U.S. patent application number 10/059376 was filed with the patent office on 2002-08-01 for 6-substituted pyrimidine 3-oxides for promoting pigmentation of the skin/hair.
Invention is credited to Gerst, Catherine, Pruche, Francis.
Application Number | 20020103216 10/059376 |
Document ID | / |
Family ID | 9495805 |
Filed Date | 2002-08-01 |
United States Patent
Application |
20020103216 |
Kind Code |
A1 |
Pruche, Francis ; et
al. |
August 1, 2002 |
6-substituted pyrimidine 3-oxides for promoting pigmentation of the
skin/hair
Abstract
Pigmentation of human skin and/or hair is promoted by
administering to individuals in need of such treatment,
advantageously topically, an effective tyrosinase
activity-stimulating amount of at least one 6-substituted
pyrimidine 3-oxide having the structural formula (I): 1 in which
R.sub.1 and R.sub.2, which may be identical or different, are each
a hydrogen atom or a C.sub.1-C.sub.12 alkyl radical; and R.sub.3
and R.sub.4, which may be identical or different, are each a
C.sub.1-C.sub.12 alkyl radical or, when taken together, form a
heterocycle with the nitrogen atom from which they depend, with the
proviso that, when R.sub.3 and R.sub.4, taken together, form a
piperidino ring, then at least one of the radicals R.sub.1 or
R.sub.2 must be other than a hydrogen atom.
Inventors: |
Pruche, Francis; (Paris,
FR) ; Gerst, Catherine; (Asnieres/Seine, FR) |
Correspondence
Address: |
Norman H. Stepno
BURNS, DOANE, SWECKER & MATHIS, L.L.P.
P.O. Box 1404
Alexandria
VA
22313-1404
US
|
Family ID: |
9495805 |
Appl. No.: |
10/059376 |
Filed: |
January 31, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10059376 |
Jan 31, 2002 |
|
|
|
08931890 |
Sep 17, 1997 |
|
|
|
Current U.S.
Class: |
514/272 ;
8/426 |
Current CPC
Class: |
A61K 31/513 20130101;
A61K 8/4953 20130101; A61Q 19/04 20130101; A61Q 5/065 20130101;
A61K 31/506 20130101 |
Class at
Publication: |
514/272 ;
8/426 |
International
Class: |
A61K 031/505; A61K
007/13 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 17, 1996 |
FR |
96-11316 |
Claims
What is claimed is:
1. A regimen for promoting pigmentation of the skin and/or hair,
comprising administering to an individual in need of such treatment
an effective tyrosinase activity-stimulating amount of at least one
6-substituted pyrimidine 3-oxide having the structural formula (I):
3in which R.sub.1 and R.sub.2, which may be identical or different,
are each a hydrogen atom or a C.sub.1-C.sub.12 alkyl radical; and
R.sub.3 and R.sub.4, which may be identical or different, are each
a C.sub.1-C.sub.12 alkyl radical or, when taken together, form a
heterocycle with the nitrogen atom from which they depend, with the
proviso that, when R.sub.3 and R.sub.4, taken together, form a
piperidino ring, then at least one of the radicals R.sub.1 or
R.sub.2 must be other than a hydrogen atom.
2. The regimen as defined by claim 1, comprising topically
administering said at least one 6-substituted pyrimidine
3-oxide.
3. The regimen as defined by claim 1, comprising systemically
administering said at least one 6-substituted pyrimidine
3-oxide.
4. The regimen as defined by claim 1, said at least one
6-substituted pyrimidine 3-oxide comprising
2,4-bis-methylamino-6-dimethylaminopyrimidi- ne 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, or
2-amino-4-isopropylamino-6-dimethylaminopyrimidine 3-oxide.
