TWI477287B - Serine derivatives and use for preparing prevention or improvement medicament for chromatosis - Google Patents

Description

Use of a serine derivative and a prophylactic or improving agent for producing a pigmentation

The present invention relates to a skin external preparation suitable for a cosmetic (including a medical external product), and more particularly to a compound represented by the following general formula (1), an isomer thereof, and/or the pharmacology thereof. A preventive or improving agent for pigmentation, which is an acceptable salt, and a skin external preparation containing the component.

Wherein R ₁ represents an unsubstituted or substituted aromatic group; R ₂ represents a hydrogen atom, a straight or branched alkyl group having a carbon number of 1 to 4, and has a carbon number of 1 to 4; A sulfhydryl group of a chain or a branched alkyl chain; R ₃ represents a hydrogen atom or a straight or branched alkyl group having a carbon number of 1 to 4].

Pigmentation, dark spots, liver spots (chloasma hepaticum), and senile pigmentation spots after sun exposure in the skin are caused by the activation of melanocytes present in the skin, and the melanin production is remarkable and hyperactive. As a component having an effect of preventing or improving the occurrence and deterioration of such skin pigmentation problems, ascorbic acid, hydrogen peroxide, colloidal sulfur, glutathione, hydroquinone, catechol, etc. have whitening effects. A compound (whitening agent) is widely known (for example, refer to Non-Patent Document 1 and Non-Patent Document 2), and a skin external preparation containing such an active ingredient is widely used. Now, in terms of the action sequence of compounds known as whitening agents, tyrosinase inhibitory inhibition, tyrosinase-related protein breakdown, and dendritic elongation inhibition in melanocytes have been reported. Inhibition of melanin transfer and other diverse mechanisms of action, but there are target molecules for the respective mechanism of action. In order to function properly for the target molecule and exhibit a high whitening effect, it is useful for organic low molecules in which the target molecules interact appropriately. Moreover, due to the difference in the target molecules, the structural characteristics of the organic low molecules that interact appropriately with the respective target molecules and the chemical structure for maximizing the pharmacological action shown by the organic low molecules are also optimized. For the prevailing. In addition, the current whitening agent research, in addition to the high-effective and selective compounds of the existing target molecules, at the same time for the compound of the molecular function of the complex whitening standard, in addition, a compound with a new action sequence, etc. A whitening agent is expected to have a high whitening effect. In fact, it is hoped that there are useful compounds having various chemical structures or pharmacological properties, and screening has been carried out in connection with compounds having excellent whitening effects, but whitening agents having novel mother nucleus are still desired.

A general term for an organic compound having an amino group and a carboxyl group in an amino acid-based molecule, in particular, an α-amino acid is widely used as a constituent unit of a protein which exhibits various functions in a living body. Alpha-amino acids such as cysteine, arginine, valine, threonine, serine, glycine, etc. present in living organisms, and α-amino acids are included in the constituent elements Peptide derivatives have been reported for a wide variety of physiological activities. With respect to the biological activity of the α-amino acid and its derivatives, anti-aging effects are known only in the field of cosmetics (for example, refer to Patent Document 1), moisturizing action (for example, refer to Patent Document 2), The effects of whitening action (for example, refer to Patent Document 3) and interface activation are combined with cosmetics and the like for the purpose of the effects. Further, in general, such amino acids and derivatives thereof are excellent in solubility, dispersibility, and water solubility, and are expected to have high safety, and blending with cosmetics and the like is widely studied. However, the biological activity of the aforementioned α-amino acid and its derivatives, such as anti-aging, moisturizing or whitening action, is difficult to be fully practicable, and the α-amino acid and its derivatives for improving biological activity are In the case of such an amino acid and its derivative, the moisturizing action of N-methyl serine is known according to the study on the serine derivative (for example, refer to Patent Document 4) The rough skin improvement and the wrinkle reduction effect (for example, refer to Patent Document 5) and the effect of enhancing the melanin production inhibitory effect of glylinin (for example, refer to Patent Document 6). Further, N-benzyl hydrazinine is known to have a moisturizing action (for example, refer to Patent Document 7), wrinkle prevention or improvement (for example, refer to Patent Document 8). However, the above-mentioned serine acid derivative does not express its whitening effect, and the compound represented by the above formula (1), its isomer and/or the pharmacologically acceptable salt thereof have pigmentation. Prevention or improvement is completely unknown.

[Advanced technical literature]

Patent literature

Patent Document 1: JP-A-2004-115438

Patent Document 2: JP-A-2002-087928

Patent Document 3: Japanese Patent Publication No. 05-301811

Patent Document 4: Japanese Patent Publication No. 11-310510

Patent Document 5: JP-A-2001-247443

Patent Document 6: Japanese Patent Publication No. 06-256156

Patent Document 7: JP-A-2006-327972

Patent Document 8: WO2007-013662

Non-patent literature

Non-Patent Document 1: Supervision of Takeda Katsuyuki, "The usefulness of cosmetics, evaluation techniques and future prospects", Pharmacy Daily News (2001)

Non-Patent Document 2: Omori Kazuyuki, FRAGRANCE JOURNAL, Temporary Supplement, No. 14, 1995, 118-126

Summary of invention

The present invention has been made in such a situation to provide a skin external preparation suitable for prevention or improvement of pigmentation.

In view of such a situation, the present inventors have found that the compound represented by the above formula (1) and its isomer are found as a result of continuous efforts to concentrate on the prevention or improvement of a novel pigmentation of a cosmetic (including a medical external product). The present invention is completed by the fact that the pharmacologically acceptable salt of the substance and/or the above is excellent in the prevention or amelioration of the pigmentation. The present invention is as follows.

<1> A preventive or improving agent for pigmentation, which is a compound represented by the following formula (1), an isomer thereof, and/or a pharmacologically acceptable salt thereof:

Wherein R ₁ represents an unsubstituted or substituted aromatic group; R ₂ represents a hydrogen atom, a straight or branched alkyl group having a carbon number of 1 to 4, and has a carbon number of 1 to 4; A sulfhydryl group of a chain or a branched alkyl chain; R ₃ represents a hydrogen atom or a straight or branched alkyl group having a carbon number of 1 to 4].

<2> The preventive or improving agent for pigmentation according to <1>, wherein, in the formula (1), R ₁ represents an unsubstituted group or an aromatic group having the substituent: the carbon number is a straight or branched alkyl group of 1 to 6, an alkoxy group having a linear or branched alkyl chain having 1 to 6 carbon atoms, or a linear or branched alkane having 1 to 6 carbon atoms; An alkylamine group of a base chain, a fluorenyl group having a linear or branched alkyl chain having 1 to 6 carbon atoms, an ester group having a linear or branched alkyl chain having 1 to 6 carbon atoms, a halogen atom or a halogenated alkyl group, a hydroxyl group or an amine group; R ₂ represents a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tertiary butyl group, an ethyl fluorenyl group. And a propyl group or a butyl group; R ₃ represents a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tertiary butyl group.

<3> The preventive or improving agent for pigmentation according to <2>, wherein, in the formula (1), R ₁ represents a phenyl group, a naphthyl group or a biphenyl group which is unsubstituted or has the following substituents. The base is a linear or branched alkyl group having 1 to 6 carbon atoms, an alkoxy group having a linear or branched alkyl chain having 1 to 6 carbon atoms, and having a carbon number of 1 to 6 An alkylamine group of a chain or a branched alkyl chain, a fluorenyl group having a linear or branched alkyl chain having 1 to 6 carbon atoms, or a linear or branched alkane having 1 to 6 carbon atoms. An ester group of a base chain, a halogen atom or a halogenated alkyl group, a hydroxyl group or an amine group; R ₂ represents a hydrogen atom, a methyl group or an ethyl fluorenyl group; and R ₃ represents a hydrogen atom, a methyl group or an ethyl group.

The preventive or improving agent for pigmentation according to any one of <1> to <3> wherein the compound represented by the formula (1) is N-benzylindenyl-serine (Compound 2), N-(p-methylbenzylindenyl)serine (compound 1, 3, 15), N-(p-ethylbenzylidene) serine (compound 7), N-(p-methoxy Benzyl hydrazide)-mine (compound 5), N-(p-fluorobenzyl) serine (compound 4), N-(p-trifluoromethylbenzyl) serine (compound 8) , N-(2-naphthylmethyl) serine (Compound 10), N-(4-phenylbenzylidene) serine (Compound 14), N-(p-methylbenzylidene) silk Methyl amide (compound 6), ethyl N-(p-methylbenzylidene) amide (compound 17), methyl N-(2-naphthylmethyl) amide (compound 12), N-benzylindenyl-O-methylserine (Compound 16), N-(p-methylbenzylindenyl)-O-methylserine (Compound 9), N-(p-methylbenzyl Indenyl)-O-acetyl-serine (Compound 11), N-(2-naphthylmethyl)-O-methylserine (Compound 13), isomers thereof and/or the like A pharmacologically acceptable salt.

<5> A preventive or improving agent for pigmentation, which is a compound represented by the following formula (2), an isomer thereof, and/or a pharmacologically acceptable salt thereof:

Wherein R ₄ represents an unsubstituted or substituted aromatic group (except for an unsubstituted phenyl group); and R ₅ represents a hydrogen atom, a straight or branched alkane having a carbon number of 1 to 4; a fluorenyl group having a linear or branched alkyl chain having a carbon number of 1 to 4; R ₆ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, wherein R ₄ has In the case of a phenyl group of an substituent or an unsubstituted naphthyl group, at least one of R ₅ or R ₆ is other than hydrogen.

<6> The preventive or improving agent for pigmentation according to <5>, wherein, in the formula (2), R ₄ represents an unsubstituted group or an aromatic group having the following substituent (unless, unsubstituted benzene) The substituents are: a linear or branched alkyl group having a carbon number of 1 to 6, an alkoxy group having a linear or branched alkyl chain having 1 to 6 carbon atoms, and having a carbon number of An alkylamino group of a linear or branched alkyl chain of 1 to 6, a fluorenyl group having a linear or branched alkyl chain having 1 to 6 carbon atoms, and a linear chain having 1 to 6 carbon atoms. Or an ester group of a branched alkyl chain, a halogen atom or a halogenated alkyl group, a hydroxyl group or an amine group; R ₅ represents a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, or an Butyl, tert-butyl, ethenyl, propyl or butyl; R ₆ represents a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tertiary A butyl group in which R ₄ is a substituted phenyl group or an unsubstituted naphthyl group, and at least one of R ₅ or R ₆ is a hydrogen atom.

<7> The preventive or improving agent for pigmentation according to <6>, wherein, in the formula (2), R ₄ represents a phenyl group having the following substituent, an unsubstituted or naphthyl group having the following substituents or a combination Phenyl, the substituent is a linear or branched alkyl group having 1 to 6 carbon atoms, an alkoxy group having a linear or branched alkyl chain having 1 to 6 carbon atoms, and having a carbon number of 1 An alkylamino group of a straight or branched alkyl chain of ~6, a fluorenyl group having a linear or branched alkyl chain having 1 to 6 carbon atoms, a linear chain having a carbon number of 1 to 6 or An ester group of a branched alkyl chain, a halogen atom or a halogenated alkyl group, a hydroxyl group or an amine group; R ₅ represents a hydrogen atom, a methyl group or an ethyl fluorenyl group; and R ₆ represents a hydrogen atom, a methyl group or an ethyl group; wherein R ₄ In the case of a substituted phenyl group or an unsubstituted naphthyl group, at least one of R ₅ or R ₆ is other than hydrogen.

<8> A skin external preparation according to any one of <1> to <7>, which is a preventive or improving agent for a pigmentation.

<9> The external preparation for skin according to <8>, which contains 0.0001% by mass to 20% by mass of the preventive or improving agent for the pigmentation with respect to the total amount of the external preparation for skin.

<10> The skin external preparation according to <8> or <9>, which is a cosmetic (including a medical external product).

<11> a compound represented by the following formula (2), an isomer thereof, and/or a pharmacologically acceptable salt thereof,

Wherein R ₄ represents an unsubstituted or substituted aromatic group (except for an unsubstituted phenyl group); and R ₅ represents a hydrogen atom, a straight or branched alkane having a carbon number of 1 to 4; a fluorenyl group having a linear or branched alkyl chain having a carbon number of 1 to 4; R ₆ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, wherein R ₄ has In the case of a phenyl group of an substituent or an unsubstituted naphthyl group, at least one of R ₅ or R ₆ is other than hydrogen.

<12> The compound according to <11>, an isomer thereof, and/or a pharmacologically acceptable salt thereof, wherein R ₄ represents unsubstituted or has the following substituents in the formula (2) The aromatic group (except for the unsubstituted phenyl group), the substituent is a linear or branched alkyl group having a carbon number of 1 to 6, and a straight chain or a branch having a carbon number of 1 to 6. An alkoxy group of an alkyl chain, an alkylamino group having a linear or branched alkyl chain having 1 to 6 carbon atoms, a fluorene having a linear or branched alkyl chain having 1 to 6 carbon atoms An ester group having a linear or branched alkyl chain having a carbon number of 1 to 6, a halogen atom or a halogenated alkyl group, a hydroxyl group or an amine group; and R ₅ represents a hydrogen atom, a methyl group, an ethyl group, or an n-propyl group. Base, isopropyl, n-butyl, isobutyl, tert-butyl, ethenyl, propyl or butyl; R ₆ represents a hydrogen atom, methyl, ethyl, n-propyl, isopropyl And n-butyl, isobutyl or tert-butyl, wherein R ₄ is a substituted phenyl group or an unsubstituted naphthyl group, and at least one of R ₅ or R ₆ is a hydrogen atom.

