Hair loss abstract
Composition for retarding hair loss and for inducing and stimulating
its growth, containing at least one compound of formula: ##STR1##
where R denotes H, alkyl or a ring of formula: ##STR2## X denotes
##STR3## --OR.sub.3, --SR.sub.4 with: the remaining variables defined
below in the body of the specification.
Hair loss claims
We claim:
1. Compound of formula: ##STR34## in which: R is a hydrogen atom
or a saturated linear C.sub.1 -C.sub.8 alkyl radical or, with the
pyrimidine ring, forms a carbon/hydrogen-containing ring, which
is spiro on the carbon to which R is attached or is an ortho fusion
placed with the adjacent carbon of the pyrimidine ring, of formula:
##STR35## with n equal to 1, 2 or 3; R' is a hydrogen atom or one
of the following radicals: ##STR36## in which: R.sub.5 and R.sub.6
are a C.sub.1 -C.sub.4 lower alkyl radical; and
R.sub.7 and R.sub.8 are a hydrogen atom or a C.sub.1 -C.sub.4 lower
alkyl radical, on condition that they do not simultaneously denote
a hydrogen atom;
Y is an oxygen atom or an --OSO.sub.3.sup..crclbar. group; and
X is:
(i) a group SR.sub.4, in which R.sub.4 is a saturated linear or
branched C.sub.1 -C.sub.12 alkyl radical which can be substituted
with a halogen atom or a trifluoromethyl radical, a linear C.sub.2
-C.sub.12 alkenyl radical, a C.sub.3 -C.sub.10 cycloalkyl radical,
a C.sub.7 -C.sub.12 aralkyl radical or a phenyl radical optionally
substituted with one or two groups which, independently of one another,
are a halogen atom, a C.sub.1 -C.sub.6 alkyl radical, a C.sub.1
-C.sub.6 alkoxy radical or a trifluoromethyl radical;
(ii) a group --OR.sub.3 in which R.sub.3 has the same meaning as
R.sub.4, on condition that, when Y is an oxygen atom, R an alkyl
group and R' denotes a hydrogen atom, R.sub.3 does not denote a
C.sub.1 -C.sub.4 alkyl radical or a phenyl group optionally substituted
with one or two halogen atoms; as well as its cosmetically or pharmaceutically
acceptable addition salts with acids.
2. Compound according to claim 1, selected from the group consisting
of:
2 amino-4-methyl-6-(2,2-dimethylpropyloxy)pyrimidine 3-oxide;
2-amino-4-methyl-6-(1-cyclohexylmethyloxy)pyrimidine 3-oxide;
2-amino-4-methyl-6-(5-hexenyloxy)pyrimidine 3-oxide;
2-amino-4-methyl-6-benzyloxypyrimidine 3-oxide;
2-amino-4-methyl-6-(2,4-dimethylphenyloxy)pyrimidine 3-oxide;
2-amino-4-methyl-6-methylthiopyrimidine 3-oxide;
2-amino-4-methyl-6-ethylthiopyrimidine 3-oxide;
the inner salt of 2-amino-4-methyl-6-methoxy-3-sulphooxypyrimidinium
hydroxide;
the inner salt of 2-amino-4-methyl-6-ethoxy-3-sulphooxypyrimidinium
hydroxide;
2-amino-4,5-tetramethylene-6-butoxypyrimidine 3-oxide; and
the inner salt of 2-amino-4,5-tetramethylene-6-butoxy-3-sulphooxypyrimidinium
hydroxide.
Hair loss description
The invention relates to compositions intended for use, in particular
in topical application, for retarding hair loss and for inducing
and stimulating its growth, containing 2-aminopyrimidine 3-oxide
derivatives, as well as to new 2-aminopyrimidine 3-oxide derivatives
used in these compositions.
