Disclosed herein are a method of inhibiting hair growth, which comprises administering an inhibitor of elastase-like enzymes or a neutral endopeptidase inhibitor, and use of an inhibitor of elastase-like enzymes or a neutral endopeptidase inhibitor for the preparation of a hair-growth inhibitor.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide a method of inhibiting hair growth, by which the growth of body hair can be effectively inhibited to reduce the number of removal treatments of the body hair.

In view of the foregoing circumstances, the present inventors have carried out an extensive investigation. As a result, it has been quite surprisingly found that inhibitors of elastase-like enzymes which digest elastin known as a structural protein in the artery, tendon, skin or the like, and inhibitors of neutral endopeptidases that are enzymes which digest opioid peptides such as enkephalin, and neuropeptides such as substance P and bradykinin have an excellent inhibitory effect on hair growth, thus leading to completion of the present invention.

According to the present invention, there is thus provided a method of inhibiting hair growth, which comprises administering an inhibitor of elastase-like enzymes or a neutral endopeptidase inhibitor.

According to the present invention, there is also provided use of an inhibitor of elastase-like enzymes or a neutral endopeptidase inhibitor for the preparation of a hair-growth inhibitor.

According to the present invention, an excellent inhibitory effect on hair growth can be achieved, and hair-growth inhibitors high in safety for the human body can also be provided.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As the inhibitor of elastase-like enzymes useful in the practice of the present invention, is preferred an elastase inhibitor, particularly, an inhibitor of elastase-like enzymes derived from a dermoepidermal fibroblast. Such inhibitors include substances which exhibit an inhibitory activity of at least 50% at 1 mM in an enzyme activity-measuring system making use of an enzyme solution extracted from, for example, cultured human fibroblasts with a 0.1% Triton X-100/0.2 M Tris-hydrochloric acid buffer solution (pH: 8.0) and containing N-succinyl-Ala-Ala-Ala-p-nitroanilide as a substrate.

As the neutral endopeptidase inhibitor useful in the practice of the present invention, is preferred an inhibitor of a neutral endopeptidase derived from a dermoepidermal fibroblast. Such inhibitors include substances which exhibit an inhibitory activity of at least 50% at 1 mM in an enzyme activity-measuring system making use of an enzyme solution extracted from, for example, cultured human fibroblasts with a 0.1% Triton X-100/0.2 M Tris-hydrochloric acid buffer solution (pH: 8.0) and containing glutaryl-Ala-Ala-Phe-4-methoxy-2-naphthylamine as a substrate in an MES (2-morpholino-ethane sulfonic acid) buffer solution (100 mM, pH: 6.5) to which sodium chloride (300 mM) has been added.

Examples of such elastase-like enzyme inhibitors or neutral endopeptidase inhibitors include phosphonic acid derivatives, mercaptopropionamide derivatives and salts thereof.

The phosphonic acid derivatives include compounds represented by the following general formula (1): ##STR1##
wherein R¹ is a hydrogen atom, a hydroxyl group, a hydrocarbon group which may be substituted, or a sugar residue which may be substituted, R² is a hydrogen atom, a hydrocarbon group which may be substituted, or a sugar residue which may be substituted, and R³ is a hydrogen atom or a —CH(R⁴)COOH (in which R⁴ is a hydrogen atom or a hydrocarbon group which may be substituted), and salts thereof.

In the formula (1), the hydrocarbon groups which are represented by R¹, R² and R⁴ and may be substituted may be either saturated hydrocarbon groups or unsaturated hydrocarbon groups, and examples thereof include alkyl, alkenyl, alkynyl, cyclic alkyl, cyclic alkenyl, aromatic hydrocarbon and aralkyl groups. These hydrocarbon groups preferably have 1 to 24 carbon atoms, particularly 1 to 18 carbon atoms.

