.pdf

865-delnp-2005-claims-(cancelled).pdf

865-DELNP-2005-Claims.pdf

865-delnp-2005-complete specification (as filed).pdf

865-delnp-2005-complete specification (granted).pdf

865-delnp-2005-correspondence-others.pdf

865-delnp-2005-correspondence-po.pdf

865-DELNP-2005-Description (Complete).pdf

865-DELNP-2005-Drawings.pdf

865-delnp-2005-form-1.pdf

865-delnp-2005-form-18.pdf

865-DELNP-2005-Form-2.pdf

865-delnp-2005-form-3.pdf

865-delnp-2005-form-5.pdf

865-delnp-2005-gpa.pdf

865-delnp-2005-pct-210.pdf

865-delnp-2005-pct-409.pdf

865-delnp-2005-petition-138.pdf


Patent Number 243032
Indian Patent Application Number 865/DELNP/2005
PG Journal Number 40/2010
Publication Date 01-Oct-2010
Grant Date 24-Sep-2010
Date of Filing 04-Mar-2005
Name of Patentee GALDERMA RESEARCH & DEVELOPMENT, S.N.C.,
Applicant Address 635, ROUTE DES LUCIOLES, QUARTER DES CLAUSONNES, F-06560 VALBONNE, SOPHIA ANTIPOLIS, FRANCE
Inventors:
# Inventor's Name Inventor's Address
1 THIBAUD BIADATTI 10 BIS, CHEMIN DU BOIS D'OPIO, F-6650 OPIO, FRANCE
2 ETIENNE THOREAU 8, ALLEE SAINT-PONS, F-06460 SAINT VALLIER DE THIEY, FRANCE
3 JOHANNES VOEGEL 195-4 CHEMIN DES COLLINES, F-06740 CHATEAUNEUF/GRASSE, FRANCE
4 ANDRE JOMARD 20 BIS, AVENUE FRANCOIS GOBY, F-06460 SAINT VALLIER DE THIEY, FRANCE
PCT International Classification Number C07C 43/23
PCT International Application Number PCT/EP2003/010159
PCT International Filing date 2003-08-25
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/407,716 2002-09-04 France
2 02/10620 2002-08-27 France