Hair loss abstract
Pharmaceutical or cosmetic composition intended to be used, by
topical application, for retarding hair loss and for inducing or
stimulating hair growth, containing at least one compound of formula:
##STR1## where: R.sub.1 denotes H or C.sub.1 -C.sub.8 alkyl; R.sub.2
denotes C.sub.1 -C.sub.8 alkyl or NHR.sub.3, where R.sub.3 denotes
H or --COOR.sub.4, where R.sub.4 denotes C.sub.1 -C.sub.4 alkyl;
X denotes ##STR2## --OR.sub.9 or --SR.sub.10 ; R.sub.5 and R.sub.6
denote H, optionally substituted C.sub.1 -C.sub.12 alkyl, or C.sub.2
-C.sub.12 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, aralkyl or aryl,
or form, with N, a saturated or unsaturated heterocycle; R.sub.9
denotes optionally substituted C.sub.1 -C.sub.12 alkyl, or C.sub.2
-C.sub.12 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.7 -C.sub.12
aralkyl or phenyl, which may optionally be substituted; R.sub.10
is identical to R.sub.9 ; and Y denotes O or OSO.sub.3.sup..crclbar.
; as well as its cosmetically or pharmaceutically acceptable acid
addition salts.
Hair loss claims
We claim:
1. A composition comprising in a physiologically acceptable medium,
an effective amount of at least one compound corresponding to formula
(I) : ##STR23## in which: R.sub.1 denotes a hydrogen atom or a C.sub.1
-C.sub.8 saturated straight-chain alkyl radical;
R.sub.2 denotes a C.sub.1 -C.sub.8 saturated straight-chain alkyl
radical, an --NHR.sub.3 group in which R.sub.3 denotes a hydrogen
atom, or the group --COOR.sub.4, where R.sub.4 represents a C.sub.1
-C.sub.12 straight-chain alkyl radical;
X denotes:
(i) a ##STR24## group in which:
R.sub.5 and R.sub.6, which may be identical or different, denote
a hydrogen atom, a straight-chain or branched C.sub.1 -C.sub.12
alkyl group, which may be substituted by one or more halogen atoms,
a C.sub.2 -C.sub.12 straight-chain alkenyl group, a C.sub.3 -C.sub.10
cycloalkyl group or an aryl or aralkyl group corresponding to the
formula: ##STR25## where n ranges from 0 to 4; and
R.sub.7 and/or R.sub.8, independently of one another, denote a
hydrogen atom, a C.sub.1 -C.sub.6 lower alkyl or alkoxy group or
a trifluoromethyl radical; or
R.sub.5 and R.sub.6, together with the nitrogen atom to which they
are bonded, form a saturated or unsaturated heterocycle selected
from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl,
piperidyl, hexamethyleneimino, heptamethyleneimino, octamethyleneimino,
tetrahydropyridinyl, dihydropyridyl, pyrrolyl, pyrazolyl, imidazolyl,
triazolyl, 4-alkylpiperazinyl, morpholino and thiomorpholino;
(ii) an --OR.sub.9 group, in which R.sub.9 denotes a straight-chain
or branched C.sub.1 -C.sub.12 alkyl radical, which is optionally
substituted by one or more halogen atoms, a C.sub.2 -C.sub.12 alkenyl
radical, C.sub.3 -C.sub.10 cycloalkyl radical, a C.sub.7 -C.sub.12
aralkyl radical or a phenyl radical, which is optionally substituted
by one or two groups which, independently of one another, denote
a C.sub.2 -C.sub.6 alkyl radical, a C.sub.1 -C.sub.6 alkoxy radical,
a halogen atom or a trifluoromethyl radical; or
(iii) an SR.sub.10 group, in which R.sub.10 has one of the same
meanings as R.sub.9 ; and
Y denotes an oxygen atom or an --OSO.sub.3.sup..crclbar. group;
or a physiologically acceptable acid addition salt thereof.
