HK1173368B - Pigmentation-preventing or-ameliorating agent - Google Patents

Description

Pigmentation preventing or improving agent

Technical Field

The present invention relates to a skin external preparation which is preferably used for a cosmetic preparation (including quasi-drugs). Specifically, the present invention relates to an external preparation for skin, characterized by containing a pigmentation-preventing or-improving agent comprising a compound represented by the following general formula (1), isomers thereof and/or pharmacologically acceptable salts thereof.

Wherein R is₁Represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms, R₂Represents a hydrogen atom, a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 8 carbon atoms, a substituted or unsubstituted aromatic group having 5 to 12 carbon atoms, a substituted or unsubstituted polycyclic condensed aromatic group or a substituted or unsubstituted heterocyclic group, R₃Represents a substituted or unsubstituted aromatic group, a substituted or unsubstituted polycyclic fused aromatic group or a substituted or unsubstituted heterocyclic group having 5 to 15 carbon atoms, n represents an integer of 1 or 2, and m represents an integer of 0 to 3.

Background

The state of presence of, for example, pigmentation, freckles, melasma and age spots caused on the skin after tanning makes it possible to extremely promote melanin production due to activation of pigment cells (melanocytes) in the skin. It is well known that components having a function of preventing or improving the occurrence and deterioration of the above-mentioned skin pigment diseases are compounds having a skin whitening function (skin whitening agents) including, for example, ascorbic acid derivatives, hydrogen peroxide, colloidal sulfur, glutathione, hydroquinone and catechol (see, for example, non-patent document 1 and non-patent document 2). Skin external preparations blended with the above components as active ingredients are widely used. At present, various mechanisms of action have been reported as those possessed by compounds called skin whitening agents, including, for example, tyrosinase inhibitory action, tyrosinase-related protein degradation, and melanin transfer inhibition by inhibiting dendritic elongation of melanocytes. The target molecule is present with respect to the corresponding mechanism of action. In order to express a high skin whitening effect, organic low molecular weight compounds that appropriately interact with target molecules are useful. In addition, organic low molecular weight compounds that properly interact with each target molecule have different structural characteristics depending on each target molecule. Therefore, in order to make maximum use of the pharmacological effects exhibited by organic low molecular weight compounds, many studies have also been conducted regarding optimization of chemical structures. Currently, research on skin whitening agents is not limited to compounds having high efficiency and high selectivity with respect to existing target molecules, and research is broadened to, for example, compounds acting on a plurality of skin whitening target molecules simultaneously and compounds having new mechanisms of action. The above skin whitening agent is expected to have a high skin whitening effect. In fact, screening has been performed on compounds having excellent skin whitening functions, while finding useful compounds having various chemical structures or pharmacological characteristics. Even now there is still a need for any skin lightening agent with a new scaffold.

In almost all cases, proteins constituting a living body are composed of 20 types of α -amino acids having different side chains called "essential amino acids". In addition to the functions constituting biological components, various biological activities of the above-mentioned α -amino acids have been reported. Further, methionine and cysteine each having a sulfur atom in the above-mentioned α -amino acid and in the chemical structure are expected to have any biological activity caused by the characteristics of the sulfur atom different from those of other α -amino acids, and they are applicable to various fields including, for example, pharmaceuticals, cosmetics, and foods. In particular, in the cosmetic field, for example, use as a reducing component of hair (see, for example, patent document 1) and a moisturizing component relating to an external preparation for skin blended with methionine and cysteine (see, for example, patent document 2) have been reported. N-acetyl-L-cysteine (which is a cysteine derivative) is metabolized to glutathione, which is an antioxidant. Thus, N-acetyl-L-cysteine is used as a supplement. However, when such α -amino acid derivatives comprising a sulfur atom in the molecular structure are applied to, for example, cosmetic preparations, problems arise, for example, the amino acids themselves or compositions such as external preparations for skin are made unstable, and unpleasant odors are caused due to their decomposition products. On the other hand, cysteic acid and any derivative having an aliphatic acyl group on its nitrogen atom are known to be involved in, for example, oil-soluble base materials (see, for example, patent document 3), surfactants (see, for example, patent document 4), mucolytic activity, and antioxidant function (see, for example, patent document 5). Further, N-benzyl derivatives of cysteic acid are known to be involved in antioxidant function (see, for example, patent document 6). However, to the extent that the present inventors know, the compounds represented by the above general formula (1), their isomers and/or their pharmacologically acceptable salts are not known to have pigmentation-preventing or-improving effects. Furthermore, to the extent that the present inventors are aware, it is not known that the compound of interest has good solubility in hydrophilic or lipophilic media, that the compound is extremely stable in compound and pharmaceutical formulation forms, and that the compound hardly causes any unpleasant odor when used in cosmetic formulations such as skin external preparations and the like.

The foregoing technical literature

Patent documents:

patent document 1: JP 2005-162699A;

patent document 2: JP 2004-323401A;

patent document 3: JP 05-117295A;

patent document 4: JP 2002-145736A;

patent document 5: JP 2005-530883A;

patent document 6: JP 11-343235A.

Non-patent documents:

non-patent document 1: "Useful of Cosmetics, Evaluation Techniques and Future Overview", reviewed by Katsuyuki TAKEDA, published by YAKUJI NIPPO LIMITED (2001);

non-patent document 2: takayuki Omori, FRAGRANCE JOURNAL, supple (JOURNAL of China), No. 14, 1995, 118-.

Summary of The Invention

The present invention has been made under the above circumstances, and an object of the present invention is to provide a pigmentation preventing or improving agent having a novel scaffold, which is preferably useful for preventing or improving pigmentation, and a skin external preparation containing the preventing or improving agent as a component.

In view of the foregoing, the present inventors have repeatedly made extensive efforts while finding new pigmentation-preventing or-improving agents, preferably usable in cosmetic preparations (provided that the cosmetic preparations contain quasi-drugs). As a result, it has been found that the compounds represented by the above general formula (1), their isomers and/or their pharmacologically acceptable salts are excellent in the effect of preventing or improving pigmentation. Thus, the present invention has been completed. The present invention is as follows.

<1> a pigmentation preventing or improving agent comprising a compound represented by the following general formula (1), an isomer thereof and/or a pharmacologically acceptable salt thereof:

(1)

[ wherein:

R₁represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms;

R₂represents a hydrogen atom, a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 8 carbon atoms, a substituted or unsubstituted aromatic group having 5 to 12 carbon atoms, a substituted or unsubstituted polycyclic fused aromatic group, or a substituted or unsubstituted heterocyclic group;

R₃represents a substituted or unsubstituted aromatic group, a substituted or unsubstituted polycyclic fused aromatic group or a substituted or unsubstituted heterocyclic group having 5 to 15 carbon atoms;

n represents an integer of 1 or 2, and m represents an integer of 0 to 3. ]

<2> the pigmentation preventing or improving agent as defined in <1>, wherein in the general formula (1):

R₁represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms;

R₂represents a hydrogen atom;

R₃represents a substituted or unsubstituted aromatic group, a substituted or unsubstituted polycyclic fused aromatic group or a substituted or unsubstituted heterocyclic group having 5 to 15 carbon atoms;

n represents an integer of 1 or 2, and m represents an integer of 0 to 3.

<3> the pigmentation preventing or improving agent as defined in <1> or <2>, wherein in the general formula (1):

R₁represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms;

R₂represents a hydrogen atom;

R₃represents a substituted or unsubstituted aromatic group, a substituted or unsubstituted polycyclic fused aromatic group or a substituted or unsubstituted heterocyclic group having 5 to 15 carbon atoms;

n represents an integer of 1 or 2, and m represents 0.

<4> the pigmentation preventing or improving agent as defined in any one of <1> to <3>, wherein in the general formula (1):

R₁represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms;

R₂represents a hydrogen atom;

R₃represents a substituted or unsubstituted aromatic group, a substituted or unsubstituted polycyclic fused aromatic group or a substituted or unsubstituted heterocyclic group having 5 to 15 carbon atoms;

n represents 1, and m represents 0.

<5> the pigmentation preventing or improving agent as defined in any one of <1> to <3>, wherein the compound represented by the general formula (1) is N- (o-toluoyl) cysteic acid (compound 1), N- (m-toluoyl) cysteic acid (compound 2), N- (p-toluoyl) cysteic acid (compound 3), N- (p-methoxybenzoyl) cysteic acid (compound 4), N- (4-phenylbenzoyl) cysteic acid (compound 5), N- (p-toluoyl) homocysteic acid (compound 6), isomers thereof and/or pharmacologically acceptable salts thereof:

n- (o-toluoyl) cysteic acid (compound 1);

n- (m-toluoyl) cysteic acid (compound 2);

n- (p-toluoyl) cysteic acid (compound 3);

n- (p-methoxybenzoyl) cysteic acid (compound 4);

n- (4-phenylbenzoyl) cysteic acid (compound 5);

n- (p-toluoyl) homocysteic acid (Compound 6).

<6> an external preparation for skin containing the pigmentation preventing or improving agent as defined in any one of <1> to <5 >.

<7> the external preparation for skin as defined in <6>, wherein the pigmentation-preventing or-improving agent is contained in an amount of 0.0001% by mass to 20% by mass relative to the total amount of the external preparation for skin.

<8> the external preparation for skin as defined in <6> or <7>, wherein the external preparation for skin is a cosmetic preparation (provided that quasi-drug is contained).

<9> an external preparation for skin whitening, which comprises the compound represented by the general formula (1), isomers thereof and/or pharmacologically acceptable salts thereof.

<10> the compound represented by the general formula (1) as defined above, the compounds as defined in <2> to <5> as defined above, their isomers and/or their pharmacologically acceptable salts for preventing or improving pigmentation.

<11> a pigmentation preventing or improving method comprising administering a compound represented by the general formula (1) as defined above, compounds as defined in <2> to <5> as defined above, isomers thereof and/or pharmacologically acceptable salts thereof to a subject in need of pigmentation prevention or improvement.

