JP2013001659A - Skin care preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a skin care preparation suitable for a cosmetic (including quasi medicine), in detail, a skin care preparation suitable for preventing or ameliorating pigment deposition.SOLUTION: The skin care preparation comprises a compound represented by the general formula [wherein Ris an unsubstituted or substituent-containing aromatic group; Ris a hydrogen atom, 1-4C straight-chain or branched alkyl, 1-4C straight-chain or branched alkyl chain-containing acyl; Ris a hydrogen atom or 1-4C straight-chain or branched alkyl], its optical isomer and/or their pharmacologically acceptable salts and a bleaching component.

Description

  The present invention relates to a skin external preparation suitable for cosmetics (however, including quasi-drugs). Specifically, 1) a compound represented by the following general formula (1), an optical isomer thereof and / or theirs A skin external preparation characterized by containing a pharmacologically acceptable salt and 2) a whitening component.

（１）
[式中、Ｒ１は、無置換又は置換基を有する芳香族基を表し、Ｒ２は、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基、炭素数１〜４の直鎖又は分岐のアルキル鎖を有するアシル基を表し、Ｒ３は、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表す。]

(1)
[Wherein, R1 represents an unsubstituted or substituted aromatic group, R2 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched group having 1 to 4 carbon atoms. R3 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. ]

  Pigmentation symptoms caused by various skin irritation such as exposure to ultraviolet rays include temporary pigmentation symptoms such as sunburn, as well as chronic pigmentation such as spots, dullness, liver spots, and senile pigment spots. Symptoms are present. In particular, chronic pigmentation symptoms have a great influence on the appearance of others, so when a survey on the skin is carried out, it is a skin symptom that is always ranked as a skin problem.

  It is known that pigmentation symptoms are complicatedly regulated by various information transmitting substances in pigment cells (melanocytes), physiologically active substances such as cytokines, and finally melanin production is enhanced. In addition, research on the mechanism of action that enhances melanin production has been actively conducted, and various whitening agents have been developed based on such information and are incorporated into cosmetics and the like. As such whitening agents, ascorbic acids, hydrogen peroxide, colloidal sulfur, glutathione, hydroquinone, catechol and the like are well known (see, for example, Non-Patent Document 1 and Non-Patent Document 2). In addition, with the progress of research on the mechanism of action related to the enhancement of melanin production, a whitening agent having an action mechanism different from the above-mentioned whitening agent, specifically, copper ions essential for the expression of tyrosinase activity are chelated. Ellagic acid and kojic acid, plant extract obtained from leguminous clara (bitter gins) having an inhibitory action on α-MSH (MSH: Melanocyte stimulating hormone) The plant extract (for example, refer patent document 2) obtained from the honeysuckle family honeysuckle which has, the chayote fruit extract (for example, refer patent document 3) which has an endothelin-1 production inhibitory effect, etc. were discovered. However, although the above-described whitening agent and cosmetics containing the whitening agent have a certain pigmentation prevention or improvement effect, the high pigmentation prevention or improvement effect desired by the user, and sufficient sustainability are obtained. It is hard to say that it is. On the other hand, as a result of active screening of materials having a whitening effect, it is difficult to create new whitening materials. For this reason, in order to make effective use of conventional whitening agents, attention has been focused on technological development relating to formulation technology, use of whitening materials, and the like, and active research has been conducted. However, it is difficult to say that the conventional whitening component effective utilization technology is sufficiently satisfactory.

In addition to the above-mentioned whitening material research, amino acid having an amino group and a carboxyl group, especially, research on about 20 kinds of α-amino acids constituting proteins of biological functional molecules has been actively conducted. Activity has been reported. Furthermore, for the purpose of improving biological activity and safety, amino acid derivatives obtained by changing various chemical structures of α-amino acids have been synthesized, and many physiological activities have been reported. Among such α-amino acids, in particular, serine is known to have a rough skin improving action (see, for example, Patent Document 4), a whitening action (see, for example, Patent Document 5), and the like. Furthermore, serine derivatives having serine as the basic skeleton are converted into, for example, N-methyl-L-serine, dermal hyaluronic acid production promoting action (for example, see Patent Document 6), whitening action (for example, Patent Document 7). O-acylserine has been reported to have a deodorizing effect (see, for example, Patent Document 8), and N- (benzoyl) serine has been reported to have an anti-aging effect (see, for example, Patent Document 9). However, the N-aromatic acyl derivative, in particular, the compound represented by the general formula (1) has the effect of preventing or improving pigmentation, and further enhancing the effect of preventing or improving pigmentation. As far as the person knows, it is not known. The skin external preparation of the present invention contains a compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof together with a whitening component, whereby the whitening component is obtained. It effectively enhances the pigmentation prevention or improvement action it has, and exhibits an excellent pigmentation prevention or improvement effect.