2. A composition according to claim 1, wherein
R.sub.1 and R.sub.2 denote a methyl radical, and X denotes piperidyl;
or
R.sub.1 denotes methyl, and R.sub.2 denotes --NHR.sub.3, in which
R.sub.3 has the same meaning as indicated in claim 1, and X denotes
dimethylamino, diethylamino, n-butylamino, piperidyl, morpholino,
4-methylpiperazinyl, benzylamino or anilino.
3. A composition according to claim 1, wherein
R.sub.1 and R.sub.2 denote methyl, and X represents the ethoxy
group; or
R.sub.1 denotes methyl, and R.sub.2 denotes --NHR.sub.3, in which
R.sub.3 has the same meaning mentioned in formula (I), and X denotes
the ethoxy, butoxy, 1-methylethoxy or 2,4-dimethylphenoxy group.
4. A pharmaceutical or cosmetic composition according to claim
1 in topical application form.
5. A composition according to claim 4, in the form of a pharmacutically
acceptable ointment, dye, cream, pomade, powder, patch, impregnated
buffer, vesicular solution, emulsion or dispersion, lotion, gel,
spray or suspension, which is anhydrous or aqueous.
6. A pharmaceutical composition according to claim 5, wherein the
compound of formula (I) is present in a concentration of between
0.1 and 10% by weight relative to the total weight of the composition.
7. A composition according to the claim 1 and which is useful in
cosmetics, in the form of a lotion, gel, soap, shampoo, aerosol
or foam and contains, in a cosmetically acceptable excipient, the
at least one compound in a concentration of between 0.01 and 5%
by weight.
8. A composition according to claim 4 which also contains a hydrating
agent and an antiseborrheic agent.
9. A process for the cosmetic treatment of hair or the scalp, which
comprises applying a composition as defined in claim 1 thereto.
10. A composition according to claim 1 which also contains a nicotinic
acid ester, a steroid or non-steroid anti-inflammatory agent, a
retinoid, an antibacterial agent, a calcium antagonist, a hormone,
an antiandrogenic agent or a compound which captures OH radicals.
11. A composition according to claim 1, which also contains a diazoxide,
a spiroxazone, a phospholipid, linoleic acid, linolenic acid, salicylic
acid or a derivative thereof, a hydroxycarboxylic or ketocarboxylic
acid, an ester, lactone or a salt or either, anthralin, a carotenoid,
5,8,11,14-eicosatetrainoic acid, an ester or amide thereof, and
5,8,11-eicosatriinoic acid, and an ester or amide thereof.
12. A composition according to claim 4 which also contains a nonionic
or amphoteric surfactant.
13. A composition according to claim 4 which the physiologically
acceptable medium consists of water, a mixture of water and one
or more organic solvents or a mixture of organic solvents. the organic
solvents being pharmaceutically or cosmetically acceptable.
14. A composition according to claim 13, wherein each organic solvent
is a C.sub.1 -C.sub.4 lower alcohol, an alkylene glycol, a monoalkylene
glycol alkyl ethers or a dialkylene glycol alkyl ether.
15. A composition according to claim 4 wherein the physiologically
acceptable medium comprises a thickening amount of thickener and/or
gelling agent and contains a member selected from the group consisting
of a preservative, a stabiliser, a pH regulator, an agent to modify
the osmotic pressure, an emulsifier, a UVA filter, a UVB filter
and an antioxidant.
