Biaromatic compounds and pharmaceutical and cosmetic...

Details Biaromatic compounds and pharmaceutical and cosmetic... Biaromatic compounds and pharmaceutical and cosmetic...

2000-05-25

2002-02-12

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C560S051000, C560S019000, C560S008000, C514S018700, C514S023000, C562S459000, C562S460000, C424S401000

Reexamination Certificate

active

06346546

ABSTRACT:

The invention relates, as novel and useful industrial products, to biaromatic compounds in which the aromatic nuclei are connected by a propynylene or allenylene divalent radical. It also relates to the use of these novel compounds in pharmaceutical compositions intended for use in human or veterinary medicine or alternatively in cosmetic compositions.
The compounds according to the invention have a marked activity in the fields of cell differentiation and proliferation, and they find applications more particularly in the topical and systemic treatment of dermatological conditions linked to a keratinization disorder, dermatological conditions (and the like) with an inflammatory and/or immunoallergic component, and dermal or epidermal proliferation, whether benign or malignant. These compounds can, in addition, be used in the treatment of degenerative diseases of the connective tissue, for combating skin ageing, whether photoinduced or chronologic, and treating cicatrization disorders. Furthermore, they find an application in the ophthalmological field, in particular in the treatment of corneopathies.
It is also possible to use the compounds according to the invention in cosmetic compositions for body and hair hygiene.
EP-661,258 has already disclosed biaromatic compounds, the aromatic nuclei of which are connected by a propynylene divalent radical, as substances which are active in pharmaceutical or cosmetic compositions.
The compounds according to EP-661,258 correspond to the following general formula:
in which:
Ar is an aromatic divalent radical optionally substituted by an R
5
radical or a heteroaromatic divalent radical optionally substituted by an R
6
radical when the heteroatom is nitrogen,
R
1
represents H, —CH
3
, —CH
2
OR
6
, —OR
6
, —COR
7
or —S(O)
t
R
9
, t being 0, 1 or 2,
R
2
and R
3
represent H, C
1
-C
20
alkyl, —OR
6
or —SR
6
,
or R
2
and R
3
, taken together, form a 5- or 6-membered ring optionally substituted by methyl groups and/or optionally interrupted by an oxygen or sulphur atom,
R
4
and R
5
represent H, a halogen, a lower alkyl or —OR
6
,
R
6
represents H, lower alkyl or —COR
9
,
R
7
represents H, lower alkyl,
 or —OR
8
,
R
8
represents H, C
1
-C
20
alkyl, which can be linear or branched, alkenyl, mono- or polyhydroxyalkyl, optionally substituted aryl or aralkyl, or a sugar or amino acid or peptide residue,
R
9
represent lower alkyl,
R and R′ represent H, lower alkyl, mono- or polyhydroxyalkyl, optionally substituted aryl or a sugar, amino acid or peptide residue or R and R′, taken together, form a heterocycle, and
X represents a divalent radical which, from right to left or vice versa, has the formula:
 in which:
R
10
represents H, lower alkyl or —OR
6
,
R
11
representing —OR
6
,
or R
10
and R
11
, taken together, form an oxo (═O) radical,
and the salts of the said compounds of above formula, when R
1
represents a carboxylic acid functional group, and the optical and geometrical isomers of these said compounds.
The compounds according to the present invention, with respect to those of EP-661,258, are essentially distinguished in that the —X—Ar—R
1
substituent is at the ortho position with respect to the R
2
radical or to the 5- or 6-membered ring when R
2
and R
3
are taken together, whereas, in EP-661,258, the —X—Ar—R
1
substituent is found at the meta position.
This is because it has been found, unexpectedly and surprisingly, that this modification in structure makes it possible to significantly increase the pharmaceutical and cosmetic properties thereof and, in addition, to decrease certain side effects thereof.
The subject-mater of the present invention is therefore novel compounds which can be represented by the following general formula:
in which:
Ar represents a radical chosen from the following formulae (a) to (c):
 Z being an oxygen or sulphur atom,
R
1
represents —CH
3
, —CH
2
—O—R
6
, —OR
6
or —COR
7
,
R
2
represents —OR
8
, —SR
8
or a polyether radical, if, in the latter case, R
4
represents linear or branched C
1
-C
20
alkyl and is at the ortho or meta position with respect to the X—Ar bond,
R
3
represents lower alkyl, or
R
2
and R
3
, taken together, form a 5- or 6-membered ring optionally substituted by at least one methyl and/or optionally interrupted by an oxygen or sulphur atom,
R
4
represents H, a halogen, linear or branched C
1
-C
20
alkyl, —OR
8
, a polyether radical or aryl,
R
5
represents H, a halogen, linear or branched C
1
-C
20
alkyl or an —OR
8
radical,
R
6
represents H, lower alkyl or a —COR
9
radical,
R
7
represents H, lower alkyl,
 or —OR
10
,
R
8
represents H, lower alkyl or —COR
9
,
R
9
represents lower alkyl,
R
10
represents H, C
1
-C
20
alkyl, which can be linear or branched, alkenyl, mono- or polyhydroxyalkyl, optionally substituted aryl or aralkyl, or a sugar residue,
r′ and r″ represent H, lower alkyl, mono- or polyhydroxyalkyl, optionally substituted aryl, or an amino acid or sugar residue or, taken together with the nitrogen atom, form a heterocycle,
X represents a divalent radical which, from right to left or vice versa, has the formula:
R
11
representing H or —OR
6
, R
6
having the same meaning as above,
R
12
representing H or lower alkyl, or
R
11
and R
12
, taken together, form an oxo (═O) radical,
and the salts of the compounds of formula (I) when R
1
represents a carboxylic acid functional group, and the optical and geometrical isomers of the said 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 present invention, lower alkyl is understood to mean a C
1
-C
6
radical, preferably the methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals.
C
1
-C
20
alkyl, which can be linear or branched, is understood to mean in particular the methyl, ethyl, propyl, isopropyl, hexyl, heptyl, 2-ethylhexyl, octyl, nonyl, dodecyl, hexadecyl and octadecyl radicals.
Monohydroxyalkyl is understood to mean a radical preferably having 2 or 3 carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.
Polyhydroxyalkyl is understood to mean a radical preferably having 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 1 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 is understood to mean a pyridyl radical, a thiophenyl radical or a phenyl radical optionally substituted by at least one halogen atom, one hydroxyl, one nitro functional group, one lower alkyl, one CF
3
radical, one amino radical optionally protected by an acetyl functional group or optionally substituted by one or two lower alkyl(s), one alkoxy radical or one polyether radical Aryl is preferably understood to mean a phenyl radical optionally substituted by at least one halogen atom, one hydroxyl, one nitro functional group, one lower alkyl, one CF
3
radical, one amino radical optionally protected by an acetyl functional group or optionally substituted by one or two lower alkyl(s), one alkoxy radical or one polyether radical, the latter being as defined above.
When the substituent is an alkoxy radical, the latter is preferably a C
1
-C
12
alkoxy radical, such as in particular the methoxy, ethoxy, propyloxy, isopropyloxy, hexyloxy, heptyloxy, octyloxy and nonyloxy radicals.
Aralkyl is preferably understood to mean the benzyl or phenethyl radical optionally substituted by at least one halogen atom, one hydroxyl or one nitro functional group.
Alkenyl is understood to mean a radical preferably having 2 to 5 carbon atoms and exhibiting one or more ethylenic unsaturations, such as more particularly the allyl radical.
Sugar residue is understood to

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