Drug – bio-affecting and body treating compositions – Hair treatment
Reexamination Certificate
1997-09-17
2002-04-30
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Hair treatment
C514S275000, C424S070600, C424S063000, C424S059000
Reexamination Certificate
active
06380263
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Technical Field of the Invention
The present invention relates to promoting pigmentation of the skin and/or the hair by administering to individuals in need of such treatment at least one pyrimidine 3-oxide derivative, substituted in position 6, and to pharmaceutical/cosmetic compositions comprising at least one such derivative.
2. Description of the Prior Art
The color of human hair and skin depends on various factors and, in particular, the seasons of the year, race, sex and age. It is principally determined by the concentration of melanin produced by the melanocytes. The melanocytes are specialized cells which synthesize melanin by means of specific organelles, the melanosomes.
The synthesis of melanin, or melanogenesis, is particularly complex and schematically involves the following principal steps:
Tyrosine→Dopa→Dopaquinone→Dopachrome→Melanin
Tyrosinase (monophenol dihydroxyl phenylalanine:oxygen oxidoreductase EC 1.14.18.1) is the essential enzyme involved in this reaction sequence. It catalyzes, in particular, the reaction for the conversion of tyrosine into dopa (dihydroxyphenyl-alanine) and the reaction for the conversion of dopa into dopaquinone.
Although the level of melanin varies from one population to another, the amount of tyrosinase does not vary significantly and the level of messenger RNAs for tyrosinase is identical in white or black skin. The variations in melanogenesis are thus due to variations in the activity of tyrosinase.
It is known that in most populations the brown coloration of the skin and the maintenance of a constant color of the hair are important aspirations.
There are, moreover, pigmentation diseases such as, for example, vitiligo, which is an autoimmune disease characterized by the appearance of white patches on the skin, associated with a pigmentation defect.
Genuine need therefore exists for products which facilitate and/or improve pigmentation of the skin and/or the hair.
In this respect, many artificial dyeing techniques have been proposed to this art, by supplying external dyes that are intended to impart to the skin and/or the hair the closest possible color to their natural color, as well as natural dyeing techniques by stimulation of the natural pigmentation route.
Although, admittedly, excellent results are obtained by the solutions proposed in the prior art, it nevertheless remains that the stimulation of pigmentation of the skin and/or the hair via the natural route remains the ideal route for pigmentation.
In this regard, WO-A-95/17,161, WO-95/11,003, WO-A-95/01,773, WO-A-94/04,674, WO-A-94/04,122,
EP-A-585,018, WO-A-93/10,804, WO-A-92/20,322 and WO-A-91/07,945 describe varied techniques for attaining the desired results, such as administration of compositions containing phosphodiesterase inhibitors, prostaglandins, DNA fragments, or tyrosine derivatives or, alternatively, administration of plant extracts.
Often, the compounds used have appreciable side-effects or are complex mixtures which have no specificity.
It has also been suggested, by Rushton and co-workers (Rushton, D. H., et coll.,
Clin. Exp. Dermatol
., 14(1), 40-46 (1989)) that Minoxidil, or 2,4-diamino-6-piperidinopyrimidine 3-oxide, can exhibit a stimulatory effect on hair pigmentation in bald men treated with this compound.
“Minoxidil” is known for its anti-hypertensive effects and for its capacity to promote hair growth. These properties are described in U.S. Pat. No. 4,596,812.
Although Minoxidil remains the reference compound in the field of hair growth, it has appreciable side-effects which complicate its use.
Thus, developing novel active agents which affect skin and/or hair pigmentation without eliciting undesirable side-effects remains a major research objective.
SUMMARY OF THE INVENTION
Accordingly, a major object of the present invention is the provision of novel compounds to promote pigmentation of the skin and/or the hair, while at the same time limiting deleterious side effects.
Briefly, it has now unexpectedly been determined that certain pyrimidine 3-oxide derivatives, substituted in position 6, display an activating effect on tyrosinase which is similar or superior to that of Minoxidil.
