Vitamin D analogues

Details Vitamin D analogues Vitamin D analogues

2002-09-05

2004-12-14

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

C-o-group doai

C514S277000, C514S438000, C514S461000, C514S428000, C568S807000, C546S344000, C549S078000, C549S502000, C548S570000

Reexamination Certificate

active

06831106

ABSTRACT:

The invention relates, as novel and useful industrial products, to triaromatic compounds which are vitamin D analogues. The invention also relates to a process for preparing them and to their use in pharmaceutical compositions intended for use in human or veterinary medicine, or alternatively in cosmetic compositions.
The compounds according to the invention have pronounced activity in the fields of cell proliferation and differentiation and find applications more particularly in the topical and systemic treatment of dermatological (or other) complaints associated with a keratinization disorder, complaints with an inflammatory and/or immunoallergic component and hyperproliferation of tissues of ectodermal origin (skin, epithelium, etc.), whether benign or malignant. These compounds can also be used to combat ageing of the skin, whether light-induced or chronological, and to treat cicatrization disorders.
The compounds according to the invention can also be used in cosmetic compositions for body and hair hygiene.
Vitamin D is an essential vitamin for preventing and treating mineralization defects of cartilage (rickets) and of bone (osteomalacia), and even of certain forms of osteoporosis in elderly people. However, it is now accepted that its functions extend well beyond regulating bone metabolism and calcium homeostasis. Among these functions, mention may be made of its actions on cell proliferation and differentiation and the control of the immune defences. Their discovery has opened the way to novel therapeutic approaches in dermatology, carcinology and in the field of autoimmune diseases and that of organ or tissue transplants.
An efficient therapeutic supply has long been confounded by the toxicity of this vitamin (occasionally fatal hypercalcaemia). Structural analogues of vitamin D are currently synthesized, some of which conserve only the differentiating properties and have no action on calcium metabolism.
One of the aims of the present invention is to propose novel compounds which are structural analogues of vitamin D and which show selective activity on cell proliferation and differentiation without displaying any hypercalcaemiant nature.
Another aim of the present invention is to propose novel compounds which are analogues of vitamin D and which are more readily synthesized and thus more economical than those known previously.
Thus, the present invention relates to compounds which can be represented by the general formula (I) below:
in which:
R
1
represents a hydrogen atom, a CH
3
radical or a radical —(CH
2
)
r
—OR
4
,
R
2
represents a radical —(CH
2
)
s
—OR
5
r, s, R
4
and R
5
having the meanings given below,
X—Y represents a bond chosen from the bonds of formulae (a) to (d) below which can be read from left to right or vice-versa:
R
6
and W having the meanings given below,
Ar
1
represents a ring of formulae (e) to (i) below:
R
7
, R
8
and R
9
having the meanings given below,
Ar
2
represents a ring of formulae (j) to (n) below:
R
10
, R
11
and R
12
having the meanings given below,
R
3
represents a radical of formula:
t, R
13
, R
14
and R
15
having the meanings given below,
r and s, which may be identical or different, being 1 or 2,
R
4
and R
5
, which may be identical or different, represent a hydrogen atom, an acetyl radical, a benzoyl radical, a trimethylsilyl radical, a tert-butyldimethylsilyl radical or a tetrahydropyranyl radical,
R
6
represents a hydrogen atom or a lower alkyl radical,
W represents an oxygen or sulphur atom, a CH
2
radical or an NH radical which can be substituted with a lower alkyl radical,
R
7
and R
10