2,4-Diamino-6-piperidinopyrimidine 3-oxide or "minoxidil"
is already known in the prior art for its properties as an antihypertensive
agent, but also for its use in the treatment of hair loss, pelade,
desquamating dermatitis and alopecia.
The Applicant has discovered new compositions for the treatment
and prevention of hair loss, used, in particular, in topical application
and especially efficacious in the treatment of diseases of the scalp
as a result of a particular family of compounds derived from 2-aminopyrimidine
3-oxide.
The compounds selected by the Applicant, in addition to the fact
that they are efficacious for hair regrowth and, in particular,
for inducing and stimulating its growth and retarding its loss,
exhibit substantially zero antihypertensive activity, or an activity
lower than that of minoxidil.
These compounds possess solubilities in the media customarily used
in cosmetics and in pharmacy which are markedly greater than those
of minoxidil.
The subject of the invention is hence new compositions intended
for the treatment and prevention of hair loss, containing particular
compounds derived from 2-aminopyrimidine 3-oxide.
The subject of the invention is also new derivatives of 2-aminopyrimidine
3-oxide used in these compositions.
Another subject relates to the use of the compounds according to
the invention for the preparation of a medicinal product intended
for the therapeutic treatment of hair loss.
Other subjects of the invention will become apparent on reading
the description and the examples which follow.
The compositions according to the invention are essentially characterized
in that they contain, in a physiologically acceptable medium, at
least one compound corresponding to the following formula: ##STR4##
in which:
R denotes a hydrogen atom or a saturated linear C.sub.1 -C.sub.8
alkyl radical or, with the pyrimidine ring, forms a carbon/hydrogen-containing
ring of formula. ##STR5## with n equal to 1, 2 or 3;
X denotes;
(i) a hydrogen atom;
(ii) a group ##STR6## in which:
R.sub.1 and R.sub.2, which may be identical or different, denote
a hydrogen atom, a saturated linear or branched C.sub.1 -C.sub.12
alkyl group which can be substituted with a halogen atom or a trifluoromethyl
radical, a linear C.sub.2 -C.sub.12 alkenyl group, a C.sub.3 -C.sub.10
cycloalkyl group, a C.sub.7 -C.sub.12 aralkyl group or an aryl group
corresponding to the formula: ##STR7## in which R.sub.9 and R.sub.10,
which may be identical or different, denote hydrogen, C.sub.1 -C.sub.4
alkyl, hydroxyl, C.sub.1 -C.sub.4 alkoxy or halogen;
R.sub.1 and R.sub.2, with the nitrogen atom to which they are attached,
can form a saturated or unsaturated heterocycle selected from the
following groups: aziridino, azetidino, pyrrolidino, piperidino,
hexamethylenimino, heptamethylenimino, octamethylenimino, tetrahydropyridino,
dihydropyridino, pyrrole, pyrrazole, imidazole, triazole, 4-alkylpiperazino,
morpholino, thiomorpholino;
(iii) a group --OR.sub.3, in which R.sub.3 denotes a saturated
linear or branched C.sub.1 -C.sub.12 alkyl radical which can be
substituted with a halogen atom or a trifluoromethyl radical, a
linear C.sub.2 -C.sub.12 alkenyl radical, a C.sub.3 -C.sub.10 cycloalkyl
radical, a C.sub.7 -C.sub.12 aralkyl radical or a phenyl radical
optionally substituted with one or two groups which, independently
of one another, denote a C.sub.1 -C.sub.6 alkyl radical, a C.sub.1
-C.sub.6 alkoxy radical, a halogen atom or a trifluoromethyl radical;
(iv) a group --SR.sub.4, in which R.sub.4 has the same meaning
as R.sub.3 defined above;
Y denotes an oxygen atom or an --OSO.sub.3.sup..crclbar. group;
and
R' denotes a hydrogen atom or one of the following groups: ##STR8##
in which:
R.sub.5 and R.sub.6 represent C.sub.1 -C.sub.4 lower alkyl radicals;
and
R.sub.7 and R.sub.6 denote a hydrogen atom or a C.sub.1 -C.sub.4
lower alkyl radical, on condition that they do not simultaneously
denote a hydrogen atom.