The subject compounds according to the invention have the following structural formula (I):
in which R
1
and R
2
, which may be identical or different, are each a hydrogen atom or a C
1
-C
12
alkyl radical; and R
3
and R
4
, which may be identical or different, are each a C
1
-C
12
alkyl radical or, when taken together, form a heterocycle with the nitrogen-atom from which they depend, with the proviso that, when R
3
and R
4
, taken together, form a piperidino ring, then at least one of the radicals R
1
or R
2
must be other than a hydrogen. atom.
DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OF THE INVENTION
More particularly according to the present invention, featured are cosmetic/pharmaceutical compositions comprising, as the active principle, an effective amount of at least one pyrimidine 3-oxide compound, substituted in position 6 and having the formula (I), for promoting pigmentation of the skin and/or the hair.
The present invention also features cosmetic/pharmaceutical compositions comprising, as the active principle, an effective amount of at least one pyrimidine 3-oxide compound, substituted in position 6 and having the formula (I), for stimulating tyrosinase activity, and formulated into a cosmetically/pharmaceutically acceptable vehicle, diluent or carrier therefor.
This invention also features use of the optical isomers of the subject compounds, singly or in admixture in all proportions, as well as use of the acyl derivatives or pharmaceutically acceptable salts thereof.
According to the invention, by the expression “C
1
-C
12
alkyl radical” is intended linear or branched C
1
-C
12
alkyl radicals, optionally substituted with at least one hydroxyl radical or benzyl radical and, in particular, the optionally substituted linear or branched methyl, ethyl, propyl, butyl, pentyl, hexyl or benzyl radicals.
By the term “heterocycle” is intended any saturated or unsaturated ring member containing at least one nitrogen atom, including, in particular, aziridino, azetidino, pyrrolidino, piperidino, hexamethyleneimino, heptamethyleneimino, octamethyleneimino, tetrahydropyridino, dihydropyridino, pyrrole, pyrazole, imidazole, triazole, 4-alkylpiperazino, morpholino or thiomorpholino rings members.
According to the invention, the heterocycle is preferably a piperidino ring member.
Of course, the derivatives of formula (I) may be administered either alone or as a mixture in any proportion.
By the term “tyrosinase” is intended any enzyme exhibiting tyrosinase activity, it being possible for this enzyme to exhibit other enzymatic activities.
The tyrosinase activity may be defined as the enzymatic activity which catalyzes the oxidation of tyrosine resulting in the formation of the melanin precursor: dopaquinone.
Many pyrimidine derivatives substituted in position 6 and techniques for the synthesis thereof are known to this art. Particularly exemplary are those described in EP-A-353,123, EP-A-356,271, EP-A-408,422, EP-A-420,707, EP-A-427,625, EP-A-459,890, EP-A-519,819, EP-A-522,964, EP-A-525,964 and EP-A-540,629.
Among the 6-substituted pyrimidine 3-oxide compounds according to the invention, particularly preferred are:
2,4 bis-methylamino-6-dimethylaminopyrimidine 3-oxide,
2,4 bis-ethylamino-6-dimethylaminopyrimidine 3-oxide,
2,4-bis-propylamino-6-dimethylaminopyrimidine 3-oxide,
2,4-bis-propylamino-6-piperidinopyrimidine 3-oxide,
2-amino-4-methylamino-6-piperidinopyrimidine 3-oxide,
2-amino-4-propylamino-6-piperidinopyrimidine 3-oxide,
2-amino-4-hexylamino-6-piperidinopyrimidine 3-oxide,
2-amino-4-benzylamino-6-piperidinopyrimidine 3-oxide,
2-amino-4-(2-hydroxyethylamino)-6-piperidinopyrimidine 3-oxide,
2-amino-4-propylamino-6-dimethylaminopyrimidine 3-oxide,
2-amino-4-butylamino-6-dimethylaminopyrimidine 3-oxide,
2-amino-4-isopropylamino-6-dimethylaminopyrimidine 3-oxide.
Even more prefe
Gerst Catherine
Pruche Francis
Nguyen Helen
Societe L'Oreal
Webman Edward J.
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