Biphenyl derivatives substituted by an aromatic or...

Details Biphenyl derivatives substituted by an aromatic or... Biphenyl derivatives substituted by an aromatic or...

1999-04-06

2001-11-13

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Cosmetic, antiperspirant, dentifrice

C514S544000, C514S569000, C558S054000, C560S053000, C560S056000, C560S102000, C562S466000, C562S492000

Reexamination Certificate

active

06316009

ABSTRACT:

The invention relates to, as novel and useful industrial products, biphenyl derivatives substituted with an aromatic or heteroaromatic radical. The invention 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 pronounced activity in the fields of cell differentiation and proliferation and find applications more particularly in the topical and systemic treatment of dermatological complaints associated with a keratinization disorder, dermatological (or other) complaints with an inflammatory and/or immunoallergic component, and dermal or epidermal proliferations, whether they are benign or malignant. These compounds can also be used in the treatment of connective tissue degenerative diseases, for controlling ageing of the skin, whether this is light-induced or chronological ageing, and for treating cicatrization disorders. They moreover find an application in the opthalmological field, in particular in the treatment of corneopathy.
The compounds according to the invention can also be used in cosmetic compositions for body and hair hygiene.
Triaromatic derivatives whose structure consists essentially of two substituted aromatic rings linked together by a 5- or 6-membered heteroaryl divalent radical containing, as hetero atom, an oxygen atom, a sulphur atom and/or at least one nitrogen atom, have already been described in EP-382,077.
The compounds according to the present invention, which are also triaromatic derivatives, differ from those of EP-382,077 essentially in that if they have a heteroaryl radical, in particular a substituted pyridyl, furyl or thienyl radical, this radical is located at the end of the chain, thus giving these compounds a chemical structure which is totally different from that of the compounds of EP-382,077.
Although the compounds according to the invention are not limited to those containing a heteroaryl radical, it has nevertheless been found, surprisingly and unexpectedly, that the compounds containing such a radical have excellent pharmaceutical and cosmetic properties which are entirely similar to those of the compounds according to the invention containing a substituted phenyl radical at the end of the chain.
It has moreover been possible to demonstrate that the compounds according to the invention are devoid of side effects, while at the same time having excellent activity.
The subject of the present invention is thus novel compounds which can be represented by the following general formula:
in which:
Ar represents an aromatic or heteroaromatic radical chosen from:
Z being O or S,
R
1
represents —CH
3
, —CH
2
—OH, —OR
8
or —COR
9
,
R
2
and R
3
, which may be identical or different, represent H, linear or branched C
1
-C
15
alkyl, cycloalkyl, —ZR
10
or a polyether radical, at least one from among R
2
and R
3
representing a linear or branched C
1
-C
15
alkyl, or
R
2
and R
3
, taken together, form a 5- or 6-membered ring, optionally substituted with at least one methyl and/or optionally interrupted by an oxygen or sulphur atom or by an SO or SO
2
radical,
R
4
represents H, a halogen atom, linear or branched C
1
-C
20
alkyl, —OR
10
, —OCOR
11
or a polyether radical,
R
5
represents H, a halogen atom, linear or branched C
1
-C
20
alkyl, —OCOR
11
, —OR
12
, mono- or polyhydroxyalkyl, —NO
2
,
—(CH
2
)
n
—NHCOCH
3
, —CH═CH—COR
13
, —(CH
2
)
n
COR
13
, n being 0 to 6, —O—(CH
2
)
m
COR
13
, —O—(CH
2
)
m
OH, m being 1 to 12, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, a polyether radical or a —CH
2
-polyether radical,
R
6
represents H, lower alkyl or —OR
10
,
R
7
represents H, a halogen atom, linear or branched C
1
-C
20
alkyl, —OR
10
or —OCOR
11
or a polyether radical,
R
8
represents H, lower alkyl or —COR
11
,
R
9
represents H, lower alkyl, —OR
14
or
R
10
represents H or lower alkyl,
R
11
represents lower alkyl,
R
12
represents H, linear or branched C
1
-C
20
alkyl, mono- or polyhydroxyalkyl, or optionally substituted aryl or aralkyl,
R
13
represents H, lower alkyl, —OR
10
, aryl or
R
14
represents H, alkyl, linear or branched C
1
-C
20
alkyl, alkenyl, mono- or polyhydroxyalkyl, optionally substituted aryl or aralkyl, or a sugar residue,
r′ and r″, which may be identical or different, represent H, OH, lower alkyl, mono- or polyhydroxyalkyl, optionally substituted aryl, an amino acid residue or a peptide 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 function, as well as the optical and geometrical isomers of the said compounds of formula (I).
When the compounds according to the invention are in the form of a salt, this 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, the expression “lower alkyl” refers to a C
1
-C
6
radical, preferably the methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals.
The term “linear or branched C
1
-C
15
alkyl” refers in particular to the methyl, ethyl, propyl, 2-ethylhexyl, octyl and dodecyl radicals. When the alkyl radical is C
1
-C
20
, the hexadecyl and octadecyl radicals are also intended.
The term “cycloalkyl” refers to an optionally substituted mono- or polycyclic radical containing from 5 to 10 carbon atoms, in particular a cyclopentyl, cyclohexyl, 1-methylcyclohexyl or 1-adamantyl radical.
The term “monohydroxyalkyl” refers to a radical preferably containing 1 to 6 carbon atoms, in particular a hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.
The term “polyhydroxyalkyl” refers to a radical preferably containing 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl and 2,3,4,5-tetrahydroxypentyl radicals or a pentaerythritol residue.
The term “polyether radical” refers to a radical containing from 2 to 6 carbon atoms which is interrupted by at least two oxygen atoms, such as the methoxymethoxy, methoxyethoxy and methoxyethoxymethoxy radicals.
The term “—CH
2
-polyether radical” refers to a radical preferably chosen, from the methoxymethoxymethyl, ethoxymethoxymethyl and methoxyethoxymethoxymethyl radicals.
The term “aryl” preferably refers to a phenyl radical optionally substituted with at least one halogen, a lower alkyl, a hydroxyl, a C
1
-C
3
alkoxy, a nitro function, a polyether radical or an amino function optionally protected with an acetyl group or optionally substituted with at least one C
1
-C
6
lower alkyl or alkoxy.
The term “aralkyl” preferably refers to a benzyl or phenethyl radical optionally substituted with at least one halogen, a lower alkyl, a hydroxyl, a C
1
-C
3
alkoxy, a nitro function, a polyether radical or an amino function optionally protected with an acetyl group or optionally substituted with at least one C
1
-C
6
lower alkyl or alkoxy.
The term “heteroaryl radical” preferably refers to a pyridyl, furyl or thienyl radical, optionally substituted with at least one halogen, a lower alkyl, a hydroxyl, a C
1
-C
3
alkoxy, a nitro function, a polyether radical or an amino function optionally protected with an acetyl group or optionally substituted with at least one C
1
-C
6
lower alkyl or alkoxy.
The term “alkenyl” refers to a radical preferably containing 2 to 5 carbon atoms and containing one or more ethylenic unsaturations, such as, more particularly, an allyl radical.
The term “sugar residue” refers to a residue derived in particular from glucose, from galactose or from mannose, or alternatively from glucuronic acid.
The term “amino acid residue” refers in particular to a residue derived from lysine, from glycine or from aspartic acid, and the term “peptide residue” refers more particularly to a dipeptide or tripeptide residue resulting from the combination of amino acids.
The term “heterocycle” preferably refers to a piperidino, mo

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