JP 2009-0667804 A JP 2003-081747 A JP 2008-094737 A Japanese Patent Laid-Open No. 11-060435 JP 11-049630 A JP 2005-206512 A JP 2000-297025 A JP-T 09-502442 Table 2007-013662

Supervised by Katsuyuki Takeda et al., “Usefulness of cosmetics, evaluation technology and future prospects”, published by Yakuji Nippo (2001) Noriyuki Omori, FRAGRANCE JOURNAL Special Issue, No. 14, 1995, 118-126

  The present invention has been made under such circumstances, and an object of the present invention is to provide a skin external preparation suitable for preventing or improving pigmentation.

In view of such a situation, the present inventors have sought for a skin external preparation suitable for preventing or improving pigmentation, and as a result of intensive efforts, 1) a compound represented by the following general formula (1), It has been found that an external preparation for skin characterized by containing an optical isomer and / or a pharmacologically acceptable salt thereof and 2) a whitening component has an excellent effect of preventing or improving pigmentation, The present invention has been completed. That is, the present invention is as follows.
<1> 1) A skin comprising a compound represented by the following general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) a whitening component. Topical agent.

（１）
[式中、Ｒ１は、無置換又は置換基を有する芳香族基を表し、Ｒ２は、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基、炭素数１〜４の直鎖又は分岐のアルキル鎖を有するアシル基を表し、Ｒ３は、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表す。]

(1)
[Wherein, R1 represents an unsubstituted or substituted aromatic group, R2 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched group having 1 to 4 carbon atoms. R3 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. ]

<2> The compound represented by the general formula (1) is a compound represented by the following general formula (2), an optical isomer thereof and / or a pharmacologically acceptable salt thereof. The external preparation for skin according to <1>.

（２）
[式中、Ｒ４は、無置換又は置換基を有する芳香族基を表し、Ｒ５は、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基、炭素数１〜４の直鎖又は分岐のアルキル鎖を有するアシル基を表す。]

(2)
[Wherein, R4 represents an unsubstituted or substituted aromatic group, R5 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched group having 1 to 4 carbon atoms. Represents an acyl group having an alkyl chain. ]

<3> The compound represented by the general formula (1) is a compound represented by the following general formula (3), an optical isomer thereof and / or a pharmacologically acceptable salt thereof. The external preparation for skin according to <1>.

（３）
[式中、Ｒ６は、無置換又は置換基を有する芳香族基を表し、Ｒ７は、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表す。]

(3)
[Wherein, R6 represents an unsubstituted or substituted aromatic group, and R7 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. ]

<4> The compound represented by the general formula (1) is a compound represented by the following general formula (4), an optical isomer thereof and / or a pharmacologically acceptable salt thereof. The skin external preparation according to any one of <1> to <3>.

（４）
[式中、Ｒ８は、無置換又は置換基を有する芳香族基を表す。]

(4)
[Wherein R8 represents an unsubstituted or substituted aromatic group. ]

<5> The compound represented by the general formula (1) is N- (p-methylbenzoyl) serine (compound 1), N- (p-ethylbenzoyl) serine (compound 2), N- (p-methoxy). Benzoyl) serine (compound 3), N- (p-fluorobenzoyl) serine (compound 4), N- (p-trifluoromethylbenzoyl) serine (compound 5), N- (2-naphthoyl) serine (compound 6) N- (4-phenylbenzoyl) serine (compound 7), N- (benzoyl) serine (compound 8), N- (p-methylbenzoyl) serine methyl ester (compound 9), N- (2-naphthoyl) serine Methyl ester (compound 10), N-benzoyl-O-methylserine (compound 11), N- (p-methylbenzoyl) -O-methylserine (compound 12), N- (p-methylbenzoyl) -O- <1 which is an acetylserine (compound 13), N- (2-naphthoyl) -O-methylserine (compound 14), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, The external preparation for skin according to any one of> to <4>.

