Hair loss abstract
Pyrimidine 3-oxide derivatives and their use for the treatment
of hair loss. The compositions contain in a physiologically acceptable
medium at least one compound corresponding to the formula (I): ##STR1##
in which: R.sub.1 denotes a methyl or NHR.sub.4 group in which R.sub.4
denotes a C.sub.1 -C.sub.4 alkyl group or hydrogen; R.sub.2 denotes
hydrogen or a group NHR.sub.4 in which R.sub.4 has the same meaning
as above; R.sub.2 may also denote methyl when R.sub.1 denotes methyl;
when R.sub.1 denotes NH.sub.2, R.sub.2 cannot be hydrogen; R.sub.3
may denote a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group which
may optionally carry; a group OR.sub.5 in which R.sub.5 denotes
a C.sub.1 -C.sub.4 alkyl group, a benzene nucleus which is optionally
substituted by one or more C.sub.1 -C.sub.4 alkoxy groups; R.sub.3
may also denote a halogen atom or a nitro or amino group; and the
physiologically acceptable acid addition salts.
Hair loss claims
We claim;
1. Composition intended for topical application, characterized
in that it contains, in a physiologically acceptable medium appropriate
for a topical application, at least one compound corresponding to
the formula (I): ##STR14## in which: R.sub.1 denotes a methyl or
NHR group in which R.sub.4 denotes a C.sub.1 -C.sub.4 alkyl group
or hydrogen;
R.sub.2 denotes hydrogen or a group NHR.sub.4 in which R.sub.4
has the same meaning as above; R.sub.2 may also denote methyl when
R.sub.1 denotes methyl; when R.sub.1 denotes NH.sub.2, R.sub.2 cannot
be hydrogen;
R.sub.3 may denote a hydrogen atom or a C.sub.1 -C.sub.4 alkyl
group which may optionally carry:
a group OR.sub.5 in which R.sub.5 denotes a C.sub.1 -C.sub.4 alkyl
group,
a benzene nucleus which is optionally substituted by one or more
C.sub.1 -C.sub.4 alkoxy groups;
R.sub.3 may also denote a halogen atom or a nitro or amino group;
and the physiologically acceptable acid addition salts.
2. Composition according to claim 1, characterized in that the
alkyl group denotes methyl or ethyl, the alkoxy group denotes methoxy
or ethoxy and the halogen atoms denote chlorine or bromine.
3. Composition according to claim 1, characterized in that the
compounds of formula (I) are chosen from the compounds corresponding
to the formula (I) in which R.sub.1 denotes amino, R.sub.2 denotes
amino and R.sub.3 denotes hydrogen or alternatively chlorine.
4. Composition according to claim 3, characterized in that the
physiologically acceptable acid addition salts are chosen from the
salts of sulfuric, hydrochloric, phosphoric, acetic, benzoic, salicylic,
glycolic, aceturic, succinic, nicotinic, tartaric, maleic, pamoic
[sic ], methanesulfonic, picric and lactic acid, and of amino acids.
5. Composition according to claim 1, characterized in that it is
provided in the form of a lotion, shampoo, gel, foam, emulsion,
vesicular dispersion, soap, spray or aerosol foam.
6. Composition according to claim 1, characterized in that the
physiologically acceptable medium is a medium in which the compound
of formula (I) is present either in the dissolved state or in the
dispersed state.
7. Composition according to claim 1, characterized in that the
physiologically acceptable medium consists of water or a mixture
of water and a solvent chosen from C.sub.1 -C.sub.4 lower alcohols,
alkylene glycols, alkylene glycol and dialkylene glycol alkyl ethers
which are present in proportions of between 1 and 80% by weight
relative to the total weight of the composition.
8. Composition according to claim 1, characterized in that the
medium is thickened by means of thickening agents.
9. Composition according to claim 1, characterized in that it contains
one or more agents chosen from esterified oligosaccharides, hexosaccharic
acid derivatives, glycosidase inhibitors, glycosaminoglycanase and
proteoglycanase inhibitors, tyrosine kinase inhibitors, hyperemics,
UV-A- and/or UV-B-screening agents, phosphodiesterase inhibitor,
adenine cyclase activators; antioxidants and free radical scavengers,
antidandruff agents, moisturizing agents, antiseborrheic agents,
steroidal and nonsteroidal anti-inflammatory agents, antiandrogenic
agents, hormones, retinoids, antibacterial agents, calcium-antagonising
agents, phospholipids, diazoxide, linoleic or linolenic acids, anthralin
andsanthracene derivatives, S-alkanoylsalicylic acid and its derivatives,
penetration activators, and vitamins or provitamins.