16. A compound corresponding to the following formula: ##STR26##
in which: R.sub.1 denotes a hydrogen atom or a C.sub.1 -C.sub.8
saturated straight-chain alkyl radical;
R.sub.2 denotes a C.sub.1 -C.sub.8 saturated straight-chain alkyl
radical, an --NHR.sub.3 group in which R.sub.3 denotes a hydrogen
atom, or the group --COOR.sub.4, where R.sub.4 represents a C.sub.1
-C.sub.4 straight-chain alkyl radical;
Y denotes an oxygen atom or the OSO.sub.3.sup..crclbar. group;
X denotes:
(i) a ##STR27## group in which:
R.sub.5 and R.sub.6, which may be identical or different, denote
a hydrogen atom, a straight-chain or branched C.sub.1 -C.sub.12
alkyl group, which may be substituted by one or more halogen atoms,
a C.sub.2 -C.sub.12 straight-chain alkenyl group, a C.sub.3 -C.sub.10
cycloalkyl group or an aryl or aralkyl group corresponding to the
formula: ##STR28## where n ranges from 0 to 4; and
R.sub.7 and/or R.sub.8, independently of one another, denote a
hydrogen atom, a C.sub.1 -C.sub.6 lower alkyl or alkoxy group or
a trifluoromethyl radical; or
R.sub.5 and R.sub.6, together with the nitrogen atom to which they
are bonded, form a saturated or unsaturated heterocycle selected
from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl,
piperidyl, hexamethyleneimino, heptamethyleneimino, octamethyleneimino,
tetrahydropyridinyl, dihydropyridyl, pyrrolyl, pyrazolyl, imidazolyl,
triazolyl, 4-alkylpiperazinyl, morpholino and thiomorpholino; with
the proviso that:
when Y denotes an oxygen atom, R.sub.1 and R.sub.2 denote, independently
of one another, a C.sub.1 -C.sub.8 saturated straight-chain alkyl
radical and do not simultaneously denote the methyl radical when
X denotes dimethylamino; and
when Y denotes an OSO.sub.3.sup..crclbar. group R.sub.2 does not
denote --NH.sub.2 ;
(ii) an --OR, group, in which R.sub.9 denotes a straight-chain
or branched C.sub.1 -C.sub.2 alkyl radical, which is optionally
substituted by one or more halogen atoms, a 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, which is optionally substituted
by 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; or
when Y denotes an oxygen atom, R.sub.2 denotes an --NHR.sub.3 group
as defined above;
(iii) an SR.sub.10 group, in which R.sub.10 has one of the same
meanings as R.sub.9 ;
or a cosmetically or pharmaceutically acceptable acid addition
salt thereof.
17. A compound according to claim 16, which is:
2-methyl-4-amino-6-ethoxypyrimidine 3-oxide;
2-methyl-4-amino-6-(2,4-dimethylphenyl)oxypyrimidine 3-oxide;
2-methyl-4-amino-6-(1-methyl)ethoxypyrimidine 3-oxide;
2-methyl-4-amino-6-butoxypyrimidine 3-oxide;
2-methyl-4-ethoxycarbonylamino-6-piperidinopyrimidine 3-oxide;
2,4-dimethyl-6-piperidinopyrimidine 3-oxide; or
the inner salt of 2,4-dimethyl-6-piperidino-3-sulphoxypyrimidinium
hydroxide.
Hair loss description
The invention relates to compositions intended to be used, in particular
by topical application, for retarding hair loss and for inducing
and stimulating hair growth, containing 2-alkyl-4-aminopyrimidine
(or 2,4-dialkylpyrimidine) 3-oxide derivatives, as well as new 2-alkyl-4-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 anti-hypertensive
agent, but also for its use in the treatment of hair loss, pelade,
desquamative dermatitis and alopecia.
The Applicant has discovered new compositions for the treatment
and the prevention of hair loss, which compositions are used in
particular by topical application and contain a particular family
of compounds derived from 2-alkyl-4-aminopyrimidine 3-oxide or 2,4-dialkylpyrimidine
3-oxide.
The compounds considered by the Applicant are effective for the
regrowth of hair and in particular for inducing and stimulating
hair growth and retarding hair loss and, in contrast to Minoxidil,
have a hypertensive activity which is substantially zero or weaker.
Moreover, these compounds have solubilities in the media customarily
used in cosmetics and in pharmacy which are clearly higher than
those of Minoxidil.