Modes for carrying out the invention

< pigmentation preventing or ameliorating agent as an essential component in the skin external preparation of the present invention >

The external preparation for skin of the present invention is characterized by containing a pigmentation-preventing or-improving agent containing the compound represented by the above general formula (1), an isomer thereof and/or a pharmacologically acceptable salt thereof. The effect of the pigmentation preventing or improving agent of the present invention includes, in addition to the pigmentation suppressing effect of lightening or eliminating already formed pigmentation, an effect of preventing pigmentation from being formed in the future. Any component is suitable for the pigmentation preventing or improving agent of the present invention without any particular limitation, provided that the component is present in the compound represented by the above general formula (1), their isomers and/or their pharmacologically acceptable salts, and that the component has the effect of preventing or improving pigmentation. More preferably, however, the component having the effect of suppressing pigmentation may be appropriately exemplified in the "ultraviolet-induced pigmentation suppression test using guinea pigs" described later. The component having the effect of inhibiting pigmentation in the above pigmentation inhibition test refers to a component for confirming the effect of inhibiting pigmentation in a group to which a substance to be evaluated is administered, as compared with a control group (solvent control group). More preferably, it is appropriate to provide a component that demonstrates a statistically significant difference in the effect of inhibiting pigmentation with respect to the group to which the substance to be evaluated is administered, as compared with the control group.

The compounds represented by the general formula (1), their isomers and/or their pharmacologically acceptable salts will now be described. In the formula, R₁Represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms; r₂Represents a hydrogen atom, a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 8 carbon atoms, a substituted or unsubstituted aromatic group having 5 to 12 carbon atoms, a substituted or unsubstituted polycyclic fused aromatic group, or a substituted or unsubstituted heterocyclic group; r₃Represents a substituted or unsubstituted aromatic group, a substituted or unsubstituted polycyclic fused aromatic group or a substituted or unsubstituted heterocyclic group having 5 to 15 carbon atoms; n represents an integer of 1 or 2; and m represents an integer of 0 to 3.

R is as defined above₁Represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms, more preferably having 1 to 4 carbon atoms. Specific examples can be preferably exemplified by, for example, a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a 1-methylbutyl group, a n-hexyl group, a 1-methylpentyl group, a n-heptyl group and a n-octyl group. More preferably, a hydrogen atom, a methyl group and an ethyl group can be appropriately exemplified.

R₂Represents a hydrogen atom, a substituted or unsubstituted aliphatic hydrocarbon having 1 to 8 carbon atoms, more preferably having 1 to 4 carbon atomsA substituted or unsubstituted aromatic group, a substituted or unsubstituted polycyclic fused aromatic group, or a substituted or unsubstituted heterocyclic group having 5 to 12 carbon atoms. As the substituent, there can be preferably exemplified, for example, an alkyl group having 1 to 6 carbon atoms, more preferably having 1 to 4 carbon atoms, an alkoxy group having an alkyl chain having 1 to 6 carbon atoms, more preferably having 1 to 4 carbon atoms, an alkoxyalkyl group (preferably composed of an alkoxy group having an alkyl chain having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms), an aromatic or polycyclic condensed aromatic group (the aromatic group or polycyclic condensed aromatic group is preferably a phenyl group or naphthyl group) having an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, and a hydroxyl group.

With respect to R₂Specific examples of the group represented by (A) are preferably exemplified by a hydrogen atom, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, hydroxyethyl group, hydroxypropyl group, phenyl group, methylphenyl group, ethylphenyl group, propylphenyl group, methoxyphenyl group, ethoxyphenyl group, propoxyphenyl group, benzyl group, methylbenzyl group, ethylbenzyl group, methoxybenzyl group, ethoxybenzyl group, propoxybenzyl group, phenylethyl group, methylphenylethyl group, ethylphenylethyl group, propylphenylethyl group, methoxyphenylethyl group, ethoxyphenylethyl group, propoxyphenylethyl group, naphthyl group, methylnaphthyl group, ethylnaphthyl group, methoxynaphthyl group, ethoxynaphthyl group, naphthylmethyl group, methylnaphthylmethyl group, ethylnaphthylmethyl group, methoxynaphthylmethyl group, ethoxynaphthylmethyl group, naphthylethyl group, methylnaphthylethyl group, n, Ethylnaphthylethyl, methoxynaphthylethyl, ethoxynaphthylethyl and biphenyl. More preferably, a hydrogen atom, a methyl group, an ethyl group and a benzyl group can be appropriately exemplified.

R₃Represents a substituted or unsubstituted aromatic group, a substituted or unsubstituted polycyclic fused aromatic group or a substituted or unsubstituted heterocyclic group having 5 to 15 carbon atoms. As the substituent, there can be preferably exemplified, for example, an alkyl group having 1 to 6 carbon atoms, more preferably having 1 to 4 carbon atoms, a group containing a group having 1 to 6 carbon atoms,More preferably an alkoxy group having an alkyl chain of 1 to 4 carbon atoms, an alkylamino group having an alkyl chain of 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, a halogen atom, a haloalkyl group (preferably having an alkyl chain of 1 to 4 carbon atoms), a hydroxyl group and an amino group.

With respect to R₃Specific examples of the group represented by (A) are preferably exemplified by pyridyl, methylpyridyl, ethylpyridyl, propylpyridyl, methoxypyridyl, ethoxypyridyl, propoxypyridyl, hydroxypyridyl, aminopyridyl, N-methylaminopyridyl, N-dimethylaminopyridyl, N-diethylaminopyridyl, chloropyridyl, fluoropyridyl, difluoropyridyl, trifluoromethylpyridyl, phenyl, methylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, hydroxyphenyl, aminophenyl, N-methylaminophenyl, N-ethylaminophenyl, N-dimethylaminophenyl, N-diethylaminophenyl, chlorophenyl, fluorophenyl, and the like, Difluorophenyl, trifluoromethylphenyl, naphthyl, methylnaphthyl, ethylnaphthyl, propylnaphthyl, methoxynaphthyl, ethoxynaphthyl, propoxytaphthyl, hydroxynaphthyl, aminonaphthyl, N-methylaminonaphthyl, N-ethylaminonaphthyl, N-dimethylaminonaphthyl, N-diethylaminonaphthyl, chloronaphthyl, fluoronaphthyl, difluoronaphthyl, trifluoromethylnaphthyl, biphenyl, methylbiphenyl, ethylbiphenyl, methoxybiphenyl, and ethoxybiphenyl. More preferably, pyridyl, phenyl, methylphenyl, ethylphenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl, trifluoromethylphenyl, naphthyl and biphenyl groups can be suitably exemplified.

The number of substituents on the aliphatic hydrocarbon group, the aromatic group, the polycyclic condensed aromatic group or the heterocyclic group can be preferably exemplified by 0 to 3, and the number is more preferably 0 or 1. One or more of the above substituents may be independently present as a substituent on the aliphatic hydrocarbon group, the aromatic group, the polycyclic condensed aromatic group or the heterocyclic group, respectively.

As described above, n represents an integer of 1 or 2, and m represents an integer of 0 to 3.

Those preferably usable as the compound represented by the above general formula (1) can be preferably exemplified by the compounds defined in the above <2>, their isomers and/or their pharmacologically acceptable salts. More preferably usable ones can be preferably exemplified by the compounds defined in the above <3>, their isomers and/or their pharmacologically acceptable salts. Very much more preferably usable ones can be preferably exemplified by the compounds defined in the above <4>, their isomers and/or their pharmacologically acceptable salts. Preferable compounds included in the compounds represented by the above general formula (1) and the compounds defined in <2> to <4> are specifically exemplified by N- (o-toluoyl) cysteic acid (compound 1), N- (m-toluoyl) cysteic acid (compound 2), N- (p-toluoyl) cysteic acid (compound 3), N- (p-methoxybenzoyl) cysteic acid (compound 4), N- (4-phenylbenzoyl) cysteic acid (compound 5), N- (p-toluoyl) homocysteic acid (compound 6), isomers thereof, and/or pharmacologically acceptable salts thereof. The above compounds have excellent effects of preventing or improving pigmentation. In addition, the compound is excellent in solubility in hydrophilic or lipophilic solvents, and pharmaceutical preparations such as external preparations for skin and the like are easily produced. In addition, the compound is excellent in skin-retaining property and stability in pharmaceutical preparations, the compound does not cause odor interfering with product recognition, and the compound exhibits an excellent effect of preventing or improving pigmentation.

Will now be described in the above<2>The compound as defined in (1). In the formula, R₁Represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms; r₂Represents a hydrogen atom; r₃Represents a substituted or unsubstituted aromatic group, a substituted or unsubstituted polycyclic fused aromatic group or a substituted or unsubstituted heterocyclic group having 5 to 15 carbon atoms; n represents an integer of 1 or 2; and m represents an integer of 0 to 3.

R is as defined above₁To representA hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms. Specific examples can be preferably exemplified by, for example, a hydrogen atom, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group and octyl group. More preferably, a hydrogen atom, a methyl group and an ethyl group can be appropriately exemplified.

R is as defined above₃Represents a substituted or unsubstituted aromatic group, a substituted or unsubstituted polycyclic fused aromatic group or a substituted or unsubstituted heterocyclic group having 5 to 15 carbon atoms. As the substituent, there can be preferably exemplified, for example, an alkyl group having 1 to 6 carbon atoms, more preferably having 1 to 4 carbon atoms, an alkoxy group having an alkyl chain having 1 to 6 carbon atoms, more preferably having 1 to 4 carbon atoms, an alkylamino group having an alkyl chain having 1 to 6 carbon atoms, more preferably having 1 to 4 carbon atoms, a halogen atom, a haloalkyl group (preferably having an alkyl chain having 1 to 4 carbon atoms), a hydroxyl group and an amino group.