When Y denotes an oxygen atom, the compounds of formula (I) according
to the invention can coexist with their tautomeric form of formula
(I.sub.2) according to the following equilibrium: ##STR9##
Depending on the nature of the medium, one of the tautomeric forms
can be preponderent relative to the other.
The compounds of formula (I) according to the invention may be
converted to their cosmetically or pharmaceutically acceptable addition
salts with acids, such as the salts with sulphuric, hydrochloric,
hydrobromic, phosphoric, acetic, benzoic, salicylic, glycolic, succinic,
nicotinic, tartaric, maleic, pamoic, methane-sulphonic, picric and
lactic acids, and the like.
Among the compounds of general formula (I), a number of compounds
are known per se and have been described as antihypertensive agents
or as synthesis intermediates.
They are, in particular, described in U.S. Pat. Nos. 3,464,987,
3,644,364, 4,013,778 and 4,287,338; French Patent No. 2,087,936;
and European Patents EP 058,476 and EP 057,546; or mentioned in
the technical literature (Can. J. Chem. 1984, 62(6), 1176-80; Muller,
Ramuz, Helv. Chim., Act. 65 (5), 1982, pages 1454-66).
New compounds according to the present invention correspond to
the following formula (I'): ##STR10## in which:
R, R' and Y have the same meanings stated in the formula (I) above,
and X denotes:
(i) a group --SR.sub.4, in which R.sub.4 denotes a saturated linear
or branched C.sub.1 -C.sub.12 alkyl radical which can be substituted
with a halogen atom or a trifluoromethyl radical, a linear C.sub.2
-C.sub.12 alkenyl radical, a C.sub.3 -C.sub.10 cycloalkyl radical,
a C.sub.7 -C.sub.12 aralkyl radical or a phenyl radical optionally
substituted with one or two groups which, independently of one another,
denote a halogen atom, a C.sub.1 -C.sub.6 alkyl radical, a C.sub.1
-C.sub.6 alkoxy radical or a trifluoromethyl radical;
(ii) a group --OR.sub.3 in which R.sub.3 has the same meaning as
R.sub.4, on condition that, when Y denotes an oxygen atom, R an
alkyl group and R' denotes a hydrogen atom, R.sub.3 does not denote
a C.sub.1 -C.sub.4 alkyl radical or a phenyl radical optionally
substituted with one or two halogen atoms.
The new compounds of formula (I') can occur in the form of physiologically
acceptable addition salts with acids.
The compounds according to the present invention corresponding
to the general formula (I) are obtained from a 2-aminopyrimidine
3-oxide derivative substituted at the 6-position, of the following
formula: ##STR11## in which:
R has the meaning stated in the general formula (I); and
Z denotes a halogen atom selected from chlorine or bromine, a sulphonate
group such as tosylate, brosylate or mesylate or a phenoxy group
substituted with electron-attracting groups such as halogen atoms
or nitro groups.
The particular compounds according to the invention corresponding
to the formula (IA): ##STR12## in which R has the meaning stated
in the formula (I) above, are obtained by hydrogenolysis of the
compounds of formula (II) in which Z more especially denotes a chlorine
or bromine atom. The reduction is performed according to the conventional
methods described in the technical literature (D. J. Brown, The
pyrimidines, Vol. 16, supplement II, Chapter X, 360). The process
for preparing them may be represented by the following scheme: ##STR13##
The particular compounds of formula (IB): ##STR14## are obtained
by reacting a solution of the alcoholate R.sub.3 O.sup..crclbar.
W.sup..sym. in which R.sub.3 has the same meaning as that stated
for the general formula (I) and W denotes an alkali metal such as
sodium, potassium or lithium, in the corresponding alcohol, with
the compounds of formula (II) in which Z denotes chlorine or bromine
or a phenoxy group substituted with electron-attracting groups.
