JP2000351716A - Hair occurrence suppressing agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a hair growth suppressing agent capable of effectively suppressing the growth of hair and reducing the number of hair removal treatment times by making the hair growth suppressing agent include a specific enzyme as an active ingredient. SOLUTION: This suppressing agent comprises a neutral endopeptidase inhibitor as an active ingredient. An inhibitor against a neutral endopeptidase derived from a dermal fibroblast is preferable as the inhibitor. Especially a malonamide derivative of formula I [R1 is H, an alkyl or the like; R2 is H, a (substitute) alkyl or the like; R3 is H, an alkyl or the like; R4 is H, a (substitute) alkyl or the like; R5 is OH, an alkoxy or the like; n is 0-5] (e.g. a compound of formula II), etc., are preferable as the inhibitor. The amount of the inhibitor is preferably 0.0001-40 wt.%. The hair occurrence supressing agent containing the inhibitor is made into a form of skin preparation for external use. The suppressing agent can be formulated with various arbitrary components generally useful in cosmetics, etc., so long as the effects of the suppressing agent are not impaired.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a hair growth inhibitor.
More specifically, the present invention relates to a hair growth inhibitor capable of effectively suppressing hair growth on feet and arms.

[0002]

2. Description of the Related Art Although hair and body hair biologically protect important organs such as the head, chest, limbs, etc., as protective means such as clothes and protective equipment appear and develop, body hair will grow. The role of organ protection has become less important.

[0003] In general, while it is desired that the hair is rich, in recent years, there is an increasing tendency that the hair, especially in the limbs and the like, should not have an aesthetic appearance. Has been developed and used.
Specifically, a mechanical removal method using a shaver, a hair remover, or the like, a method of removing body hair from a hair root using a hair remover, a method of removing body hair by a chemical action using a hair remover, and the like can be given. .

[0004]

However, these hair removal methods involve physical or chemical irritation to the skin, and although there are some differences depending on the hair removal method, the effect of hair removal is small. There is a limit to sustainability.
For this reason, after a certain period of time, the hair removal processing must be performed again, and reduction of the hair removal processing is desired.

Accordingly, it is an object of the present invention to provide a hair growth inhibitor which can effectively suppress the growth of body hair and reduce the number of hair removal treatments.

[0006]

Means for Solving the Problems The present inventors examined the relationship between dermal fibroblast-derived neutral endopeptidase activity and the growth of body hair, and found that neutral endopeptidase activity was inhibited. They found that hair growth could be suppressed.

That is, the present invention provides a hair growth inhibitor containing a neutral endopeptidase inhibitor as an active ingredient.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Neutral endopeptidase is an enzyme that degrades opioid peptides such as enkephalin and neuropeptides such as substance P and bradykinin. This inhibitor is useful as a substitute for morphine-based substances, that is, an analgesic. However, there is no report suggesting a relationship between this enzyme activity and hair growth.

The neutral endopeptidase inhibitor used in the present invention is preferably an inhibitor against neutral endopeptidase derived from dermal fibroblasts. Such inhibitors include, for example, 0.1% Triton X-100 / 0.2M Tris-HCl buffer (pH
8.0), and sodium chloride (3
MES buffer (100 mM, pH 6.
In 5), a substance showing 50% or more inhibitory activity at 1 mM in an enzyme activity measurement system using glutaryl-Ala-Ala-Phe-4-methoxy-2-naphthylamine as a substrate.

[0010] Examples of the neutral endopeptidase inhibitor include compounds represented by the following general formulas (1) to (7).

(A) A malonic acid amide derivative represented by the general formula (1) or a salt thereof.

[0012]

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Wherein R ¹ represents a hydrogen atom, an alkyl group, an alkenyl group or an aralkyl group; R ² represents a hydrogen atom,
Or an alkyl, alkenyl or aralkyl group which may have a substituent; R ³ represents a hydrogen atom, an alkyl group or an alkenyl group, or forms a heterocyclic ring together with R ⁴ together with an adjacent nitrogen atom; R ⁴ represents a hydrogen atom or an optionally substituted alkyl, alkenyl or aralkyl group, or may form together with R ³ the above-mentioned heterocyclic ring; ⁵ is a hydroxyl group,
Represents an alkoxy group, an alkenyloxy group or an amino acid residue; n represents an integer of 0 to 5]

(B) A hydroxamic acid derivative represented by the general formula (2) or a salt thereof (JP-A-58-77852)

[0015]

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(In the formula, Ar ¹ represents a phenyl group which may have a substituent, R ⁶ represents a hydrogen atom, an alkyl group or a methylthioalkyl group, and Z represents a hydroxy group, an alkoxy group, an aralkyloxy group. Group, phenoxy group, amino group, alkylamino group or dialkylamino group)

(C) A mercaptopropionylamide derivative represented by the general formula (3) or a salt thereof (JP-A-60-1)
No. 366554).