With respect to R₃Specific examples of the group represented can be preferably described as, for example, pyridyl, methylpyridyl, ethylpyridyl, propylpyridyl, methoxypyridyl, ethoxypyridyl, propoxypyridyl, hydroxypyridyl, aminopyridyl, N-methylaminopyridyl, N-dimethylaminopyridyl, N-diethylaminopyridyl, chloropyridyl, fluoropyridyl, difluoropyridyl, trifluoromethylpyridyl, phenyl, methylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, hydroxyphenyl, aminophenyl, N-methylaminophenyl, N-ethylaminophenyl, N-dimethylaminophenyl, N-diethylaminophenyl, chlorophenyl, fluorophenyl, o-butyl, N-diethylaminophenyl, N-chlorophenyl, N-fluorophenyl, N-butyl, N, Difluorophenyl, trifluoromethylphenyl, naphthyl, methylnaphthyl, ethylnaphthyl, propylnaphthyl, methoxynaphthyl, ethoxynaphthyl, propoxytaphthyl, hydroxynaphthyl, aminonaphthyl, N-methylaminonaphthyl, N-ethylaminonaphthyl, N-dimethylaminonaphthyl, N-diethylaminonaphthyl, chloronaphthyl, fluoronaphthyl, difluoronaphthyl, trifluoromethylnaphthyl, biphenyl, methylbiphenyl, ethylbiphenyl, methoxybiphenyl and ethoxybiphenyl. More preferably, pyridyl, phenyl, methylphenyl, ethylphenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl, trifluoromethylphenyl, naphthyl and biphenyl groups can be suitably exemplified.

The number of substituents on the aromatic group, polycyclic condensed aromatic group or heterocyclic group can be preferably exemplified by 0 to 3, and the number is more preferably 0 or 1. One or more of the above substituents may be independently present as a substituent on the aliphatic hydrocarbon group, the aromatic group, the polycyclic condensed aromatic group or the heterocyclic group, respectively.

As described above, n represents an integer of 1 or 2, and m represents an integer of 0 to 3.

Specifically, the compounds defined in <2> above are not included in the compounds defined in <3> or <4> above. N- (phenylethylcarbonyl) cysteic acid, N- (phenylpropylcarbonyl) cysteic acid, N- (benzylcarbonyl) cysteic acid, N- (methylbenzylcarbonyl) cysteic acid, N- (ethylbenzylcarbonyl) cysteic acid, N- (propylbenzylcarbonyl) cysteic acid, N- (butylbenzylcarbonyl) cysteic acid, N- (methoxybenzylcarbonyl) cysteic acid, N- (ethoxybenzylcarbonyl) cysteic acid, N- (propoxybenzylcarbonyl) cysteic acid, N- (butoxybenzylcarbonyl) cysteic acid, N- (hydroxybenzylcarbonyl) cysteic acid, N- (aminobenzylcarbonyl) cysteic acid, N- (N' -methylaminobenzylcarbonyl) cysteic acid, N- (benzylcarbonyl) cysteic acid, N- (N ' -ethylaminobenzylcarbonyl) cysteic acid, N- (N ', N ' -dimethylaminobenzylcarbonyl) cysteic acid, N- (N ', N ' -diethylaminobenzylcarbonyl) cysteic acid, N- (chlorobenzylcarbonyl) cysteic acid, N- (fluorobenzylcarbonyl) cysteic acid, N- (difluorobenzylcarbonyl) cysteic acid, N- (trifluoromethylbenzylcarbonyl) cysteic acid, N- (phenylethylcarbonyl) cysteic acid ethyl ester, N- (phenylpropylcarbonyl) cysteic acid ethyl ester, [ N- (benzylcarbonyl) cysteic acid ] ethyl ester, [ N- (methylbenzylcarbonyl) cysteic acid ] ethyl ester, [ N- (ethylbenzylcarbonyl) cysteic acid ] ethyl ester, N- (ethylbenzylcarbonyl) cysteic acid ethyl ester, N- (N ', N ' -dimethylaminobenzylcarbonyl) cysteic acid, [ N- (propylbenzylcarbonyl) cysteic acid ethyl ester, [ N- (butylbenzylcarbonyl) cysteic acid ethyl ester, [ N- (methoxybenzylcarbonyl) cysteic acid ethyl ester, [ N- (ethoxybenzylcarbonyl) cysteic acid ethyl ester, [ N- (propoxybenzylcarbonyl) cysteic acid ethyl ester, [ N- (butoxybenzylcarbonyl) cysteic acid ethyl ester, [ N- (hydroxybenzylcarbonyl) cysteic acid ethyl ester, [ N- (aminobenzylcarbonyl) cysteic acid ethyl ester, [ N- (N '-methylaminobenzylcarbonyl) cysteic acid ethyl ester, [ N- (N' -ethylaminobenzylcarbonyl) cysteic acid ethyl ester, [ N- (N ', N' -dimethylaminobenzylcarbonyl) cysteic acid ethyl ester, [ N- (N ', N' -diethylaminobenzylcarbonyl) cysteic acid ] ethyl ester, [ N- (chlorobenzylcarbonyl) cysteic acid ] ethyl ester, [ N- (fluorobenzylcarbonyl) cysteic acid ] ethyl ester, [ N- (difluorobenzylcarbonyl) cysteic acid ] ethyl ester, [ N- (trifluoromethylbenzylcarbonyl) cysteic acid ] ethyl ester, N- (phenylethylcarbonyl) homocysteic acid, N- (phenylpropylcarbonyl) homocysteic acid, N- (benzylcarbonyl) homocysteic acid, N- (methylbenzylcarbonyl) homocysteic acid, N- (ethylbenzylcarbonyl) homocysteic acid, N- (propylbenzylcarbonyl) homocysteic acid, N- (butylbenzylcarbonyl) homocysteic acid, N- (methoxybenzylcarbonyl) homocysteic acid, N- (ethoxybenzylcarbonyl) homocysteic acid, N- (propoxybenzylcarbonyl) homocysteic acid, N- (butoxybenzylcarbonyl) homocysteic acid, N- (hydroxybenzylcarbonyl) homocysteic acid, N- (aminobenzylcarbonyl) homocysteic acid, N- (N '-methylaminobenzylcarbonyl) homocysteic acid, N- (N' -ethylaminobenzylcarbonyl) homocysteic acid, N- (N ', N' -dimethylaminobenzylcarbonyl) homocysteic acid, N- (N ', N' -diethylaminobenzylcarbonyl) homocysteic acid, N- (chlorobenzylcarbonyl) homocysteic acid, N- (fluorobenzylcarbonyl) homocysteic acid, N- (difluorobenzylcarbonyl) homocysteic acid, N- (propoxybenzylcarbonyl) homocysteic acid, N- (butoxybenzylcarbonyl) homocysteic acid, N- (hydroxybenzylcarbonyl), N- (trifluoromethylbenzylcarbonyl) homocysteic acid, ethyl N- (phenylethylcarbonyl) homocysteic acid, ethyl N- (phenylpropylcarbonyl) homocysteic acid, [ N- (benzylcarbonyl) homocysteic acid ] ethyl, [ N- (methylbenzylcarbonyl) homocysteic acid ] ethyl, [ N- (ethylbenzylcarbonyl) homocysteic acid ] ethyl, [ N- (propylbenzylcarbonyl) homocysteic acid ] ethyl, [ N- (butylbenzylcarbonyl) homocysteic acid ] ethyl, [ N- (methoxybenzylcarbonyl) homocysteic acid ] ethyl, [ N- (ethoxybenzylcarbonyl) homocysteic acid ] ethyl, [ N- (propoxybenzylcarbonyl) homocysteic acid ] ethyl, [ N- (butoxybenzylcarbonyl) homocysteic acid ] ethyl ester, [ N- (hydroxybenzylcarbonyl) homocysteic acid ethyl ester, [ N- (aminobenzylcarbonyl) homocysteic acid ethyl ester, [ N- (N '-methylaminobenzylcarbonyl) homocysteic acid ethyl ester, [ N- (N' -ethylaminobenzylcarbonyl) homocysteic acid ethyl ester, [ N- (N ', N' -dimethylaminobenzylcarbonyl) homocysteic acid ethyl ester, [ N- (N ', N' -diethylaminobenzylcarbonyl) homocysteic acid ethyl ester, [ N- (chlorobenzylcarbonyl) homocysteic acid ethyl ester, [ N- (fluorobenzylcarbonyl) homocysteic acid ethyl ester, [ N- (difluorobenzylcarbonyl) homocysteic acid ethyl ester, [ N- (trifluoromethylbenzylcarbonyl) homocysteic acid ethyl ester, Their isomers and/or their pharmacologically acceptable salts.

The above compounds have excellent effects of preventing or improving pigmentation. In addition, the compound is excellent in solubility in hydrophilic or lipophilic solvents, and pharmaceutical preparations such as external preparations for skin and the like are easily produced. In addition, the compound is excellent in skin retentivity and stability in preparation, and the compound exhibits an excellent effect of preventing or improving pigmentation.

Will now be described in the above<3>The compound as defined in (1). In the formula, R₁Represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms; r₂Represents a hydrogen atom; r₃Represents a substituted or unsubstituted aromatic group, a substituted or unsubstituted polycyclic fused aromatic group or a substituted or unsubstituted heterocyclic group having 5 to 15 carbon atoms; n represents an integer of 1 or 2; and m represents 0.

R is as defined above₁Represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms, more preferably having 1 to 4 carbon atoms. Specific examples can be preferably exemplified by, for example, a hydrogen atom, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group and octyl group. More preferably, hydrogen can be suitably exemplifiedAtom, methyl group and ethyl group.

R is as defined above₃Represents a substituted or unsubstituted aromatic group, a substituted or unsubstituted polycyclic fused aromatic group, or a substituted or unsubstituted heterocyclic group having 5 to 15 carbon atoms. As the substituent, there can be preferably exemplified, for example, an alkyl group having 1 to 6 carbon atoms, more preferably having 1 to 4 carbon atoms, an alkoxy group having an alkyl chain having 1 to 6 carbon atoms, more preferably having 1 to 4 carbon atoms, an alkylamino group having an alkyl chain having 1 to 6 carbon atoms, more preferably having 1 to 4 carbon atoms, a halogen atom, a haloalkyl group (preferably having an alkyl chain having 1 to 4 carbon atoms), a hydroxyl group and an amino group.