5. The regimen as defined by claim 1, said at least one
6-substituted pyrimidine 3-oxide comprising
2-amino-4-propylamino-6-dimethylaminopyrimi- dine 3-oxide,
2-amino-4-methylamino-6-piperidinopyrimidine 3-oxide,
2,4-bis-propylamino-6-dimethylaminopyrimidine 3-oxide,
2,4-bis-propylamino-6-piperidinopyrimidine 3-oxide,
2,4-bis-methylamino-6-dimethylaminopyrimidine 3-oxide, or
2,4-bis-ethylamino-6-dimethylaminopyrimidine 3-oxide.
6. The regimen as defined by claim 1, comprising coadministering to
said individual at least one substrate of at least one enzyme
exhibiting tyrosinase activity.
7. The regimen as defined by claim 6, said at least one substrate
comprising tyrosine or derivative thereof, or
3,4-dihydroxy-.alpha.-pheny- lalanine (DOPA).
8. A cosmetic/pharmaceutical composition of matter suited for
promoting pigmentation of the skin and/or hair, comprising an
effective tyrosinase activity-stimulating amount of at least one
6-substituted pyrimidine 3-oxide having the structural formula (I):
4in which R.sub.1 and R.sub.2, which may be identical or different,
are each a hydrogen atom or a C.sub.1-C.sub.12 alkyl radical; and
R.sub.3 and R.sub.4, which may be identical or different, are each
a C.sub.1-C.sub.12 alkyl radical or, when taken together, form a
heterocycle with the nitrogen atom from which they depend, with the
proviso that, when R.sub.3 and R.sub.4, taken together, form a
piperidino ring, then at least one of the radicals R.sub.1 or
R.sub.2 must be other than a hydrogen atom, formulated into a
cosmetically/pharmaceutically acceptable vehicle, diluent or
carrier therefor.
9. The cosmetic/pharmaceutical composition as defined by claim 8,
further comprising at least one substrate of at least one enzyme
exhibiting tyrosinase activity.
10. The cosmetic/pharmaceutical composition as defined by claim 9,
said at least one substrate comprising tyrosinase or derivative
thereof, or 3,4-dihydroxy-.alpha.-phenylalanine.
11. The cosmetic/pharmaceutical composition as defined by claim 8,
comprising from 0.01% to 20% by weight of said at least one
6-substituted pyrimidine 3-oxide.
12. The cosmetic/pharmaceutical composition as defined by claim 11,
comprising from 0.1% to 10% by weight of said at least one
6-substituted pyrimidine 3-oxide.
13. The cosmetic/pharmaceutical composition as defined by claim 8,
comprising from 1% to 30% by weight of said at least one
6-substituted pyrimidine 3-oxide.
14. The cosmetic/pharmaceutical composition as defined by claim 13,
comprising from 2% to 15% by weight of said at least one
6-substituted pyrimidine 3-oxide.
15. The cosmetic/pharmaceutical composition as defined by claim 8,
comprising a solution, dispersion, lotion, serum, emulsion, milk,
cream, gel, microcapsules, microparticles, vesicle dispersion,
mousse, aerosol, shampoo, dyeing formulation, permanent-wave,
syrup, granules, tablets or soap.
16. The cosmetic/pharmaceutical composition as defined by claim 8,
further comprising an oil, wax, emulsifier and/or
co-emulsifier.
17. The cosmetic/pharmaceutical composition as defined by claim 8,
further comprising at least one active agent selected from among
antibacterial agents, antiparasitic agents, antifungal agents,
antiviral agents, anti-inflammatory agents, antipruriginous agents,
anaesthetics, keratolytic agents, anti-free-radical agents,
antiseborrhoeic agents, antidandruff agents, antiacne agents and/or
agents for reducing skin differentiation and/or proliferation
and/or pigmentation, and extracts of plant or bacterial origin.
18. The cosmetic/pharmaceutical composition as defined by claim 8,
further comprising at least one active agent promoting regrowth
and/or retarding loss of hair, and/or at least one active agent
decreasing differentiation and/or proliferation.
