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Hair Loss Patent

Composition intended to be used for retarding hair loss and for inducing and stimulating hair growth, containing 2-alkyl-4-aminopyrimidine (or 24-dialkylpyrimidine) 3-oxide derivatives and new compounds derived from 2-alkyl-4-aminopyrimidine 3-oxide

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.


Photodynamic therapy for the treatment of hair loss
Nutrient composition for preventing hair loss
Compositions and methods for treating hair loss using oximyl and hydroxylamino prostaglandins

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