<13> A compound according to <12>, an isomer thereof, and/or a pharmacologically acceptable salt thereof, wherein, in the formula (2), R ₄ represents a phenyl group having the following substituent, a naphthyl or biphenyl group substituted or having the following substituents: a straight or branched alkyl group having a carbon number of 1 to 6, a linear or branched alkane having a carbon number of 1 to 6. Alkoxy group of a base chain, alkylamino group having a linear or branched alkyl chain having 1 to 6 carbon atoms, fluorenyl group having a linear or branched alkyl chain having 1 to 6 carbon atoms An ester group having a linear or branched alkyl chain having a carbon number of 1 to 6, a halogen atom or a halogenated alkyl group, a hydroxyl group or an amine group; R ₅ represents a hydrogen atom, a methyl group or an ethyl group; and R ₆ represents A hydrogen atom, a methyl group or an ethyl group; wherein R ₄ is a substituted phenyl group or an unsubstituted naphthyl group, at least one of R ₅ or R ₆ is other than hydrogen.

<14> A compound represented by the above formulas (1) and (2), a compound defined by the above <2>, <3>, <4>, <6>, <7>, an isomer thereof, and/or Or such pharmacologically acceptable salts for the prevention or amelioration of pigmentation.

<15> A method for preventing or improving pigmentation, comprising the compound represented by the above formulas (1) and (2), the above <2>, <3>, <4>, <6>, <7> The defined compounds, their isomers and/or such pharmacologically acceptable salts are administered to those essential for the prevention or improvement of pigmentation.

Form for implementing the invention

<Precipitation prevention or improvement agent for essential components in the external preparation for skin of the present invention>

The skin external preparation of the present invention is characterized by containing a compound represented by the above formula (1), an isomer thereof, and/or a pharmacologically acceptable salt thereof. The dye deposition preventing or improving agent of the present invention contains an effect of preventing pigmentation in addition to a pigmentation-preventing effect of lightening or removing a pigment precipitate which has already been formed. The pigment precipitation prevention or improvement agent of the present invention is a compound represented by the above formula (1), an isomer thereof, and/or a pharmacologically acceptable salt thereof, as long as it has a function of preventing or improving pigmentation. The component is not particularly limited as long as it is suitable, and a component having a pigmentation inhibiting action in "Evaluation of Pigment Precipitation Inhibition by Ultraviolet Irradiation Using Colored Tinted Mice", which will be described later, is preferably exemplified. The component having a pigmentation-preventing inhibitory effect in the evaluation of the pigmentation-precipitation inhibition is a component which is considered to have a pigmentation-preventing action in the evaluation substance administration group, and more preferably a control group, as compared with the control group (vehicle control group). In comparison, it is preferable to evaluate a component which is considered to be statistically inferior in the pigmentation inhibition action of the substance administration group.

Wherein, if a compound represented by the formula (1), an isomer thereof, and/or a pharmacologically acceptable salt thereof are recited, wherein R ₁ represents an unsubstituted or substituted aromatic group. R ₂ represents a hydrogen atom, a linear or branched alkyl group having a carbon number of 1 to 4, a fluorenyl group having a linear or branched alkyl chain having 1 to 4 carbon atoms; and R ₃ represents a hydrogen atom or A linear or branched alkyl group having a carbon number of 1 to 4.

R ₁ represents an unsubstituted or substituted aromatic group; and as the substituent on the aromatic group, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, and more preferably a carbon number of 1 to 1 is preferable. An alkyl group having 3; an alkoxy group having an alkyl chain having 1 to 6 carbon atoms; more preferably an alkoxy group having an alkyl chain having 1 to 3 carbon atoms; and an alkyl group having 1 to 6 carbon atoms; An alkylamine group of a chain, more preferably an alkylamine group having an alkyl chain having 1 to 3 carbon atoms; a fluorenyl group having an alkyl chain having 1 to 6 carbon atoms, more preferably having a carbon number of 1 a mercapto group of an alkyl chain of ~3; an ester group having an alkyl chain having 1 to 6 carbon atoms, more preferably an ester group having an alkyl chain having 1 to 3 carbon atoms; a halogen atom or a halogenated alkyl group ( It is preferably a halogenated alkyl group having a carbon number of 1 to 4; a hydroxyl group, an amine group or the like.

Preferable examples of the unsubstituted or substituted aromatic group include phenyl, methylphenyl, ethylphenyl, propylphenyl, butylphenyl and methoxybenzene. , ethoxyphenyl, propoxyphenyl, butoxyphenyl, N-methylaminophenyl, N-ethylaminophenyl, N-propylaminophenyl, N-butyl Aminophenyl, N,N-dimethylaminophenyl, N,N-diethylaminophenyl, N,N-dipropylaminophenyl, N,N-dibutylamine Phenyl, ethyl phenyl, propyl phenyl, butyl phenyl, methoxycarbonyl phenyl, ethoxycarbonyl phenyl, propoxy phenyl phenyl, butoxycarbonyl phenyl, fluorobenzene , chlorophenyl, bromophenyl, trifluoromethylphenyl, hydroxyphenyl, aminophenyl, pyridyl, methylpyridyl, ethylpyridyl, propylpyridyl, butylpyridyl, A Oxypyridyl, ethoxypyridyl, propoxypyridyl, butoxypyridyl, N-methylaminopyridinyl, N-ethylaminopyridyl, N-propylaminopyridinyl, N-butylaminopyridinyl, N,N-dimethylaminopyridinyl, N,N-diethylaminopyridinium Pyridyl, N,N-dipropylaminopyridinyl, N,N-dibutylaminopyridinyl, ethinylpyridinyl, propylpyridylpyridyl, butylpyridylpyridyl, methoxycarbonylpyridinyl, Ethoxycarbonylpyridyl, propoxycarbonylpyridyl, butoxycarbonylpyridinyl, fluoropyridyl, chloropyridyl, bromopyridinyl, trifluoromethylpyridyl, hydroxypyridyl, aminopyridyl, naphthalene , methylnaphthyl, ethylnaphthyl, propylnaphthyl, butylnaphthyl, methoxynaphthyl, ethoxynaphthyl, propoxynaphthyl, butoxynaphthyl, N-methyl Aminonaphthyl, N-ethylaminonaphthyl, N-propylaminonaphthyl, N-butylaminonaphthyl, N,N-dimethylaminonaphthyl, N,N-diethyl Aminonaphthyl, N,N-dipropylaminonaphthyl, N,N-dibutylaminonaphthyl, ethenylnaphthyl, propenylnaphthyl, butanylnaphthyl, methoxycarbonyl Naphthyl, ethoxycarbonylnaphthyl, propoxycarbonylnaphthyl, butoxycarbonylnaphthyl, fluoronaphthyl, chloronaphthyl, bromonaphthyl, trifluoromethylnaphthyl, hydroxynaphthyl, aminylnaphthalene Base, biphenyl, methylbiphenyl, ethylbiphenyl, propylbiphenyl, butyl Biphenyl, methoxybiphenyl, ethoxybiphenyl, propoxybiphenyl, butoxybiphenyl, N-methylaminobiphenyl, N-ethylaminobiphenyl , N-propylaminobiphenyl, N-butylaminobiphenyl, N,N-dimethylaminobiphenyl, N,N-diethylaminobiphenyl, N, N-dipropylaminobiphenyl, N,N-dibutylaminobiphenyl, acetoxybiphenyl, propyl phenyl, butyl phenyl, methoxycarbonyl biphenyl , ethoxycarbonylbiphenyl, propoxycarbonylbiphenyl, butoxycarbonylbiphenyl, fluorobiphenyl, chlorobiphenyl, bromobiphenyl, trifluoromethylbiphenyl, hydroxy linkage Phenyl, aminobiphenyl, etc., among these, phenyl, methylphenyl, ethylphenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl, trifluoro is preferably exemplified. Methylphenyl, naphthyl, biphenyl, and the like.

The number of the substituents of the above-mentioned aromatic group is preferably 0 to 3, more preferably 0 or 1, and the substituent on the aromatic ring may have one or two or more substituents each independently.

The above R ₂ represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a fluorenyl group having a linear or branched alkyl chain having 1 to 4 carbon atoms, and specific examples thereof Examples thereof include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tertiary butyl group, an ethyl fluorenyl group, a propyl fluorenyl group, a butyl fluorenyl group, etc., and more preferably exemplified. Hydrogen atom, methyl group, ethyl hydrazine group.

R ₃ represents a hydrogen atom or a linear or branched alkyl group having a carbon number of 1 to 4, and specific examples thereof include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group. The n-butyl group, the isobutyl group, the tertiary butyl group and the like are more preferably a hydrogen atom, a methyl group or an ethyl group.

Among the compounds represented by the above formula (1), a compound defined by the above <2>, an isomer thereof and/or a pharmacologically acceptable salt thereof, and the like are preferable. A compound represented by the formula (2), an isomer thereof and/or a pharmacologically acceptable salt thereof.

Among the compounds defined in the above <2>, preferred are the compounds defined by the above <3>, the isomers thereof and/or the pharmacologically acceptable salts thereof, and more preferably exemplified. The compound defined as the above <4>, an isomer thereof and/or such a pharmacologically acceptable salt are preferred.

Further, among the compounds represented by the above formula (2), a compound defined by the above <6>, an isomer thereof, and/or a pharmacologically acceptable salt thereof are preferably exemplified as a compound. More preferably, it is a compound defined by the above <7>, an isomer thereof, and/or a pharmacologically acceptable salt thereof.

The compound represented by the above formula (2), the compound defined by the above <6>, the compound defined by the above <7>, the isomer thereof and/or the pharmacologically acceptable salt thereof are novel compounds.

Wherein, if a compound represented by the formula (2), an isomer thereof, and/or a pharmacologically acceptable salt thereof are recited, wherein R ₄ represents an unsubstituted or substituted aromatic group (except for the unsubstituted phenyl group), R ₅ represents a hydrogen atom, a linear or branched alkyl group having a carbon number of 1 to 4, or a linear or branched alkyl group having a carbon number of 1 to 4. A fluorenyl group of the chain, R ₆ represents a hydrogen atom or a straight or branched alkyl group having a carbon number of 1 to 4, and R ₄ is a substituted phenyl group or an unsubstituted naphthyl group, R ₅ or R At least one of ₆ is other than a hydrogen atom.

R ₄ represents an unsubstituted or substituted aromatic group, and as the substituent on the aromatic group, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, more preferably a carbon number of 1 is preferable. An alkyl group of 3, an alkoxy group having an alkyl chain having 1 to 6 carbon atoms, more preferably an alkoxy group having an alkyl chain having 1 to 3 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. The alkylamino group of the chain, more preferably an alkylamino group having an alkyl chain having 1 to 3 carbon atoms, a fluorenyl group having an alkyl chain having 1 to 6 carbon atoms, more preferably having a carbon number of 1 a mercapto group of an alkyl chain of ~3, an ester group having an alkyl chain having 1 to 6 carbon atoms, more preferably an ester group having an alkyl chain having 1 to 3 carbon atoms, a halogen atom or a halogenated alkyl group ( It is preferably a halogenated alkyl group having a carbon number of 1 to 4, a hydroxyl group, an amine group or the like.

Preferred examples of the unsubstituted or substituted aromatic group include methylphenyl, ethylphenyl, propylphenyl, butylphenyl, methoxyphenyl, and B. Oxyphenyl, propoxyphenyl, butoxyphenyl, N-methylaminophenyl, N-ethylaminophenyl, N-propylaminophenyl, N-butylamino Phenyl, N,N-dimethylaminophenyl, N,N-diethylaminophenyl, N,N-dipropylaminophenyl, N,N-dibutylaminophenyl , ethoxyphenyl, propyl phenyl, butyl phenyl, methoxycarbonyl phenyl, ethoxycarbonyl phenyl, propoxy phenyl phenyl, butoxycarbonyl phenyl, fluorophenyl, chloro Phenyl, bromophenyl, trifluoromethylphenyl, hydroxyphenyl, aminophenyl, pyridyl, methylpyridyl, ethylpyridyl, propylpyridyl, butylpyridyl, methoxy Pyridyl, ethoxypyridyl, propoxypyridyl, butoxypyridyl, N-methylaminopyridinyl, N-ethylaminopyridinyl, N-propylaminopyridinyl, N- Butylaminopyridyl, N,N-dimethylaminopyridinyl, N,N-diethylaminopyridinyl , N,N-dipropylaminopyridinyl, N,N-dibutylaminopyridinyl, ethinylpyridinyl, propylpyridylpyridyl, butylpyridinyl, methoxycarbonylpyridyl, ethoxy Carbocarbonylpyridyl, propoxycarbonylpyridyl, butoxycarbonylpyridyl, fluoropyridyl, chloropyridyl, bromopyridyl, trifluoromethylpyridyl, hydroxypyridyl, aminopyridinyl, naphthyl, Methylnaphthyl, ethylnaphthyl, propylnaphthyl, butylnaphthyl, methoxynaphthyl, ethoxynaphthyl, propoxynaphthyl, butoxynaphthyl, N-methylamino Naphthyl, N-ethylaminonaphthyl, N-propylaminonaphthyl, N-butylaminonaphthyl, N,N-dimethylaminonaphthyl, N,N-diethylamine Naphthyl, N,N-dipropylaminonaphthyl, N,N-dibutylaminonaphthyl, ethenylnaphthyl, propenylnaphthyl, butanylnaphthyl, methoxycarbonylnaphthyl , ethoxycarbonylnaphthyl, propoxycarbonylnaphthyl, butoxycarbonylnaphthyl, fluoronaphthyl, chloronaphthyl, bromonaphthyl, trifluoromethylnaphthyl, hydroxynaphthyl, aminonaphthyl, Biphenyl, methylbiphenyl, ethylbiphenyl, propylbiphenyl, butyl , methoxybiphenyl, ethoxybiphenyl, propoxybiphenyl, butoxybiphenyl, N-methylaminobiphenyl, N-ethylaminobiphenyl, N-propylaminobiphenyl, N-butylaminobiphenyl, N,N-dimethylaminobiphenyl, N,N-diethylaminobiphenyl, N,N- Dipropylaminobiphenyl, N,N-dibutylaminobiphenyl, acetoxybiphenyl, propyl phenyl, butyl phenyl, methoxycarbonyl biphenyl, B Oxycarbonylcarbonylbiphenyl, propoxycarbonylbiphenyl, butoxycarbonylbiphenyl, fluorobiphenyl, chlorobiphenyl, bromobiphenyl, trifluoromethylbiphenyl, hydroxybiphenyl , aminobiphenyl, etc., among these, preferred are preferably methylphenyl, ethylphenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl, trifluoro. Methylphenyl, naphthyl, biphenyl, and the like.