19. The cosmetic/pharmaceutical composition as defined by claim 8,
further comprising at least one hydrophilic or lipophilic gelling
agent, hydrophilic or lipophilic additive, preservative,
antioxidant, solvent, fragrance, filler, UV-screening agent, odor
absorber or colorant or dyestuff.
20. A kit comprising at least two separate compartments, at least
one of which comprising at least one 6-substituted pyrimidine
3-oxide as defined in claim 1, and at least one of which comprising
at least one substrate of at least one enzyme exhibiting tyrosinase
activity.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Technical Field of the Invention
[0002] 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.
[0003] 2. Description of the Prior Art
[0004] 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.
[0005] The synthesis of melanin, or melanogenesis, is particularly
complex and schematically involves the following principal
steps:
[0006]
Tyrosine.fwdarw.Dopa.fwdarw.Dopaquinone.fwdarw.Dopachrome.fwdarw.Me-
lanin
[0007] 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 (dihydroxyphenylalanine)
and the reaction for the conversion of dopa into dopaquinone.
[0008] 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.
[0009] 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.
[0010] 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.
[0011] Genuine need therefore exists for products which facilitate
and/or improve pigmentation of the skin and/or the hair.
[0012] 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.
[0013] 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.
[0014] 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.
[0015] Often, the compounds used have appreciable side-effects or
are complex mixtures which have no specificity.
[0016] 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.
[0017] "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.
[0018] Although Minoxidil remains the reference compound in the
field of hair growth, it has appreciable side-effects which
complicate its use.
[0019] 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
[0020] 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.
[0021] 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.
[0022] The subject compounds according to the invention have the
following structural formula (I): 2
[0023] in which R.sub.1 and R.sub.2, which may be identical or
different, are each a hydrogen atom or a C.sub.1-C.sub.12 alkyl
radical; and R.sub.3 and R.sub.4, which may be identical or
different, are each a C.sub.1-C.sub.12 alkyl radical or, when taken
together, form a heterocycle with the nitrogen atom from which they
depend, with the proviso that, when R.sub.3 and R.sub.4, taken
together, form a piperidino ring, then at least one of the radicals
R.sub.1 or R.sub.2 must be other than a hydrogen atom.
DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED
EMBODIMENTS OF THE INVENTION
[0024] 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.
[0025] 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.
[0026] 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.
[0027] According to the invention, by the expression
"C.sub.1-C.sub.12 alkyl radical" is intended linear or branched
C.sub.1-C.sub.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.
[0028] 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.
[0029] According to the invention, the heterocycle is preferably a
piperidino ring member.
[0030] Of course, the derivatives of formula (I) may be
administered either alone or as a mixture in any proportion.
[0031] By the term "tyrosinase" is intended any enzyme exhibiting
tyrosinase activity, it being possible for this enzyme to exhibit
other enzymatic activities.
[0032] 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.
[0033] 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.
[0034] Among the 6-substituted pyrimidine 3-oxide compounds
according to the invention, particularly preferred are:
[0035] 2,4 bis-methylamino-6-dimethylaminopyrimidine 3-oxide,
[0036] 2,4 bis-ethylamino-6-dimethylaminopyrimidine 3-oxide,
[0037] 2,4-bis-propylamino-6-dimethylaminopyrimidine 3-oxide,
[0038] 2,4-bis-propylamino-6-piperidinopyrimidine 3-oxide,
[0039] 2-amino-4-methylamino-6-piperidinopyrimidine 3-oxide,
[0040] 2-amino-4-propylamino-6-piperidinopyrimidine 3-oxide,
[0041] 2-amino-4-hexylamino-6-piperidinopyrimidine 3-oxide,
[0042] 2-amino-4-benzylamino-6-piperidinopyrimidine 3-oxide,
[0043] 2-amino-4-(2-hydroxyethylamino)-6-piperidinopyrimidine
3-oxide,
[0044] 2-amino-4-propylamino-6-dimethylaminopyrimidine 3-oxide,
[0045] 2-amino-4-butylamino-6-dimethylaminopyrimidine 3-oxide,
[0046] 2-amino-4-isopropylamino-6-dimethylaminopyrimidine
3-oxide.
