Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1998-09-23
2001-01-30
Geist, Gary (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S569000, C562S405000
Reexamination Certificate
active
06180674
ABSTRACT:
The subject-matter of the present invention is new unsaturated derivatives at the 4-position of 6-tert-butyl-1-1 dimethylindane, their process of preparation and their use in human or veterinary medicine and in cosmetics.
It is well known that all-trans-retinoic acid (AtRA) and certain synthetic analogues (retinoids) play a fundamental role in cell proliferation and differentiation. These pharmacological properties confer an advantage on retinoids in the treatment of dermatological conditions, such as acne or psoriasis. In addition, these compounds have applications in oncolocgy in the treatment and prevention of certain cancers.
The compounds according to the invention, which are synthetic compounds also of the retinoid type, exhibit an activity in the fields of cell differentiation and proliferation. These compounds can consequently be used in the topical and systemic treatment of dermatological conditions linked to a disorder of keratinization, dermatological conditions (or others) having an inflammatory, viral and/or immunoallergic component, and dermal or epidermal proliferations, whether benign or malignant. These compounds can additionally be used in the treatment of degenerative diseases of the connective tissue, for controlling ageing of the skin, whether photoinduced or chronologic, and treating disorders of cicatrization. Finally, they find an application in the ophthalmological field, in particular in the treatment of corneopathies.
They can also be used in cosmetic compositions for body or hair hygiene.
The compounds according to the invention can be represented by the following general formula (I):
in which:
X represents:
(i) either a divalent radical of following formula:
and Y then represents a divalent radical of following formula:
(ii) or a divalent radical of formula:
and Y then represents either a divalent radical corresponding to the divalent radical of formula (b) above or one of the divalent radicals of following formula:
Z being —O—, —S— or
R
1
represents —CH
3
, —(CH
2
)
p
—OR
4
, —(CH
2
)
p
—COR
5
or —S(O)
t
—R
6
,
p being 0, 1, 2 or 3,
t being 0, 1 or 2,
R
2
represents H or lower alkyl,
R
3
represents H, lower alkoxy or —OCOR
7
,
R
4
represents H, lower alkyl, —COR
7
, aryl, aralkyl, mono- or polyhydroxyalkyl, or a polyether radical,
R
5
represents H, lower alkyl, —OR
8
or
R
6
represents H or lower alkyl,
R
7
represents lower alkyl,
R
8
represents H, alkyl, alkenyl, alkynyl, aryl, aralkyl, mono- or polyhydroxyalkyl, a sugar residue or an amino acid residue,
r′ and r″, identical or different, represent H, lower alkyl, —COR
7
, aryl, a sugar residue or an amino acid residue or r′ and r″, taken together, form a heterocycle, and the salts of the compounds of formula (I), when R
1
represents a carboxylic acid group, and the geometrical and optical isomers of the compounds of formula (I).
When the compounds according to the invention are provided in the form of a salt, it is preferably a salt of an alkali metal or alkaline earth metal or alternatively of zinc or of an organic amine.
According to the invention, lower alkyl radical is understood to mean a linear or branched C
1
-C
6
radical, preferably methyl, ethyl, propyl, isopropyl, tert-butyl and n-hexyl radicals.
Alkyl radical is understood to mean a linear or branched C
1
-C
20
radical, preferably methyl, ethyl, isopropyl, butyl, tert-butyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals.
Lower alkoxy radical is understood to mean a radical having 1 to 6 carbon atoms, preferably methoxy, ethoxy, isopropoxy and butoxy radical.
Alkenyl radical is understood to mean a linear or branched radical preferably having from 2 to 5 carbon atoms and exhibiting one or two ethylenic unsaturation(s), such as the allyl radical.
Alkynyl radical is understood to mean a radical, having from 3 to 6 carbon atoms, comprising 1 or 2 triple bond(s), such as the 2-propynyl, 2-butynyl and 2,4-hexadiynyl radicals.
The radical of formula —COR
7
(R
7
being lower alkyl) or acyl radical is preferably selected from the acetyl, propionyl or pivaloyl radicals.
Monohydroxyalkyl radical is understood to mean a radical preferably having from 2 to 4 carbon atoms, preferably the 1-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl or 4-hydroxybutyl radicals.