The number of the substituents of the above aromatic group is preferably 0 to 3, more preferably 0 or 1, and the substituent on the aromatic ring may each independently have one or more substituents. .

The above R ₅ represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a fluorenyl group having a linear or branched alkyl chain having 1 to 4 carbon atoms, and specific examples thereof Examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tertiary butyl group, an ethyl fluorenyl group, a propyl fluorenyl group, a butyl fluorenyl group, etc., and more preferably a hydrogen atom. Methyl, ethyl fluorenyl.

R ₆ represents a hydrogen atom or a linear or branched alkyl group having a carbon number of 1 to 4, and specific examples thereof include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n- group. A butyl group, an isobutyl group, a tertiary butyl group or the like is more preferably exemplified by a hydrogen atom, a methyl group or an ethyl group.

If a compound, an isomer thereof and/or a pharmacologically acceptable salt thereof as defined in the above <2> are stated, R ₁ represents an aromatic group which is unsubstituted or has the following substituent, and the substituent is carbon. The number is 1 to 6, more preferably an alkyl group having 1 to 3 carbon atoms; and an alkoxy group having a carbon number of 1 to 6, more preferably an alkyl chain having 1 to 3 carbon atoms; 1 to 6, more preferably an alkylamino group having an alkyl chain having 1 to 3 carbon atoms; and a fluorenyl group having a carbon number of 1 to 6, more preferably an alkyl chain having 1 to 3 carbon atoms. An ester group having a carbon number of 1 to 6, more preferably an alkyl chain having a carbon number of 1 to 3; a halogen atom or a halogenated alkyl group (preferably a halogenated alkyl group having 1 to 4 carbon atoms); , amine base. Preferable examples of the unsubstituted or substituted aromatic group include a phenyl group, a methylphenyl group, an ethylphenyl group, a propylphenyl group, a butylphenyl group, and a methoxybenzene. , ethoxyphenyl, propoxyphenyl, butoxyphenyl, N-methylaminophenyl, N-ethylaminophenyl, N-propylaminophenyl, N-butyl Aminophenyl, N,N-dimethylaminophenyl, N,N-diethylaminophenyl, N,N-dipropylaminophenyl, N,N-dibutylamine Phenyl, ethyl phenyl, propyl phenyl, butyl phenyl, methoxycarbonyl phenyl, ethoxycarbonyl phenyl, propoxy phenyl phenyl, butoxycarbonyl phenyl, fluorobenzene , chlorophenyl, bromophenyl, trifluoromethylphenyl, hydroxyphenyl, aminophenyl, pyridyl, methylpyridyl, ethylpyridyl, propylpyridyl, butylpyridyl, A Oxypyridyl, ethoxypyridyl, propoxypyridyl, butoxypyridyl, N-methylaminopyridinyl, N-ethylaminopyridyl, N-propylaminopyridinyl, N-butylaminopyridinyl, N,N-dimethylaminopyridinyl, N,N-diethylaminopyridinium Pyridyl, N,N-dipropylaminopyridinyl, N,N-dibutylaminopyridinyl, ethinylpyridinyl, propylpyridylpyridyl, butylpyridylpyridyl, methoxycarbonylpyridinyl, Ethoxycarbonylpyridyl, propoxycarbonylpyridyl, butoxycarbonylpyridinyl, fluoropyridyl, chloropyridyl, bromopyridinyl, trifluoromethylpyridyl, hydroxypyridyl, aminopyridyl, naphthalene , methylnaphthyl, ethylnaphthyl, propylnaphthyl, butylnaphthyl, methoxynaphthyl, ethoxynaphthyl, propoxynaphthyl, butoxynaphthyl, N-methyl Aminonaphthyl, N-ethylaminonaphthyl, N-propylaminonaphthyl, N-butylaminonaphthyl, N,N-dimethylaminonaphthyl, N,N-diethyl Aminonaphthyl, N,N-dipropylaminonaphthyl, N,N-dibutylaminonaphthyl, ethenylnaphthyl, propenylnaphthyl, butanylnaphthyl, methoxycarbonyl Naphthyl, ethoxycarbonylnaphthyl, propoxycarbonylnaphthyl, butoxycarbonylnaphthyl, fluoronaphthyl, chloronaphthyl, bromonaphthyl, trifluoromethylnaphthyl, hydroxynaphthyl, aminylnaphthalene Base, biphenyl, methylbiphenyl, ethylbiphenyl, propylbiphenyl, butyl Biphenyl, methoxybiphenyl, ethoxybiphenyl, propoxybiphenyl, butoxybiphenyl, N-methylaminobiphenyl, N-ethylaminobiphenyl , N-propylaminobiphenyl, N-butylaminobiphenyl, N,N-dimethylaminobiphenyl, N,N-diethylaminobiphenyl, N, N-dipropylaminobiphenyl, N,N-dibutylaminobiphenyl, acetoxybiphenyl, propyl phenyl, butyl phenyl, methoxycarbonyl biphenyl , ethoxycarbonylbiphenyl, propoxycarbonylbiphenyl, butoxycarbonylbiphenyl, fluorobiphenyl, chlorobiphenyl, bromobiphenyl, trifluoromethylbiphenyl, hydroxy linkage Phenyl, aminobiphenyl, etc., among these, preferred are phenyl, methylphenyl, ethylphenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl. , trifluoromethylphenyl, naphthyl, biphenyl, and the like.

The number of the substituents of the aromatic group is preferably 0 to 3, more preferably 0 or 1, and the substituent on the aromatic ring may each independently have one or more substituents.

The above R ₂ represents a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an ethyl fluorenyl group, a propyl fluorenyl group, a butyl group, and a specific example. For example, a hydrogen atom, a methyl group, or an ethyl group can be mentioned.

R ₃ represents a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tertiary butyl group. Specific examples thereof include a hydrogen atom, a methyl group and a methyl group. base.

The compound defined by the above <2>, an isomer thereof, and/or a pharmacologically acceptable salt thereof, and a compound defined by the above <6>, an isomer thereof, and/or pharmacologically acceptable thereof The salt has an excellent pigmentation prevention or improvement effect. In addition, it is excellent in solubility in a hydrophilic or lipophilic medium, and it is easy to prepare a preparation for external use of the skin, and the like, and is excellent in stability and skin storage property in the preparation, and exhibits excellent effects of prevention or improvement of pigmentation. .

If a compound, an isomer thereof, and/or a pharmacologically acceptable salt thereof, as defined in the above <6>, is recited, wherein R ₄ represents an aromatic group which is unsubstituted or has the following substituent (wherein , except for the unsubstituted phenyl group): an alkyl group having a carbon number of 1 to 6, more preferably a carbon number of 1 to 3; an alkyl group having a carbon number of 1 to 6, more preferably having a carbon number of 1 to 3 Alkoxy group of a chain; alkylamino group having a carbon number of 1 to 6, more preferably an alkyl chain having 1 to 3 carbon atoms; having a carbon number of 1 to 6, more preferably having a carbon number of 1 a mercapto group of an alkyl chain of ~3; an ester group having a carbon number of 1 to 6, more preferably an alkyl chain having 1 to 3 carbon atoms; a halogen atom or a halogenated alkyl group (preferably having a carbon number of 1) ~4 of a halogenated alkyl group), a hydroxyl group, an amine group.

Specific examples of the unsubstituted or substituted aromatic group include methylphenyl, ethylphenyl, propylphenyl, butylphenyl, methoxyphenyl, ethoxy. Phenyl, propoxyphenyl, butoxyphenyl, N-methylaminophenyl, N-ethylaminophenyl, N-propylaminophenyl, N-butylaminophenyl , N,N-Dimethylaminophenyl, N,N-diethylaminophenyl, N,N-dipropylaminophenyl, N,N-dibutylaminophenyl, B Nonylphenyl, propyl phenyl, butyl phenyl, methoxycarbonyl phenyl, ethoxycarbonyl phenyl, propoxy phenyl phenyl, butoxycarbonyl phenyl, fluorophenyl, chlorophenyl , bromophenyl, trifluoromethylphenyl, hydroxyphenyl, aminophenyl, pyridyl, methylpyridyl, ethylpyridyl, propylpyridyl, butylpyridyl, methoxypyridyl, Ethoxypyridyl, propoxypyridyl, butoxypyridyl, N-methylaminopyridyl, N-ethylaminopyridyl, N-propylaminopyridinyl, N-butylamine Pyridyl, N,N-dimethylaminopyridinyl, N,N-diethylaminopyridinyl, N,N-di Aminopyridinyl, N,N-dibutylaminopyridinyl, ethinylpyridinyl, propylpyridylpyridyl, butylphosphonium, methoxycarbonylpyridyl, ethoxycarbonylpyridyl, propoxy Carbocarbonylpyridyl, butoxycarbonylpyridyl, fluoropyridyl, chloropyridyl, bromopyridyl, trifluoromethylpyridyl, hydroxypyridyl, aminopyridyl, naphthyl, methylnaphthyl, ethyl Naphthyl, propylnaphthyl, butylnaphthyl, methoxynaphthyl, ethoxynaphthyl, propoxynaphthyl, butoxynaphthyl, N-methylaminonaphthyl, N-ethyl Aminonaphthyl, N-propylaminonaphthyl, N-butylaminonaphthyl, N,N-dimethylaminonaphthyl, N,N-diethylaminonaphthyl, N,N -dipropylaminonaphthyl, N,N-dibutylaminonaphthyl, ethenylnaphthyl, propenylnaphthyl, butanylnaphthyl, methoxycarbonylnaphthyl, ethoxycarbonylnaphthyl , propoxycarbonylnaphthyl, butoxycarbonylnaphthyl, fluoronaphthyl, chloronaphthyl, bromonaphthyl, trifluoromethylnaphthyl, hydroxynaphthyl, aminonaphthyl, biphenyl, methyl Phenyl, ethylbiphenyl, propylbiphenyl, butylbiphenyl, A Base phenyl, ethoxybiphenyl, propoxybiphenyl, butoxybiphenyl, N-methylaminobiphenyl, N-ethylaminobiphenyl, N-propyl Aminobiphenyl, N-butylaminobiphenyl, N,N-dimethylaminobiphenyl, N,N-diethylaminobiphenyl, N,N-dipropylamine Base phenyl, N,N-dibutylaminobiphenyl, acetoxybiphenyl, propyl phenyl, butyl phenyl, methoxycarbonyl biphenyl, ethoxycarbonyl Phenyl, propoxycarbonylbiphenyl, butoxycarbonylbiphenyl, fluorobiphenyl, chlorobiphenyl, bromobiphenyl, trifluoromethylbiphenyl, hydroxybiphenyl, amine linkage Phenyl or the like, among these, preferred are methylphenyl, ethylphenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl, trifluoromethylphenyl, naphthalene. Base, biphenyl, etc.

The number of the substituents of the above-mentioned aromatic group is, for example, 0 to 3, more preferably 0 or 1, and the substituent on the aromatic ring may each independently have one or two or more substituents.

The above R ₅ represents a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tertiary butyl group, an ethyl fluorenyl group, a propyl fluorenyl group, a butyl fluorenyl group, and a specific example. Preferably, a hydrogen atom, a methyl group or an ethyl fluorenyl group is exemplified.

R ₆ represents a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tertiary butyl group. Preferred examples thereof include a hydrogen atom and a methyl group. , ethyl.

Wherein R ₄ is a phenyl group having a substituent or an unsubstituted naphthyl group, and at least one of R ₅ or R ₆ is a hydrogen atom.

If a compound, an isomer thereof, and/or a pharmacologically acceptable salt thereof, as defined in the above <3>, is recited, wherein R ₁ represents a phenyl group or a naphthyl group which is unsubstituted or has the following substituents. And a biphenyl group, the substituent is: an alkyl group having a carbon number of 1 to 6, more preferably a carbon number of 1 to 3; and having an alkyl group having 1 to 6 carbon atoms, more preferably having a carbon number of 1 to 3 Alkoxy group of a base chain; alkylamino group having a carbon number of 1 to 6, more preferably an alkyl chain having 1 to 3 carbon atoms; having a carbon number of 1 to 6, more preferably having a carbon number a mercapto group of an alkyl chain of 1 to 3; an ester group having a carbon number of 1 to 6, more preferably an alkyl chain having 1 to 3 carbon atoms; a halogen atom or a halogenated alkyl group (preferably carbon) The number is a halogenated alkyl group of 1 to 4, a hydroxyl group, and an amine group.

Specific examples of the unsubstituted or substituted phenyl group, naphthyl group, and biphenyl group include phenyl, methylphenyl, ethylphenyl, propylphenyl, butylphenyl, and a Oxyphenyl, ethoxyphenyl, propoxyphenyl, butoxyphenyl, N-methylaminophenyl, N-ethylaminophenyl, N-propylaminophenyl, N-butylaminophenyl, N,N-dimethylaminophenyl, N,N-diethylaminophenyl, N,N-dipropylaminophenyl, N,N-di Butylaminophenyl, ethyl phenyl, propyl phenyl, butyl phenyl, methoxycarbonyl phenyl, ethoxycarbonyl phenyl, propoxy phenyl phenyl, butoxycarbonyl phenyl , fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, hydroxyphenyl, aminophenyl, naphthyl, methylnaphthyl, ethylnaphthyl, propylnaphthyl, butylnaphthalene , methoxynaphthyl, ethoxynaphthyl, propoxynaphthyl, butoxynaphthyl, N-methylaminonaphthyl, N-ethylaminonaphthyl, N-propylamino Naphthyl, N-butylaminonaphthyl, N,N-dimethylaminonaphthyl, N,N-diethylaminonaphthyl, N,N-dipropylaminonaphthyl, N, N- Butylaminonaphthyl, ethenylnaphthyl, propenylnaphthyl, butanylnaphthyl, methoxycarbonylnaphthyl, ethoxycarbonylnaphthyl, propoxycarbonylnaphthyl, butoxycarbonylnaphthyl ,fluoronaphthyl, chloronaphthyl, bromonaphthyl, trifluoromethylnaphthyl, hydroxynaphthyl, aminonaphthyl, biphenyl, methylbiphenyl, ethylbiphenyl, propylbiphenyl Butylbiphenyl, methoxybiphenyl, ethoxybiphenyl, propoxybiphenyl, butoxybiphenyl, N-methylaminobiphenyl, N-ethylamine Base phenyl, N-propylaminobiphenyl, N-butylaminobiphenyl, N,N-dimethylaminobiphenyl, N,N-diethylaminobiphenyl , N,N-dipropylaminobiphenyl, N,N-dibutylaminobiphenyl, acetoxybiphenyl, propyl phenyl, butyl phenyl, methoxycarbonyl Biphenyl, ethoxycarbonylbiphenyl, propoxycarbonylbiphenyl, butoxycarbonylbiphenyl, fluorobiphenyl, chlorobiphenyl, bromobiphenyl, trifluoromethylbiphenyl , hydroxybiphenyl, aminobiphenyl, and the like. Among these, preferred are phenyl, methylphenyl, ethylphenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl, trifluoromethylphenyl, naphthyl. , biphenyl, and the like.