The invention therefore relates to new compositions intended for
the treatment and the prevention of hair loss, containing particular
compounds derived from 2-alkyl-4-aminopyrimidine (or 2,4-dialkylpyrimidine)
3-oxide.
The invention also relates to new 2-alkyl-4-aminopyrimidine 3-oxide
derivatives used in these compositions.
A further subject relates to the use of the compounds according
to the invention for the preparation of a medicament 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 characterised
in that they contain, in a physiologically acceptable medium, at
least one compound corresponding to the following formula: ##STR3##
in which: R.sub.1 denotes a hydrogen atom or a C.sub.1 -C.sub.8
saturated straight-chain alkyl radical;
R.sub.2 denotes a C.sub.1 -C.sub.8 saturated straight-chain alkyl
radical, an --NHR.sub.3 group in which R.sub.3 denotes a hydrogen
atom, or the group --COOR.sub.4, where R.sub.4 represents a C.sub.1
-C.sub.4 straight-chain alkyl radical;
X denotes:
(i) a ##STR4## group in which:
R.sub.5 and R.sub.6, which may be identical or different, denote
a hydrogen atom, a straight-chain or branched C.sub.1 -C.sub.12
alkyl group, which may be substituted by one or more halogen atoms,
a C.sub.2 -C.sub.12 straight-chain alkenyl group, a C.sub.3 -C.sub.10
cycloalkyl group or an aryl or aralkyl group corresponding to the
formula: ##STR5## where n ranges from 0 to 4; and
R.sub.7 and/or R.sub.8, independently of one another, denote a
hydrogen atom, a C.sub.1 -C.sub.6 lower alkyl or alkoxy group or
a trifluoromethyl radical; and
R.sub.5 and R.sub.6, together with the nitrogen atom to which they
are bonded, may form a saturated or unsaturated heterocycle chosen
from the following groups: aziridinyl, azetidinyl, pyrrolidinyl,
piperidinyl, hexamethyleneimino, heptamethyleneimino, octamethyleneimino,
tetrahydropyridyl, dihydropyridyl, pyrrolyl, pyrazolyl, imidazolyl,
triazolyl, 4-alkylpiperazinyl, morpholino and thiomorpholino;
(ii) an --OR.sub.9 group, in which R.sub.9 denotes a straight-chain
or branched C.sub.1 -C.sub.12 alkyl radical, which may be substituted
by one or more halogen atoms, a C.sub.2 -C.sub.12 alkenyl radical,
a C.sub.3 -C.sub.12 cycloalkyl radical, a C.sub.7 -C.sub.12 aralkyl
radical or a phenyl radical, which may optionally be substituted
by 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; or
(iii) an --SR.sub.10 group, in which R.sub.10 has the same meaning
as the radical R.sub.9 defined above; and
Y denotes an oxygen atom or an --OSO.sub.3.sup..crclbar. group.
Amongst the compounds of general formula ( I ), according to the
present invention, in which X denotes a ##STR6## group, the compounds
which are particularly preferred are those for which: R.sub.2 denotes
a methyl radical and X denotes the piperidino group; or
R.sub.2 denotes an --NHR.sub.3 group, in which R.sub.3 has the
meaning mentioned in the definition of formula (I) and X denotes
one of the following amino groups: dimethylamino, diethylamino,
n-butylamino, piperidino, morpholino, 4-methylpiperazinyl, benzylamino
or anilino.
Amongst the compounds of general formula (I), according to the
present invention, in which X denotes the --OR.sub.9 group, the
compounds which are particularly preferred are chosen from those
for which:
R.sub.2 denotes a methyl radical and X denotes the ethoxy group;
or
R.sub.2 denotes the --NHR.sub.3 group, in which R.sub.3 has the
meaning indicated in formula (I) and X denotes the following alkoxy
groups: ethoxy, butoxy, 1-methylethoxy and 2,4-dimethylphenoxy.