N−（p−メチルベンゾイル）セリン（化合物１）

N- (p-methylbenzoyl) serine (Compound 1)

N−（p−エチルベンゾイル）セリン（化合物２）

N- (p-ethylbenzoyl) serine (compound 2)

N−（p−メトキシベンゾイル）セリン（化合物３）

N- (p-methoxybenzoyl) serine (compound 3)

N−（p−フルオロベンゾイル）セリン（化合物４）

N- (p-fluorobenzoyl) serine (compound 4)

N−（p−トリフルオロメチルベンゾイル）セリン（化合物５）

N- (p-trifluoromethylbenzoyl) serine (compound 5)

N−（２−ナフトイル）セリン（化合物６）

N- (2-naphthoyl) serine (Compound 6)

N−（４−フェニルベンゾイル）セリン（化合物７）

N- (4-Phenylbenzoyl) serine (Compound 7)

N−（ベンゾイル）セリン（化合物８）

N- (benzoyl) serine (compound 8)

N−（p−メチルベンゾイル）セリン メチルエステル（化合物９）

N- (p-methylbenzoyl) serine methyl ester (compound 9)

N−（２−ナフトイル）セリン メチルエステル（化合物１０）

N- (2-naphthoyl) serine methyl ester (compound 10)

N−ベンゾイル−O−メチルセリン（化合物１１）

N-benzoyl-O-methylserine (compound 11)

N−（p−メチルベンゾイル）−O−メチルセリン（化合物１２）

N- (p-methylbenzoyl) -O-methylserine (compound 12)

N−（p−メチルベンゾイル）−O−アセチルセリン（化合物１３）

N- (p-methylbenzoyl) -O-acetylserine (compound 13)

N−（２−ナフトイル）−O−メチルセリン（化合物１４）

N- (2-naphthoyl) -O-methylserine (Compound 14)

<6> The compound represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof are 0.0001% by mass to 20% by mass with respect to the total amount of the external preparation for skin. The skin external preparation according to any one of <1> to <5>, which is contained.
<7> The whitening component is one or more selected from the group consisting of a melanin production inhibitor, an α-MSH (MSH: Melanocyte stiumulating hormone) inhibitor, a melanocyte dendrite elongation inhibitor, and a proton pump inhibitor. The skin external preparation according to any one of <1> to <6>, which contains
<8> One selected from the group consisting of the melanin production inhibitor, α-MSH inhibitor, melanocyte dendrite elongation inhibitor, and proton pump inhibitor is any of the following: <1 The external preparation for skin according to any one of> to <7>.
(Melanin production inhibitor): 4-alkylresorcinol and / or salt thereof, ascorbic acid derivative and / or salt thereof, hydroquinone and / or salt thereof, tranexamic acid derivative and / or salt thereof, Vitamin E and / or its derivative, pantethein-S-sulfonic acid and / or its salt, ursolic acid derivative and / or their salt (α-MSH inhibitor): plant extract obtained from legume Clara (Melanosite dendriide elongation inhibitor): Methyl ophiopogononone B, Sophoraflavanone A, Plant extract obtained from Asteraceae Achillea millefolium, Plant extract obtained from Liliaceae saccharum (proton pump inhibitor) Plant extract obtained from Musk genus Thyme, plant extract obtained from Clariaceae Clara , Plant extract obtained from ginger ginger genus ginger, plant extract obtained from taro family ginger genus ginger, plant extract obtained from cucurbitaceae genus gneiss, plant extract obtained from saxifragae hydrangea amacha, A plant extract obtained from the pine fungus pine phyllum, a plant extract obtained from the leguminous genus Kihagi, a plant extract obtained from the leguminous genus Tokusahagi <9> The whitening component is based on the total amount of the external preparation for skin. The external preparation for skin according to any one of <1> to <8>, characterized by containing 0.000001% by mass to 15% by mass.
<10> The external preparation for skin according to any one of <1> to <9>, which is a cosmetic (including quasi-drugs).
<11> The external preparation for skin according to any one of <1> to <10>, which is for preventing or improving pigmentation.