[0047] Even more preferred are:
[0048] 2-amino-4-propylamino-6-dimethylaminopyrimidine 3-oxide,
[0049] 2-amino-4-methylamino-6-piperidinopyrimidine 3-oxide,
[0050] 2,4-bis-propylamino-6-dimethylaminopyrimidine 3-oxide,
[0051] 2,4-bis-propylamino-6-piperidinopyrimidine 3-oxide,
[0052] 2,4-bis-methylamino-6-dimethylaminopyrimidine 3-oxide,
[0053] 2,4-bis-ethylamino-6-dimethylaminopyrimidine 3-oxide.
[0054] The amount of compound required to promote pigmentation of
the skin and/or the hair is an amount required to stimulate the
tyrosinase activity. This amount is, of course, dependent on the
nature of the derivative and on the nature of the tyrosinase in
question and may vary over a wide range.
[0055] In order to provide an order of magnitude, if the derivative
according to the invention is used in a cosmetic composition, the
amount of derivative which is advantageously used may range from
0.01% to 20% of the total weight of the composition and preferably
from 0.1% to 10% of the total weight of the composition.
[0056] In order to provide an order of magnitude, if the derivative
according to the invention is used in a pharmaceutical composition,
the amount of derivative which is advantageously used may range
from 1% to 30% of the total weight of the composition and
preferably from 2% to 15% of the total weight of the
composition.
[0057] The compositions according to the invention are essentially
intended to promote pigmentation of the skin and/or the hair and to
stimulate the endogenous tyrosinase activity of the skin and/or the
hair.
[0058] Thus, this invention features a cosmetic or pharmaceutical
composition comprising at least one derivative corresponding to the
structural formula (I) and at least one substrate of at least one
enzyme exhibiting a tyrosinase activity.
[0059] Among the substrates which are suitable according to the
invention, exemplary are tyrosine and derivatives thereof, and
3,4-dihydroxy-a-phenylalanine (DOPA).
[0060] It is possible to combine the derivative of formula (I) and
the substrate in a single composition. However, other specific
embodiments are intended, in particular the derivative and the
substrate may be administered simultaneously, separately or
variously over time.
[0061] Thus, the present invention features a product comprising at
least one derivative corresponding to the structural formula (I)
and at least one substrate of at least one enzyme exhibiting a
tyrosinase activity, as a combination product for a simultaneous or
separate use, or for use divided or spread out over time, in order
to promote pigmentation of the skin and/or the hair.
[0062] In a specific embodiment, the derivative and the substrate
may be packaged separately in the form of a kit whose components
will be mixed together at the time of use.
[0063] The invention thus also features a kit comprising at least
one derivative corresponding to the structural formula (I) and at
least one substrate of at least one enzyme exhibiting a tyrosinase
activity for simultaneous or separate use, or for use spread out
over time, in order to promote pigmentation of the skin and/or the
hair.
[0064] The compositions according to the invention may be ingested,
injected or topically applied to the skin (onto any area of body
skin) or the hair. According to the particular mode of
administration, the compositions according to the invention may be
in any pharmaceutical form normally used.
[0065] For topical application to the skin, the composition may be
in the form, in particular, of an aqueous or oily solution or of a
dispersion of the lotion or serum type, emulsions of liquid or
semi-liquid consistency of the milk type, obtained by dispersion of
a fatty phase in an aqueous phase (O/W) or, conversely, (W/O), or
suspensions or emulsions of soft consistency of the cream or
aqueous or anhydrous gel type, or alternatively microcapsules or
microparticles, or vesicle dispersions of the ionic and/or nonionic
type. These compositions are formulated according to the usual
techniques.