When Y denotes an oxygen atom and R.sub.2 denotes the --NHR.sub.3
group, the compounds of formula (I) exist in two tautomeric forms,
in accordance with the equilibrium below: ##STR7##
Depending on the nature of the medium, one of the forms may be
predominant relative to the other.
The compounds of formula (I), according to the present invention,
may be converted into their cosmetically or pharmaceutically acceptable
acid addition salts, such as the salts of sulphuric, hydrochloric,
hydrobromic, phosphoric, acetic, benzoic, salicylic, glycolic, succinic,
nicotinic, tartaric, maleic, pamoic, methanesulphonic, picric and
lactic acids, etc.
Amongst the compounds of general formula (I), some compounds are
known per se and have been described as anti-hypertensive agents
or as synthesis intermediates.
They are, in particular, described in the U.S. Pat. Nos. 3,464,987
and 4,287,338; or cited in the technical literature (Chem. Pharm.
Bull. 29 (1), 98-104 (1981 )).
The new compounds, which constitute another subject of the invention,
correspond to the following formula (I'): ##STR8## in which X, Y,
R.sub.2 and R.sub.1 have the same meanings as those indicated in
formula (I) above, with the proviso that:
1) When X denotes ##STR9## in which R.sub.5 and R.sub.6 have the
same meaning indicated in formula (I);
if Y denotes O, R.sub.1 and R.sub.2 denote, independently of one
another, a C.sub.1 -C.sub.8 saturated straight-chain alkyl group;
and
if Y denotes OSO.sub.3.sup..crclbar., R.sub.2 does not denote NH.sub.2
; and
2) when X denotes OR.sub.9, in which R.sub.9 has the same meaning
as that indicated above, if Y denotes O, R.sub.2 denotes the NHR.sub.3
group as defined above.
The new compounds of formula (I') may be in the form of physiologically
acceptable acid addition salts.
The compounds according to the present invention which correspond
to the general formula (I) are obtained from a pyrimidine 3-oxide
derivative substituted in the 6-position, of following formula (II):
##STR10## in which: R.sub.1 denotes a hydrogen atom or a C.sub.1
-C.sub.8 saturated straight-chain alkyl radical;
R.sub.2 denotes an amino group or a C.sub.1 -C.sub.8 saturated
straight-chain alkyl radical; and
Z denotes a halogen atom chosen from chlorine or bromine, a sulphonate
group, such as tosylate, brosylate or mesylate, or a phenoxy group
substituted by electron-attracting groups such as halogen atoms
or nitro groups.
The compounds of formula (II), depending on the nature of the group
Z, may be synthesised in accordance with the following reaction
scheme: ##STR11## Step 1
The compounds of formula (III) which are hydroxylated in the 6-position
are converted to their halogenated or sulphonated derivatives of
formula (IV) in which Z.sub.1 denotes a halogen atom or a sulphonate
group.
The halogenation methods are conventional and described in the
technical literature (JERRY MARCH, Advanced Organic Chemistry, 3rd
edition, page 593); the halogenating agent most frequently used
is a phosphorus oxyhalide, such as phosphorus oxychloride for the
chlorination.
The sulphonation methods used are conventional and described in
the technical literature (JERRY MARCH, Advanced Organic Chemistry,
3rd edition, page 444). They consist in reacting a sulphonic acid
halide, in the presence of a base, with the compounds of formula
(III).
Step 2:
The compounds of formula (IV) are easily oxidised in the position
para to the Z.sub.1 group by the action of an organic peracid, such
as metachloroperbenzoic acid, in the presence of a protic or aprotic
solvent such as dichloromethane.
Step 3:
The compounds (IV) may be substituted by phenoxy groups Z.sub.2
carrying electron-attracting groups, in accordance with the conventional
methods described in the literature, in particular French Patent
No. 1,513,739 (in particular in the case where R.sub.2 denotes NH.sub.2).