With respect to R₃Specific examples of the group represented by (A) are preferably exemplified by pyridyl, methylpyridyl, ethylpyridyl, propylpyridyl, methoxypyridyl, ethoxypyridyl, propoxypyridyl, hydroxypyridyl, aminopyridyl, N-methylaminopyridyl, N-dimethylaminopyridyl, N-diethylaminopyridyl, chloropyridyl, fluoropyridyl, difluoropyridyl, trifluoromethylpyridyl, phenyl, methylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, hydroxyphenyl, aminophenyl, N-methylaminophenyl, N-ethylaminophenyl, N-dimethylaminophenyl, N-diethylaminophenyl, chlorophenyl, fluorophenyl, and the like, Difluorophenyl, trifluoromethylphenyl, naphthyl, methylnaphthyl, ethylnaphthyl, propylnaphthyl, methoxynaphthyl, ethoxynaphthyl, propoxytaphthyl, hydroxynaphthyl, aminonaphthyl, N-methylaminonaphthyl, N-ethylaminonaphthyl, N-dimethylaminonaphthyl, N-diethylaminonaphthyl, chloronaphthyl, fluoronaphthyl, difluoronaphthyl, trifluoromethylnaphthyl, biphenyl, methylbiphenyl, ethylbiphenyl, methoxybiphenyl, and ethoxybiphenyl. More preferably, pyridyl, phenyl, methylphenyl, ethylphenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl, trifluoromethylphenyl, naphthyl and biphenyl groups can be suitably exemplified.

The number of substituents on the aromatic group, polycyclic condensed aromatic group or heterocyclic group can be preferably exemplified by 0 to 3, and the number is more preferably 0 or 1. One or more of the above substituents may be independently present as a substituent on the aliphatic hydrocarbon group, the aromatic group, the polycyclic condensed aromatic group or the heterocyclic group, respectively.

As described above, n represents an integer of 1 or 2, and m represents 0.

Specifically, the compounds defined in <3> above are exemplified excluding the compounds defined in <4> above. N- (benzoyl) homocysteic acid, N- (p-toluoyl) homocysteic acid (Compound 6), N- (ethylbenzoyl) homocysteic acid, N- (propylbenzoyl) homocysteic acid, N- (butylbenzoyl) homocysteic acid, N- (methoxybenzoyl) homocysteic acid, N- (ethoxybenzoyl) homocysteic acid, N- (propoxybenzoyl) homocysteic acid, N- (butoxybenzoyl) homocysteic acid, N- (hydroxybenzoyl) homocysteic acid, N- (aminobenzoyl) homocysteic acid, N- (N ' -methylaminobenzoyl) homocysteic acid, N- (N ' -ethylacyl) homocysteic acid, N- (p-toluoyl) homocysteic acid, Compound 6, N- (p-toluoyl) homocysteic acid, N- (methoxybenzoyl) homocysteic acid, N- (N ' -methylamino, N- (N ', N' -dimethylaminobenzoyl) homocysteic acid, N- (N ', N' -diethylaminobenzoyl) homocysteic acid, N- (chlorobenzoyl) homocysteic acid, N- (fluorobenzoyl) homocysteic acid, N- (difluorobenzoyl) homocysteic acid, N- (trifluoromethylbenzoyl) homocysteic acid, [ N- (benzoyl) homocysteic acid ] ethyl ester, [ N- (toluoyl) homocysteic acid ] ethyl ester, [ N- (ethylbenzoyl) homocysteic acid ] ethyl ester, [ N- (propylbenzoyl) homocysteic acid ] ethyl ester, [ N- (butylbenzoyl) homocysteic acid ] ethyl ester, [ N- (methoxybenzoyl) homocysteic acid ] ethyl ester, [ N- (ethoxybenzoyl) homocysteic acid ] ethyl ester, [ N- (propoxybenzoyl) homocysteic acid ] ethyl ester, [ N- (butoxybenzoyl) homocysteic acid ] ethyl ester, [ N- (hydroxybenzoyl) homocysteic acid ] ethyl ester, [ N- (aminobenzoyl) homocysteic acid ] ethyl ester, [ N- (N '-methylaminobenzoyl) homocysteic acid ] ethyl ester, [ N- (N' -ethylaminobenzoyl) homocysteic acid ] ethyl ester, [ N- (N ', N' -dimethylaminobenzoyl) homocysteic acid ] ethyl ester, [ N- (N ', N' -diethylaminobenzoyl) homocysteic acid ] ethyl ester, [ N- (chlorobenzoyl) homocysteic acid ] ethyl ester, and mixtures thereof, [ N- (fluorobenzoyl) homocysteic acid ] ethyl ester, [ N- (difluorobenzoyl) homocysteic acid ] ethyl ester, [ N- (trifluoromethylbenzoyl) homocysteic acid ] ethyl ester, N- (naphthoyl) homocysteic acid, N- (methylnaphthoyl) homocysteic acid, N- (ethylnaphthoyl) homocysteic acid, N- (propylnaphthoyl) homocysteic acid, N- (butylnaphthoyl) homocysteic acid, N- (methoxynaphthoyl) homocysteic acid, N- (ethoxynaphthoyl) homocysteic acid, N- (propoxytnaphthoyl) homocysteic acid, N- (butoxynaphthoyl) homocysteic acid, N- (hydroxynaphthoyl) homocysteic acid, N- (difluorobenzoyl) homocysteic acid, N- (ethylnaphthoyl) homo, N- (carbamoyl) homocysteic acid, N- (N '-methylcarbamoyl) homocysteic acid, N- (N' -ethylcarbamoyl) homocysteic acid, N- (N ', N' -dimethylcarbamoyl) homocysteic acid, N- (N ', N' -diethylcarbamoyl) homocysteic acid, N- (chloronaphthoyl) homocysteic acid, N- (fluoronaphthoyl) homocysteic acid, N- (difluoronaphthoyl) homocysteic acid, N- (trifluoromethylnaphthoyl) homocysteic acid, [ N- (naphthoyl) homocysteic acid ] ethyl ester, [ N- (methylnaphthoyl) homocysteic acid ] ethyl ester, [ N- (ethylnaphthoyl) homocysteic acid ] ethyl ester, [ N- (propylnaphthoyl) homocysteic acid ethyl ester, [ N- (butylnaphthoyl) homocysteic acid ethyl ester, [ N- (methoxynaphthoyl) homocysteic acid ethyl ester, [ N- (ethoxynaphthoyl) homocysteic acid ethyl ester, [ N- (propoxaphthoyl) homocysteic acid ethyl ester, [ N- (butoxynaphthoyl) homocysteic acid ethyl ester, [ N- (hydroxynaphthoyl) homocysteic acid ethyl ester, [ N- (carbamoyl) homocysteic acid ethyl ester, [ N- (N ' -methylcarbamoyl) homocysteic acid ethyl ester, [ N- (N ' -ethylcarbamoyl) homocysteic acid ethyl ester, [ N- (N ', n ' -dimethylcarbamoylnaphthoyl) homocysteic acid ethyl ester, [ N- (N ', N ' -diethylcarbamoylhomocysteic acid ] ethyl ester, [ N- (chloronaphthoyl) homocysteic acid ] ethyl ester, [ N- (fluoronaphthoyl) homocysteic acid ] ethyl ester, [ N- (difluoronaphthoyl) homocysteic acid ] ethyl ester, [ N- (trifluoromethylnaphthoyl) homocysteic acid ] ethyl ester, N- (biphenylcarbonyl) homocysteic acid, N- (methylbiphenylcarbonyl) homocysteic acid, N- (ethylbiphenylcarbonyl) homocysteic acid, N- (propylbiphenylcarbonyl) homocysteic acid, N- (butylbiphenylcarbonyl) homocysteic acid, N- (methoxybiphenylcarbonyl) homocysteic acid, N- (ethoxybiphenylcarbonyl) homocysteic acid, N- (propoxybiphenylcarbonyl) homocysteic acid, N- (butoxybiphenylcarbonyl) homocysteic acid, N- (hydroxybiphenylcarbonyl) homocysteic acid, N- (aminobiphenylcarbonyl) homocysteic acid, N- (N '-methylaminobiphenylcarbonyl) homocysteic acid, N- (N' -ethylaminobiphenylcarbonyl) homocysteic acid, N- (N ', N' -dimethylaminobiphenylcarbonyl) homocysteic acid, N- (N ', N' -diethylaminobiphenylcarbonyl) homocysteic acid, N- (chlorobiphenylcarbonyl) homocysteic acid, N- (fluorobiphenylcarbonyl) homocysteic acid, N- (difluorobiphenylcarbonyl) homocysteic acid, N- (trifluoromethylbiphenylcarbonyl) homocysteic acid, [ N- (biphenylcarbonyl) homocysteic acid ] ethyl ester, [ N- (methylbiphenylcarbonyl) homocysteic acid ] ethyl ester, [ N- (ethylbiphenylcarbonyl) homocysteic acid ] ethyl ester, [ N- (propylbiphenylcarbonyl) homocysteic acid ] ethyl ester, [ N- (butylbiphenylcarbonyl) homocysteic acid ] ethyl ester, [ N- (methoxybiphenylcarbonyl) homocysteic acid ] ethyl ester, [ N- (ethoxybiphenylcarbonyl) homocysteic acid ] ethyl ester, [ N- (propoxybiphenylcarbonyl) homocysteic acid ] ethyl ester, [ N- (butoxybiphenylcarbonyl) homocysteic acid ] ethyl ester, and mixtures thereof, [ N- (hydroxybiphenylcarbonyl) homocysteic acid ethyl ester, [ N- (aminobiphenylcarbonyl) homocysteic acid ethyl ester, [ N- (N '-methylaminobiphenylcarbonyl) homocysteic acid ethyl ester, [ N- (N' -ethylaminobiphenylcarbonyl) homocysteic acid ethyl ester, [ N- (N ', N' -dimethylaminobiphenylcarbonyl) homocysteic acid ethyl ester, [ N- (N ', N' -diethylaminobiphenylcarbonyl) homocysteic acid ethyl ester, [ N- (chlorobiphenylcarbonyl) homocysteic acid ethyl ester, [ N- (fluorobiphenylcarbonyl) homocysteic acid ethyl ester, [ N- (difluorobiphenylcarbonyl) homocysteic acid ethyl ester, [ N- (trifluoromethylbiphenylcarbonyl) homocysteic acid ethyl ester, Their isomers and/or their pharmacologically acceptable salts. More preferably, N- (o-toluoyl) homocysteic acid, N- (m-toluoyl) homocysteic acid, N- (p-toluoyl) homocysteic acid (compound 6), isomers thereof, and/or pharmacologically acceptable salts thereof are appropriately exemplified.