The number of the substituents on the phenyl group, the naphthyl group, and the biphenyl group is preferably 0 to 3, more preferably 0 or 1. The substituents on the phenyl group, the naphthyl group, and the biphenyl group may each independently. The above one or two or more substituents are present.

The above R ₂ represents a hydrogen atom, a methyl group or an ethyl fluorenyl group.

The above R ₃ represents a hydrogen atom, a methyl group or an ethyl group.

The compound defined by the above <3>, an isomer thereof, and/or a pharmacologically acceptable salt thereof, and a compound defined by the above <7>, an isomer thereof, and/or pharmacologically acceptable thereof The salt has an excellent pigmentation prevention or improvement effect. In addition, it is excellent in solubility in a hydrophilic or oleophilic medium, and it is easy to prepare a preparation for external use of the skin, and the like, and it is excellent in stability and skin retention property in the preparation, and is excellent in prevention or improvement of pigmentation. effect.

If a compound, an isomer thereof, and/or a pharmacologically acceptable salt thereof, as defined in the above <7>, is recited, wherein R ₄ represents a phenyl group, a naphthyl group which is unsubstituted or has the following substituents, a biphenyl group (excluding an unsubstituted phenyl group), the substituent group being: a carbon number of 1 to 6, more preferably an alkyl group having 1 to 3 carbon atoms; and having a carbon number of 1 to 6, more preferably An alkoxy group having an alkyl chain having 1 to 3 carbon atoms; an alkylamine group having a carbon number of 1 to 6, more preferably an alkyl chain having 1 to 3 carbon atoms; having a carbon number of 1~ 6, more preferably a fluorenyl group having an alkyl chain having a carbon number of 1 to 3; an ester group having a carbon number of 1 to 6, more preferably an alkyl chain having 1 to 3 carbon atoms; a halogen atom or A halogenated alkyl group (preferably a halogenated alkyl group having 1 to 4 carbon atoms), a hydroxyl group or an amine group.

Specific examples of the unsubstituted or substituted phenyl group, naphthyl group, and biphenyl group include methylphenyl group, ethylphenyl group, propylphenyl group, butylphenyl group, and methoxybenzene. , ethoxyphenyl, propoxyphenyl, butoxyphenyl, N-methylaminophenyl, N-ethylaminophenyl, N-propylaminophenyl, N-butyl Aminophenyl, N,N-dimethylaminophenyl, N,N-diethylaminophenyl, N,N-dipropylaminophenyl, N,N-dibutylamine Phenyl, ethyl phenyl, propyl phenyl, butyl phenyl, methoxycarbonyl phenyl, ethoxycarbonyl phenyl, propoxy phenyl phenyl, butoxycarbonyl phenyl, fluorobenzene , chlorophenyl, bromophenyl, trifluoromethylphenyl, hydroxyphenyl, aminophenyl, naphthyl, methylnaphthyl, ethylnaphthyl, propylnaphthyl, butylnaphthyl, a Oxynaphthyl, ethoxynaphthyl, propoxynaphthyl, butoxynaphthyl, N-methylaminonaphthyl, N-ethylaminonaphthyl, N-propylaminonaphthyl, N-butylaminonaphthyl, N,N-dimethylaminonaphthyl, N,N-diethylaminonaphthyl, N,N-dipropylaminonaphthyl, N,N-di Butyl Naphthyl, ethenylnaphthyl, propenylnaphthyl, butanylnaphthyl, methoxycarbonylnaphthyl, ethoxycarbonylnaphthyl, propoxycarbonylnaphthyl, butoxycarbonylnaphthyl, fluoronaphthalene , chloronaphthyl, bromonaphthyl, trifluoromethylnaphthyl, hydroxynaphthyl, aminonaphthyl, biphenyl, methylbiphenyl, ethylbiphenyl, propylbiphenyl, butyl Biphenyl, methoxybiphenyl, ethoxybiphenyl, propoxybiphenyl, butoxybiphenyl, N-methylaminobiphenyl, N-ethylaminobiphenyl , N-propylaminobiphenyl, N-butylaminobiphenyl, N,N-dimethylaminobiphenyl, N,N-diethylaminobiphenyl, N, N-dipropylaminobiphenyl, N,N-dibutylaminobiphenyl, acetoxybiphenyl, propyl phenyl, butyl phenyl, methoxycarbonyl biphenyl , ethoxycarbonylbiphenyl, propoxycarbonylbiphenyl, butoxycarbonylbiphenyl, fluorobiphenyl, chlorobiphenyl, bromobiphenyl, trifluoromethylbiphenyl, hydroxy linkage Phenyl, aminobiphenyl, etc., among these, preferably, methylphenyl or ethylbenzene is exemplified. , Methoxyphenyl, ethoxyphenyl, fluorophenyl, trifluoromethylphenyl, naphthyl, biphenyl and the like.

The number of the substituents on the phenyl group, the naphthyl group, and the biphenyl group is preferably 0 to 3, more preferably 0 or 1. The substituents on the phenyl group, the naphthyl group, and the biphenyl group may each independently. The above one or two or more substituents are present.

The above R ₅ represents a hydrogen atom, a methyl group or an ethyl fluorenyl group.

The above R ₆ represents a hydrogen atom, a methyl group or an ethyl group.

Wherein R ₄ is a phenyl group having a substituent or an unsubstituted naphthyl group, and at least one of R ₅ or R ₆ is a hydrogen atom.