The Williamson method is applied, as described in European Patent
EP 57,546, at a temperature of between 40.degree. and 100.degree.
C.
The preparation of these compounds may be represented by the following
scheme: ##STR15##
The particular compounds of the following formula (IC): ##STR16##
are prepared by reacting the compounds of formula (II) with a thiolate
of formula R.sub.4 S.sub..crclbar. W.sup..sym., in which R.sub.4
and W have the meanings stated above, in the presence of a solvent
selected from ethers, preferably Methyl cellosolve or ethylene glycol
dimethyl ether, at a temperature of the order of 50.degree. to 150.degree.
C.
The reaction is performed according to the conventional methods
of the literature (D. J. Brown, the PYRIMIDINES, Vol. 16, Supplement
II, Chapter VI, Section F).
The preparation of these compounds may be represented by the following
scheme: ##STR17##
The particular compounds of the following formula (ID): ##STR18##
are obtained by reacting an amine ##STR19## in which R.sub.1 and
R.sub.2 have the same meanings as those stated for the general formula
(I), with the compounds of formula (II). The reaction is performed
in the presence of a solvent which can be an alcohol, preferably
ethanol, or the amine serving as a reactant and at the same time
as a solvent, at a temperature of between 20.degree. and 150.degree.
C., according to the processes described in U.S. Pat. Nos. 3,644,364
and 3,464,987.
The preparation of these compounds may be represented by the following
scheme: ##STR20##
The particular compounds according to the invention of formula
(I) in which Y denotes an oxygen atom, obtained according to the
different processes described above, may be converted to their O-sulphate
homologues by chemical sulphation according to the conventional
methods described in the literature (J. Med. Chem. 1983, 26, p.
1791-1793).
The sulphur trioxide/pyridine, sulphur trioxide/triethylamine or
sulphur trioxide/ethyldiisopropylamine complexes are used as a sulphating
reagent.
The solvents used are preferably dimethylformamide, acetonitrile,
chloroform or binary mixtures thereof. The temperature is of the
order of 0.degree. to 25.degree. C. and the reaction time varies
between 1 hour and 24 hours.
The particular compounds according to the invention of formula
(I) in which Y denotes an oxygen atom may be converted to their
amide, ureide or carbamate homologues according to the conventional
methods described in the literature (J. MARCH, Advanced Organic
Chemistry, 3rd edition, p. 370), by the action of an acid chloride,
an acid anhydride, a carbamic acid chloride or an alkyl chloroformate,
respectively; the reaction is performed in the presence of a tertiary
amine such as pyridine.
The compounds thereby obtained, of formula: ##STR21## in which
R, R' and X have the same meaning as that stated for the formula
(I) defined above, are readily hydrolyzable, in an alcoholic potassium
hydroxide medium for example, and can give rise once more to their
precursors of formula (I) in which R' denotes a hydrogen.
The conversion of the compounds of formula (I) in which Y is oxygen
and R' is hydrogen to their O-sulphate, amide, ureide or carbamate
homologues may be represented by the following scheme: ##STR22##
The compounds of formula (IE) according to the invention can constitute
intermediates for the synthesis of the oxadiazolopyrimidines of
the following formula (III): ##STR23## in which R and X have the
meaning stated in the general formula (I).
The compounds (III) are obtained by internal cyclization/elimination
of the carbamate or ureide derivatives of the formula (IE) according
to the methods described in the literature (J. C. MULLER, Helvetica
Chimica Acta, Vol. 66, 1983, p. 669-672).
The compounds of formula (III) and their salts are new, with the
exception of the following compound, namely 2-oxo-2,8-dihydro[1,2,4]oxadiazolo[2,3-a]pyrimidine
carbamate which is described in the document (MULLER, RAMUZ, Helvetica
Chimica Acta 65 (5), 1982, p. 1454-66) and constitute another subject
of the invention. They can receive various applications, and in
particular in the use for the treatment and prevention of hair loss.