The above compounds have excellent effects of preventing or improving pigmentation. In addition, the compound is excellent in solubility in hydrophilic or lipophilic solvents, and pharmaceutical preparations such as external preparations for skin and the like are easily produced. In addition, the compound is excellent in skin retentivity and stability in preparation, and the compound exhibits an excellent effect of preventing or improving pigmentation.

Will now be described in the above<4>The compound as defined in (1). In the formula, R₁Represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms; r₂Represents a hydrogen atom; r₃Represents a substituted or unsubstituted aromatic group, a substituted or unsubstituted polycyclic fused aromatic group or a substituted or unsubstituted heterocyclic group having 5 to 15 carbon atoms; n represents 1; and m represents 0.

R is as defined above₁Represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms, more preferably having 1 to 4 carbon atoms. Specific examples can be preferably exemplified by, for example, a hydrogen atom, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group and octyl group. More preferably, a hydrogen atom, a methyl group and an ethyl group can be appropriately exemplified.

R is as defined above₃Represents a substituted or unsubstituted aromatic group, a substituted or unsubstituted polycyclic fused aromatic group or a substituted or unsubstituted heterocyclic group having 5 to 15 carbon atoms. As the substituent, there may be preferably exemplified, for exampleAn alkyl group having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, an alkoxy group having an alkyl chain having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, an alkylamino group having an alkyl chain having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, a halogen atom, a haloalkyl group (preferably having an alkyl chain having 1 to 4 carbon atoms), a hydroxyl group and an amino group.

With respect to R₃Specific examples of the group represented by (A) are preferably exemplified by pyridyl, methylpyridyl, ethylpyridyl, propylpyridyl, methoxypyridyl, ethoxypyridyl, propoxypyridyl, hydroxypyridyl, aminopyridyl, N-methylaminopyridyl, N-dimethylaminopyridyl, N-diethylaminopyridyl, chloropyridyl, fluoropyridyl, difluoropyridyl, trifluoromethylpyridyl, phenyl, methylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, hydroxyphenyl, aminophenyl, N-methylaminophenyl, N-ethylaminophenyl, N-dimethylaminophenyl, N-diethylaminophenyl, chlorophenyl, fluorophenyl, and the like, Difluorophenyl, trifluoromethylphenyl, naphthyl, methylnaphthyl, ethylnaphthyl, propylnaphthyl, methoxynaphthyl, ethoxynaphthyl, propoxytaphthyl, hydroxynaphthyl, aminonaphthyl, N-methylaminonaphthyl, N-ethylaminonaphthyl, N-dimethylaminonaphthyl, N-diethylaminonaphthyl, chloronaphthyl, fluoronaphthyl, difluoronaphthyl, trifluoromethylnaphthyl, biphenyl, methylbiphenyl, ethylbiphenyl, methoxybiphenyl, and ethoxybiphenyl. More preferably, pyridyl, phenyl, methylphenyl, ethylphenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl, trifluoromethylphenyl, naphthyl and biphenyl groups can be preferably exemplified.

The number of substituents on the aromatic group, polycyclic condensed aromatic group or heterocyclic group can be preferably exemplified by 0 to 3, and the number is more preferably 0 or 1. One or more of the above substituents may be independently present as a substituent on the aliphatic hydrocarbon group, the aromatic group, the polycyclic condensed aromatic group or the heterocyclic group, respectively.

As described above, n represents 1, and m represents 0.

Specific examples are exemplified with respect to the compounds defined in the above <4 >. N- (pyridylcarbonyl) cysteic acid, N- (methylpyridinylcarbonyl) cysteic acid, N- (ethylpyridinylcarbonyl) cysteic acid, N- (propylpyridylcarbonyl) cysteic acid, N- (methoxypyridinylcarbonyl) cysteic acid, N- (ethoxypyridylcarbonyl) cysteic acid, N- (propoxypyridinylcarbonyl) cysteic acid, N- (hydroxypyridinylcarbonyl) cysteic acid, N- (aminopyridinylcarbonyl) cysteic acid, N- (N '-methylaminopyridinylcarbonyl) cysteic acid, N- (N' -ethylaminopyridylcarbonyl) cysteic acid, N- (N ', N' -dimethylaminopyridinylcarbonyl) cysteic acid, n- (N ', N' -diethylaminopyridylcarbonyl) cysteic acid, N- (chloropyridylcarbonyl) cysteic acid, N- (fluoropyridylcarbonyl) cysteic acid, N- (trifluoromethylpyridylcarbonyl) cysteic acid, N- (benzoyl) cysteic acid, N- (o-toluoyl) cysteic acid (Compound 1), N- (m-toluoyl) cysteic acid (Compound 2), N- (p-toluoyl) cysteic acid (Compound 3), N- (ethylbenzoyl) cysteic acid, N- (propylbenzoyl) cysteic acid, N- (butylbenzoyl) cysteic acid, N- (o-methoxybenzoyl) cysteic acid, N- (o-toluoyl) cysteic acid, N- (trifluoromethyl) cysteic acid, N- (, N- (m-methoxybenzoyl) cysteic acid, N- (p-methoxybenzoyl) cysteic acid (Compound 4), N- (ethoxybenzoyl) cysteic acid, N- (propoxybenzoyl) cysteic acid, N- (butoxybenzoyl) cysteic acid, N- (hydroxybenzoyl) cysteic acid, N- (aminobenzoyl) cysteic acid, N- (N '-methylaminobenzoyl) cysteic acid, N- (N' -ethylaminobenzoyl) cysteic acid, N- (N ', N' -dimethylaminobenzoyl) cysteic acid, N- (N ', N' -diethylaminobenzoyl) cysteic acid, N- (chlorobenzoyl) cysteic acid, N- (p-methoxybenzoyl) cysteic acid, N- (N-methylbenzoyl) cysteic acid, N, N- (fluorobenzoyl) cysteic acid, N- (difluorobenzoyl) cysteic acid, N- (trifluoromethylbenzoyl) cysteic acid, N- (naphthoyl) cysteic acid, N- (methylnaphthoyl) cysteic acid, N- (ethylnaphthoyl) cysteic acid, N- (propylnaphthoyl) cysteic acid, N- (butylnaphthoyl) cysteic acid, N- (methoxynaphthoyl) cysteic acid, N- (ethoxynaphthoyl) cysteic acid, N- (propoxytnaphthoyl) cysteic acid, N- (butoxynaphthoyl) cysteic acid, N- (hydroxynaphthoyl) cysteic acid, N- (aminonaphthoyl) cysteic acid, N- (N' -methylcarbamoyl) cysteic acid, N- (trifluoromethylnaphthoyl) cysteic acid, N- (butyl, N- (N ' -ethylcarbamoylcysteic acid, N- (N ', N ' -dimethylcarbamoylcysteic acid), N- (N ', N ' -diethylcarbamoylcysteic acid, N- (chloronaphthoyl) cysteic acid, N- (fluoronaphthoyl) cysteic acid, N- (difluoronaphthoyl) cysteic acid, N- (trifluoromethylnaphthoyl) cysteic acid, N- (biphenylcarbonyl) cysteic acid (Compound 5), N- (methylbiphenylcarbonyl) cysteic acid, N- (ethylbiphenylcarbonyl) cysteic acid, N- (propylbiphenylcarbonyl) cysteic acid, N- (butylbiphenylcarbonyl) cysteic acid, N- (methoxybiphenylcarbonyl) cysteic acid, N- (N ', N ' -dimethylcarbamoylcysteic acid), N- (trifluoromethylnaphthoyl) cysteic acid, N- (difluoromethylnaphthoyl) cysteic, N- (ethoxybiphenylcarbonyl) cysteic acid, N- (propoxybiphenylcarbonyl) cysteic acid, N- (butoxybiphenylcarbonyl) cysteic acid, N- (hydroxybiphenylcarbonyl) cysteic acid, N- (aminobiphenylcarbonyl) cysteic acid, N- (N '-methylaminobiphenylcarbonyl) cysteic acid, N- (N' -ethylaminobiphenylcarbonyl) cysteic acid, N- (N ', N' -dimethylaminobiphenylcarbonyl) cysteic acid, N- (N ', N' -diethylaminobiphenylcarbonyl) cysteic acid, N- (chlorobiphenylcarbonyl) cysteic acid, N- (fluorobiphenylcarbonyl) cysteic acid, N- (difluorobiphenylcarbonyl) cysteic acid, N- (hydroxybiphenylcarbonyl) cysteic, N- (trifluoromethyl biphenylcarbonyl) cysteic acid, isomers thereof, and/or pharmacologically acceptable salts thereof. More preferably, N- (o-toluoyl) cysteic acid (compound 1), N- (m-toluoyl) cysteic acid (compound 2), N- (p-toluoyl) cysteic acid (compound 3), N- (o-methoxybenzoyl) cysteic acid, N- (m-methoxybenzoyl) cysteic acid, N- (p-methoxybenzoyl) cysteic acid (compound 4), N- (2-phenylbenzoyl) cysteic acid, N- (3-phenylbenzoyl) cysteic acid, and N- (4-phenylbenzoyl) cysteic acid (compound 5) can be appropriately exemplified.