10. Composition according to claim 1, characterized in that the
composition additionally contains preservatives, stabilizers, pH-regulating
agents, osmotic pressure modifying agents, emulsifiers, UV-A- and
UV-B-sunscreens, antioxidants and perfumes.
11. Composition according to claim 1, characterized in that it
contains, by way of surface-active agent, surface-active agents
chosen from nonionic and amphoteric surface-active agents.
12. Composition according to claim 11, characterized in that the
nonionic surface-active agents are chosen from polyhydroxypropyl
ethers, oxyethylenated (C.sub.8 -C.sub.9)-alkylphenols containing
from 1 to 100 moles of ethylene oxide, alkylpolyglucosides of formula:
and in that the amphoteric surface-active agents are chosen from
amphocarboxyglycinates and amphocarboxypropionates.
13. Composition according to claim 1, characterized in that the
medium consists of a ternary volatile mixture of alkylene glycol
alkyl ether, ethyl alcohol and water.
14. Composition according to claim 1, characterized in that the
medium is provided in the form of a gel or a thickened medium containing,
by way of thickeners, heterobiopolysaccharides, cellulose derivatives,
polyhydroxyethyl acrylates or methacrylates or polyacrylic acids
crosslinked by means of a polyfunctional agent.
15. Composition according to claim 1, characterized in that it
also contains a cationic and/or anionic surface-active agent.
16. Use of the compound corresponding to the formula (I) as defined
in claim 1 in the nontherapeutic treatment of hair loss.
17. Process for the cosmetic treatment of hair or the scalp, characterized
in that at least one composition as defined in claim 1 is applied
to the scalp.
18. Composition according to claim 1, for application in the therapeutic
treatment of hair loss.
19. Use of compounds corresponding to the formula (I) as defined
in claim 1 for the preparation of a composition intended to be used
in the therapeutic treatment of hair loss, in particular of alopecia.
Hair loss description
The present invention relates to the use of pyrimidine 3-oxide
derivatives for slowing down hair loss and to the compositions containing
these derivatives and intended for topical application to the scalp.
Compounds which are effective for the treatment of hair loss without,
however, exhibiting side effects which could be inconvenient during
prolonged application have been sought for many years.
Mucopolysaccharide-based compositions which are used for slowing
down hair loss are particularly known.
The applicant company has discovered new pyrimidine 3-oxide derivatives
which are particularly effective for slowing down hair loss. In
particular, it has observed an increase in the number of hairs in
the anagen phase or in the growth phase and a decrease in the number
of hairs in the telogen phase or in the terminal phase of the hair.
The increase in the ratio of the number of hairs in the anagen phase
to the number of hairs in the telogen phase is an indication of
the effect of these compounds on the treatment of hair loss. Moreover,
these compounds have the advantage of not having side effects which
may be inconvenient during prolonged application.
The subject of the invention is the use of pyrimidine 3-oxide derivatives
for slowing down hair loss.
Another subject of the invention consists of the topical compositions
intended for use in slowing down hair loss.
Other subjects of the invention will become apparent on reading
the following description and examples.
The compounds used in conformity with the invention for slowing
down hair loss are of the general formula: ##STR2## in which: R.sub.1
denotes a methyl or NHR.sub.4 group in which R.sub.4 denotes a C.sub.1
-C.sub.4 alkyl group or a hydrogen atom;
R.sub.2 denotes hydrogen or a group NHR.sub.4 in which R.sub.4
has the same meaning as above; R.sub.2 may also denote methyl when
R.sub.1 denotes methyl; when R.sub.1 denotes NH.sub.2, R.sub.2 cannot
be hydrogen;
R.sub.3 may denote a hydrogen atom a C.sub.1 -C.sub.4 alkyl group
which may optionally carry:
a group OR.sub.5 in which R.sub.5 denotes a C.sub.1 -C.sub.4 alkyl
group,
a benzene nucleus which is optionally substituted by one or more
C.sub.1 -C.sub.4 alkoxy groups;
R.sub.3 may also denote a halogen atom or a nitro or amino group;
and the physiologically acceptable acid addition salts.
An alkyl group preferably denotes, in conformity with the invention,
a methyl or ethyl group, the alkoxy group preferably denotes methoxy
or ethoxy, the halogen atoms preferably denote chlorine or bromine.