The compositions according to the present invention, containing,
in a physiologically acceptable medium, at least one compound corresponding
to the formula (I) or one of its physiologically acceptable addition
salts with acids, may be applied in the cosmetic or pharmaceutical
field, in particular in topical application. They are intended for
the treatment and prevention of hair loss, and in particular of
pelade, alopecia and also desquamating dermatitis.
These compositions can contain, by way of a physiologically acceptable
medium, any medium suitable for topical application, either in cosmetics
or in pharmacy, and which is compatible with the active substance.
The compounds according to the invention can be present in this
medium either in the dissolved state or in the dispersed state,
in particular in micronized form.
The compositions intended for use in pharmacy are presented in
the form of an ointment, tincture, cream, pomade, powder, patch,
impregnated pad, solution, emulsion or vesicular dispersion, lotion,
gel, spray or suspension. They may be either anhydrous or aqueous,
depending on the clinical indication.
The compounds according to the invention are present in these pharmaceutical
compositions at concentrations of between 0.1 and 10% by weight,
and especially between 0.2 and 5% by weight.
The cosmetic compositions are, in particular, intended for use
in the form of a lotion, gel, soap, shampoo, aerosol or foam, and
contain, in a cosmetically acceptable vehicle, at least one compound
of formula (I) or one of its addition salts with acids.
The concentration of these compounds of formula (I) in these compositions
is preferably between 0.01 and 5% by weight, and especially between
0.05 and 3% by weight.
The compositions according to the invention can contain different
additives customarily used in cosmetics or in pharmacy, and especially
active substances such as hydrating agents, for example thiamorpholinone
and its derivatives or urea; antiseborrhoeic agents such as S-carboxymethylcysteine,
S-benzylcysteamine and their derivatives; and thioxolone.
The compounds according to the invention may be combined with compounds
further improving their activity with respect to hair regrowth and/or
to retarding its loss, such as, more especially, the following compounds:
nicotinic acid esters including, more especially, C.sub.1 -C.sub.6
alkyl nicotinates, and in particular methylnicotinate;
steroidal and non-steroidal anti-inflammatory agents well known
in the prior art, and especially hydrocortisone, its salts and its
derivatives and niflumic acid;
retinoids, and more especially all-trans-retinoic acid also known
as tretinoin, isotretinoin, retinol or vitamin A and its derivatives
such as the acetate, palmitate or propionate, motretinide, etretinate
and zinc all-trans-retinoate;
antibacterial agents selected, more especially, from macrolides,
pyranosides and tetracyclines, and in particular erythromycin;
calcium antagonists such as, more especially, cinnarizine and diltiazem;
hormones such as oestriol or analogues or thyroxine and its salts;
anti-androgens such as oxendolone, spironolactone and diethylstilboestrol;
and
OH radical-trapping agents such as dimethyl sulphoxide.
It is also possible to combine with the compounds of the invention,
where appropriate mixed with the others, compounds such as diazoxide
corresponding to 3-methyl-7-chloro-2H-1,2,4-benzothiadiazine 1,1-dioxide;
spiroxasone or 7-(acetylthio)-4',5'-dihydrospiro[androst-4-ene-17,2'(3'H)-furan]-3-one;
phospholipids such as lecithin; linoleic and linolenic acids; salicylic
acid and its derivatives described, more especially, in French Patent
2,581,542, and more especially salicylic acid derivatives bearing
an alkanoyl group having 2 to 12 carbon atoms at the 5-position
of the benzene ring; hydroxy-carboxylic or keto-carboxylic acids
and their esters and lactones and their corresponding salts; anthralin
or 1,8,9-trihydroxyanthracene; carotenoids; and 5,8,11,14-eicosatetraynoic
and 5,8,11-eicosatriynoic acids, their esters and amides.