The above compounds have excellent effects of preventing or improving pigmentation. In addition, the compound is excellent in solubility in hydrophilic or lipophilic solvents, and pharmaceutical preparations such as external preparations for skin and the like are easily produced. In addition, the compound is excellent in skin retentivity and stability in preparation, and the compound exhibits an excellent effect of preventing or improving pigmentation.

As the above-mentioned compounds, their isomers may be used. The isomers are, for example, stereoisomers, e.g., optical isomers. Further, with respect to each of the compound represented by the above general formula (1) and the compounds defined in <2> to <4>, in addition to the racemic compound (DL-isomer), optical isomers of D-isomer and L-isomer exist. Either isomer exhibits an excellent effect of preventing or improving pigmentation. However, the L-isomer can be preferably exemplified in view of, for example, safety in living bodies and stability in pharmaceutical preparations.

The compounds represented by the above general formula (1), the compounds defined in <2> to <4>, their isomers and/or their pharmacologically acceptable salts can also be prepared by the following production methods described in the present specification or the usual methods described in "Fundamental and Experiments for Peptide synthesis" (MARUZEN) "or the like, by deprotection, coupling and protection reactions starting from commercially available cysteic acid, homocysteic acid and/or their derivatives.

The above compounds can also be used directly as pigmentation preventing or improving agents. Further, they can also be used as salts after they are converted into salt forms by treatment with pharmacologically acceptable acids or bases. There can be preferably exemplified, for example, inorganic acid salts including, for example, hydrochloride, sulfate, nitrate, phosphate and carbonate; organic acid salts including, for example, maleate, fumarate, oxalate, citrate, lactate, tartrate, mesylate, p-toluenesulfonate and benzenesulfonate salts; alkali metal salts including, for example, sodium and potassium salts; alkaline earth metal salts including, for example, calcium and magnesium salts; organic amine salts including, for example, triethylamine salts, triethanolamine salts, ammonium salts, monoethanolamine salts, and piperidine salts; and basic amino acid salts including, for example, lysine salts and alginic acid salts.

The compound represented by the general formula (1), the compounds defined in <2> to <4>, their isomers and/or their pharmacologically acceptable salts obtained as described above have an excellent effect of preventing or improving pigmentation. Therefore, they are useful as active ingredients of skin external preparations. With respect to the pharmacological effects of the above-mentioned active ingredients, it is estimated that their preventive or ameliorating activities are caused by the inhibition of melanin production by a melanocyte activation inhibitory activity, such as a tyrosinase activity inhibitory activity, e.g., tyrosinase enzyme inhibition activity, tyrosinase gene expression inhibitory activity, tyrosinase protein expression inhibitory activity, and tyrosinase-related protein degradation activity.

As shown in the test examples later, the compounds represented by the above general formula (1), the compounds defined in the above <2> to <4>, their isomers and/or their pharmacologically acceptable salts have been confirmed to have an excellent effect of inhibiting the activation of melanocytes in an in vitro evaluation system. For example, based on the effect of inhibiting melanocyte activation as described above, it is considered that the compound represented by the above general formula (1), the compounds defined in the above <2> to <4>, their isomers and/or their pharmacologically acceptable salts exhibit a confirmed effect of inhibiting pigmentation in an in vivo evaluation system by inhibiting melanin production. That is, the compound represented by the above general formula (1), the compounds defined in the above <2> to <4>, their isomers and/or their pharmacologically acceptable salts can be used as an active ingredient of a pigmentation preventing or improving agent.

Any compound that provides any effect other than the effect of preventing or ameliorating pigmentation is also present in the compound represented by the above general formula (1), the compounds defined in <2> to <4>, their isomers and/or their pharmacologically acceptable salts. Since any external preparation for skin containing the above-mentioned compound for expressing the above-mentioned effect also falls within the technical scope of the present invention as utilizing the effect of the present invention, provided that the main object thereof is to provide the effect of preventing or improving pigmentation as the effect of the compound represented by the above-mentioned general formula (1), the compounds defined in <2> to <4>, their isomers and/or their pharmacologically acceptable salts. The skin external preparation of the present invention is provided to prevent or improve pigmentation. The purpose of "preventing or improving pigmentation" also includes a purpose having any of the main objectives aimed at by preventing or improving pigmentation, for example, for the purposes of "skin whitening" and "pigmentation spot improvement" and the like.

< skin external preparation of the present invention >

The external preparation for skin of the present invention is characterized by containing a pigmentation-preventing or-improving agent containing any one of the compounds represented by the above general formula (1), the compounds defined in <2> to <4>, isomers thereof, and/or pharmacologically acceptable salts thereof.

In order to effectively express the effect of preventing or improving pigmentation of the compound represented by the general formula (1), the compound defined in <2> to <4>, an isomer thereof, and/or a pharmacologically acceptable salt thereof, it is preferable that a substance containing one or more compounds selected from the group consisting of the compound represented by the general formula (1), the compound defined in <2> to <4>, an isomer thereof, and/or a pharmacologically acceptable salt thereof is contained in a total amount of 0.0001% by mass to 20% by mass, more preferably 0.001% by mass to 10% by mass, still more preferably 0.005% by mass to 5% by mass, relative to the total amount of the external preparation for skin. If the content is less than 0.0001% by mass relative to the total amount of the skin external preparation, the effect of preventing or improving pigmentation is reduced. On the other hand, even if the amount exceeding 20% by mass is used, the effect reaches a steady state. Therefore, it is preferable to use the above content with respect to the total amount of the skin external preparation.

In the skin external preparation of the present invention, any arbitrary component generally used in cosmetic preparations may be contained in addition to the above-mentioned essential components. With respect to any of the above components, there may be contained, for example, hydrocarbons including, for example, squalane, petrolatum, and microcrystalline wax; esters including, for example, jojoba oil, carnauba wax, and octyl dodecyl oleate; triglycerides, including, for example, olive oil, tallow, and coconut oil; fatty acids including, for example, stearic acid, oleic acid, and retinoic acid; higher alcohols including, for example, oleyl alcohol, stearyl alcohol, and octyldodecanol; anionic surfactants including, for example, sulfosuccinates and sodium polyoxyethylene alkyl sulfates; amphoteric surfactants including, for example, alkyl betaines; cationic surfactants including, for example, dialkylammonium; nonionic surfactants including, for example, sorbitan fatty acid esters, fatty acid monoglycerides, polyoxyethylene adducts thereof, polyoxyethylene alkyl ethers, and polyoxyethylene fatty acid esters; polyols including, for example, polyethylene glycol, glycerol, and 1, 3-butanediol; a thickener/gelling agent; an antioxidant; an ultraviolet absorber; a coloring material; a preservative; and powders. The skin external preparation of the present invention can be produced without any difficulty by treating the above components according to a usual method except for the pigmentation preventing or improving agent of the present invention.

The skin external preparation of the present invention can be produced as follows: the essential and optional components are treated according to usual methods, the components being processed, for example, into lotions, milks, essences, creams, mask cosmetic preparations or washing preparations. Any form of external preparation for skin may be used, provided that it can be applied to the skin. Since the active ingredient permeates into the skin to express the effect, it is more preferable to use a form of external preparation conforming to the skin, such as a cosmetic water, lotion, cream, essence, etc.

The present invention will be described in more detail by way of examples. However, it is a matter of course that the present invention is not limited to only the embodiments described below.

Examples

Production example 1: synthesis of L-isomer of Compound 1>

N- (o-toluoyl) -L-cysteic acid (L-isomer of Compound 1)

In a recovery flask having a volume of 100 (mL) were placed 3 (g) (17.7 mmol) of L-cysteic acid (Tokyo Chemical Industry Co., Ltd.), tetrahydrofuran 18 (mL) (Wako Pure Chemical Industries, Ltd.) and 18 (mL) of water, followed by cooling the flask in an ice bath. After cooling was sufficiently performed, potassium carbonate 4.40 (g) (31.6 mmol) (Wako Pure Chemical Industries, Ltd.) was added. O-toluoyl chloride 3.28 (g) (Tokyo Chemical Industry co., Ltd.) was gradually added so that the temperature of the reaction mixture did not increase. After addition, the ice bath was removed and the reaction mixture was stirred at room temperature. The progress of the reaction was confirmed by thin layer chromatography, followed by evaporation of tetrahydrofuran under reduced pressure. The resulting residue was washed with ethyl acetate, followed by adjusting the pH to not more than 2 using hydrochloric acid. The filtrate was concentrated, to which was added water (20 ml). Precipitated crystals were obtained by filtration and the crystals were subjected to washing with acetone. The filtered crystals were dried at 60 ℃ to give 0.78 (g) (2.72 mmol) of compound 1 having the above structure. The characteristic values are as follows.

¹H-NMR (D₂O)：δ 2.31 (3H，s)，3.42 (2H，m)，4.86 (1H，m)，7.24 (2H，m)，7.35 (2H，m)。

FAB-MS (negative ion mode): m/z =286 ([ M-H ]]^-)。

< production example 2: synthesis of L-isomer of Compound 2>

N- (m-toluoyl) -L-cysteic acid (L-isomer of Compound 2)

In a recovery flask having a volume of 100 (mL), 3 (g) (17.7 mmol) of L-cysteic acid (Tokyo Chemical Industry Co., Ltd.), 18 (mL) of tetrahydrofuran (Wako Pure Chemical Industries, Ltd.) and 18 (mL) of water were placed, and then the flask was cooled in an ice bath. After cooling was sufficiently performed, 4.40 (g) (31.6 mmol) (Wako Pure Chemical Industries, Ltd.) and m-toluyl chloride 2.19 (g) (Tokyo Chemical Industry Co., Ltd.) were added in this order so that the temperature of the reaction mixture was not increased. The reaction was carried out in an ice bath for 1 hour, followed by the addition of m-toluoyl chloride 1.09 (g) (Tokyo Chemical Industry Co., Ltd.). After addition, the ice bath was removed and the reaction mixture was stirred at room temperature. The progress of the reaction was confirmed by thin layer chromatography, followed by evaporation of tetrahydrofuran under reduced pressure. The resulting residue was washed with ethyl acetate, followed by adjusting the pH to not more than 2 using hydrochloric acid. The filtrate was concentrated, to which was added water (18 ml). After aging at 4 ℃, the precipitated crystals were separated by filtration. The resulting crystals were subjected to washing with acetone, followed by filtration. The filtered crystals were dried at 60 ℃ to give 1.65 (g) (5.74 mmol) of compound 2 having the above structure. The characteristic values are as follows.