The preferred compounds which may be used in conformity with the
invention are the compounds corresponding to the formula (I) in
which R.sub.1 denotes amino, R.sub.2 denotes amino and R.sub.3 denotes
hydrogen or alternatively R.sub.1 denotes amino, R.sub.2 denotes
amino and R.sub.3 denotes chlorine.
The compounds corresponding to the general formula (I) can also
be obtained for example by hydrogenolysis, in the presence of palladium
on charcoal, of compounds corresponding to the formula (II) which
is defined below, in which Z denotes a halogen atom and preferably
chlorine or bromine.
The reduction is performed according to the conventional method
described in the literature (D. J. Brown, The pyrimidines, supplement
II, Vol. 16, chapter X, page 360, Interscience Pub. 1985; Cowden
and Waring, Aust. J. Chem. 94, 1539 (1981) according to the following
reaction scheme: ##STR3##
The compounds of formula (I) can also be used in the form of their
physiologically acceptable acid additional salts such as the salts
of sulfuric, hydrochloric, phosphoric, acetic, benzoic, salicylic,
glycolic, aceturic, succinic, nicotinic, tartaric, maleic, pamoic
[sic], methanesulfonic, picric and lactic acid, of amino acids and
more particularly of aceturic acid.
These compounds are generally used for the treatment of hair loss
in compositions which can be provided in the form of a lotion, shampoo,
gel, foam, emulsion, vesicular dispersion, soap, spray or aerosol
foam.
The compositions intended for topical application are essentially
characterized in that they contain, in a physiologically acceptable
medium appropriate for topical application, at least one compound
Corresponding to the formula (I) or one of its acid addition salts
defined above.
The compound of formula (I) is present in proportions of between
0.1 and 10% by weight and preferably between 0.2 and 5% by weight
relative to the total weight of the composition.
The physiologically acceptable medium may consist of any medium
appropriate for a topical application, either in the cosmetic field
or in the pharmaceutical field, which is compatible with the active
substance. The compounds conforming to the invention may be present
in this medium either in the dissolved state or in the dispersed
state, especially in micronized form.
The physiologically acceptable medium may consist of water or a
mixture of water and a solvent or a mixture of solvents. The solvents
are chosen from cosmetically or pharmaceutically acceptable organic
solvents and are chosen more particularly from C.sub.1 -C.sub.4
lower alcohols such as ethyl alcohol, isopropyl alcohol, tert-butyl
alcohol, alkylene glycols, alkylene glycol and dialkylene glycol
alkyl ethers such as ethylene glycol monoethyl ether, propylene
glycol monomethyl ether and diethylene glycol monoethyl ether. The
solvents, when they are present, are in proportions of between 1
and 80% by weight relative to the total weight of the composition.
The medium may be thickened by means of thickening agents commonly
used in the cosmetic or pharmaceutical field.
The thickeners are preferably present in proportions of between
0.1 and 5% by weight and in particular between 0.4 and 3% by weight
relative to the total weight of the composition.
These compositions may also contain:
esterified oligosaccharides such as those described in EP-A-0,211,610
and EP-A-0,064,012;
hexosaccharic acid derivatives such as those described in EP-A-0,375,388,
in particular glucosaccharic acid;
glycosidase inhibitors such as those described in EP-A-0,334,586,
in particular D-glucaro-l,5-lactam;
glycosaminoglycanase and proteoglycanase inhibitors such as those
mentioned in EP-A-0,277,428, in particular L-galactono-1,4-lactone;
tyrosine kinase inhibitors such as those described in EP-A-0,403,238,
in particular 1-amido1-cyano-(3,4-dihydroxyphenyl)ethylene;
hyperemics such as:
nicotinic acid esters including more particularly benzyl and C.sub.1
-C.sub.6 alkyl nicotinates, and especially methyl and benzyl nicotinate,
as well as tocopherol nicotinate;
xanthine bases including more particularly caffeine and theophylline;
capsicin;
UV-A- and UV-B-screening agents such as methoxycinnamates and benzophenone
derivatives;
phosphodiesterase inhibitors such as Visnadine.sup..RTM. ;
adenine cyclase activators such as Forskolin;
antioxidants and free radical scavengers, in particular
OH radicals such as DMSO;
.alpha.-tocopherol, BHA, BHT;
superoxide dismutase (SOD);
antidandruff agents such as omadine and octopirox;
moisturizing agents such as urea, glycerine, lactic acid, .alpha.-hydroxyacids,