[0066] They may also be applied to the hair in the form of aqueous,
alcoholic or aqueous-alcoholic solutions, or in the form of creams,
gels, emulsions or mousses or alternatively in the form of aerosol
compositions also comprising a propellant under pressure.
[0067] The compositions according to the invention may also be
compositions for hair care, and in particular a shampoo, a
hair-setting lotion, a treating lotion, a styling cream or gel, a
composition for dyeing (in particular oxidation dyeing) optionally
in the form of dye shampoos, restructuring lotions for the hair, a
permanent-wave composition (in particular a composition for the
first stage of a permanent-wave operation), a lotion or gel to
combat hair loss, an antiparasitic shampoo, etc.
[0068] For injection, the subject compositions may be formulated as
an aqueous or oily lotion or as a serum, and for ingestion, they
may be formulated as capsules, granules, syrups or tablets.
[0069] The amounts of the various constituents of the compositions
according to the invention are those conventionally used in the
particular fields under consideration.
[0070] The compositions according to the invention may also be
formulated as solid preparations constituting cleansing soaps or
bars.
[0071] The subject compositions may also be packaged in the form of
an aerosol composition, also comprising a propellant under
pressure.
[0072] When the composition is an emulsion, the proportion of the
fatty phase advantageously ranges from 5% to 80% by weight, and
preferably from 5% to 50% by weight, relative to the total weight
of the composition. The oils, waxes, emulsifiers and co-emulsifiers
formulated into the composition in emulsion form are selected from
among those conventionally used in the cosmetics field. The
emulsifier and the co-emulsifier are advantageously present in the
composition in a proportion ranging from 0.3% to 30% by weight, and
preferably from 0.5 to 20% by weight, relative to the total weight
of the composition. The emulsion may also contain lipid
vesicles.
[0073] When the composition is an oily gel or solution, the fatty
phase may constitute more than 90% of the total weight of the
composition.
[0074] In known manner, the cosmetic compositions may also contain
additives and adjuvants that are conventional in the cosmetics
field, such as hydrophilic or lipophilic gelling agents,
hydrophilic or lipophilic additives, preservatives, antioxidants,
solvents, fragrances, fillers, UV-screening agents, odor absorbers
and colorants and dyestuffs. The amounts of these various additives
and adjuvants are those conventionally used in the cosmetics field,
and, for example, advantageously range from 0.01 to 10% of the
total weight of the composition. Depending on their nature, these
additives and adjuvants may be introduced into the fatty phase,
into the aqueous phase and/or into the lipid spherules.
[0075] Exemplary such oils or waxes according to the invention
include mineral oils (liquid petroleum jelly), plant oils (liquid
fraction of karite butter, sunflower oil), animal oils
(perhydrosqualene), synthetic oils (purcellin oil), silicone oils
or waxes (cyclomethicone) and fluoro oils (perfluoropolyethers),
beeswax, carnauba wax or paraffin wax. Fatty alcohols and fatty
acids (stearic acid) may be added to these oils. Exemplary
emulsifiers according to the invention include glyceryl stearate,
polysorbate 60 and the mixture of PEG-6/PEG-32/glycol stearate
marketed under the trademark Tefose.sup.R 63 by Gattefosse.
[0076] And exemplary solvents include the lower alcohols and, in
particular, ethanol and isopropanol, and propylene glycol.
[0077] Exemplary hydrophilic gelling agents according to the
invention include carboxyvinyl polymers (carbomer), acrylic
copolymers such as copolymers of acrylates/alkyl acrylates,
polyacrylamides, polysaccharides such as hydroxypropylcellulose,
natural gums and clays, and exemplary lipophilic gelling agents
include modified clays such as bentones, metal salts of fatty acids
such as aluminum stearates and hydrophobic silica, ethylcellulose
and polyethylene.