¹H-NMR (DMSO-d₆)：δ2.36 (3H，s)，2.94 (2H，m)，4.41 (1H，m)，7.36 (2H，d)，7.58 (2H，t)，8.84 (1H，d)，12.5 (1H，bs)。

FAB-MS (negative ion mode): m/z =286 ([ M-H ]]^-)。

< production example 3: synthesis of L-isomer of Compound 3>

N- (p-toluoyl) -L-cysteic acid (L-isomer of Compound 3)

In a recovery flask having a volume of 100 (mL) were placed 5 (g) (26.7 mmol) of L-cysteic acid monohydrate (Sigma-Aldrich Co.), 20 (mL) of 1, 4-dioxane (Wako Pure Chemical Industries, Ltd.) and 10 (mL) of water, followed by cooling the flask in an ice bath. After cooling was sufficiently performed, 8 (N) aqueous sodium hydroxide solution 10.7 (mL) and p-toluoyl chloride 3.36 (mL) (Sigma-Aldrich Corporation) were added dropwise in this order so that the temperature of the reaction mixture was not increased. After completion of the dropwise addition, the ice bath was removed and the reaction mixture was stirred at room temperature. The progress of the reaction was confirmed by thin layer chromatography, followed by evaporation of 1, 4-dioxane under reduced pressure. The resulting residue was washed with ethyl acetate, followed by adjusting the pH to not more than 2 using hydrochloric acid. The resulting aqueous solution was dried by freeze-drying, and the target substance was extracted with methanol. Methanol was evaporated under reduced pressure, followed by crystallization, followed by filtration. The filtered crystals were dried to give 5.79 (g) (20.2 mmol) of compound 3 having the above structure. The characteristic values are as follows.

¹H-NMR (D₂O)：δ 2.32 (3H，s)，3.46 (2H，m)，4.87 (1H，m)，7.25 (2H，d)，7.64 (2H，d)。

FAB-MS (negative ion mode): m/z =286 ([ M-H ]]^-)，308 ([M+Na-H]^-)。

< production example 4: synthesis of L-isomer of Compound 4>

N- (p-methoxybenzoyl) -L-cysteic acid (L-isomer of Compound 4)

In a recovery flask having a volume of 100 (mL), 2 (g) (11.8 mmol) of L-cysteic acid (Tokyo Chemical Industry Co., Ltd.), 12 (mL) of tetrahydrofuran (Wako Pure Chemical Industries, Ltd.) and 12 (mL) of water were placed, and then the flask was cooled in an ice bath. After cooling was sufficiently performed, potassium carbonate 2.94 (g) (21.3 mmol) (Wako Pure Chemical Industries, Ltd.) and 4-methoxybenzoyl chloride 1.61 (g) (Tokyo Chemical Industry Co., Ltd.) were added in this order so that the temperature of the reaction mixture was not increased. The reaction was carried out in an ice bath for 1 hour, followed by the addition of 4-methoxybenzoyl chloride 0.81 (g) again (Tokyo Chemical Industry Co., Ltd.). After addition, the ice bath was removed and the reaction mixture was stirred at room temperature. The progress of the reaction was confirmed by thin layer chromatography, followed by evaporation of tetrahydrofuran under reduced pressure. The resulting residue was washed with ethyl acetate, followed by adjusting the pH to not more than 2 using hydrochloric acid. The precipitated crystals were filtered and washed with water. The filtrate was concentrated and the re-precipitated crystals were filtered. The resulting crystals were combined and then subjected to washing with acetone. The crystals were filtered and the filtered crystals were dried at 60 ℃ to give 2.47 (g) (8.14 mmol) of compound 4 having the above structure. The characteristic values are as follows.

¹H-NMR (D₂O)：δ 3.45 (2H，m)，3.81 (3H，s)，4.85 (1H，m)，7.00 (2H，d)，7.72 (2H，d)。

FAB-MS (negative ion mode): m/z =302 ([ M-H ]]^-)。

< production example 5: synthesis of L-isomer of Compound 5>

(N-Biphenylcarbonyl) -L-cysteic acid (L-isomer of Compound 5)

In a recovery flask having a volume of 100 (mL), 2 (g) (11.8 mmol) of L-cysteic acid (Tokyo Chemical Industry Co., Ltd.), 12 (mL) of tetrahydrofuran (Wako Pure Chemical Industries, Ltd.) and 12 (mL) of water were placed, and then the flask was cooled in an ice bath. After cooling was sufficiently performed, potassium carbonate 2.94 (g) (21.3 mmol) (Wako Pure Chemical Industries, Ltd.) and 4-phenylbenzoyl chloride 2.05 (g) (Tokyo Chemical Industry Co., Ltd.) were added in this order so that the temperature of the reaction mixture was not increased. The reaction was carried out in an ice bath for 1.5 hours, followed by the addition of 4-phenylbenzoyl chloride 1.02 (g) again (Tokyo Chemical Industry Co., Ltd.). After addition, the ice bath was removed and the reaction mixture was stirred at room temperature. The progress of the reaction was confirmed by thin layer chromatography, followed by evaporation of tetrahydrofuran under reduced pressure. The resulting residue was washed with ethyl acetate, followed by adjusting the pH to not more than 2 using hydrochloric acid. The precipitated crystals were filtered and washed with water. The resulting crystals were subjected to washing with acetone, followed by filtration. The filtered crystals were dried at 60 ℃ to give 2.37 (g) (6.78 mmol) of compound 5 having the above structure. The characteristic values are as follows.

¹H-NMR (DMSO-d₆)：δ 2.96 (2H，m)，4.54 (1H，q)，7.42 (1H，m)，7.51 (2H，m)，7.74 (2H，d)，7.80 (2H，d)，7.90 (2H，d)，8.94 (1H，d)。

FAB-MS (negative ion mode): m/z =348 ([ M-H)]^-)。

< production example 6: synthesis of Compound 6>

N- (p-toluoyl) homocysteic acid (Compound 6)

In a recovery flask having a volume of 100 (mL), 2 (g) (10.9 mmol) of DL-homocysteic acid (Sigma-Aldrich Co.), 12 (mL) of tetrahydrofuran (Wako Pure Chemical Industries, Ltd.) and 12 (mL) of water were placed, and then the flask was cooled in an ice bath. After cooling was sufficiently performed, potassium carbonate 2.71 (g) (19.6 mmol) (Wako Pure Chemical Industries, Ltd.) was added. P-toluoyl chloride 1.49 (g) (Sigma-Aldrich Corporation) was gradually added so that the temperature of the reaction mixture did not rise. The reaction was carried out in an ice bath for 1 hour, followed by the addition of p-toluoyl chloride 0.76 (g) (Sigma-Aldrich Corporation) again. After addition, the ice bath was removed and the reaction mixture was stirred at room temperature. The progress of the reaction was confirmed by thin layer chromatography, followed by evaporation of tetrahydrofuran under reduced pressure. The resulting residue was washed with ethyl acetate, followed by adjusting the pH to not more than 2 using hydrochloric acid. The solution was filtered, and then the filtrate was concentrated, to which methanol was added. The precipitated crystals were separated by filtration and then subjected to water washing. The crystals were filtered and the filtered crystals were dried at 60 ℃ to give 1.95 (g) (6.47 mmol) of compound 6 having the above structure. The characteristic values are as follows.

¹H-NMR (DMSO-d₆)：δ 2.12 (2H，m)，2.35 (3H，s)，2.57 (2H，t)，4.37 (1H，m)，7.26 (2H，d)，7.79 (2H，d)，9.02 (1H，d)。

FAB-MS (negative ion mode): m/z =300 ([ M-H)]^-)。

< test example 1: UVB-induced inhibition of cell activation Using Normal human melanocytes test >

The inhibitory effect of compounds on the activation of melanocytes by activating factors produced and released from normal human keratinocytes by ultraviolet b (uvb) was evaluated using an index of cell proliferation of normal human melanocytes.

In a 24-well plate, at 10X 10⁴Concentration of cells/well Normal human keratinocytes (Kurabo Industries, Ltd.) were inoculated into Humedia-KG2 medium (Kurabo Industries, Ltd.). Subsequently, the cells were cultured for 24 hours.

The compound was dissolved in DMSO at a concentration of 100 mM, diluted 1,000-fold using Humedia-KG2 medium, and used as a sample solution. For the positive control group, tranexamic acid was dissolved in DMSO at a concentration of 100 mM, and diluted 1,000-fold using Humedia-KG2 medium as a positive control sample solution. For the negative control group, DMSO was diluted 1,000 times using Humedia-KG2 medium as a negative control sample solution. The concentration of the compounds is adjusted so that they do not inhibit the proliferation of the cells.

The medium of normal human keratinocytes was exchanged with Humedia-KG2 medium (sample solution) containing a predetermined concentration of the compound, and the cells were cultured for another 24 hours. Thereafter, the medium was exchanged for PBS (phosphate buffered saline) at 5 mJ/cm by using an ultraviolet lamp (FL20SE-30/DMR, Toshiba Medical Supply Co., Ltd.) as a light source²Cells were irradiated with ultraviolet b (uvb). After uv irradiation, PBS was exchanged for sample solution. The cells were cultured for another 24 hours, and then the conditioned medium was collected. Normal human melanocyte is cultured at 3 × 10⁴Cell/well concentrations were seeded in 96-well plates by Medium 254 (Kurabo Industries, Ltd.). The cells were cultured for 24 hours. Thereafter, the medium was exchanged for the conditioned medium collected from normal human keratinocytes, and the cells were cultured for another 24 hours. After 24 hours, the medium was exchanged for Humedia-KG2 medium containing 0.5 mg/mL of 3- (4, 5-dimethyl-2-thiazolyl) -2, 5-diphenyl-2H-tetrazolium bromide (MTT) and cultured for 3 hours.