The skin external preparation of the present invention can provide a skin external preparation suitable for preventing or improving pigmentation.

  The skin external preparation of the present invention contains 1) the compound represented by the above general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof, and 2) a whitening component. It is characterized by. The skin external preparation of the present invention contains 1) the compound represented by the above general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof, and 2) a whitening component. Exhibits superior pigmentation prevention or improvement effect. The pigmentation preventing or improving action of the external preparation for skin of the present invention includes an action for preventing pigmentation in addition to a pigmentation improving action for thinning or eliminating the pigmentation already formed. The pigmentation prevention or amelioration action in the present invention can be applied without particular limitation as long as it is a pigmentation prevention or amelioration action. Among these actions, specific examples are described below. In “Evaluation of pigmentation inhibitory effect of topical skin preparation in humans” described in the above, it can be judged by whether or not it has a pigmentation inhibitory action. In "Evaluation of pigmentation inhibitory effect of topical skin preparations in humans" in Example 2, it is said that it has a pigmentation inhibitory action compared to the control group (evaluation substance-free formulation group). Ingredients that have an effect of preventing or improving pigmentation (a component with a small ΔL * value in the formulation group of the evaluation substance compared to the control group) can be preferably exemplified, and more preferably, the effect of preventing or improving pigmentation The component which a statistically significant difference is recognized can be illustrated suitably.

<The compound represented by the general formula (1) of the present invention, its optical isomer and / or pharmacologically acceptable salt thereof>
The skin external preparation of the present invention contains 1) the compound represented by the above general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof, and 2) a whitening component. It is characterized by. The skin external preparation of the present invention comprises 1) a compound represented by the above general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) a skin whitening component. It exhibits an excellent effect of preventing or improving pigmentation when contained in an agent. Such an action effectively enhances the pigmentation preventing or improving action of the whitening component by the compound represented by the general formula (1), its optical isomer and / or pharmacologically acceptable salt thereof. It is thought that it expresses by doing. In addition, regarding the compound represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof, pigmentation prevention or improvement action, and further, pigmentation prevention or improvement effect can be obtained. The enhancing action is not known as far as the inventors know. Among the compounds represented by the general formula (1) of the present invention, optical isomers thereof and / or pharmacologically acceptable salts thereof, preferred are those represented by the general formula (2). Compound, its optical isomer and / or pharmacologically acceptable salt thereof, and compound represented by the above general formula (3), its optical isomer and / or pharmacologically acceptable A salt can be preferably exemplified, and a compound represented by the general formula (4), an optical isomer thereof and / or a pharmacologically acceptable salt thereof can be suitably exemplified as a salt. In addition, the compounds represented by the general formulas (1) to (4) have an asymmetric carbon in their chemical structure, so that the (L) isomer, the (D) isomer or the racemic isomer, Various forms of existence such as a racemic mixture in which (L) -form and (D) -form are in any mixing ratio are conceivable. The compounds represented by the general formulas (1) to (4) of the present invention include all possible forms such as (D) isomer, (L) isomer, racemate, racemic mixture and the like. Of the compounds represented by the general formulas (1) to (4) and optical isomers thereof, the (L) isomer can be preferably exemplified as a particularly preferable one. This is because it is excellent in properties such as the efficacy and safety of pigmentation prevention or improvement. In addition, one or more of the compounds represented by the general formulas (1) to (4) of the present invention, optical isomers thereof and / or pharmacologically acceptable salts thereof are selected, and It can be contained in the skin external preparation of the invention.