Of the hydrocarbon groups represented by R¹, R² and R⁴, the alkyl, cyclic alkyl, aromatic hydrocarbon and aralkyl groups are preferred. The alkyl groups are preferably linear or branched alkyl groups having 1 to 12 carbon atoms, with n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and isoamyl groups being more preferred. The cyclic alkyl groups are preferably 5- to 7-membered alicyclic alkyl groups, with cyclopentyl and cyclohexyl group being more preferred. The aromatic hydrocarbon groups are preferably aromatic hydrocarbon groups having 6 to 14 carbon atoms, such as phenyl and naphthyl groups. The aralkyl groups are preferably alkyl groups having 1 to 5 carbon atoms, which have been substituted by an aromatic hydrocarbon group having 6 to 12 carbon atoms, and examples thereof include 2-phenylethyl (=phenethyl), 2-(1-naphthyl)ethyl and 2-(2-naphthyl)ethyl groups.

Examples of atoms or groups which may be substituted on the hydrocarbon groups represented by R¹, R² and R⁴ include halogen atoms, a hydroxyl group, alkoxyl groups, acyl groups, an amino group which may be protected, and heterocyclic groups. The halogen atoms include chlorine, bromine and iodine atoms. The alkoxyl groups are preferably alkoxyl groups having 1 to 12 carbon atoms, and examples thereof include methoxy, ethoxy and isopropoxy groups. The acyl groups are preferably alkanoyl groups having 1 to 12 carbon atoms, and examples thereof include acetyl, propionyl and butyryl groups. Examples of the amino group which may be protected include amino, C_1-8-acylamino and C_1-6-alkylamino di-(C_1-6-alkyl)amino groups. The heterocyclic groups are preferably 5- to 14-membered monocyclic or fused ring groups having, as heteroatom(s), 1 to 3 nitrogen, oxygen and/or sulfur atoms, and examples thereof include pyridyl, pyridazinyl, furyl, thienyl, indolyl, thiazolyl, imidazolyl, benzofuryl and benzothienyl groups.

The sugar residues include monosaccharide residues and oligosaccharide residues. Examples of groups which may be substituted on these sugar residues include alkyl, acyl and aralkyl groups. Examples of the alkyl, acyl and aralkyl groups include the same C_1-12 alkyl, C_1-6 acyl and C_6-12-aryl-C_1-6-alkyl groups as mentioned above.

These phosphonic acid derivatives can be prepared in accordance with, for example, the process described in Japanese Patent Application Laid-Open No. 105698/1993.

The mercaptopropionamide derivatives include, for examples, compounds represented by the following general formula (2): ##STR2##
wherein R⁵ is a hydrogen atom or an acyl group, R⁶ is a hydrogen atom or a hydrocarbon group which may be substituted, R⁷ is a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or an acyl group, and n is a number of 1 to 20.

In the formula (2), the acyl groups represented by R⁵ and R⁷ include alkanoyl groups and arylcarbonyl groups. The alkanoyl groups are preferably alkanoyl groups having 1 to 12 carbon atoms, and examples thereof include acetyl, propionyl and butyryl groups. The arylcarbonyl groups are preferably having 7 to 15 carbon atoms, and examples thereof include benzoyl, substituted benzoyl, naphthylcarbonyl and substituted naphthylcarbonyl groups. Examples of groups or atoms substituted on the benzoyl and naphthylcarbonyl groups include C_1-6 alkyl groups, C_1-6 alkoxyl groups, halogen atoms, an amino group, a hydroxyl group and C_1-6 alkanoyloxy groups. n is preferably 1 to 6, more preferably 1 or 2.

The hydrocarbon groups which are represented by R⁶ and R⁷ and may be substituted include the same groups as those mentioned above as to R¹, R² and R⁴.