[0078] The subject compositions may contain other hydrophilic
active agents such as proteins or protein hydrolysates, amino
acids, polyols, urea, allantoin, sugars and sugar derivatives,
water-soluble vitamins, plant extracts and hydroxy acids.
[0079] Representative lipophilic active agents include retinol
(vitamin A) and derivatives thereof, tocopherol (vitamin E) and
derivatives thereof, essential fatty acids, ceramides, essential
oils and salicylic acid and derivatives thereof.
[0080] According to the invention, the subject compositions may
combine at least one compound of formula (I) with other active
agents. Among these active agents, particularly exemplary are:
[0081] (a) agents which improve activity in respect of regrowth
and/or retarding the loss of hair, already known to this art for
this activity, such as, for example, nicotinic acid esters,
including, in particular, tocopheryl nicotinate, benzyl nicotinate
and C.sub.1-C.sub.6 alkyl nicotinates such as methyl or hexyl
nicotinate, agents which promote the regrowth of hair, such as
those described in EP-0,648,488, assigned to the assignee
hereof;
[0082] (b) agents which decrease differentiation and/or
proliferation, such as retinoic acid and isomers thereof, retinol
and esters thereof, vitamin D and derivatives thereof, and
estrogens such as estradiol;
[0083] (c) antibacterial agents such as clindamycin phosphate,
erythromycin or antibiotics of the tetracyclin class;
[0084] (d) antiparasitic agents, in particular metronidazole,
crotamiton or pyrethroids;
[0085] (e) antifungal agents, in particular compounds of the
imidazole class such as econazole, ketoconazole or miconazole or
salts thereof, polyene compounds such as amphotericin B, compounds
of the allylamine family such as terbinafine, or, alternatively,
octopirox;
[0086] (f) antiviral agents such as acyclovir;
[0087] (g) steroidal anti-inflammatory agents such as
hydrocortisone, betamethasone valerate or clobetasol propionate, or
nonsteroidal anti-inflammatory agents such as, for example,
ibuprofen and salts thereof, diclofenac and salts thereof,
acetylsalicylic acid, acetaminophene or glycyrrhizic acid;
[0088] (h) anaesthetics such as lidocaine hydrochloride and
derivatives thereof;
[0089] (i) antipruriginous agents such as thenaldine, trimeprazine
or cyproheptadine;
[0090] (j) keratolytic agents such as .alpha.- and
.beta.-hydroxycarboxyli- c acids or .beta.-ketocarboxylic acids,
and the salts, amides or esters thereof and, more particularly,
hydroxy acids such as glycolic acid, lactic acid, salicylic acid,
citric acid and fruit acids in general, and 5-n-octanoylsalicylic
acid;
[0091] (k) anti-free-radical agents such as .alpha.-tocopherol and
esters thereof, superoxide dismutases, certain metal-chelating
agents or ascorbic acid and esters thereof;
[0092] (l) antiseborrhoeic agents such as progesterone;
[0093] (m) antidandruff agents such as octopirox or zinc
pyrithione;
[0094] (n) antiacne agents such as retinoic acid or benzoyl
peroxide;
[0095] (o) extracts of plant or bacterial origin.
[0096] Other such compounds include, for example, Diazoxide,
Spiroxazone, phospholipids such as lecithin, linoleic acid,
linolenic acid, salicylic acid and derivatives thereof described in
FR-2,581,542, e.g., salicylic acid derivatives bearing an alkanoyl
group having from 2 to 12 carbon atoms in position 5 of the benzene
ring, hydroxycarboxylic or ketocarboxylic acids and their esters,
lactones and their corresponding salts, anthralin, carotenoids,
eicosatetraynoic and eicosatriynoic acids or the esters and amides
thereof, vitamin D and derivatives thereof, and extracts of plant
or bacterial origin.