Step 4:
The compounds (V) resulting from step 3 are oxidised in the position
para to the group Z.sub.2 by the action of an organic peracid, in
accordance with the methods described in French Patent No. 1,513,739.
The particular compounds, according to the invention, corresponding
to the formula (IA): ##STR12## in which R.sub.1, R.sub.2, R.sub.5
and R.sub.6 have the meanings indicated in the general formula (I)
above, are obtained by reacting an amine ##STR13## with the compounds
of formula (II).
The reaction is carried out in the presence of a solvent, which
may be an alcohol, preferably ethanol, or of the amine serving as
reagent and solvent at the same time, at a temperature of between
20.degree. and 150.degree. C., in accordance with the processes
described in U.S. Pat. Nos. 3,644,364 and 3,464,987 where Z denotes
a phenoxy group.
The preparation of these compounds may be represented by the following
scheme: ##STR14##
The particular compounds, according to the invention, of formula
(IB) ##STR15## are obtained by reacting a solution of the alcoholate
R.sub.9 O.sup..crclbar. W.sup..sym., in which R.sub.9 has the same
meaning indicated in 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 by electron-attracting
groups.
The Williamson method, as described in European Patent EP-57546,
is applied at a temperature of between 40.degree. and 100.degree.
C.
The preparation of these compounds may be represented by the following
scheme: ##STR16##
The compounds of formula (IB) may be obtained by another process
represented by the following scheme: ##STR17##
This process consists in carrying out a Williamson reaction on
the compound of formula (VI), in which R.sub.2, R.sub.1 and Z have
the same meanings indicated in formula (II), in order to obtain
a derivative alkoxylated in the 6-position of formula (VII). The
latter derivative is then oxidised selectively in the 3-position
by a mild organic peracid, such as metachloroperbenzoic acid or
magnesium monoperphthalate.
The compounds of formula (IB) are, in general, more accessible
by the route of process B.sub.2, in particular for branching of
alcoholates sterically hindered in the 6-position, such as the isopropylate.
The particular compounds, according to the invention, corresponding
to the formula (IC): ##STR18## in which R.sub.1, R.sub.2 and R.sub.10
have the meanings indicated above, are obtained by reacting a thiolate
of formula R.sub.10 S.sup..crclbar. W.sup..sym., in which R.sub.10
and W.sup..sym. have the same meanings as above, with the compounds
of formula (II) in the presence of a solvent chosen from ethers,
preferably ethylene glycol monomethyl or dimethyl ether, at a temperature
of the order of 50.degree. to 150.degree. C.
The reaction is carried out in accordance with the conventional
methods from 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 C: ##STR19##
The particular compounds, according to the invention, of formula
(I), in which Y denotes an oxygen atom, obtained by the various
processes described above, may be converted to their O-sulphate
homologues of formula (ID) defined below, by chemical sulphation,
in accordance with the conventional methods described in the literature
(J. Med. Chem., 1983, 26, p. 1791-1793).
The sulphation reagents used are sulphur trioxide/pyridine, sulphur
trioxide/triethylamine or sulphur trioxide/ethyldiisopropylamine
complexes.
The solvents used are preferably dimethylformamide, acetonitrile,
chloroform or their binary mixtures. 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 preparation of the compounds of formula (ID) thus obtained
may be represented by the following scheme: ##STR20##
The compounds of general formula (I), according to the invention,
in which Y denotes an oxygen atom and R.sub.2 denotes the amino
group --NH.sub.2 may be converted to their carbamate homologues
of formula (IE) as defined below.
The compounds (IE) are prepared in accordance with the conventional
methods from the literature (J. March, Advanced Organic Chemistry,
3rd edition, p.370) by the action of an alkyl chloroformate in the
presence of a tertiary amine such as pyridine, as represented by
the following scheme: ##STR21##
The compounds of formula (IE) are easily hydrolysable in an alcoholic
potassium hydroxide medium and may give rise again to their precursors
of formula (I) in which Y denotes an oxygen atom and R.sub.2 an
amino group --NH.sub.2.