With respect to the compound represented by the above formula (1) or the compound represented by the formula (2), a specific example thereof is preferably exemplified by 3-hydroxy-2-(benzylideneamino)propionic acid (Compound 2). , 3-hydroxy-2-(methylbenzylideneamino)propionic acid (compound 1, 3, 15), 3-ethyloxy-2-(methylbenzylamino) propionic acid (compound 11 , 3-ethyloxy-2-(ethylbenzylidene)propionic acid, 3-ethyloxy-2-(methoxybenzylhydra)propionic acid, 3-ethyloxy-2- (methylnaphthyl)propionic acid, 3-acetoxy-2-(methoxynaphthyl)propionic acid, 2-(methylbenzylidene)-3-propoxyoxypropionic acid, 2-( Ethylbenzylamino)-3-hydroxypropionic acid (Compound 7), 3-hydroxy-2-(propylbenzylideneamino)propionic acid, 2-(butylbenzylamino)-3 -hydroxypropionic acid, 3-hydroxy-2-(methoxybenzylguanidino)propionic acid (compound 5), 2-(ethoxybenzylguanidino)-3-hydroxypropionic acid, 3-hydroxyl -2-(propoxybenzylhydrazinyl)propionic acid, 2-(butoxybenzylamino)-3-hydroxypropionic acid, 3-hydroxy-2-(N-methylbenzylguanamine) Propionate, 2-(N-ethylbenzylideneamino)-3-hydroxypropionic acid, 3-hydroxy-2-(N-propylbenzylideneamino)propionic acid, 2-(N, N-dimethylbenzyl hydrazino 3-hydroxypropionic acid, 2-(N,N-diethylbenzylideneamino)-3-hydroxypropionic acid, 2-(N,N-dipropylbenzylideneamino)-3 -hydroxypropionic acid, 2-(ethylhydrazinobenzylamino)-3-hydroxypropionic acid, 3-hydroxy-2-(pentamethylenebenzylamino)propionic acid, 3-hydroxy-2-( Propionylbenzylamino)propionic acid, 3-hydroxy-2-(methoxycarbonylbenzylideneamino)propionic acid, 2-(ethoxycarbonylbenzylideneamino)-3-hydroxypropane Acid, 3-hydroxy-2-(propoxycarbonylbenzylideneamino)propionic acid, 2-(chlorobenzylamino)-3-hydroxypropionic acid, 2-(fluorobenzylamino)- 3-hydroxypropionic acid (compound 4), 3-hydroxy-2-(trifluoromethylbenzylideneamino)propionic acid (compound 8), 3-hydroxy-2-(hydroxybenzylamino)propionic acid , 2-(Aminobenzylbenzylamino)-3-hydroxypropionic acid, 3-hydroxy-2-(biphenylylamino)propionic acid (Compound 14), 3-hydroxy-2-(methylbiphenyl) Amino acid) propionic acid, 2-(ethylbiphenylamino)-2-hydroxypropionic acid, 3-hydroxy-2-(methoxybiphenylamino)propionic acid, 2-(ethoxyl) Biphenylamino)-3-hydroxypropionic acid, 3-hydroxy-2-(pyridinecarbonylamino)propionic acid, 3-hydroxy-2-(methylpyridinecarbonylamino)propionic acid, 2-(ethyl Pyridylcarbonylamino)-3 -hydroxypropionic acid, 3-hydroxy-2-(propylpyridinecarbonylamino)propionic acid, 2-(butylpyridylcarbonylamino)-3-hydroxypropionic acid, 3-hydroxy-2-(methoxypyridine) Carbonylamino)propionic acid, 2-(ethoxypyridinecarbonylamino)-3-hydroxypropionic acid, 3-hydroxy-2-(propoxypyridinecarbonylamino)propionic acid, 2-(butoxypyridine) Carbonylamino)-3-hydroxypropionic acid, 3-hydroxy-2-(N-methylaminopyridinecarbonylamino)propionic acid, 2-(N-ethylaminopyridinecarbonylamino)-3-hydroxyl Propionic acid, 2-(N,N-dimethylaminopyridinecarbonylamino)-3-hydroxypropionic acid, 2-(N,N-diethylaminopyridinecarbonylamino-3-hydroxypropionic acid, 2-(Ethylpyridinylcarbonylamino)-3-hydroxypropionic acid, 3-hydroxy-2-(pentanylpyridinecarbonylamino)propionic acid, 2-(chloropyridinecarbonylamino)-3-hydroxypropane Acid, 2-(fluoropyridinecarbonylamino)-3-hydroxypropionic acid, 3-hydroxy-2-(trifluoromethylpyridinecarbonylamino)propionic acid, 3-hydroxy-2-(hydroxypyridinecarbonylamino) Propionic acid, 2-(aminopyridinecarbonylamino)-3-hydroxypropionic acid, 3-hydroxy-2-(naphthylmethylamino)propionic acid (compound 10), 3-hydroxy-2-(methyl Naphthylmethylamino)propionic acid, 2-(ethylnaphthylmethylamino)-3-hydroxypropionic acid 3-hydroxy-2-(propylnaphthylmethylamino)propionic acid, 3-hydroxy-2-(methoxynaphthylmethylamino)propionic acid, 2-(ethoxynaphthylmethylguanamine) 3-hydroxypropionic acid, 3-hydroxy-2-(N-methylnaphthylmethylamino)propionic acid, 2-(N-ethylnaphthylmethylamino)-3-hydroxypropionic acid , 2-(N,N-dimethylaminonaphthylmethylamino)-3-hydroxypropionic acid, 2-(N,N-diethylaminonaphthylmethylamino)-3-hydroxyl Propionic acid, 2-(ethylmercapto-naphthylamino)-3-hydroxypropionic acid, 3-hydroxy-2-(pentamethylenenaphthylmethylamino)propionic acid, 3-hydroxy-2-( Methoxycarbonylnaphthylmethylamino)propionic acid, 2-(ethoxycarbonylnaphthylmethylamino)-3-hydroxypropionic acid, 2-(chloronaphthylmethylamino)-3-hydroxyl Propionic acid, 2-(fluoronaphthylamino)-3-hydroxypropionic acid, 3-hydroxy-2-(trifluoromethylnaphthylmethylamino)propionic acid, 3-hydroxy-2-(hydroxyl) Naphthylmethylamino)propionic acid, 2-(aminonaphthylmethylamino)-3-hydroxypropionic acid, 3-hydroxy-2-(biphenylcarbonylamino)propionic acid, 3-hydroxy- 2-(methylbiphenylcarbonylamino)propionic acid, 2-(ethylbiphenylcarbonylamino)-3-hydroxypropionic acid, 3-hydroxy-2-(propylbiphenylcarbonylamino) Propionic acid, 3-hydroxy-2-( Methoxybiphenylcarbonylamino)propionic acid, 2-(ethoxybiphenylcarbonylamino)-3-hydroxypropionic acid, 3-hydroxy-2-(N-methylaminobiphenylcarbonyl) Amino)propionic acid, 2-(N-ethylaminobiphenylcarbonylamino)propionic acid, 2-(N,N-dimethylaminobiphenylcarbonylamino)-3-hydroxypropionic acid , 2-(N,N-diethylaminobiphenylcarbonylamino)-3-hydroxypropionic acid, 2-(ethenylbiphenylcarbonylamino)-3-hydroxypropionic acid, 3-hydroxyl 2-(2-pentamethylenebiphenylcarbonylamino)propionic acid, 3-hydroxy-2-(methoxycarbonylbiphenylcarbonylamino)propionic acid, 2-(ethoxycarbonylbiphenyl Carbonylamino)-3-hydroxypropionic acid, 2-(chlorobiphenylcarbonylamino)-3-hydroxypropionic acid, 2-(fluorobiphenylcarbonylamino)-3-hydroxypropionic acid, 3-hydroxyl -2-(trifluoromethylbiphenylcarbonylamino)propionic acid, 3-hydroxy-2-(hydroxybiphenylcarbonylamino)propionic acid, 2-(aminobiphenylcarbonylamino)-3 -hydroxypropionic acid, 3-methoxy-2-(benzylideneamino)propionic acid (compound 16), 3-methoxy-2-(methylbenzylideneamino)propionic acid (compound 9) , 2-(ethylbenzylideneamino)-3-methoxypropionic acid, 3-methoxy-2-(propylbenzylamino)propionic acid, 3-methoxy -2-(Methoxybenzylhydrazino)propionic acid ethoxybenzylamino)-3-methoxypropionic acid, 2-(chlorobenzylamino)-3-methoxypropane Acid, 2-(fluorobenzylamino)-3-methoxypropionic acid, 3-methoxy-2-(trifluoromethylbenzylguanidino)propionic acid, 3-ethoxy-2 -(methylbenzylamino)propionic acid, 3-ethoxy-2-(ethylbenzylideneamino)propionic acid, 3-ethoxy-2-(propylbenzylideneamino) Propionic acid, 3-ethoxy-2-(methoxybenzylhydrazino)propionic acid, 3-ethoxy-2-(ethoxybenzylguanidino)propionic acid, 3-ethoxyl -2-(Chlorobenzylamino)propionic acid, 3-ethoxy-2-(fluorobenzylamino)propionic acid, 3-ethoxy-2-(trifluoromethylbenzylguanamine) Propionate, 3-hydroxy-2-(methylbenzylamino)propionic acid methyl ester (compound 6), 2-(ethylbenzylideneamino)-3-hydroxypropionic acid methyl ester , 3-hydroxy-2-(propylbenzylideneamino)propionic acid methyl ester, 3-hydroxy-2-(methoxybenzylguanidino)propionic acid methyl ester, 2-(chlorbenzylhydrazine) Methylamino)-3-hydroxypropionate methyl ester, 2-(fluorobenzylideneamino)propionic acid methyl ester, 3-hydroxy-2-(trifluoromethylbenzylideneamino)propionic acid Base ester, 3-hydroxy-2-(methylbenzylamino) Acid ethyl ester (compound 17), 2-(ethylbenzylideneamino)-3-hydroxypropionic acid ethyl ester, 3-hydroxy-2-(propylbenzylideneamino)propionic acid ethyl ester , 3-hydroxy-2-(methoxybenzylguanidino)propionic acid ethyl ester, 2-(chlorobenzylamino)-3-hydroxypropionic acid ethyl ester, 2-(fluorobenzyl) Ethyl)-3-hydroxypropionic acid ethyl ester, 3-hydroxy-2-(trifluoromethylbenzylideneamino)propionic acid ethyl ester, 3-methoxy-2-(methylbenzyl) Amino)methyl propionate, methyl 3-methoxy-2-(ethylbenzylideneamino)propionate, 3-methoxy-2-(propylbenzylamino)propyl Acid methyl ester, 3-methoxy-2-(methoxybenzylguanidino)propionic acid methyl ester, 2-(chlorobenzylamino)-3-methoxypropionic acid methyl ester , 2-(fluorobenzyl guanylamino)-3-methoxypropionic acid methyl ester, 3-methoxy-2-(trifluoromethylbenzyl hydrazino) propionic acid methyl ester, 3- Ethyl ethoxy-2-(methylbenzylamino)propionic acid ethyl ester, ethyl 3-ethoxy-2-(ethylbenzylideneamino)propanoate, 3-ethoxy- 2-(propylbenzylamino)propionic acid ethyl ester, 3-ethoxy-2-(methoxybenzylguanidino)propionic acid ethyl ester, 2-(chlorobenzylamino) )-3-ethoxypropionic acid Ester, ethyl 3-ethoxy-2-(fluorobenzyl) aminopropionate, ethyl 3-ethoxy-2-(trifluoromethylbenzyl) aminopropionate, 3 -Methoxy-2-(pyridinecarbonylamino)propionic acid, 3-methoxy-2-(methylpyridinecarbonylamino)propionic acid, 2-(ethylpyridinecarbonylamino)-3-methoxy Propionic acid, 3-methoxy-2-(methoxypyridinecarbonylamino)propionic acid, 2-(ethoxypyridinecarbonylamino)-3-methoxypropionic acid, 2-(chloropyridinecarbonyl) Amino)-3-methoxypropionic acid, 2-(fluoropyridinecarbonylamino)-3-methoxypropionic acid, 3-methoxy-2-(trifluoromethylpyridinecarbonylamino)propionic acid , 2-(hydroxypyridinecarbonylamino)-3-methoxypropionic acid, 2-(aminopyridinecarbonylamino)-3-methoxypropionic acid, 3-ethoxy-2-(pyridinecarbonylamine Propionate, 3-ethoxy-2-(methylpyridinecarbonylamino)propionic acid, 3-ethoxy-2-(ethylpyridinecarbonylamino)propionic acid, 3-ethoxy-2 -(methoxypyridinecarbonylamino)propionic acid, 3-ethoxy-2-(ethoxypyridinecarbonylamino)propionic acid, 2-(chloropyridinecarbonylamino)-3-ethoxypropionic acid , 3-ethoxy-2-(fluoropyridinecarbonylamino)propionic acid, 3-ethoxy-2-(trifluoromethylpyridinecarbonylamino)propionic acid , 3-ethoxy-2-(hydroxypyridinecarbonylamino)propionic acid, 2-(aminopyridinecarbonylamino)-3-ethoxypropionic acid, 3-hydroxy-2-(pyridinecarbonylamino) Methyl propionate, methyl 3-hydroxy-2-(methylpyridinecarbonylamino)propionate, methyl 2-(ethylpyridinecarbonylamino)-3-hydroxypropionate, 3-hydroxy- 2-(methoxypyridinecarbonylamino)propionic acid methyl ester, 2-(ethoxypyridinecarbonylamino)-3-hydroxypropionic acid methyl ester, 2-(chloropyridinecarbonylamino)-3- Methyl hydroxypropionate, methyl 2-(fluoropyridinecarbonylamino)propionate, methyl 3-hydroxy-2-(trifluoromethylpyridinecarbonylamino)propionate, 3-hydroxy-2- (Hydroxypyridinecarbonylamino)propionic acid methyl ester, 2-(aminopyridinecarbonylamino)-3-hydroxypropionic acid methyl ester, 3-hydroxy-2-(pyridinecarbonylamino)propionic acid ethyl ester , 3-hydroxy-2-(methylpyridinecarbonylamino)propionic acid ethyl ester, 2-(ethylpyridinecarbonylamino)-3-hydroxypropionic acid ethyl ester, 3-hydroxy-2-(methoxy Ethyl pyridylcarbonylamino)ethyl propionate, ethyl 2-(ethoxypyridinecarbonylamino)-3-hydroxypropionate, ethyl 2-(chloropyridinecarbonylamino)-3-hydroxypropionate Ester, 2-(fluoropyridinecarbonylamino)propionic acid Ethyl ester, ethyl 3-hydroxy-2-(trifluoromethylpyridinecarbonylamino)propionate, ethyl 3-hydroxy-2-(hydroxypyridinecarbonylamino)propionate, 2-(amino group) Pyridylcarbonylamino)-3-hydroxypropionic acid ethyl ester, 3-methoxy-2-(pyridinecarbonylamino)propionic acid methyl ester, 3-methoxy-2-(methylpyridinecarbonylamino group ) methyl propionate, methyl 2-(ethylpyridinecarbonylamino)-3-methoxypropionate, methyl 3-methoxy-2-(methoxypyridinecarbonylamino)propionate Ester, 2-(ethoxypyridinecarbonylamino)-3-methoxypropionic acid methyl ester, 2-(chloropyridinecarbonylamino)-3-methoxypropionic acid methyl ester, 2-(fluorine Pyridylcarbonylamino)-3-methoxypropionic acid methyl ester, 3-methoxy-2-(trifluoromethylpyridinecarbonylamino)propionic acid methyl ester, 2-(hydroxypyridinecarbonylamino) Methyl 3-methoxypropionate, methyl 2-(aminopyridinecarbonylamino)-3-methoxypropionate, 3-ethoxy-2-(pyridinecarbonylamino)propionic acid Ethyl ester, ethyl 3-ethoxy-2-(methylpyridinecarbonylamino)propionate, ethyl 3-ethoxy-2-(ethylpyridinecarbonylamino)propionate, 3- Ethoxy-2-(methoxypyridinecarbonylamino)propionic acid ethyl ester, 3-ethoxy Ethyl 2-(ethoxypyridinecarbonylamino)propionic acid ethyl ester, 2-(chloropyridinecarbonylamino)-3-ethoxypropionic acid ethyl ester, 3-ethoxy-2-(fluoride) Pyridylcarbonylamino)propionic acid ethyl ester, 3-ethoxy-2-(trifluoromethylpyridinecarbonylamino)propionic acid ethyl ester, 3-ethoxy-2-(hydroxypyridinecarbonylamino) Ethyl propionate, ethyl 2-(aminopyridinecarbonylamino)-3-ethoxypropionate, 3-methoxy-2-(naphthylmethylamino)propionic acid (compound 13) , 3-methoxy-2-(methylnaphthylmethylamino)propionic acid, 2-(ethylnaphthylmethylamino)-3-methoxypropionic acid, 3-methoxy-2 -(propylnaphthylmethylamino)propionic acid, 3-methoxy-2-(methoxynaphthylmethylamino)propionic acid, 3-methoxy-2-(ethoxynaphthalene) Mercaptoamine)propionic acid, 2-(chloronaphthylamino)-3-methoxypropionic acid, 2-(fluoronaphthylamino)-3-methoxypropionic acid, 3- Methoxy-2-(trifluoromethylnaphthylmethyl)propionic acid, 3-ethoxy-2-(methylnaphthylmethylamino)propionic acid, 3-ethoxy-2-(B Naphthylmethylamino)propionic acid, 3-ethoxy-2-(propylnaphthylmethylamino)propionic acid, 3-ethoxy-2-(methoxynaphthylmethylamino) Propionic acid, 3-ethoxy -2-(ethoxynaphthylmethylamino)propionic acid, 3-ethoxy-2-(chloronaphthylmethylamino)propionic acid, 3-ethoxy-2-(fluoronaphthoquinone) Amino acid) propionic acid, 3-ethoxy-2-(trifluoromethylnaphthylmethyl)propionic acid, 3-hydroxy-2-(naphthylmethylamino)propionic acid methyl ester (Compound 12 , 3-hydroxy-2-(methylnaphthylmethylamino)propionic acid methyl ester, 2-(ethylnaphthylmethylamino)-3-hydroxypropionic acid methyl ester, 3-hydroxy- 2-(propylnaphthylmethylamino)propionic acid methyl ester, 3-hydroxy-2-(methoxynaphthylmethylamino)propionic acid methyl ester, 2-(ethoxynaphthoquinone) Methylamino)-3-hydroxypropionic acid methyl ester, 2-(chloronaphthylmethylamino)-3-hydroxypropionic acid methyl ester, 2-(fluoronaphthylmethylamino)-3-hydroxyl Methyl propionate, methyl 3-hydroxy-2-(trifluoromethylnaphthylmethyl)propionate, ethyl 3-hydroxy-2-(naphthylmethylamino)propionate, 3- Ethyl 2-(methylnaphthylamino)propanoate, ethyl 2-(ethylnaphthylamino)-3-hydroxypropionate, 3-hydroxy-2-(propyl) Ethylnaphthylamino)ethyl propionate, ethyl 3-hydroxy-2-(methoxynaphthylamino)propanoate, 2-(ethoxynaphthylmethylamino) -3-hydroxypropane Acid ethyl ester, 2-(chloronaphthylamino)-3-hydroxypropionic acid ethyl ester, 2-(fluoronaphthylamino)-3-hydroxypropionic acid ethyl ester, 3-hydroxyl -2-(Trifluoromethylnaphthylmethyl)propionic acid ethyl ester, 3-methoxy-2-(methylnaphthylmethylamino)propionic acid methyl ester, 2-(ethylnaphthalene) Methyl decylamino)-3-methoxypropionate, methyl 3-methoxy-2-(propylnaphthylmethylamino)propionate, 3-methoxy-2-( Methoxynaphthylmethylamino)propionic acid methyl ester, 3-methoxy-2-(ethoxynaphthylmethylamino)propionic acid methyl ester, 2-(chloronaphthylguanidinoamine) Methyl 3-methoxypropionate, methyl 2-(fluoronaphthylamino)-3-methoxypropionate, 3-methoxy-2-(trifluoromethyl) Naphthylmethyl)propionic acid methyl ester, 3-ethoxy-2-(methylnaphthylmethylamino)propionic acid ethyl ester, 3-ethoxy-2-(ethylnaphthylmethyl fluorenyl) Amino)ethyl propionate, ethyl 3-ethoxy-2-(propylnaphthylmethylamino)propanoate, 3-ethoxy-2-(methoxynaphthylguanidinoamine Ethyl propionate, ethyl 3-ethoxy-2-(ethoxynaphthylmethylamino) propionate, 3-ethoxy-2-(chloronaphthylmethylamino) Ethyl propionate, 3-ethoxyl Ethyl 2-(fluoronaphthylmethylamino)propionate, ethyl 3-ethoxy-2-(trifluoromethylnaphthylmethyl)propanoate, isomers thereof and/or Such pharmacologically acceptable salts.