[0018]

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[0019] (wherein, R ⁷ represents a hydrogen atom or an acyl group, R ⁸ is aralkyl or heteroaralkyl group, R ⁹ represents a hydrogen atom, an alkyl group, an aralkyl group, or heteroaralkyl group, R ¹⁰ Represents a hydroxy group, an alkoxy group, an aralkyloxy group, a heteroaralkyloxy group, an amino group, an alkylamino group or a dialkylamino group, and m represents a number of 1 to 15.)

(D) N-substituted butyramide derivative represented by the general formula (4) or a salt thereof (JP-A-61-50246)
No. 8).

[0021]

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Wherein A and B are hydroxymethyl groups,
Carboxyl group, esterified carboxyl group,
A rubamoyl group or an N-substituted carbamoyl group;¹¹
And R ¹²Is an alkyl group, aryl group, heteroaryl group
Or an aralkyl group, and Y may have a substituent.
Represents an alkylene group)

(E) a hydroxamic acid derivative represented by the general formula (5) or a salt thereof (JP-A-63-101353);
issue).

[0024]

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[0025] (wherein, R ¹³ represents a hydrogen atom or an acyl group, R ¹⁴ and R ¹⁶ represents a hydrogen atom, an alkyl group or an aralkyl group, R ¹⁵ represents a CONH or NHCO, R ¹⁷
Represents a hydrogen atom or an amino group, R ¹⁸ is a hydroxy group,
Represents an alkoxy group, an amino group, or an N-substituted amino group)

(F) Dipeptides represented by the general formula (6).

[0027]

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[In the formula, R ¹⁹ may represent a hydrogen atom or an alkyl group, or may form a heterocycle together with R ²⁰ together with an adjacent nitrogen atom; R ²⁰ represents a hydrogen atom or a substituent. May represent an alkyl group which may be substituted or an aralkyl group which may have a substituent, or may form together with R ¹⁹ the above-mentioned heterocyclic ring; R ²¹ represents a hydrogen atom, an alkyl group,
Represents an alkenyl group or an aralkyl group; l represents an integer of 0 to 4]

(G) Dipeptides represented by the general formula (7).

[0030]

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(Wherein R ²² and R ²³ represent a hydrogen atom, an alkyl group or an aralkyl group)

In the above formulas (1) to (7),
Group, alkoxy group, alkyloxy group, methylthioal
The alkyl moiety such as a kill group preferably has 1 to 6 carbon atoms.
As the aralkyl group, phenyl-C_1-6Alkyl group
preferable. Heteroaralkyl groups include heteroaryl
Le-C_1-6Alkyl groups are preferred, especially pyridyl-C_{1 -6}
Alkyl group, pyrimidinyl-C_1-6Alkyl group, purine
-C_1-6Alkyl groups and the like are preferred. As an alkylene group
Is preferably an alkylene group having 1 to 8 carbon atoms. Aryl group
Are preferably a phenyl group and a naphthyl group. Aralki
Phenyl-C_1-6Alkyl groups are preferred
New Heteroaryl as a heteroaralkyloxy group
Le-C_1-6Alkyloxy groups are preferred and pyridyl-C
_1-6Alkyloxy group, pyrimidinyl-C_1-6Alkylo
Xy group, Purine-C_1-6Alkyloxy groups are particularly preferred
No. The alkenyl group preferably has 2 to 6 carbon atoms.
No. Substituents such as alkyl, aralkyl and phenyl groups
Represents a carboxy group, a halogen atom, an alkoxy group
And the like. Also, R^ThreeAnd R^FourOr R¹⁹And R ²⁰But one
Heterocycles formed by tying a pyrrolidine ring and pipe
And a lysine ring.

Of the above, malonamide derivatives of the general formula (1) and dipeptides of the general formulas (6) and (7) are particularly preferred.

The alkyl group or alkenyl group represented by R ¹ and R ³ in the general formula (1) includes those having 1 to 8 carbon atoms, particularly those having 1 to 4 carbon atoms, and those having 1 to 4 carbon atoms. preferable. Among them, methyl group, ethyl group,
An n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a t-butyl group is particularly preferred. Examples of the aralkyl group include a phenylalkyl group, a biphenylalkyl group, and a naphthylalkyl group. Of these, a phenyl-C _1-6 alkyl group is preferable, and a benzyl group is more preferable. R ¹ is a hydrogen atom, carbon number 1-8
And a phenyl-C _1-6 alkyl group are particularly preferred. R ³ is most preferably a hydrogen atom.