The compounds according to the invention may also be combined with
surfactants including, more especially, those selected from nonionic
and amphoteric surfactants.
Among nonionic surfactants, there will be mentioned, more especially,
the polyhydroxypropyl ethers described, in particular, 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 alkyl)phenols 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 varies from 8 to 15 inclusive and x from 1 to 10 inclusive.
Among amphoteric surfactants, there will be mentioned, more especially,
the amphocarboxyglycinates and amphocarboxypropionates defined in
the CTFA Dictionary, 3rd edition, 1982, and sold, in particular,
under the name MIRANOL.RTM. by the company MIRANOL.
The compounds according to the invention may be introduced into
vehicles which further improve the activity in respect of regrowth,
at the same time possessing advantageous properties from a cosmetic
standpoint, such as ternary volatile mixtures of alkylene glycol
alkyl ether, especially (C.sub.1 -C.sub.4 alkylene) glycol or dialkylene
glycol and preferably (C.sub.1 -C.sub.4 dialkylene) glycol (C.sub.1
-C.sub.4 alkyl) ether, ethyl alcohol and water, the glycol solvent
denoting, more especially, ethylene glycol monoethyl ether, propylene
glycol monomethyl ether or diethylene glycol monomethyl ether.
The compounds according to the invention may also be introduced
into gelled or thickened vehicles, such as essentially aqueous vehicles
gelled with heterobiopolysaccharides such as xanthangumor cellulose
derivatives, aqueous-alcoholic vehicles gelled with polyhydroxyethyl
acrylates or methacrylates or essentially aqueous vehicles thickened,
in particular, with polyacrylic acids crosslinked with a polyfunctional
agent, such as the Carbopols sold by the company GOODRICH.
These compositions can also contain preservatives, stabilizers,
pH regulators, osmotic pressure-modifying agents, emulsifiers, UV-A
and UV-B screening agents and antioxidants such as .alpha.-tocopherol,
butylated hydroxyanisole and butylated hydroxytoluene.
The physiologically acceptable mediumcan consist of water or a
mixture of water and a solvent or a mixture of solvents, the solvents
being selected from organic solvents which are acceptable from a
cosmetic or pharmaceutical standpoint, and selected more especially
from C.sub.1 -C.sub.4 lower alcohols such as ethyl alcohol, isopropyl
alcohol and tert-butyl alcohol, alkylene glycols and alkylene glycol
and dialkylene glycol alkyl ethers such as ethylene glycol monoethyl
ether, propylene glycol monomethyl ether and diethylene glycol monomethyl
ether. The solvents, if any, are present in proportions of between
1 and 80% by weight relative to the total weight of the composition.
The physiologically acceptable media may be thickened by means
of thickening agents customarily used in cosmetics or pharmacy,
and heterobiopolysaccharides such as xanthangum, scleroglucans,
cellulose derivatives such as cellulose ethers and acrylic polymers,
crosslinked or otherwise, may be mentioned more especially.
The thickeners are preferably present in proportions of between
0.1 and 5% by weight, and especially between 0.4 and 3% by weight,
relative to the total weight of the composition.
The subject of the invention is also a process for cosmetic treatment
of the hair or scalp, consisting in applying thereon at least one
composition as defined above, for the purpose of enhancing the appearance
of the hair.
Another subject of the invention consists of the use of the composition
containing the compounds of formula (I) defined above, for the preparation
of a medicinal product having the effect of inducing or stimulating
hair growth and retarding its loss.
The treatment consists chiefly in applying the composition as defined
above on the alopecic areas of an individual's scalp.
The preferred method of application consists in applying 1 to 2
g of the composition on the alopecic area at the rate of one or
two applications per day for 1 to 7 days per week over a period
of 1 to 6 months.
The compositions can, in particular, be used in the treatment of
pelade, hair loss and desquamating dermatitis. |