More preferably, it is 3-hydroxy-2-(benzylideneamino)propionic acid (Compound 2), 3-hydroxy-2-(methylbenzylamino)propionic acid (Compound 1, 3, 15) 3-Ethyloxy-2-(methylbenzylideneamino)propionic acid (Compound 11), 2-(ethylbenzylideneamino)-3-hydroxypropionic acid (Compound 7), 3- Hydroxy-2-(methoxybenzylhydrazino)propionic acid (compound 5), 2-(fluorobenzylamino)-3-hydroxypropionic acid (compound 4), 3-hydroxy-2-(three Fluoromethylbenzylamino)propionic acid (compound 8), 3-hydroxy-2-(biphenylylamino)propionic acid (compound 14), 3-hydroxy-2-(naphthylmethylamino) Propionic acid (compound 10), 3-methoxy-2-(benzylideneamino)propionic acid (compound 16), 3-methoxy-2-(methylbenzylideneamino)propionic acid (compound) 9) 3-Hydroxy-2-(methylbenzylideneamino)propionic acid methyl ester (Compound 6), 3-hydroxy-2-(methylbenzylideneamino)propionic acid ethyl ester (compound) 17) 3-methoxy-2-(naphthylmethylamino)propionic acid (compound 13), 3-hydroxy-2-(naphthylmethylamino)propionic acid methyl ester (compound 12), Isomers thereof and/or such pharmacologically acceptable salts.

More preferably, it is exemplified by 3-hydroxy-2-(benzylideneamino)propionic acid (Compound 2) and 3-hydroxy-2-(methylbenzylideneamino)propionic acid (Compounds 1, 3, 15), 2-(Ethylbenzylamino)-3-hydroxypropionic acid (Compound 7), 3-hydroxy-2-(methoxybenzylguanidino)propionic acid (Compound 5), 2- (Fluorobenzylamino)-3-hydroxypropionic acid (Compound 4), 3-hydroxy-2-(trifluoromethylbenzylideneamino)propionic acid (Compound 8), 3-methoxy-2 -(benzylideneamino)propionic acid (Compound 16), 3-methoxy-2-(methylbenzylamino)propionic acid (Compound 9), 3-hydroxy-2-(methylbenzylhydrazine) Methylamino)propionic acid methyl ester (compound 6), isomers thereof and/or such pharmacologically acceptable salts.

The most preferable examples are 3-hydroxy-2-(methylbenzylamino)propionic acid (Compound 1), 2-(fluorobenzylamino)-3-hydroxypropionic acid (Compound 4), 3- Hydroxy-2-(trifluoromethylbenzylideneamino)propionic acid (Compound 8), isomers thereof and/or such pharmacologically acceptable salts.

This compound has an excellent pigmentation prevention or improvement effect. In addition, it is excellent in solubility in a hydrophilic or lipophilic medium, and it is easy to be formulated into a skin external preparation or the like, and further exhibits excellent stability and skin retention properties in a preparation, and is excellent in prevention or improvement of pigmentation. effect.

a compound represented by the above formulas (1) and (2), a compound defined by the above <2>, <3>, <4>, <6>, <7>, an isomer thereof, and/or a pharmacological agent thereof The above-mentioned salt which can be tolerated is commercially available as a starting material of a serine or a serine derivative, and is described in the following description of the production method of the present specification and, for example, "Basic and Experimental Synthesis of Peptide (Maruzen)" The method can be produced by performing deprotection, coupling, and introduction reaction of a protecting group.

The compound may use an isomer thereof, and the term "isomer" means a stereoisomer such as an optical isomer. Further, the compound represented by the above formulas (1) and (2), the compound defined by the above <2>, <3>, <4>, <6>, <7>, an isomer thereof and/or the like The pharmacologically acceptable salt can be a racemic form of a 1:1 mixture of (L) and (D), in addition to the form of the optical isomer (L) and (D). The (L) body and the (D) body may exist in the form of a racemic mixture existing at any mixing ratio. a compound represented by the above formula (1), (2), a compound defined by the above <2>, <3>, <4>, <6>, <7>, an isomer thereof and/or These pharmacologically acceptable salts can also be used in any of the above forms, but it is preferred to use the (L) body for the optically active substance from the medicinal or safe side.

The compound can also be used as a pigment precipitation preventing or improving agent, but it can also be converted into a salt form by treatment with a pharmacologically acceptable acid or base, or can be used as a salt. For example, preferred are the mineral salts of hydrochloride, sulfate, nitrate, phosphate, carbonate, etc.; maleate, fumarate, oxalate, citrate, lactic acid An organic acid salt of a salt, a tartrate, a methanesulfonate, a p-toluenesulfonate or a besylate; an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; An organic amine salt such as an ethylamine salt, a triethanolamine salt, an ammonium salt, a monoethanolamine salt or a piperidine salt; or a basic amino acid salt such as an amine salt or an alginate.

The compound represented by the general formulae (1) and (2) thus obtained, the compound defined by the above <2>, <3>, <4>, <6>, <7>, an isomer thereof and/or These pharmacologically acceptable salts are useful as an active ingredient of a skin external preparation because of their excellent pigmentation prevention or improvement. With regard to the pharmacological action of the active ingredient, it is presumed that activation inhibition by melanocytes, inhibition of tyrosinase enzyme, inhibition of tyrosinase gene expression, inhibition of tyrosinase protein expression, and casein It is preferred that the action of the tyrosinase activity such as the aminase-related protein decomposition inhibits the production of melanin, and it is preferable to use it for the purpose of preventing or improving the pigmentation.

Further, as shown in the test examples described later, the compounds represented by the above formulas (1) and (2), and the compounds defined by the above <2>, <3>, <4>, <6>, and <7>, The isomers and/or these pharmacologically acceptable salts have been confirmed to have excellent inhibition of the activation of melanocytes in the in vitro evaluation system. a compound represented by the above formulas (1) and (2), a compound defined by the above <2>, <3>, <4>, <6>, <7>, an isomer thereof, and/or a pharmacological agent thereof It is considered that the salt which is acceptable in the above-mentioned evaluation of the melanin production by the inhibition of melanin production and the in vivo evaluation system is considered to exhibit the confirmed pigmentation inhibitory effect. That is, the compound represented by the above formulas (1) and (2), the compound defined by the above <2>, <3>, <4>, <6>, and <7>, the isomer thereof, and/or the like The pharmacologically acceptable salt is useful as an active ingredient for a pigmentation prevention or improvement agent.

Further, the compounds represented by the above formulas (1) and (2), the compounds defined by the above <2>, <3>, <4>, <6>, and <7>, the isomers thereof, and/or the like The pharmacologically acceptable salts also have a role other than the prevention or improvement of pigmentation. The external preparation for skin contained for the purpose of the performance of the above-mentioned functions (1), (2), and/or the pharmacologically acceptable salt thereof, if it is pigmented The main purpose of the prevention or improvement is to take advantage of the effects of the present invention, and is therefore within the scope of the technology of the present invention. Moreover, the external preparation for skin of the present invention is used for prevention or improvement of pigmentation, and the use of "prevention or improvement of pigmentation" is achieved by the prevention or improvement of pigmentation, and the use thereof is mainly used for purposes of "whitening". And the use of "black spot improvement".

<The skin external preparation of the present invention>

The skin external preparation of the present invention is characterized by containing a compound represented by the above formulas (1) and (2), a compound defined by the above <2>, <3>, <4>, <6>, and <7>, A pigmentation preventing or improving agent comprising a heterologous body and/or such a pharmacologically acceptable salt.

To effectively produce a compound represented by the general formulae (1) and (2), a compound defined by the above <2>, <3>, <4>, <6>, <7>, an isomer thereof, and/or the like The pharmacologically acceptable salt pigment precipitation prevention or amelioration effect, which is selected from the compounds represented by the general formulae (1) and (2), the aforementioned <2>, <3>, <4>, <6> And 1 or 2 or more types of the compound defined by <7>, the isomer thereof, and/or the pharmacologically acceptable salt thereof, and the total amount of the external preparation for skin is preferably 0.0001% by mass to 20% by mass, more preferably 0.001% by mass to 10% by mass, still more preferably 0.005 to 5% by mass. With respect to the total amount of the external preparation for skin, once the content is less than 0.0001% by mass, the effect of preventing or improving pigmentation is lowered, and even if the amount is more than 20% by mass, since the effect has reached the highest point, the total amount of the external preparation for skin is The above content is preferred.

The skin external preparation of the present invention may contain only one of the compounds represented by the above formulas (1) and (2), and the compounds defined by the above <2>, <3>, <4>, <6>, and <7>. The heterogeneous body and/or the pharmacologically acceptable salt thereof may be contained in combination of two or more kinds.

The external preparation for skin of the present invention comprises a compound represented by the above formula (1), (2), a compound defined by the above <2>, <3>, <4>, <6>, <7>, A compound represented by a heterogeneous body and/or such a pharmacologically acceptable salt and/or a pharmacologically acceptable salt thereof, which is used for "prevention or improvement of pigmentation", "whitening", "black" For the prevention or improvement of plaque improvement, etc., related to abnormality of pigmentation.

In addition to the above-mentioned essential components, the external preparation for skin of the present invention may contain any component used in a usual cosmetic. As such an optional component, a hydrocarbon such as squalane, petrolatum or microcrystalline wax, jojoba oil, carnauba wax, octyl lauryl oleate or the like, olive oil or tallow may be contained. , higher oils such as triglycerides such as coconut oil, stearic acid, oleic acid, retinyl acid, oleyl alcohol, stearyl alcohol, octyldodecanol, etc., sulfosuccinate or poly Anionic surfactants such as sodium oxyalkylalkyl sulfate, amphoteric surfactants such as alkylbetaine salts, cationic surfactants such as dialkylammonium salts, sorbitan fatty acid esters, and fatty acid monomers Nonionic surfactants such as glycerides, such polyoxyethylene adducts, polyoxyethylene alkyl ethers, polyoxyethylene fatty acid esters, polyethylene glycol, glycerin, 1,3-butanediol, etc. Polyols, viscosity-enhancing ‧ gelling agents, antioxidants, UV absorbers, colorants, preservatives, powders, etc. The production of the external preparation for skin of the present invention is carried out in addition to the pigment precipitation prevention or improvement agent of the present invention by treating the components in accordance with a conventional method without difficulty.

The external preparation for skin of the present invention can be produced by treating the essential components and optional components according to the usual method through a lotion, an emulsion, an essence, a cream, a mask cosmetic, a cleansing, and the like. Any dosage form may be used as long as it can be adapted to the skin. However, it is preferred that the active ingredient is infiltrated into the skin to exert an effect on the skin, such as a lotion, lotion, cream, serum or the like.

Hereinafter, the present invention will be further described in detail with reference to the present invention, but it should be understood that the invention is not limited to the embodiment.

Example

<Manufacturing Example 1: Production of Compound 1>

[step 1]

Synthesis of p-methylbenzylhydrazine chloride

P-toluic acid (100 g, 0.734 mol) (Tokyo Chemical Industry Co., Ltd.) and toluene (500 mL) (Wako Pure Chemical Industries Co., Ltd.) were placed in a sufficiently dried eggplant type flask to dissolve p-toluic acid. . To the solution, sulfite chloride (132.4 mL, 1.84 mol) was added dropwise for 1 hour (Wako Pure Chemical Industries Co., Ltd.). After dropping, it was heated to reflux for 2 hours. After the reaction, after cooling to room temperature, the residual sulfoxide and toluene were distilled off by a rotary evaporator. Toluene (200 mL) was added to the concentrate, and the mixture was concentrated twice.

The residue obtained was dissolved in tetrahydrofuran (200 mL) (Wako Pure Chemical Industries, Ltd.) and delivered to the next step.

[Step 2] Synthesis of N-(p-methylbenzyl)-L-serine

In the eggplant type flask, L-serine (100g, 0.952mol) (Wako Pure Chemical Industries Co., Ltd.), potassium carbonate (131.5g, 0.952mol) (Wako Pure Chemical Industries Co., Ltd.), and water 1L were placed. Stirring vigorously. In the solution, p-methylbenzylidene chloride prepared in the step 1 was dissolved in tetrahydrofuran (Wako Pure Chemical Industries Co., Ltd.) for 30 minutes. On the way, while maintaining potassium carbonate while maintaining potassium carbonate. After the completion of the dropwise addition, the mixture was stirred for 1 hour. The reaction liquid was added to 1 L of water prepared in another container, and the mixture was made to pH 3 or less with hydrochloric acid, and cooled to 4 °C. After the precipitated crystals were filtered, recrystallization was carried out in a mixed solvent of ethanol (Wako Pure Chemical Industries Co., Ltd.) / water-6/4 to obtain 106.0 g (yield 64.7%) of the object.

¹ H-NMR (d ₆ -DMSO): δ 2.36 (3H, s), 3.80 (2H, d), 4.47 (1H, q), 7.29 (2H, d), 7.80 (2H, d), 8.29 ( 1H, d).

N-(p-methylbenzyl)-L-serine (Compound 1)

<Production Example 2: Production of Compound 2>

Using the benzoic acid and L-serine, Compound 2 was synthesized in the same manner as in the above Compound 1.

¹ H-NMR (d ₆ -DMSO): δ 3.70 (2H, m), 4.23 (1H, q), 7.49 (3H, m), 7.88 (2H, d), 8.23 (1H, d).

N-benzylindenyl-L-serine (Compound 2)

<Manufacturing Example 3: Production of Compound 3>

Using the p-toluic acid and DL-serine, Compound 3 was synthesized in the same manner as in the above Compound 1.

¹ H-NMR (d ₆ -DMSO): δ 2.36 (3H, s), 3.68 (2H, m), 4.19 (1H, m), 7.26 (2H, d), 7.76 (2H, d), 8.07 ( 1H, d).