R ² and R ⁴ are preferably a hydrogen atom, a linear or branched alkyl or alkenyl group having 1 to 12 carbon atoms or an aralkyl group. Among them, a hydrogen atom or a linear or branched alkyl or alkenyl group having 3 to 6 carbon atoms is more preferable, and among them, a hydrogen atom, an n-propyl group, an isopropyl group, an isobutyl group,
A tert-butyl group is particularly preferred. Examples of the aralkyl group include a phenylalkyl group and a naphthylalkyl group. Of these, a phenyl-C _1-6 alkyl group is preferable, and a benzyl group and a phenethyl group are more preferable.

Examples of the heterocyclic ring formed by R ³ and R ⁴ together include a pyrrolidine ring and a piperidine ring, and a pyrrolidine ring is preferred.

As the alkoxy group or alkenyloxy group for R ^5, an alkoxy or alkenyloxy group having 1 to 8 carbon atoms, particularly 1 to 4 carbon atoms,
An alkoxy group of 4 is preferred. Examples of the amino acid residue include essential amino acid residues. Here, the amino group of the amino acid and the carbonyl group in the general formula (1) have an amide bond. R ⁵ is a hydroxyl group or a group having 1 to 1 carbon atoms.
The alkoxy group of 4 is preferable, and a hydroxyl group, a methoxy group, an ethoxy group, an n-propyloxy group, an isopropyloxy group, an n-butyloxy group, an isobutyloxy group, and a t-butyloxy group are particularly preferable. n is most preferably 0 or 1.

In the general formula (6), R ¹⁹ is preferably a hydrogen atom. R ²⁰ represents a hydrogen atom, a methyl group, an isopropyl group, an isobutyl group, a t-butyl group, a benzyl group,
Phenethyl, carboxymethyl and carboxyethyl groups are preferred. R ²¹ is preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group, or a benzyl group. n is preferably 0, 1 or 2.

In the general formula (7), R ²² is preferably a hydrogen atom, and R ²³ is preferably a hydrogen atom or a methyl group.

The salts of the compounds of the general formulas (1) to (7) include alkali metal salts, alkaline earth metal salts, amine salts,
Examples include amino acid salts and acid addition salts. Preferred are alkali metal salts and amino acid salts. The general formula (1)
The compounds of (7) to (7) may have optical activity, and the configuration may be any of R and S, and may be a racemic form. Also,
The compound may be in the form of a hydrate.

Among the compounds of the general formula (1), particularly preferred compounds include the following.

[0042]

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The compound represented by the general formula (1) can be prepared, for example, by the method of Nakano et al. (Chem. Lett., 505-8 (199)
0)).

[0044]

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(R ^{1 to} R ⁵ , n are the same as described above) That is, malonic acid half ester (2) and amino acid ester (3) are reacted in the presence of a dehydrating condensing agent. If necessary, a base such as sodium hydroxide is reacted to obtain the desired product. The compound represented by the general formula (1) is represented by the following formula:
Katsuki et al. Method (Bull. Chem. Soc. Jpn., 49, 3287-3)
290 (1976)).

[0046]

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(R ^{1 to} R ⁵ , n are the same as described above) That is, malonic acid half ester chloride (4) and amino acid ester (3) are reacted in the presence of a base.
If necessary, an alkylation reaction with an alkyl halide or a hydrolysis reaction with a base such as sodium hydroxide is performed to obtain a target product.

Examples of the dipeptides represented by the general formula (6) include Phe-Gly, Phe-β-Ala, Ph
e-Phe, Phe-Leu, Phe-Ala, Phe
-Asp and the like. These are described, for example, in K. Ien
aga, K .; Higashihara and H .; K
imura, Chem. Pharm. Bull. , 3
5 , 1249-1254 (1987). Examples of the dipeptide represented by the general formula (7) include Asp-Phe-OMe (aspartame) and Asp-Phe. As these compounds of the general formulas (6) and (7), commercially available products can also be used.

The hair growth inhibitor of the present invention is not particularly limited, but is preferably in the form of an external preparation for the skin, in particular, a cosmetic for hair removal, depilation or shaving. Specific examples of such cosmetics include pastes, creams, hair removers such as aerosols, waxes, gels,
Depilatory agent in sheet form, lotion used for depilation or post-treatment of depilation, post-treatment fee such as cream, deodorant lotion, deodorant powder, deodorant spray,
Examples include anti-perspirant and deodorant cosmetics such as deodorant sticks, pre-shave treatments such as pre-shave lotion, shavings such as shaving cream, and post-shave treatments such as after-shave lotions.