Here, the compound represented by the general formula (1) will be described. In the formula, R1 represents an unsubstituted or substituted aromatic group, R2 represents a hydrogen atom, having 1 to 4 carbon atoms. A linear or branched alkyl group or an acyl group having a linear or branched alkyl chain having 1 to 4 carbon atoms is represented, and R3 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. R1 represents an unsubstituted or substituted aromatic group, and specific examples include phenyl group, methylphenyl group, ethylphenyl group, propylphenyl group, butylphenyl group, methoxyphenyl group, ethoxyphenyl group, Propyloxyphenyl group, butyloxyphenyl group, N-methylaminophenyl group, N-ethylaminophenyl group, N-propylaminophenyl group, N-butylaminophenyl group, N, N-dimethylaminophenyl group, N, N -Diethylaminophenyl group, N, N-dipropylaminophenyl group, N, N-dibutylaminophenyl group, acetylphenyl group, propionylphenyl group, butyrylphenyl group, methoxycarbonylphenyl group, ethoxycarbonylphenyl group, propyloxycarbonyl Phenyl group, butyloxycarbonyl group Nyl group, fluorophenyl group, chlorophenyl group, bromophenyl group, trifluoromethylphenyl group, hydroxyphenyl group, aminophenyl group, pyridyl group, methylpyridyl group, ethylpyridyl group, propylpyridyl group, butylpyridyl group, methoxypyridyl group , Ethoxypyridyl group, propyloxypyridyl group, butyloxypyridyl group, N-methylaminopyridyl group, N-ethylaminopyridyl group, N-propylaminopyridyl group, N-butylaminopyridyl group, N, N-dimethylaminopyridyl group Group, N, N-diethylaminopyridyl group, N, N-dipropylaminopyridyl group, N, N-dibutylaminopyridyl group, acetylpyridyl group, propionylpyridyl group, butyrylpyridyl group, methoxycarbonylpyridyl group, ethoxycarbonylpyridyl group The Group, propyloxycarbonylpyridyl group, butyloxycarbonylpyridyl group, fluoropyridyl group, chloropyridyl group, bromopyridyl group, trifluoromethylpyridyl group, hydroxypyridyl group, aminopyridyl group, naphthyl group, methylnaphthyl group, ethylnaphthyl group , Propylnaphthyl group, butylnaphthyl group, methoxynaphthyl group, ethoxynaphthyl group, propyloxynaphthyl group, butyloxynaphthyl group, N-methylaminonaphthyl group, N-ethylaminonaphthyl group, N-propylaminonaphthyl group, N- Butylaminonaphthyl group, N, N-dimethylaminonaphthyl group, N, N-diethylaminonaphthyl group, N, N-dipropylaminonaphthyl group, N, N-dibutylaminonaphthyl group, acetylnaphthyl group, propionylnaphthyl group, butyryl Phthyl group, methoxycarbonylnaphthyl group, ethoxycarbonylnaphthyl group, propyloxycarbonylnaphthyl group, butyloxycarbonylnaphthyl group, fluoronaphthyl group, chloronaphthyl group, bromonaphthyl group, trifluoromethylnaphthyl group, hydroxynaphthyl group, aminonaphthyl group , Biphenyl group, methylbiphenyl group, ethylbiphenyl group, propylbiphenyl group, butylbiphenyl group, methoxybiphenyl group, ethoxybiphenyl group, propyloxybiphenyl group, butyloxybiphenyl group, N-methylaminobiphenyl group, N-ethylaminobiphenyl group Group, N-propylaminobiphenyl group, N-butylaminobiphenyl group, N, N-dimethylaminobiphenyl group, N, N-diethylaminobiphenyl group, N, N-dipropylaminobiphenyl Nenyl, N, N-dibutylaminobiphenyl, acetylbiphenyl, propionylbiphenyl, butyrylbiphenyl, methoxycarbonylbiphenyl, ethoxycarbonylbiphenyl, propyloxycarbonylbiphenyl, butyloxycarbonylbiphenyl, fluorobiphenyl A chlorobiphenyl group, a bromobiphenyl group, a trifluoromethylbiphenyl group, a hydroxybiphenyl group, an aminobiphenyl group, and the like can be suitably exemplified. Among these, a methylphenyl group, an ethylphenyl group, a methoxyphenyl group, An ethoxyphenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a naphthyl group, and a biphenyl group can be suitably exemplified, and more preferably a 4-methylphenyl group, 4-ethylpheny group. Preferred examples include a ruthel group, 4-methoxyphenyl group, 4-fluorophenyl group, 4-trifluoromethylphenyl group, phenyl group, 2-naphthyl group, and 4-biphenyl group. Among the compounds represented by the general formula (1), R1 is a 4-methylphenyl group, a 4-ethylphenyl group, a 4-methoxyphenyl group, a 4-fluorophenyl group, a 4-trifluoromethylphenyl group, Compounds having a phenyl group, a 2-naphthyl group, and a 4-biphenyl group are particularly excellent in preventing or improving pigmentation. The number of substituents on the aromatic ring can be suitably exemplified by 0 to 3, more preferably 0 or 1, and the substituents on the aromatic ring can be present independently. In addition, the substitution position of the substituent on the aromatic ring is not particularly limited, but more preferably a para position with respect to the amide bond to which the serine structure