N-(p-methylbenzyl)-DL-serine (Compound 3)

<Production Example 4: Production of Compound 4>

After weighed L-serine (2.01 g, 19.1 mmol) (Korean Peptide Co., Ltd.) and potassium carbonate (2.89 g, 20.9 mmol) (Wako Pure Chemical Industries Co., Ltd.), water (10 mL) was added. . Under ice cooling, a solution of p-fluorobenzhydryl chloride (3.61 g, 22.8 mmol) (Wako Pure Chemical Industries Co., Ltd.) / tetrahydrofuran (10 mL) (Wako Pure Chemical Industries Co., Ltd.) was added dropwise thereto for 9 minutes while stirring. The water bath was removed, returned to room temperature, and after stirring for 43.5 hours, tetrahydrofuran was distilled off under reduced pressure. Under ice cooling, hydrochloric acid (4 mL) (Wako Pure Chemical Industries Co., Ltd.) was added while stirring to prepare a pH of 2 or less. Water (40 mL) was added, and the solid was collected by filtration and washed thoroughly with water. After drying under reduced pressure for 4 hours, it was dissolved in ethyl acetate (200 mL) (Wako Pure Chemical Industries, Ltd.), followed by saturated brine (50 mL) and 5N hydrochloric acid (5 mL) (Wako Pure Chemical Industries Co., Ltd.) The mixed solution and saturated saline (100 mL × 2) were washed. The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries Co., Ltd.), filtered, and the filtrate was concentrated under reduced pressure. To the concentrated residue, tertiary butyl methyl ether (Tokyo Chemical Industry Co., Ltd.) was added, and insoluble matter was collected by filtration to obtain 1.65 g (yield: 38.0%) of Compound 4.

¹ H-NMR (CD ₃ OD): δ 4.01 (2H, m), 4.71 (1H, m), 7.22 (2H, m), 7.96 (2H, m).

N-(p-fluorobenzyl)-L-serine (Compound 4)

<Manufacturing Example 5: Production of Compound 5>

Using the p-methoxybenzylhydrazine chloride and L-serine, Compound 5 was synthesized in the same manner as in the above Compound 4.

¹ H-NMR (CD ₃ OD): δ 3.87 (3H, s), 4.00 (2H, m), 4.71 (1H, m), 7.02 (2H, d), 7.88 (2H, d).

N-(p-methoxybenzyl)-L-serine (Compound 5)

<Manufacturing Example 6: Production of Compound 6>

L-serine methyl ester hydrochloride (1.55 g, 9.96 mmol) (Tokyo Chemical Industry Co., Ltd.) was dispersed in dichloromethane (30 mL) (Wako Pure Chemical Industries Co., Ltd.), and triethyl group was added. Amine (2.25, 22.2 mmol) (Wako Pure Chemical Industries, Ltd.), and ice-cooled, while stirring, p-methylbenzylphosphonium chloride (1.78 g, 11.5 mmol) (Aldrich)/dichloromethane was added dropwise for 3 minutes. (5 mL) solution. The water bath was removed, and the mixture was stirred at room temperature. After stirring for 6 hours, the reaction mixture was diluted with ethyl acetate (100 mL) (Wako Pure Chemical Industries, Ltd.), followed by saturated sodium bicarbonate solution (30 mL), 1N hydrochloric acid. (50 mL) and saturated brine (30 mL, 60 mL × 2 L) were washed. The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries Co., Ltd.), filtered, and the filtrate was concentrated under reduced pressure. The residue was transferred to a gum column chromatography (n-hexane: ethyl acetate = 1:2), and the fractions of the desired material were collected, and concentrated under reduced pressure to obtain 1.88 g (yield: 79.5%) of Compound 6.

¹ H-NMR (CDCl ₃ ): δ 2.41 (3H, s), 2.58 (1H, br s), 3.83 (3H, s), 4.07 (2H, m), 4.88 (1H, m), 7.06 (1H) , d), 7.25 (2H, d), 7.73 (2H, d).

N-(p-methylbenzyl)-L-serine methyl ester (Compound 6)

<Manufacturing Example 7: Production of Compound 7>

After weighing L-serine (1.18 g, 11.2 mmol) (Korean Peptides Co., Ltd. and potassium carbonate (1.71 g, 12.4 mmol) (Wako Pure Chemical Industries Co., Ltd.), water (5 mL) and tetrahydrofuran were added. (5 mL) (Wako Pure Chemical Industries Co., Ltd.). Under ice cooling, p-ethylbenzylidene chloride (2.24 g, 13.3 mmol) was added dropwise for 5 minutes while stirring (Wako Pure Chemical Industries Co., Ltd.). After returning to the room temperature and stirring for 16 hours, the tetrahydrofuran was distilled off under reduced pressure, and hydrochloric acid (3 mL) (Wako Pure Chemical Industries Co., Ltd.) was added thereto under stirring to obtain pH 2. Water (20 mL) was added. The solid was collected by filtration, and washed with water, and then dissolved by triethyl butyl ether (20 mL) (Tokyo Chemical Industry Co., Ltd.), and then washed with saturated brine (10 mL). After drying, the product was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added tris-butyl methyl ether, and the insoluble material was filtered to afford 1.08 g (yield 40.5%) of Compound 7.

¹ H-NMR (CD ₃ OD): δ 1.27 (3H, t), 2.73 (3H, q), 4.02 (2H, m), 4.72 (1H, m), 7.34 (2H, d), 7.82 (2H) , d).

N-(p-ethylbenzylidene)-L-serine (Compound 7)

<Production Example 8: Production of Compound 8>

Using the p-(trifluoromethyl)benzylhydrazine chloride and L-silicic acid, the compound 8 was synthesized in the same manner as in the above compound 7.

¹ H-NMR (CD ₃ OD): δ 4.02 (2H, m), 4.74 (1H, m), 7.81 (2H, d), 8.07 (2H, d).

N-(p-trifluoromethylbenzylbenzyl)-L-serine (Compound 8)

<Manufacturing Example 9: Production of Compound 9>

Compound 9 was synthesized in the same manner as in the above Compound 7 using p-methylbenzylhydrazine chloride and DL-O-methyl-silic acid.

¹ H-NMR (d ₆ -DMSO): δ 2.36 (3H, s), 3.28 (3H, s), 3.71 (2H, m), 4.63 (1H, m), 7.28 (2H, d), 7.80 ( 2H, d), 8.49 (1H, d).

N-(p-methylbenzyl)-DL-O-methylserine (Compound 9)

<Production Example 10: Production of Compound 10>

L-serine (2.00 g, 19.0 mmol) (Symbol Peptide Co., Ltd.) was dispersed in tetrahydrofuran (19 mL) (Wako Pure Chemical Industries Co., Ltd.), and under ice cooling, 2N sodium hydroxide was added while stirring. Aqueous solution (19 mL). Next, 2-naphthylmethyl chloride (3.64 g, 19.1 mmol) (Tokyo Chemical Industry Co., Ltd.) was added. The water bath was removed, returned to room temperature, and stirred for 16 hours, and the tetrahydrofuran was distilled off under reduced pressure. Under ice cooling, hydrochloric acid (4 mL) (Wako Pure Chemical Industries Co., Ltd.) was added while stirring to prepare a pH of 2 or less. The solid was collected by filtration and washed thoroughly with water. Tertiary butyl methyl ether (30 mL) (Tokyo Chemical Industry Co., Ltd.) was added, and insolubles were collected by filtration. It was thoroughly washed with tertiary butyl methyl ether. Further, it was washed with a third-stage butyl methyl ether: ethyl acetate (= 4:1) and n-hexane to obtain 2.92 g (yield: 59.2%) of Compound 10.

¹ H-NMR (CD ₃ OD): δ 4.04 (2H, m), 4.77 (1H, m), 7.59 (2H, m), 7.94 (4H, m), 8.46 (1H, s).

N-(2-naphthylmethyl)-L-serine (Compound 10)

<Production Example 11: Production of Compound 11>

Compound 11 was synthesized in the same manner as in the above compound 6 using p-methylbenzylidene chloride and O-ethinyl-L-seramine hydrochloride.

¹ H-NMR (d ₆ -DMSO): δ 1.91 (3H, s), 2.36 (3H, s), 4.28 (1H, dd), 4.46 (1H, dd), 4.71 (1H, m), 7.29 ( 2H, d), 7.78 (2H, d), 8.68 (1H, d).

N-(p-methylbenzylindenyl)-O-acetamido-L-serine (Compound 11)

<Production Example 12: Production of Compound 12>

Compound 12 was synthesized in the same manner as in the above-mentioned compound 6 using 2-naphthylmethyl chloride and L-silyl acid methyl ester hydrochloride.

¹ H-NMR (d ₆ -DMSO): δ 3.67 (3H, s), 3.84 (2H, m), 4.61 (1H, m), 5.12 (1H, t), 7.62 (2H, m), 8.02 ( 4H, m), 8.53 (1H, s), 8.75 (1H, d).

N-(2-naphthylmethyl)-L-serine methyl ester (Compound 12)

<Production Example 13: Production of Compound 13>

Compound 13 was synthesized in the same manner as in the above Compound 4, using 2-naphthylmethyl chloride and DL-O-methyl-synamic acid.

¹ H-NMR (d ₆ -DMSO): δ 3.31 (3H, s), 3.78 (2H, m), 4.72 (1H, m), 7.62 (2H, m), 8.01 (4H, m), 8.53 ( 1H, s), 8.78 (1H, d).

N-(2-naphthomethyl)-DL-O-methylserine (Compound 13)

<Manufacturing Example 14: Production of Compound 14>

Compound 14 was synthesized in the same manner as in the above Compound 4 using 4-phenylbenzylidene chloride and L-silicic acid.

¹ H-NMR (CD ₃ OD): δ 4.03 (2H, m), 4.75 (1H, m), 7.45 (3H, m), 7.73 (4H, m), 7.99 (2H, s), 8.37 (, H, d).

N-(p-phenylbenzylidene)-L-serine (Compound 14)

<Production Example 15: Production of Compound 15>

To the eggplant type flask, D-serine (1.67 g, 15.9 mmol) (Tokyo Chemical Industry Co., Ltd.), water (9 mL), and potassium carbonate (16.6 g, 16.6 mmol) (Wako Pure Chemical Industries Co., Ltd.) were added. Tetrahydrofuran (9 mL) (Wako Pure Chemical Industries, Ltd.) was added dropwise p-methylbenzylidene chloride (2.59 g, 16.7 mmol) (Aldrich) under ice cooling for 2 minutes while stirring. After the water bath was removed and the mixture was stirred at room temperature for 26 hours, hydrochloric acid (4 mL) (Wako Pure Chemical Industries Co., Ltd.) was added to the reaction mixture to prepare a pH of 2 or less, and the mixture was stirred under ice cooling for 20 minutes. The precipitated crystals were collected by filtration and washed with water. After drying the solid under reduced pressure, 12 mL of ethyl acetate (Wako Pure Chemical Industries Co., Ltd.) was added, and the insoluble matter was collected by filtration. It was washed with ethyl acetate. After drying under reduced pressure for 24 hours, it was recrystallized from a mixed solvent of ethanol (Wako Pure Chemical Industries Co., Ltd.) / water = 5/5 to obtain 2.20 g (yield 62.0%) of Compound 15.

¹ H-NMR (d ₆ -DMSO): δ 2.36 (3H, s), 3.79 (2H, d), 4.46 (1H, q), 7.29 (2H, d), 7.79 (2H, d), 8.28 ( 1H, d).

N-(p-methylbenzyl)-D-serine (Compound 15)

<Manufacturing Example 16: Production of Compound 16>

Compound 16 was synthesized in the same manner as in the above compound 7 using benzhydryl chloride and DL-O-methyl-synamic acid.

¹ H-NMR (d ₆ -DMSO): δ 3.28 (3H, s), 3.72 (2H, m), 4.63 (1H, m), 7.62 (2H, m), 7.51 (3H, m), 7.88 ( 2H, s), 8.58 (1H, d).

N-benzylhydrazine-DL-O-methylserine (Compound 16)

<Manufacturing Example 17: Production of Compound 17>

Compound 17 was synthesized in the same manner as in the above Compound 6 using p-methylbenzylhydrazinyl chloride and L-silylamine ethyl ester hydrochloride.

¹ H-NMR (CDCl ₃ ): δ 1.33 (3H, t), 2.41 (3H, s), 2.70 (1H, t), 4.07 (2H, m), 4.29 (2H, q), 4.84 (1H, m), 7.09 (1H, d), 7.26 (2H, d), 7.73 (2H, d).

N-(p-methylbenzyl)-L-serine ethyl ester (Compound 17)

<Test Example 1: Review of the inhibitory effect against the activation of human normal melanocytes by B-wave ultraviolet rays>

The inhibitory effect of each compound against the melanocyte activation of melanocyte activation factor produced by human keratinocytes by B-wave ultraviolet rays is examined by using the cell proliferation of human normal melanocytes as an indicator. .

Humedia-KG2 medium (Kurabo) was inoculated with a human normal keratinocyte (Kurabo) at a density of 10 × 10 ⁴ /well in a 24-well plate and cultured for 24 hours.

The evaluation compound was dissolved in DMSO at a concentration of 100 mM, and it was diluted 1,000-fold in Humedia-KG2 medium as a sample solution. Further, as a positive control group, tranexamic acid was dissolved in DMSO at a concentration of 100 mM, and it was diluted 1,000-fold in Humedia-KG2 medium as a positive control sample solution. Further, as a negative control group, DMSO was diluted 1,000-fold in Humedia-KG2 medium as a negative control sample solution. Each compound simultaneously sets a concentration that does not affect the cell proliferation of human normal melanocytes.

The culture medium of human normal keratinocytes was exchanged with Humedi-KG2 medium (sample solution) containing a compound of a predetermined concentration, and cultured for further 24 hours. Thereafter, the medium was exchanged with PBS (phosphate buffered physiological saline), and ultraviolet light (FL20S‧E-30/DMR, Toshiba medical product) was used as a light source, and B-wave ultraviolet rays of 5 mJ/cm ^{2 were} irradiated to the cells. After the ultraviolet irradiation, the PBS was exchanged with the sample solution, and after further culturing for 24 hours, the culture supernatant was recovered.

Human normal melanocytes were seeded at a density of 3 × 10 ⁴ /well using Medium 254 medium (Kurabo), seeded in 96-well plates, and cultured for 24 hours. Thereafter, the culture medium was exchanged with the culture supernatant recovered from human normal keratinocytes, and cultured for further 24 hours. After 24 hours of incubation, with Humedia- containing 0.5 mg/mL of 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) KG2 medium was exchanged and cultured for 3 hours.

A The absorbance of the cell lysate dissolved in 2-propanol at 570 nm and 690 nm was measured by a microplate reader (Benchmark Plus, Bio-Rad), and the difference was obtained by subtracting the absorbance at 690 nm from the absorbance at 570 nm.