The amount of the neutral endopeptidase inhibitor in the hair growth inhibitor of the present invention is usually preferably 0.0001 to 40% by weight from the viewpoints of hair growth inhibitory effect, economy and the like. 0.001 to 10% by weight is particularly preferred.

In the hair growth inhibitor of the present invention, various optional components usually used in cosmetics, quasi-drugs, pharmaceuticals and the like can be appropriately compounded as needed, as long as the effects of the present invention are not impaired. Such optional components include, for example, purified water, ethanol, oily substances, humectants, thickeners, preservatives, emulsifiers, medicinal ingredients, powders, ultraviolet absorbers, pigments,
Perfumes, emulsion stabilizers and the like can be mentioned.

[0052]

EXAMPLES Synthesis Example 1 Synthesis of Compound 1 16.05 g (114 mm) of glycine ethyl ester hydrochloride
ol) and 23.27 g (228 mmol) of triethylamine
Was dissolved in 50 mL of chloroform, and cooled to 5 ° C. with ice cooling. Ethylmalonic chloride 10.0 at the same temperature
0 g (57 mmol) was added dropwise, and after completion of the addition, the disappearance of the raw materials was confirmed by thin-layer chromatography. After that, a 5% phosphoric acid aqueous solution was added to terminate the reaction. The organic layer was washed with distilled water and saturated saline, and then dried by adding anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate-n-hexane. The solvent was distilled off, and 9.40 g of Compound 1 (yield 7) was obtained.
6%). NMR (DMSO-d ₆ ) δ: 2.48-2.51 (m, 6H), 3.30 (d, 2H, J = 9 Hz),
3.85 (d, 2H, J = 6Hz), 4.02-4.20 (m, 4H), 8.49 (t, 1H, J = 5H
z).

Synthesis Example 2 Synthesis of Compound 2 5.00 g (23.0 mmol) of Compound 1 was dissolved in 50 mL of anhydrous tetrahydrofuran. This was mixed with 1.10 g (27.6 mmol) of sodium hydride in tetrahydrofuran 3
It was added to a solution suspended in 0 mL and heated to 50 ° C. Further, 3.74 g (21.9 mmol) of benzyl bromide was slowly added dropwise, and the mixture was stirred at the same temperature for 3 hours to complete the reaction. After cooling, a 5% aqueous solution of phosphoric acid was added to the reaction solution, and the mixture was extracted with 300 mL of ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline. Anhydrous sodium sulfate was added and dried. Then the solvent was distilled off and the residue was subjected to column chromatography to give ethyl acetate-
Elution was carried out with a mixed solvent of n-hexane. The solvent was distilled off to obtain 3.89 g of compound 2 (55% yield). NMR (DMSO-d ₆ ) δ: 1.16 (t, 1H, J = 7 Hz), 2.93-3.19 (m, 2H),
3.71 (t, 1H, J = 7Hz), 3.80 (d, 2H, J = 6Hz), 4.06 (q, 4H, J = 7H
z), 7.13-7.29 (m, 5H), 8.61 (t, 1H, J = 6Hz).

[Synthesis Example 3] Synthesis of Compound 3 3.00 g (9.8 mmol) of Compound 2 was added to methanol 30
Dissolved in mL. 1.20 g of potassium hydride (21.5 mm
ol) in 10 mL of water was added, and the mixture was stirred at room temperature for 2 hours to complete the reaction. After distilling off methanol under reduced pressure, 5
% Phosphoric acid aqueous solution was added, and the resulting crystals were filtered. The crystals were washed with water and dried under reduced pressure to give 2.17 g of Compound 2 (yield 88
%). NMR (DMSO-d ₆ ) δ: 2.90 (m, 2H), 3.59 (t, 1H, J = 7 Hz), 3.74
(d, 2H, J = 6Hz), 7.12-7.32 (m, 5H), 8.37 (t, 1H, J = 6Hz), 1
2.49 (br.s, 2H).

Synthesis Examples 4 to 6 Compounds 4 to 6 were synthesized according to the methods of Synthesis Examples 1 to 3 using the amino acid esters and alkyl halides shown in Table 1.