of the aromatic ring is bonded. R2 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or an acyl group having a linear or branched alkyl chain having 1 to 4 carbon atoms. Methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, acetyl group, propionyl group, butyryl group and the like can be suitably exemplified, more preferably , A hydrogen atom, a methyl group, an ethyl group, and an acetyl group. Among the compounds represented by the general formula (1), the compound in which R2 is a hydrogen atom, a methyl group or an acetyl group is particularly excellent in preventing or improving pigmentation. R3 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. Specific examples include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isobutyl group, and an n-butyl group. , Isobutyl group, sec-butyl group, tert-butyl group and the like can be preferably exemplified, and more preferably, a hydrogen atom and a methyl group can be suitably exemplified. Among the compounds represented by the general formula (1), the compound in which R3 is a hydrogen atom or a methyl group is particularly excellent in preventing or improving pigmentation.
Among the compounds represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof, preferred are compounds represented by the general formula (2), Preferred are optical isomers and / or pharmacologically acceptable salts thereof, and compounds represented by the general formula (3), optical isomers and / or pharmacologically acceptable salts thereof. More preferably, a compound represented by the general formula (4), an optical isomer thereof and / or a pharmacologically acceptable salt thereof can be preferably exemplified. Specific examples of preferred compounds relating to the compound represented by the general formula (1) include N- (methylbenzoyl) serine, N- (ethylbenzoyl) serine, N- (methoxybenzoyl) serine, N- ( Fluorobenzoyl) serine, N- (trifluoromethylbenzoyl) serine, N- (naphthoyl) serine, N- (phenylbenzoyl) serine, N- (benzoyl) serine, N- (methylbenzoyl) serine methyl ester, N- ( Naphthoyl) serine methyl ester, N-benzoyl-O-methylserine, N- (methylbenzoyl) -O-methylserine, N- (methylbenzoyl) -O-acetylserine, N- (naphthoyl) -O-methylserine, N-benzoyl -DL-O-methylserine, its optical isomers and / or pharmacologically acceptable salts thereof are preferred examples More preferably, N- (p-methylbenzoyl) serine (compound 1), N- (p-ethylbenzoyl) serine (compound 2), N- (p-methoxybenzoyl) serine (compound 3), N- (P-fluorobenzoyl) serine (compound 4), N- (p-trifluoromethylbenzoyl) serine (compound 5), N- (2-naphthoyl) serine (compound 6), N- (4-phenylbenzoyl) serine (Compound 7), N- (benzoyl) serine (Compound 8), N- (p-methylbenzoyl) serine methyl ester (Compound 9), N- (2-naphthoyl) serine methyl ester (Compound 10), N-benzoyl -O-methylserine (compound 11), N- (p-methylbenzoyl) -O-methylserine (compound 12), N- (p-methylbenzoyl) -O-acetylserine (compound) 13), N- (2-naphthoyl) -O-methylserine (compound 14), optical isomers thereof and / or pharmacologically acceptable salts thereof can be preferably exemplified. The compounds represented by the general formulas (1) to (4) of the present invention, optical isomers thereof and / or pharmacologically acceptable salts thereof are to be contained in a skin external preparation together with a whitening component described later. Thus, it exhibits an excellent effect of preventing or improving pigmentation. In addition, the compounds represented by the general formulas (1) to (4), optical isomers thereof and / or pharmacologically acceptable salts thereof are effective in preventing or improving pigmentation of the whitening component. And exerts a pharmacological additive or synergistic effect. Such actions include the ability of the compounds represented by the general formulas (1) to (4) to effectively enhance the pigmentation prevention or amelioration action of the whitening component, It is considered that an excellent effect is exhibited by increasing the storage ability. Furthermore, the compound represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof are natural amino acid derivatives, and the compound itself has high safety. In addition, when it is contained in an external preparation for skin, it has high safety in terms of skin sensitization and irritation. In addition, the compound represented by the general formula (1), its optical isomer and / or pharmacologically acceptable salt thereof is a general-purpose polar or nonpolar medium used for the manufacture of a skin external preparation. Because of its high solubility in the skin, it is possible to produce various forms of external preparations for skin, and the production thereof is also easy.