The heterocyclic group represented by R⁷ is preferably a 5- to 14-membered monocyclic or fused ring group having, as heteroatom(s), 1 to 3 nitrogen, oxygen and/or sulfur atoms, and examples thereof include pyridyl, pyridazinyl, furyl, thienyl, indolyl, thiazolyl, imidazolyl, benzofuryl, benzothienyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl groups. Examples of atoms or groups which may be substituted on the heterocyclic group include halogen atoms, a hydroxyl group, alkoxyl groups, acyl groups and an amino group which may be protected. Specific examples of these substituents include the same substituents as the substituents of the hydrocarbon groups mentioned above as to R¹, R² and R⁴.

The alkoxycarbonyl group represented by R⁷ includes alkoxycarbonyl groups the alkoxy moiety of which has 1 to 12 carbon atoms, and specific examples thereof include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and butoxycarbonyl groups.

These mercaptopropionamide derivatives can be prepared in accordance with, for example, the process described in Japanese Patent Application Laid-Open No. 24354/1982. Incidentally, these mercaptopropionamide derivatives are known to have an inhibitory effect on mammalian collagenases, but not known at all to have an inhibitory effect on elastase-like enzymes.

The phosphonic acid derivatives and mercapto-propionamide derivatives may be used in the form of pharmaceutically acceptable salts or hydrates. Examples of the salts include alkali metal salts, alkaline earth metal salts, organic amine salts and amino acid salts. Examples of the alkali metal salts include the sodium salt and potassium salt. The examples of the alkaline earth metal salts include the calcium salt and magnesium salt. Examples of the organic amine salts include the ammonium salts, methylamine salt, triethylamine salt and pyridinium salt. Examples of the amino acid salts include the arginine salt, lysine salt and histidine salt. The alkali metal salts and amino acid salts are more preferred. As sites at which a salt is formed, may be mentioned the moieties of the phosphonic acid residue and carboxyl group in the phosphonic acid derivatives and the moieties of the thiol group and carboxyl group in the mercaptopropionamide derivatives. In the case where a salt is formed, the salt may be formed at both or one of these residues.

No particular limitation is imposed on the hair-growth inhibitor useful in the practice of the present invention. However, it is preferably used in the form of an external skin-care composition, particularly, a cosmetic composition related to hair removal, depilation or shaving. Specific examples of such a cosmetic composition include hair removers in the form of paste, cream or aerosol, depilatories in the form of wax, gel or sheet, after-treatment compositions used for a treatment after hair removal or depilation, such as lotion and cream, antiperspirant and deodorant cosmetics such as deodorant lotion, deodorant powder, deodorant spray and deodorant stick, treatment compositions before shaving, such as pre-shave lotion, shaving compositions such as shaving cream, and treatment compositions after shaving, such as after-shave lotion.

It is preferred that the amount of the active ingredient incorporated into the hair-growth inhibitor according to the present invention be generally 0.0001 to 10% by weight, particularly, 0.001 to 3% by weight based on the total weight of the inhibitor from the viewpoints of the inhibitory effect on hair growth, profitability, etc.

In the hair-growth inhibitor according to the present invention, various optional ingredients commonly used for cosmetics, quasi-drugs and drugs may be suitably incorporated as needed so far as no detrimental influence is thereby imposed on the effects of the present invention. Examples of such optional ingredients include purified water, ethanol, oily substances, moisturizers, thickeners, preservatives, emulsifiers, medicinally-effective agents, powders, ultraviolet absorbents, pigments, perfume bases and emulsion stabilizers.
 

Claim 1 of 6 Claims

1. A method of inhibiting hair growth, which comprises topically administering to an affected area of a subject in need thereof a neutral endopeptidase inhibitor having a structure according to Formula (1): ##STR11## (see Original Patent)

wherein R1 is a hydrogen atom, a hydroxyl group, a hydrocarbon group which may be substituted, or a sugar residue which may be substituted, R2 is a hydrogen atom, a hydrocarbon group which may be substituted, and R3 is a hydrogen atom or a CH(R4)COOH. in which R4 is ahydrogen atom or a hydrocarbon group which may be substituted; and salts thereof.

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