[0056]

[Table 1]

Test Example 1 Test for Inhibition of Neutral Endopeptidase Activity of Cultured Human Fibroblasts Normal human fibroblasts commercially available from Dainippon Pharmaceutical Co., Ltd. were subcultured in a DME medium containing 10% fetal bovine serum and subjected to this test. Was served. The cells detached from the Petri dish using a rubber policeman are suspended in a phosphate buffered saline, and the cells are collected using a low-speed centrifuge.
Washed twice. Cells were 0.1% Triton X-100 /
The suspension was suspended in a 0.2 M Tris-HCl buffer (pH 8.0) and sonicated to prepare an enzyme solution. Enzyme activity was measured using MES buffer (1 mM) to which sodium chloride (300 mM) was added.
(100 mM, pH 6.5) 100 μL, 2 μL of enzyme solution, 1 μL of the compound solution, 20 mM glutaryl-Ala-Ala-Phe-4-methoxy-2-methoxy-substrate as a substrate for enzyme activity measurement
Naphthylamine (1 μL) was added, the reaction was carried out at 37 ° C. for 1 hour, and phosphoramidone was added to a final concentration of 0.4 μM to stop the reaction. Aminopeptidase M at a final concentration of 20 mU was added, reacted at 37 ° C. for 15 minutes, and the amount of 4-methoxy-2-naphthylamine generated was measured at a fluorescence spectrophotometer at an excitation wavelength of 340 nm and a fluorescence wavelength of 425 nm. The enzyme activity inhibition rate of the compound was determined. Table 2 shows the results.

[0058]

[Table 2]

[0059] The C ₃ H mice per group Five dorsal hair hair growth inhibition test age 6 weeks by Test Example 2 mice, using an electric clipper and an electric shaver, razor over 2 × 4 cm ² so as not to damage the skin I had hair. Place a sample on the shaved area
The solution was applied twice a day in 100 μL portions for 4 weeks. The test substance was dissolved in a solvent (80% ethanol) and adjusted to the concentration shown in Table 3. Only the solvent was applied to the symmetric group. Three weeks later, in order to observe the regenerated hair, the shaved part was photographed at a fixed magnification, and the ratio of the regenerated hair area (regenerated hair area / shaved area) was compared with the control group using an image analyzer. The hair growth inhibition rate was shown as a relative value (%) when the regenerated hair area ratio of the target group was set to 100. Table 3 shows the results.

[0060]

[Table 3]

From the results shown in Table 3, the compounds of general formulas (1) to (7), which are neutral endopeptidase inhibitors, have excellent hair growth inhibitory effects.

Formulation Example 1 A hair growth inhibiting lotion was manufactured with the following formulation. That is, the component belonging to A was dissolved, and the component belonging to B was dissolved separately. B was added to A and mixed uniformly with stirring to obtain a hair growth suppressing lotion. (% By weight) Polyoxyethylene hydrogenated castor oil 0.8 ethanol 30.0 B. Compound 1, Phe-Phe or Asp-Phe 1.0 Sodium dodecyl sulfate 0.12 Dodecyl methylamine oxide 0.18 Isopropyl alcohol 15.0 Benzyl alcohol 12.0 Glycerin 2.0 Purified water Total balance 100.0

Formulation Example 2 A hair growth-inhibiting aerosol was produced with the following formulation. That is, the components belonging to A were uniformly mixed and put into a container, and B was filled into the container by a conventional method to produce a hair growth suppressing aerosol. (% By weight) Compound 2, Phe-Asp or Asp-Phe 1.0 Cetanol 1.2 Propylene glycol 4.0 Ethanol 8.0 Purified water Balance B. Liquefied petroleum gas (propellant) 4.0 Total 100.0

[0064]

According to the hair growth inhibitor of the present invention, the growth of body hair can be effectively suppressed, and in particular, the removal of body hair from the legs and arms becomes easy.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Yasuhito Suzuki 2606 Kabane-cho, Akaga-cho, Haga-gun, Tochigi Pref. In the Kao Co., Ltd. (72) Inventor Yukihiro Ohashi 2606 Akabane, Kaiga-cho, Haga-gun, Tochigi Prefecture F-term in Kao Corporation Research Laboratory 4C083 AC012 AC072 AC102 AC122 AC152 AC432 AC792 AD411 AD412 CC04 CC31 DD27 EE21 4C084 AA02 AA03 BA44 CA25 DC02 MA13 MA22 MA28 MA63 NA05 NA14 ZA922 ZC202 4C206 AA01 AA02 GA13 GA14 GA26 GA28 MA01 MA04 MA83 ZA92 ZC20

Claims (3)

[Claims] A hair growth inhibitor comprising a neutral endopeptidase inhibitor as an active ingredient. 2. The hair growth inhibitor according to claim 1, wherein the neutral endopeptidase inhibitor is an inhibitor of dermal fibroblast-derived neutral endopeptidase. 3. The hair growth inhibitor according to claim 1, which is an external preparation.