[0097] Thus, in a preferred embodiment the subject compositions
according to the invention also comprise at least one active agent
selected from among antibacterial agents, antiparasitic agents,
antifungal agents, antiviral agents, anti-inflammatory agents,
antipruriginous agents, anaesthetics, keratolytic agents,
anti-free-radical agents, antiseborrhoeic agents, antidandruff
agents, antiacne agents and/or agents for reducing skin
differentiation and/or proliferation and/or pigmentation, and
extracts of plant or bacterial origin.
[0098] The subject compositions may also comprise at least one
active agent as described above is in liposomal form, in particular
as described in WO-94/22468, filed Oct. 13, 1994 by Anti-Cancer
Inc. Thus, the compound encapsulated in the liposomes may be
delivered selectively to the hair follicle.
[0099] The pharmaceutical compositions according to the invention
may be administered parenterally, systemically, enterally or
topically. These pharmaceutical compositions are preferably
administered topically.
[0100] In order to determine the activity of the pyrimidine
derivatives substituted in position 6, the simple and rapid
technique is employed that entails measurement by incubating an
optionally purified tyrosinase and one of its substrates in a
suitable medium in the presence of a test compound, and then
comparing the measurements taken with the results of identical
measurements taken during the incubation of optionally purified
tyrosinase with one of its substrates in the absence of the test
compound.
[0101] In order to further illustrate the present invention and the
advantages thereof, the following specific examples are given, it
being understood that same are intended only as illustrative and in
nowise limitative.
EXAMPLE 1
[0102] Modulation of Tyrosinase Activity by Pyrimidine 3-oxide
Derivatives, Substituted in Position 6:
[0103] General Principles of the Measurement:
[0104] A purified tyrosinase was incubated in the presence of one
of its substrates in a suitable medium, in the presence or absence
of a pyrimidine 3-oxide derivative, substituted in position 6. The
activity of the enzyme was evaluated by measuring the amount of a
product of conversion of the substrate formed during the reaction.
The result obtained in the presence of a derivative was compared
with the result obtained in the absence of a derivative.
[0105] This comparison made it possible to evaluate the influence
of a derivative on the activity of the enzyme.
[0106] Preparation for the Measurements:
[0107] The substrate used was L-tyrosine (marketed by Sigma), a
stock solution of which was prepared in phosphate-buffered saline
(PBS) at a concentration of 0.5 mM.
[0108] The enzyme used was a purified fungal tyrosinase (EC
1.14.18.1) marketed by Sigma. A stock solution of this enzyme was
prepared in PBS at a concentration of 5 mg/ml, which represents a
concentration of about 19,500 international units of tyrosinase per
milliliter.
[0109] The product of conversion of the tyrosine by tyrosinase,
dopachrome, was measured by spectrophotometry at a wavelength of
475 nm using a Perkin Elmer type apparatus.
[0110] The derivative to be tested was prepared in solution in PBS
containing 1% ethanol at a concentration of 1 mM.
[0111] Measurements:
[0112] The following reagents were mixed together in a
spectrophotometer cell:
[0113] 500 .mu.l of tyrosine solution,
[0114] 390 .mu.l of phosphate buffer,
[0115] 10 .mu.l of fungal tyrosinase solution,
[0116] 100 .mu.l of solution of test derivative or of PBS/1%
ethanol (control).
[0117] The mixture was then incubated at a temperature of
37.degree. C. and the dopachrome formed was measured continuously
for at least 30 minutes.
[0118] Results:
[0119] The results obtained are expressed as a % of activation of
the tyrosinase activity relative to the value obtained with the
control (in the absence of derivative).