The compounds of formula (IE), according to the invention, may
be intermediates for the synthesis of oxadiazolopyrimidinones having
the formula (VIII) defined below: ##STR22## in which R.sub.1 and
X have the meaning indicated in general formula (I).
The compounds (VIII) are obtained by cyclisation/internal elimination
of the carbamate derivatives of formula (IE), in accordance with
the methods described in the literature (J. C. MULLER, Helvetica
Chimica Acta, Vol. 66, 1983, p. 669-672).
The compounds of formula (VIII) and their cosmetically and pharmaceutically
acceptable acid addition salts are new and constitute another subject
of the invention. They may receive various applications and in particular
in the use for the treatment and the prevention of hair loss and
the stimulation of hair regrowth.
The compositions according to the present invention, containing
at least one compound corresponding to the formula (I), or one of
its physiologically acceptable acid addition salts, in a physiologically
acceptable media may be applied in the cosmetics or pharmaceutical
field, in particular by topical application. They are intended for
the treatment and the prevention of hair loss, and in particular
of pelade or alopecia, as well as desquamative dermatites, and the
stimulation of hair regrowth.
These compositions may contain, as physiologically acceptable medium,
any medium which is suitable for topical application, either in
cosmetics or in pharmacy, and which is compatible with the active
substance.
The compounds according to the invention may be present in this
medium either in the dissolved state or in the dispersed state,
in particular in micronised form.
The compositions intended to be used in pharmacy are in the form
of an ointment, dye, cream, pomade, powder, patch, impregnated buffer,
vesicular solution, emulsion or 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 in concentrations of between 0.1 and 10% by weight,
and in particular of between 0.2 and 5% by weight.
The cosmetic compositions are, in particular, intended to be used
in the form of a lotion, gel, soap, shampoo, aerosol or foam and
contain, in a cosmetically acceptable excipient, at least one compound
of formula (I) or one of its acid addition salts.
The concentration of these compounds of formula (I) in these compositions
is preferably between 0.01 and 5% by weight and in particular between
0.05 and 3% by weight.
The compositions according to the invention may contain various
additives customarily used in cosmetics or in pharmacy and in particular
active substances such as hydrating agents, such as thiamorpholinone
and its derivatives or urea; antiseborrheic agents, such as S-carboxymethylcysteine,
S-benzylcysteamine and their derivatives; or thioxolone.
The compounds according to the invention may be combined with compounds
which further improve their activity in respect of hair regrowth
and/or retardation of hair loss, such as the following compounds:
nicotinic acid esters, and amongst these more particularly the
C.sub.1 -C.sub.6 alkyl nicotinates and in particular methyl nicotinate
or benzyl nicotinate;
steroid and non-steroid anti-inflammatory agents well known in
the state of the art, and in particular hydrocortisone, its salts
and its derivatives, and niflumic acid;
retinoids, and more particularly t-transretinoic acid, which is
also termed tretinoin, isotretinoin, retinol or vitamin A and its
derivatives, such as the acetate, the palmitate or the propionate,
or zinc motretinide, etretinate or t-trans-retinoate;
antibacterial agents chosen more particularly from macrolides,
pyranosides and tetracyclines, and in particular erythromycin;
calcium antagonists, such as, more particularly, cinnarizine and
diltiazem;
hormones, such as estriol or analogues or thyroxine and its salts;
antiandrogenic agents, such as oxendolone, spironolactone or diethylstilbestrol;
and
compounds which capture OH radicals, such as dimethyl sulphoxide.
Compounds such as diazoxide, corresponding to 3-methyl-7-chloro-2H-1,2,4-benzothiadiazine-1,1-dioxide;
spiroxazone, 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 in French Patent 2,581,542, and
more particularly the salicylic acid derivatives carrying an alkanoyl
group having 2 to 12 carbon atoms in the 5-position of the benzene
ring; hydroxycarboxylic or ketocarboxylic acids and their esters,
lactones and their corresponding salts; anthralin or 1,8,9-trihydroxyanthracene,
carotenoids, and 5,8,11,14-eicosatetrainoic or 5,8,11-eicosatriinoic
acids, their esters and amides may also be combined with the compounds
of the invention, optionally in a mixture with the others.