The amount of formazan was measured by subtracting the absorbance at 690 nm from the absorbance at 570 nm, using a microplate reader (Benchmark Plus, Bio-Rad), by the absorbance of 2-propanol-lysed cell lysates at 570 nm and 690 nm.

When the absorbance of the negative control group to which DMSO was added and subjected to UVB irradiation was defined as 100%, the inhibitory effect of each compound on the proliferation of melanocytes was calculated as a nail production ratio (%).

It can be evaluated that the rate of production of nail mites indicates low melanocyte proliferation. Therefore, the small production rate of nail means that the inhibitory effect of the compound is strong against the activation of melanocytes by melanocyte activating factor released from keratinocytes.

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Melanocyte proliferation ratio showed mean ± s.d. of 3 samples.

Table 1 shows that all these compounds have excellent inhibitory effects, but the inhibitory effects of the compounds are different. Therefore, it was revealed that all the compounds had excellent inhibitory effects on the activation of melanocytes caused by activating factors produced and released from normal human keratinocytes.

< test example 2: ultraviolet-induced pigmentation inhibition test Using Guinea pigs >

The dorsal skin of each of eight colored guinea pigs was depilated and shaved using an electric clipper and razor, each site covered with a black cloth having a total of 4 (two above and below, two right and left) irradiation windows of 2X 2 cm size, followed by using FL20S · E30 lamp as the light source, 300 mJ/cm²Ultraviolet radiation of (1). The procedure was repeated on days 1,3, 5 and 8 after the start of the test to induce pigmentation on the four test sites. Compound 3 was dissolved in ethanol at a concentration of 0.5% (w/v) to prepare an administration sample. In addition, as a control, ethanol alone was used as the applied sample. After uv irradiation, the sample application was started on the first day of the test. The respective samples were applied to the predetermined test sites once a day in an amount of 30 μ L, which was continued for 6 weeks (until day 42 of the test). Before and 6 weeks (on day 43 of the test) on the day of starting application (day 1), skin brightness (L value) was measured at each test site by a colorimeter (CR-200, Konica Minolta Holdings, Inc.) and calculated by subtracting L value before uv irradiation from L value on day 43 of the test. Table 2 shows the results. As the degree of pigmentation becomes stronger, the value becomes smaller. Therefore, it can be evaluated that when the value becomes larger (high value), the pigmentation is more suppressed. Result is revealedCompound 3 showed significant inhibition of pigmentation induced by uv light at 0.5% concentration when applied to the skin.

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Concentration of test sample Delta L* Value of

Solvent control group-10.07 +/-0.78

Compound (I) 3 0.5% -8.88±0.54

Δ L values represent the "mean ± standard deviation" of 8 animals.

< example 1: production example 1 of skin external preparation of the present invention

Cosmetics (lotions) which are skin external preparations of the present invention were prepared according to the formulations shown in table 3. That is, the formulation components were heated to 80 ℃, stirred, dissolved and cooled by stirring to obtain the cosmetic liquid 1. In the same manner as described above, by substituting water for "compound (compound 3) represented by general formula (1) of the present invention", a cosmetic lotion of comparative example 1 was prepared.

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< test example 3: effect of cosmetics (lotions) on the inhibition of ultraviolet-induced pigmentation in humans >

The effect of compound 3 on the suppression of pigmentation was investigated by using toning lotion 1 and the cosmetic preparation of comparative example 1. On the day of test initiation (day 1), two sites each having a size of 1.5 cm × 1.5 cm were set on the inner side of the upper arm of each volunteer panelist. The skin brightness (L value) was measured for each test site by a colorimeter (CR-300, Konica Minolta Holdings, Inc.). After measuring the skin brightness of the site on the day the test began, the ultraviolet irradiation site was used at twice the minimum erythema dose (2 MED). Starting on the first day after completion of irradiation, 50 μ L of each sample (toning lotion 1 and comparative example 1) was applied to a predetermined test site three times a day for 14 consecutive days. At 24 hours after completion of the application (on day 15), the skin brightness (L value) of each test site was measured using a colorimeter (CR-300, Konica Minolta Holdings, Inc.) and values were calculated based on the L values of the untreated sites. Table 4 shows the results. As the degree of pigmentation becomes stronger, the value becomes smaller. Therefore, it can be evaluated that when the value becomes larger (high value), the pigmentation is more suppressed. It was found that the cosmetic water 1, which is the skin external preparation of the present invention, has an excellent pigmentation-suppressing effect. This is considered to be provided by the inhibitory effect of the compound represented by the general formula (1) (compound 3) of the present invention on melanin production.

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< example 2: production example 2 of skin external preparation of the present invention

Water-in-oil creams were prepared according to the formulations shown in table 5. Specifically, the components of a and B were heated to 80 ℃ respectively, the component of B was gradually added to the component of a, and the emulsified particles were then homogenized by a homogenizer to obtain cream 1. In the same manner as described above, the cream of comparative example 2 was prepared by replacing "the compound represented by the general formula (1) of the present invention (compound 3)" with water, and the cream of comparative example 3 was prepared by replacing "the compound represented by the general formula (1) of the present invention (compound 3)" with arbutin.

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< test example 4: effect of cosmetics (creams) on inhibition of ultraviolet-induced pigmentation in humans >

The effect of the cream 1 and the cosmetics of comparative example 2 and comparative example 3 on the suppression of pigmentation was examined. Four sites each having a size of 1.5 cm × 1.5 cm (respectively divided into upper or lower parts) were set inside the upper arm of each of 10 volunteer panelists. The site was irradiated once a day for 3 consecutive days, i.e., 3 times, with a minimum erythema dose (1 MED). After the third uv irradiation, 50 μ L of each sample (cream 1, comparative example 2 and comparative example 3) was applied to the predetermined test site three times a day for 28 consecutive days. One part was untreated. At 24 hours after completion of the application (on day 29), the skin brightness (L value) of each test site was measured using a colorimeter (CR-300, Konica Minolta Holdings, Inc.) and values were calculated based on the L values of the untreated sites. As the degree of pigmentation becomes stronger, the L value becomes smaller. Therefore, it can be evaluated that when the value becomes larger (high value), the pigmentation is more suppressed. Table 6 shows the results. It was found that the cream 1, which is the skin external preparation of the present invention, has an excellent pigmentation-suppressing effect. This is considered to be provided by the inhibitory effect of the compound represented by the general formula (1) (compound 3) of the present invention on melanin production.

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INDUSTRIAL APPLICABILITY

The present invention can be applied to external preparations for skin, including, for example, cosmetic preparations for skin whitening.

Claims (11)

1. Use of a pigmentation preventing or improving agent comprising a compound represented by the following general formula (1), its L-isomer or DL-isomer and/or a pharmacologically acceptable salt thereof for the production of a medicament for a method for preventing or improving pigmentation:

　　　　　　　　(1)

wherein:

R₁represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms;

R₂represents a hydrogen atom or an unsubstituted aliphatic hydrocarbon group having 1 to 8 carbon atoms;

R₃represents phenyl, methylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, ethoxyphenyl or biphenyl;

n represents an integer of 1 or 2, and m represents 0.

2. Use according to claim 1, wherein in formula (1):

R₁represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms;

R₂represents a hydrogen atom;

R₃represents phenyl, methylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, ethoxyphenyl or biphenyl;

n represents an integer of 1 or 2, and m represents 0.

3. Use according to claim 1, wherein in formula (1):

R₁represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms;

R₂represents a hydrogen atom;

R₃represents phenyl, methylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, ethoxyphenyl or biphenyl;

n represents 1, and m represents 0.

4. The use according to claim 1, wherein the compound represented by the general formula (1) is N- (o-toluoyl) cysteic acid (compound 1), N- (m-toluoyl) cysteic acid (compound 2), N- (p-toluoyl) cysteic acid (compound 3), N- (p-methoxybenzoyl) cysteic acid (compound 4), N- (4-phenylbenzoyl) cysteic acid (compound 5), N- (p-toluoyl) homocysteic acid (compound 6), their L-or DL-isomers and/or their pharmacologically acceptable salts:

n- (o-toluoyl) cysteic acid (compound 1);

n- (m-toluoyl) cysteic acid (compound 2);

n- (p-toluoyl) cysteic acid (compound 3);

n- (p-methoxybenzoyl) cysteic acid (compound 4);

n- (4-phenylbenzoyl) cysteic acid (compound 5);

n- (p-toluoyl) homocysteic acid (Compound 6).

5. Use of an external preparation for skin containing the pigmentation preventing or improving agent as defined in claim 1 for the preparation of a medicament for a pigmentation preventing or improving method.

6. The use according to claim 5, wherein the pigmentation-preventing or-improving agent is contained in an amount of 0.0001% by mass to 20% by mass relative to the total amount of the skin external preparation.

7. The use according to claim 5, wherein the external preparation for skin is a cosmetic preparation.

8. Use of a skin external preparation for skin whitening, which contains a compound represented by the general formula (1) as defined in claim 1, its L-isomer or DL-isomer and/or a pharmacologically acceptable salt thereof, in the manufacture of a medicament for a pigmentation preventing or improving method.

9. The use according to claim 1, wherein the compound represented by the general formula (1) is N- (p-toluoyl) cysteic acid (compound 3):

n- (p-toluoyl) cysteic acid (compound 3).

10. The use according to claim 1, wherein the compound represented by the general formula (1) is N- (p-methoxybenzoyl) cysteic acid (compound 4):

n- (p-methoxybenzoyl) cysteic acid (compound 4).

11. The use according to claim 1, wherein the compound represented by the general formula (1) is N- (4-phenylbenzoyl) cysteic acid (compound 5):

n- (4-Phenylbenzoyl) cysteic acid (Compound 5).