thiamorpholinone and its derivatives, and lactones;
antiseborrheic agents such as S-carboxymethylcysteine, S-benzylcysteamine
and their derivatives, and thioxolone;
steroidal and nonsteroidal anti-inflammatory agents such as hydrocortisone,
betamethasone, dexamethasone and niflumic acid;
antiandrogens and hormones such as estriol, estradiol, thyroxine,
oxendolone and diethylstilbestrol;
retinoids including more particularly alltrans-retinoic acid also
called tretinoin, isotretinoin, retinol or vitamin A and its derivatives
such as the acetate, palmirate or propionate, motretinide, etretinate,
and zinc all-trans-retinoate;
antibacterials chosen more particularly from macrolides, pyranosides
and tetracyclines, and especially erythromycin;
calcium antagonists among which Cinnarizine and Diltiazem may be
mentioned by way of nonlimiting examples;
phospholipids such as lecithin;
diazoxide (3-methyl-7-chloro[2H]-1,2,4-benzothiadiazine 1,1-dioxide);
linoleic and linolenic acids;
anthralin and its derivatives;
5-alkanoylsalicylic acid and its derivatives as described in Patent
FR-25 81 542;
penetration activators such as THF, 1,4-dioxane, oleyl alcohol,
2-pyrrolidone, benzyl salicylate and the like;
vitamins or provitamins such as .beta.-carotene, biotin, panthenol
and its derivatives, vitamin C, and vitamins B.sub.2, B.sub.4 and
B.sub.6.
These compositions may also contain cyclic AMP and MPS.
These compositions may also contain preservatives, stabilizers,
pH-regulating agents, osmotic pressure modifying agents and emulsifiers.
The compounds conforming to the invention may also be combined
with surface-active agents including especially those chosen from
nonionic and amphoteric surface-active agents.
Among the nonionic surface-active agents, there may be mentioned
the polyhydroxypropyl ethers described especially in French Patents
Nos. 1,477,048; 2,091,516; 2,169,787; 2,328,763 and 2,574,786; oxyethylenated
(C.sub.8 -C.sub.9)alkylphenols containing from 1 to 100 moles of
ethylene oxide and preferably 5 to 35 moles of ethylene oxide; and
alkylpolyglycosides of formula:
in which n ranges from 8 to 15 inclusive and x from 1 to 10 inclusive.
Among the amphoteric surface-active agents, there may be mentioned
more particularly the amphocarboxyglycinates and the amphocarboxypropionates
defined in the CTFA dictionary, 3rd edition, 1982, and sold especially
under the name Miranol.sup..RTM. by the company Miranol.
The compounds according to the invention may be introduced into
carriers which further improve the regrowth activity while at the
same time possessing advantageous properties from the cosmetic point
of view, such as ternary volatile mixtures of alkylene glycol alkyl
ethers, especially C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkylene
glycol or dialkylene glycol, preferably C.sub.1 -C.sub.4 dialkylene
glycol, of ethyl alcohol and of water; the preferred alkylene glycol
alkyl ethers are ethylene glycol monoethyl ethers, propylene glycol
monomethyl ether and diethylene glycol monomethyl ether.
Cationic and/or anionic surface-active agents may also be used.
The compounds conforming to the invention may also be introduced
into gelled or thickened carriers such as essentially aqueous carriers
gelled by means of heterobiopolysaccharides, such as xanthan gum,
scleroglucans or cellulose derivatives, in particular cellulose
ethers, aqueous alcoholic carriers gelled by means of polyhydroxyethyl
acrylates or methacrylates or essentially aqueous carriers thickened
in particular by means of polyacrylic acids crosslinked by means
of a polyfunctional agent such as the Carbopols sold by the company
Goodrich.
The subject of the invention is also a process for the cosmetic
treatment of hair or of the scalp, consisting in applying to them
at least one composition as defined above, for the purpose of improving
the appearance of the hair.
The treatment mainly consists in applying the composition as defined
above to the alopecic areas of the scalp of an individual.
The preferred method of application consists in applying 1 to 2
g of the composition to the alopecic area, at a rate of one to two
applications per day, for 1 to 7 days per week and this for a period
of 1 to 6 months.
The subject of the invention is also a composition intended for
the therapeutic treatment of hair loss, especially alopecia, this
composition corresponding to the definition of the compositions
for topical application defined above.
The following examples are intended to illustrate the invention
without, however, being of a limiting nature. |