The compounds according to the invention may also be combined with
surfactants, and amongst these in particular those chosen from the
nonionic and amphoteric surfactants.
Amongst the nonionic surfactants, those which will be mentioned
are 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;
the 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 the alkylpolyglycosides of formula:
in which n varies from 8 to 15 inclusive and x from 1 to 10 inclusive.
Amongst the amphoteric surfactants, those which will be mentioned
more particularly are the amphocarboxyglycinates and the amphocarboxypropionates
defined in the CTFA Dictionary, 3rd edition, 1982, and sold, in
particular, under the name MIRANOL.RTM. by MIRANOL.
The compounds according to the invention may be introduced in excipients
which further improve the activity in respect of regrowth, having,
at the same time, advantageous properties in respect of cosmetic
characteristics, such as ternary volatile mixtures of alkylene glycol
alkyl ether, in particular C.sub.1 -C.sub.4 -alkylene glycol or
dialkylene glycol C.sub.1 -C.sub.4 -alkyl ether, 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 particularly
ethylene glycol monoethyl ethers, propylene glycol monomethyl ether
or diethylene glycol monomethyl ether.
The compounds according to the invention may also be introduced
into gelled or thickened excipients, such as essentially aqueous
excipients gelled by means of heterobiopolysaccharides, such as
xanthan gum or cellulose derivatives, aqueous-alcoholic excipients
gelled by means of polyhydroxyethyl acrylates or methacrylates,
or essentially aqueous excipients thickened in particular by means
of polyacrylic acids crosslinked by a polyfunctional agent, such
as the Carbopols sold by GOODRICH.
These compositions may also contain preservatives, stabilisers,
pH regulators, agents which modify the osmotic pressure, emulsifiers,
UVA and UVB filters, and antioxidants, such as .alpha.-tocopherol,
butylhydroxyanisole or butylhydroxytoluene.
The physiologically acceptable medium may consist of water or a
mixture of water and a solvent or a mixture of solvents, the solvents
being chosen from the cosmetically or pharmaceutically acceptable
organic solvents and chosen more particularly from C.sub.1 -C.sub.4
lower alcohols, such as ethyl alcohol, isopropyl alcohol or tert-butyl
alcohol, alkylene glycols, alkylene glycol alkyl ethers and dialkylene
glycol alkyl ethers, such as ethylene glycol monoethyl ether, propylene
glycol monomethyl ether and diethylene glycol monomethyl ether.
The solvents, when they are present, 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 with the
aid of thickeners customarily used in cosmetics or in pharmacy,
and the heterobiopolysaccharides, such as xanthan gum, scleroglucans,
cellulose derivatives, such as cellulose ethers, and acrylic polymers,
which may or may not be crosslinked, may be mentioned more particularly.
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.
The invention also relates to a process for the cosmetic treatment
of hair or the scalp, consisting in applying thereto at least one
composition as defined above, with a view to improving the appearance
of the hair.
Another subject of the invention consists in the use of the composition
containing the compounds of formula (I) defined above, for the preparation
of a medicament having the effect of inducing or stimulating hair
growth and retarding hair loss.
The treatment consists in the main in applying the composition
as defined above to the alopecic zones of the scalp of an individual.
The preferred method of application consists in applying 1 to 2
g of the composition to the alopecic zone at a rate of one to two
applications per day, for 1 to 7 days per week and continuing this
treatment for a period of 1 to 6 months.
The compositions may, in particular, be used in the treatment of
pelade, hair loss and desquamative dermatites.
The following examples are intended to illustrate the invention
without, however, having a limiting character. |