1 Derivatives Activation Control 0%
2,4-diamino-6-piperidinopyrimidine 3-oxide (Minoxidil) 41%
2,4-bis-methylamino-6-dimethylaminopyrimidine 3-oxide 61%
2,4-bis-ethylamino-6-dimethylaminopyrimidine 3-oxide 60%
2,4-bis-propylamino-6-dimethylaminopyrimidine 3-oxide 55%
2,4-bis-propylamino-6-piperidinopyrimidine 3-oxide 57%
2-amino-4-methylamino-6-piperidinopyrimidine 3-oxide 50%
2-amino-4-propylamino-6-piperidinopyrimidine 3-oxide 46%
2-amino-4-hexylamino-6-piperidinopyrimidine 3-oxide 47%
2-amino-4-benzylamino-6-piperidinopyrimidine 3-oxide 45%
2-amino-4-(2-hydroxyethylamino)-6-piperidinopyrimidine 43% 3-oxide
2-amino-4-propylamino-6-dimethylaminopyrimidine 3-oxide 50%
2-amino-4-butylamino-6-dimethylaminopyrimidine 3-oxide 51%
2-amino-4-isopropylamino-6-dimethylaminopyrimidine 46% 3-oxide
[0120] These results evidence that the pyrimidine derivatives,
substituted in position 6, tested have stimulators properties on
tyrosinase which are superior to Minoxidil.
EXAMPLE 2
[0121] Specific Examples of Compositions of the Invention
Containing an Aryl 2,4-dioxooxazolidine (These Compositions were
Formulated via the Usual Techniques Currently Employed in Cosmetics
or Pharmacy):
2 Dermal cream: 2,4-Bis-propylamino-6-piperidin- opyrimidine 1,000
g 3-oxide Ceteareth 30 7,000 g Glyceryl stearate 2,000 g Cetyl
alcohol 1,500 g Polydimethylsiloxane 1,500 g Liquid petroleum jelly
15,000 g Pure glycerol codex 20,000 g Preservatives q.s.
Demineralized water q.s. 100,000 g Dermal lotion to be sprayed:
2,4-Bis-methylamino-6-dimethylaminopyrimidine 5,000 g 3-oxide
Ethanol 30,000 g Demineralized water q.s. 100,000 g Lotion for the
hair: 2,4-Bis-ethylamino-6-dime- thylaminopyrimidine 3,000 g
3-oxide Propylene glycol 30,000 g Ethylene alcohol 40,500 g Water
qs 100,000 g
[0122] This lotion was applied to the scalp, once or twice a day,
at a rate of 1 ml per application.
3 Thickened lotion: 2,4-Bis-propylamino-6-piperidinopyrimidine
5,000 g 3-oxide Kawaine 2,000 g Hydroxypropylcellulose (Klucel G
marketed 3,500 g by Hercules) Ethyl alcohol qs 100,000 g
[0123] This thickened lotion was applied to the scalp, once or
twice a day, at a rate of 1 ml per application.
4 Niosomal lotion: Chimexane NL .RTM. 0.475 g Cholesterol 0.475 g
Monosodium stearoylglutamate 0.050 g
2,4-Bis-propylamino-6-piperidinopyrimid- ine 0.100 g 3-oxide
Preservatives qs Dyes qs Fragrance qs Demineralized water qs
100,000 g
[0124] This lotion was applied to the scalp, once or twice a day,
at a rate of 1 ml per application.
5 Lotion: 2,4-Bis-propylamino-6-dimethylaminopyrimidine 5,000 g
3-oxide Propylene glycol monomethyl ether (Dowanol PM 20,000 g
marketed by Dow Chemical) Hydroxypropylcellulose (Klucel G marketed
by 3000 g Hercules) Ethyl alcohol 40,000 g Minoxidil 2000 g Water
qs 100,000 g
[0125] This thickened lotion was applied to the scalp, once or
twice a day, at a rate of 1 ml per application.
[0126] While the invention has been described in terms of various
preferred embodiments, the skilled artisan will appreciate that
various modifications, substitutions, omissions, and changes may be
made without departing from the spirit thereof. Accordingly, it is
intended that the scope of the present invention be limited solely
by the scope of the following claims, including equivalents
thereof.
* * * * *