, which may be identical or different, represent a hydrogen atom or a lower alkyl radical,
R
8
, R
9
, R
11
and R
12
, which may be identical or different, represent a hydrogen atom, a lower alkyl radical, a halogen atom, a radical —OR
16
, a polyether radical, a CF
3
radical, an NO
2
radical or an amino radical which may be substituted with one or two lower alkyl radicals,
R
16
having the meanings given below,
t being 0 or 1,
R
13
and R
14
, which may be identical or different, represent a hydrogen atom, a lower alkyl radical, a cycloalkyl radical, a CF
3
radical or a C
2
F
5
radical,
R
15
represents a hydrogen atom, an acetyl radical, a trimethylsilyl radical, a tert-butyldimethylsilyl radical or a tetrahydropyranyl radical,
R
16
represents a hydrogen atom or a lower alkyl radical.
The invention is also directed towards the optical and geometrical isomers of the said compounds of formula (I) as well as to the salts thereof when X—Y represent a bond of formula (a) and W represents an —NH— radical optionally substituted with a lower alkyl radical.
When the compounds according to the invention are in the form of salts, they are pharmaceutically or cosmetically acceptable salts obtained by addition of an inorganic or organic acid, in particular hydrochloric acid, sulphuric acid, acetic acid, fumaric acid, hemisuccinic acid, maleic acid or mandelic acid.
According to the present invention, the expression “lower alkyl radical” means a linear or branched radical containing from 1 to 6 carbon atoms, and preferably methyl, ethyl, isopropyl, tert-butyl and hexyl radicals.
The expression “cycloalkyl radical” means a cyclic alkane radical containing from 3 to 6 carbon atoms. The cycloalkyl radical is preferably chosen from a cyclopropyl, cyclopentyl or cyclohexyl radical.
The expression “halogen atom” preferably means a fluorine, chlorine or bromine atom.
The expression “polyether radical” means a radical containing from 2 to 5 carbon atoms interrupted with at least two oxygen atoms, such as methoxymethoxy, methoxyethoxy and methoxyethoxymethoxy radicals.
Among the compounds of formula (I) falling within the context of the present invention, mention may be made in particular of the following:
{5-[4′-(1-ethyl-1-hydroxypropyl)biphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{2-hydroxymethyl-5-[4′-(1-hydroxy-1-methylethyl)biphenyl-3-yloxymethyl]phenyl}methanol
{5-[4′-(1-ethyl-1-hydroxypropyl)-2′-methylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{2-hydroxymethyl-5-[4′-(1-hydroxy-1-methylethyl)-2′-methylbiphenyl-3-yloxymethyl]phenyl}methanol
(5-{2-[3′-(1-ethyl-1-hydroxypropyl)biphenyl-3-yl]ethyl)-2-hydroxymethylphenyl}methanol
{2-hydroxymethyl-5-[3′-(1-hydroxy-1-methylethyl)-biphenyl-3-yloxymethyl]phenyl}methanol
{5-[4′-(2-ethyl-2-hydroxybutyl)biphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{5-[3′-(2-ethyl-2-hydroxybutyl)biphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
1-[3′-(3,4-bis-hydroxymethyl-benzyloxy)biphenyl-3-yl]-2-methyl-2-propanol
{4-[4′-(1-ethyl-1-hydroxypropyl)-2′-methylbiphenyl-3-ylsulphanylmethyl]-2-hydroxymethylphenyl}methanol
{4-[4′-(1-ethyl-1-hydroxypropyl)-2,2-dimethylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{2-hydroxymethyl-4-[4′-(1-hydroxy-1-propylbutyl)-2,2-dimethylbiphenyl-3-yloxymethyl]phenyl}methanol
{4-[4′-(1-ethyl-1-hydroxypropyl)-2-methylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{4-[4′-(1-ethyl-1-hydroxypropyl)-2,2′,6′-trimethylbiphenyl-3-yloxymethyl]-2-hydroxymethyl-phenyl}methanol
(4-{3-[5-(1-ethyl-1-hydroxypropyl)-2-pyridyl]phenoxymethyl}-2-hydroxymethylphenyl)methanol
{4-[4′-(1-ethyl-1-hydroxypropyl)-6,2′-dimethylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{4-[4′-(1-ethyl-1-hydroxypropyl)-6,2′,6′-trimethylbiphenyl-3-yloxymethyl]-2-hydroxymethyl-phenyl}methanol
{4-[4′-(1-ethyl-1-hydroxypropyl)-6-methylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{4-[4′-(1-ethyl-1-hydroxypropyl)-2′,6′-dimethylbiphen

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