Polyhydroxyalkyl radical is understood to mean a radical preferably having from 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl or 2,3,4,5-tetrahydroxypentyl radicals or the pentaerythritol residue.
Polyether radical is understood to mean a radical having from 2 to 6 carbon atoms and from 1 to 3 oxygen or sulphur atoms, such as the methoxymethyl ether, methoxyethoxymethyl ether or methylthiomethyl ether radicals.
Aryl radical is understood to mean preferably the phenyl radical, optionally substituted by at least one halogen atom, such as Br, Cl or I, one hydroxyl group, one nitro group, one methoxy group or one optionally substituted amine group.
Aralkyl radical is understood to mean preferably the benzyl or phenethyl radical, optionally substituted by at least one halogen atom as defined above, one hydroxyl group, one nitro group or one methoxy group.
Amino acid residue is understood to mean in particular a residue deriving from lysine, glycine or aspartic acid.
Sugar residue is understood to mean a residue deriving from glucose, galactose or mannose or alternatively glucuronic acid.
Heterocycle is understood to mean preferably a piperidino, morpholino, pyrrolidino or piperazino radical, the latter being optionally substituted in the 4-position by a lower C
1
-C
6
alkyl or a mono- or polyhydroxyalkyl as defined above.
According to a first preferred embodiment, the compounds according to the invention correspond to the following general formula:
in which:
Y
1
represents one of the divalent radicals of formula:
R
2
, R
3
and Z having the same meanings as those given for the formula (I) above,
R′
1
represents —(CH
2
)
p′
—COOR′
8
, p′ being 0 and R′
8
representing H or lower alkyl.
According to a second preferred embodiment, the compounds according to the invention correspond to the following general formula:
in which:
R
2
represents H or lower alkyl, and
R′
1
represents —(CH
2
)
p′
—COOR′
8
, p′ being 0 and R′
8
being H or lower alkyl.
Among the compounds corresponding to the above formulae (I), (II) and (III), mention may be made of the following examples:
methyl (2E,4E)-6-[4-(6-tert-butyl-1,1-dimethylindanyl)]-3-methylhepta-2,4,6-trienoate,
(2E,4E)-6-[4-(6-tert-butyl-1,1-dimethylindanyl)]-3-methylhepta-2,4,6-trienoic acid,
methyl (2E,4E)-6-[4-(6-tert-butyl-1,1-dimethylindanyl)]hepta-2,4,6-trienoate,
(2E,4E)-6-[4-(6-tert-butyl-1,1-dimethylindanyl)]hepta-2,4,6-trienoic acid,
methyl (2E,4E,6E)-7-[4-(6-tert-butyl-1,1-dimethylindanyl)]-3,7-dimethylhepta-2,4,6-trienoate,
(2E,4E,6E)-7-[4-(6-tert-butyl-1,1-dimethylindanyl)]-3,7-dimethylhepta-2,4,6-trienoic acid,
methyl (2E,4E,6E)-7-[4-(6-tert-butyl-1,1-dimethylindanyl)]-7-methylhepta-2,4,6-trienoate,
(2E,4E,6E)-7-[4-(6-tert-butyl-1,1-dimethylindanyl)]-7-methylhepta-2,4,6-trienoic acid,
ethyl 4-[1-[4-(6-tert-butyl-1,1-dimethylindanyl)]ethenyl]benzoate,
4-[1-[4-(6-tert-butyl-1,1-dimethylindanyl)]ethenyl]benzoic acid,
5-[1-[4-(6-tert-butyl-1,1-dimethylindanyl)]ethenyl]-2-thiophenecarboxylic acid.
The present invention is also directed to the process for the preparation of the compounds of formula (I) according to the reaction schemes of Tables A and B.
With reference to Table A, 4-acetyl-6-tert-butyl-1,1-dimethylindane (1) is converted into the intermediate 6-tert-butyl-4-ethenyl-1,1-dimethylindane by treatment with lithium diisopropylamide (LDA) and is then treated with an alkyl chlorophosphate, such as diethyl chlorophosphate. The resulting mixed phosphate intermediate is subsequently again treated with LDA a
De Lera Angel
Dominguez Beatriz
Galderma Research & Development
Geist Gary
Nixon & Vanderhye P.C.
Oh Taylor V.
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