The inhibitory effect of each compound on melanocyte proliferation was measured by the absorbance of B-wave ultraviolet irradiation DMSO addition group (negative control group) as 100 The generation rate is expressed as a percentage (%).

A The lower the rate of production, the lower the melanocyte proliferation rate, and thus the activation of melanocytes by the melanocyte activation factor produced and released by human normal keratinocytes can be judged. In order to evaluate the compound, the inhibitory power is large.

The melanocyte proliferation rate showed the mean and standard deviation of 3 cases.

As a result of Table 1, although the melanocyte activation inhibitory price of the compound was different, all the compounds showed an excellent inhibitory effect. Therefore, it is understood that all of the compounds have an excellent inhibitory effect on the activation of melanocytes by melanocyte activation factors produced and released by human normal keratinocytes.

<Test Example 2: Pigment precipitation inhibition by ultraviolet irradiation of Compound 1 using colored guinea pig>

The back skin of 8 colored guinea pigs was removed and shaved with electric hair clippers and razors. This part was covered with a black cloth with 2 × 2 cm illumination windows at 4 places on the upper left and right sides, and then FL20S-E30 The lamp was used as a light source to irradiate ultraviolet rays of 300 mJ/cm ² . This operation was repeated on the 1, 3, 5, and 8 days of the test, and the test sites at 4 sites induced pigmentation. The evaluation compound (Compound 1) was dissolved in ethanol to prepare 3% (w/v). Further, ethanol was applied as a solvent control group. At the end of the ultraviolet irradiation at the first day of the test, the application of each of the evaluation compounds was started. Each of the evaluation compounds was applied to 30 μL of each of the designated test sites once a day, and the application was continued for 5 weeks (test to the 35th day). Before the ultraviolet irradiation before the coating start date (the first day of the test) and after 5 weeks (the 36th day of the test), the skin brightness (L* value) of each test site was measured using a color difference meter (CR-200, Konica Minolta Co., Ltd.). The value of the difference ΔL* of the L* value before the ultraviolet irradiation was subtracted from the L* value on the 36th day of the test. That is, the L* value is lower as the degree of pigmentation is stronger, and the larger the ΔL* value, the more the pigmentation can be suppressed. The results are shown in Table 2.

<Example 1 : Production Example 1 of the external preparation for skin of the present invention>

According to the description of Table 3, the cosmetic (cosmetic) of the external preparation for skin of the present invention was produced. That is, the prescription component was heated to 80 ° C, stirred, dissolved, and stirred and cooled to obtain a cosmetic (makeup 1). In the same manner, the lotion of Comparative Example 1 in which "the pigmentation inhibitor of the present invention (Compound 1)" was replaced with water, and "The pigment precipitation inhibitor (Compound 1) of the present invention" were replaced with Arbutin (arbutin). Comparative Example 2.

<Example 2: Production Example 2 of the external preparation for skin of the present invention>

According to the prescription shown in Table 4, a water cream in oil was prepared. Specifically, the components of each of 1 and 2 were heated to 80 ° C, and the components of 2 were slowly added in 1 to be emulsified, and the particles were homogenized by a homogenizer, followed by stirring and cooling to obtain a cosmetic (cream 1).

<Example 3: Production Example of Cosmetic of the Present Invention>

According to the formulation shown in Table 5, a cosmetic (emulsion 1) of the external composition for skin of the present invention was prepared. Specifically, the components of 1, 2, and 3 were heated to 80 ° C, and the mixture was added to 2 while stirring, and after neutralizing, 1 was slowly stirred, and the emulsified particles were homogenized by a homogenizer to obtain an emulsion.

<Test Example 3: Pigment precipitation inhibitory effect by ultraviolet irradiation of lotion 1 by humans>

The pigmentation inhibiting effect was examined using the cosmetic materials of the lotion 1, the comparative example 1, and the comparative example 2. In the inner part of the wrist of the member who participated in the free will, the 1.5 cm × 1.5 cm part is divided into two upper and lower sections, each of which takes 2 places and a total of 4 places, and the minimum amount of erythema (1 MED) is irradiated once a day for 1 day. 3 times for 3 days. One day after the end of the irradiation, 50 μL of the sample was applied every 28 days for 28 consecutive days. The 1 part serves as a non-treated part. 24 hours after the application was completed, the skin brightness (L* value) of each test portion was measured with a color difference meter (CR-300, Konica Minolta Co., Ltd.), and ΔAL with respect to the L value of the untreated portion was calculated. The L* value is a value in which the degree of pigmentation is higher and lower. Therefore, the larger the ΔL* value, the more the pigmentation can be suppressed. The results are shown in Table 6. From this, it is understood that the cosmetic (cosmetic water 1) of the external preparation for skin of the present invention has an excellent pigmentation inhibiting effect. It is considered to be a pigmentation inhibiting action of the aforementioned Compound 1 contained in the lotion 1.

Industrial use possibility

The present invention can be applied to a skin external preparation such as a cosmetic for whitening.

Claims (13)

A use of a compound represented by the following formula (1), an isomer thereof, and/or a pharmacologically acceptable salt thereof, for use in the manufacture of a prophylactic or improving agent for pigmentation: Wherein R ₁ represents an unsubstituted or substituted aromatic group; R ₂ represents a hydrogen atom, a straight or branched alkyl group having a carbon number of 1 to 4, and a linear chain having a carbon number of 1 to 4; Or a sulfhydryl group of a branched alkyl chain; R ₃ represents a hydrogen atom or a linear or branched alkyl group having a carbon number of 1 to 4. The use of the first aspect of the patent application, wherein in the formula (1), R ₁ is an unsubstituted or aromatic group having the following substituent: the substituent is a straight chain or a fraction having a carbon number of 1 to 6. An alkyl group, an alkoxy group having a linear or branched alkyl chain having 1 to 6 carbon atoms, an alkylamino group having a linear or branched alkyl chain having 1 to 6 carbon atoms, a mercapto group having a linear or branched alkyl chain having 1 to 6 carbon atoms, an ester group having a linear or branched alkyl chain having 1 to 6 carbon atoms, a halogen atom or a halogenated alkyl group, or a hydroxyl group Or an amine group; R ₂ is a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an ethyl group, a propyl group or a butyl group; ₃ is a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tertiary butyl group. The use of the second aspect of the patent application, wherein in the formula (1), R ₁ is a phenyl group, a naphthyl group or a biphenyl group which is unsubstituted or has the following substituents, and the substituent is: a carbon number of 1~ a linear or branched alkyl group of 6 , an alkoxy group having a linear or branched alkyl chain having 1 to 6 carbon atoms, or a linear or branched alkyl chain having 1 to 6 carbon atoms; An alkylamino group, a fluorenyl group having a linear or branched alkyl chain having 1 to 6 carbon atoms, an ester group having a linear or branched alkyl chain having 1 to 6 carbon atoms, a halogen atom Or an alkyl group, a hydroxyl group or an amine group; R ₂ is a hydrogen atom, a methyl group or an ethyl group; and R ₃ is a hydrogen atom, a methyl group or an ethyl group. The use according to any one of claims 1 to 3, wherein the compound represented by the formula (1) is N-benzylindenyl-serine, N-(p-methylbenzylidene) silk Amino acid, N-(p-ethylbenzylidene) serine, N-(p-methoxybenzyl) serine, N-(p-fluorobenzyl) serine, N- (p-trifluoromethylbenzylbenzyl) serine, N-(2-naphthylmethyl) serine, N-(4-phenylbenzyl) serine, N-(p-A Methyl benzyl amide, methyl N-methyl, N-(p-methylbenzylindenyl) urinate, methyl N-(2-naphthylmethyl) amide, N-benzyl fluorenyl- O-methylserine, N-(p-methylbenzyl)-O-methylserine, N-(p-methylbenzyl)-O-acetyl-serine, N -(2-Naphthylmethyl)-O-methylserine, its isomers and/or such pharmacologically acceptable salts. A use of a compound represented by the following formula (2), an isomer thereof, and/or a pharmacologically acceptable salt thereof, for use in the manufacture of a prophylactic or improving agent for pigmentation: Wherein R ₄ represents an unsubstituted or substituted aromatic group, except for an unsubstituted phenyl group; R ₅ represents a hydrogen atom, a straight or branched alkyl group having a carbon number of 1 to 4, a fluorenyl group having a linear or branched alkyl chain having a carbon number of 1 to 4; R ₆ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, wherein R ₄ is a substituent In the case of a phenyl group or an unsubstituted naphthyl group, at least one of R ₅ or R ₆ is not hydrogen. The use of the fifth aspect of the patent application, wherein in the formula (2), R ₄ is an unsubstituted or aromatic group having the following substituents, except for the unsubstituted phenyl group, the substituent is: carbon a straight or branched alkyl group of 1 to 6 , an alkoxy group having a linear or branched alkyl chain having 1 to 6 carbon atoms, or a linear or branched having a carbon number of 1 to 6. An alkylamine group of an alkyl chain, a fluorenyl group having a linear or branched alkyl chain having 1 to 6 carbon atoms, an ester having a linear or branched alkyl chain having 1 to 6 carbon atoms. a halogen atom or a halogenated alkyl group, a hydroxyl group or an amine group; R ₅ is a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tertiary butyl group, and a Anthracenyl, propyl fluorenyl or butyl fluorenyl; R ₆ is a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tertiary butyl group, wherein R ₄ is substituted In the case of a phenyl group or an unsubstituted naphthyl group, at least one of R ₅ or R ₆ is not a hydrogen atom. The use according to claim 6, wherein in the formula (2), R ₄ is a phenyl group having the following substituent, an unsubstituted or naphthyl group or a biphenyl group having the following substituents: a linear or branched alkyl group having 1 to 6 carbon atoms, an alkoxy group having a linear or branched alkyl chain having 1 to 6 carbon atoms, or a linear or branched carbon number of 1 to 6 An alkylamino group of an alkyl chain of a branch, a fluorenyl group having a linear or branched alkyl chain having 1 to 6 carbon atoms, or a linear or branched alkyl chain having 1 to 6 carbon atoms; An ester group, a halogen atom or a halogenated alkyl group, a hydroxyl group or an amine group; R ₅ is a hydrogen atom, a methyl group or an ethyl fluorenyl group; and R ₆ is a hydrogen atom, a methyl group or an ethyl group; wherein R ₄ is a substituted phenyl group; In the case of an unsubstituted naphthyl group, at least one of R ₅ or R ₆ is not hydrogen. A use of a compound, an isomer thereof and/or a pharmacologically acceptable salt thereof according to any one of claims 1 to 7 for the manufacture of a prophylactic or ameliorating agent for pigmentation Skin external preparation. The use of the invention of claim 8, wherein the compound, the isomer thereof and/or the pharmacologically acceptable salt thereof are contained in an amount of from 0.0001% by mass to 20% by mass based on the total amount of the external preparation for skin. The use of the skin external application agent according to claim 8 or 9, wherein the external preparation for skin is a cosmetic containing a medical external product. a compound represented by the following formula (2), an isomer thereof, and/or a pharmacologically acceptable salt thereof, Wherein R ₄ represents an unsubstituted or aromatic group having the following substituents, except for the unsubstituted phenyl group; the substituent is a straight or branched alkyl group having a carbon number of 1 to 6, having An alkoxy group having a linear or branched alkyl chain having 1 to 6 carbon atoms, an alkylamino group having a linear or branched alkyl chain having 1 to 6 carbon atoms, having a carbon number of 1~ a mercapto group of a linear or branched alkyl chain of 6 , an ester group having a linear or branched alkyl chain having 1 to 6 carbon atoms, a halogen atom or a halogenated alkyl group, a hydroxyl group or an amine group; R ₅ Represents a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tertiary butyl group, an ethyl fluorenyl group, a propyl fluorenyl group or a butyl group; R ₆ represents a hydrogen atom, a group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tertiary butyl group, wherein R ₄ is a substituted phenyl group or an unsubstituted naphthyl group, R ₅ Or at least one of R ₆ is not hydrogen. The compound of claim 11, the isomer thereof and/or the pharmacologically acceptable salt thereof, wherein in the formula (2), R ₄ represents a phenyl group having the following substituents, a naphthyl group or a biphenyl group substituted or having a substituent of a straight or branched alkyl group having 1 to 6 carbon atoms or a linear or branched alkyl group having 1 to 6 carbon atoms. Alkoxy group of a chain, an alkylamino group having a linear or branched alkyl chain having 1 to 6 carbon atoms, a fluorenyl group having a linear or branched alkyl chain having 1 to 6 carbon atoms, An ester group having a linear or branched alkyl chain having a carbon number of 1 to 6, a halogen atom or a halogenated alkyl group, a hydroxyl group or an amine group; R ₅ represents a hydrogen atom, a methyl group or an ethyl group; and R ₆ represents hydrogen. In the case of an atom, a methyl group or an ethyl group, wherein R ₄ is a substituted phenyl group or an unsubstituted naphthyl group, at least one of R ₅ or R ₆ is not a hydrogen atom. A compound represented by the following formula: N-(p-methylbenzyl)-L-serine (Compound 1), N-benzylindenyl-L-serine (Compound 2), N-(p-methylbenzyl)-DL-serine (Compound 3), N-(p-fluorobenzyl)-L-serine (Compound 4), N-(p-methylbenzylindenyl)-L-serine methyl ester (compound 6), N-(p-ethylbenzylidene)-L-serine (Compound 7), N-(p-trifluoromethylbenzylidene)-L-serine (Compound 8), N-(p-methylbenzyl)-DL-O-methylserine (Compound 9), N-(2-naphthylmethyl)-L-serine (Compound 10), N-(p-methylbenzyl)-O-acetyl-L-serine (Compound 11), N-(2-naphthomethyl)-L-serine methyl ester (compound 12), N-(2-naphthomethyl)-DL-O-methylserine (Compound 13), N-(p-phenylbenzylidene)-L-serine (Compound 14), N-(p-methylbenzyl)-D-serine (Compound 15), N-benzylhydrazine-DL-O-methylserine (Compound 16), or N-(p-Methylbenzylidene)-L-serine ethyl ester (Compound 17).