Here, the compound represented by the general formula (2) will be described. In the formula, R4 represents an unsubstituted or substituted aromatic group, and R5 represents a hydrogen atom having 1 to 4 carbon atoms. A linear or branched alkyl group or an acyl group having a linear or branched alkyl chain having 1 to 4 carbon atoms is represented. R4 represents an unsubstituted or substituted aromatic group, and examples thereof include the same substituents as the substituent R1 of the compound represented by the general formula (1). Among these, preferred are A methylphenyl group, an ethylphenyl group, a methoxyphenyl group, an ethoxyphenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a naphthyl group, and a biphenyl group can be preferably exemplified, and more preferably a 4-methylphenyl group, 4-ethyl Preferred examples include a phenyl group, a 4-methoxyphenyl group, a 4-fluorophenyl group, a 4-trifluoromethylphenyl group, a phenyl group, a 2-naphthyl group, and a 4-biphenyl group. Among the compounds represented by the general formula (2), R4 is a 4-methylphenyl group, a 4-ethylphenyl group, a 4-methoxyphenyl group, a 4-fluorophenyl group, a 4-trifluoromethylphenyl group, Compounds having a phenyl group, a 2-naphthyl group, and a 4-biphenyl group are particularly excellent in preventing or improving pigmentation. The number of substituents on the aromatic ring can be suitably exemplified by 0 to 3, more preferably 0 or 1, and the substituents on the aromatic ring can be present independently. Further, the substitution position of the substituent on the aromatic ring is not particularly limited, but the para position is more preferred. R5 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or an acyl group having a linear or branched alkyl chain having 1 to 4 carbon atoms. Atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, acetyl group, propionyl group, butyryl group and the like can be suitably exemplified, and more Preferably, a hydrogen atom, a methyl group, and an acetyl group can be illustrated suitably. Among the compounds represented by the general formula (2), the compound in which R5 is a hydrogen atom, a methyl group or an acetyl group is particularly excellent in preventing or improving pigmentation.
Specific examples of the compound represented by the general formula (2) that are not included in the compound represented by the general formula (4) include N-benzoyl-O-methylserine, N- (methyl Benzoyl) -O-methylserine, N- (ethylbenzoyl) -O-methylserine, N- (propylbenzoyl) -O-methylserine, N- (methoxybenzoyl) -O-methylserine, N- (ethoxybenzoyl) -O-methylserine N- (propyloxybenzoyl) -O-methylserine, N- (hydroxybenzoyl) -O-methylserine, N- (aminobenzoyl) -O-methylserine, N- (bromobenzoyl) -O-methylserine, N- (chloro Benzoyl) -O-methylserine, N- (fluorobenzoyl) -O-methylserine, N- (trifluoromethylbenzoyl) -O-methylseri N- (pyridinecarbonyl) -O-methylserine, N- (methylpyridinecarbonyl) -O-methylserine, N- (ethylpyridinecarbonyl) -O-methylserine, N- (methoxypyridinecarbonyl) -O-methylserine, N- (Ethoxypyridinecarbonyl) -O-methylserine, N- (naphthoyl) -O-methylserine, N- (methylnaphthoyl) -O-methylserine, N- (ethylnaphthoyl) -O-methylserine, N- (methoxynaphthoyl) ) -O-methylserine, N- (ethoxynaphthoyl) -O-methylserine, N- (biphenylcarbonyl) -O-methylserine, N- (methylbiphenylcarbonyl) -O-methylserine, N- (ethylbiphenylcarbonyl) -O -Methylserine, N- (methoxybiphenylcarbonyl) -O-methylserine, N- (ethoxy Phenylcarbonyl) -O-methylserine, N-benzoyl-O-ethylserine, N- (methylbenzoyl) -O-ethylserine, N- (ethylbenzoyl) -O-ethylserine, N- (propylbenzoyl) -O-ethylserine, N -(Methoxybenzoyl) -O-ethylserine, N- (ethoxybenzoyl) -O-ethylserine, N- (propyloxybenzoyl) -O-ethylserine, N- (hydroxybenzoyl) -O-ethylserine, N- (aminobenzoyl) -O-ethylserine, N- (bromobenzoyl) -O-ethylserine, N- (chlorobenzoyl) -O-ethylserine, N- (fluorobenzoyl) -O-ethylserine, N- (trifluoromethylbenzoyl) -O-ethylserine N- (pyridinecarbonyl) -O-ethylserine, N- (methylpyridine cal Nyl) -O-ethylserine, N- (ethylpyridinecarbonyl) -O-ethylserine, N- (methoxypyridinecarbonyl) -O-ethylserine, N- (ethoxypyridinecarbonyl) -O-ethylserine, N- (naphthoyl) -O -Ethylserine, N- (methylnaphthoyl) -O-ethylserine, N- (ethylnaphthoyl) -O-ethylserine, N- (methoxynaphthoyl) -O-ethylserine, N- (ethoxynaphthoyl) -O-ethylserine N- (biphenylcarbonyl) -O-ethylserine, N- (methylbiphenylcarbonyl) -O-ethylserine, N- (ethylbiphenylcarbonyl) -O-ethylserine, N- (methoxybiphenylcarbonyl) -O-ethylserine, N- (Ethoxybiphenylcarbonyl) -O-ethylserine, N-benzoyl-O-acetylseri N- (methylbenzoyl) -O-acetylserine, N- (ethylbenzoyl) -O-acetylserine, N- (propylbenzoyl) -O-acetylserine, N- (methoxybenzoyl) -O-acetylserine, N -(Ethoxybenzoyl) -O-acetylserine, N- (propyloxybenzoyl) -O-acetylserine, N- (hydroxybenzoyl) -O-acetylserine, N- (aminobenzoyl) -O-acetylserine, N- (Bromobenzoyl) -O-acetylserine, N- (chlorobenzoyl) -O-acetylserine, N- (fluorobenzoyl) -O-acetylserine, N- (trifluoromethylbenzoyl) -O-acetylserine, N- (Pyridinecarbonyl) -O-acetylserine, N- (methylpyridinecarbonyl) -O-acetylserine, N- (ethylpyriline) Gincarbonyl) -O-acetylserine, N- (methoxypyridinecarbonyl) -O-acetylserine, N- (ethoxypyridinecarbonyl) -O-acetylserine, N- (naphthoyl) -O-acetylserine, N- (methyl Naphthoyl) -O-acetylserine, N- (ethylnaphthoyl) -O-acetylserine, N- (methoxynaphthoyl) -O-acetylserine, N- (ethoxynaphthoyl) -O-acetylserine, N- (Biphenylcarbonyl) -O-acetylserine, N- (methylbiphenylcarbonyl) -O-acetylserine, N- (ethylbiphenylcarbonyl) -O-acetylserine, N- (methoxybiphenylcarbonyl) -O-acetylserine, N -(Ethoxybiphenylcarbonyl) -O-acetylserine, N-benzoyl-O-propionylserine, N- (me Tylbenzoyl) -O-propionylserine, N- (ethylbenzoyl) -O-propionylserine, N- (propylbenzoyl) -O-propionylserine, N- (methoxybenzoyl) -O-propionylserine, N- (ethoxybenzoyl) ) -O-propionylserine, N- (propyloxybenzoyl) -O-propionylserine, N- (hydroxybenzoyl) -O-propionylserine, N- (aminobenzoyl) -O-propionylserine, N- (bromobenzoyl) -O-propionylserine, N- (chlorobenzoyl) -O-propionylserine, N- (fluorobenzoyl) -O-propionylserine, N- (trifluoromethylbenzoyl) -O-propionylserine, N- (pyridinecarbonyl) -O-propionylserine, N- (methylpyridine cal Nyl) -O-propionylserine, N- (ethylpyridinecarbonyl) -O-propionylserine, N- (methoxypyridinecarbonyl) -O-propionylserine, N- (ethoxypyridinecarbonyl) -O-propionylserine, N- ( Naphthoyl) -O-propionylserine, N- (methylnaphthoyl) -O-propionylserine, N- (ethylnaphthoyl) -O-propionylserine, N- (methoxynaphthoyl) -O-propionylserine, N- ( Ethoxynaphthoyl) -O-propionylserine, N- (biphenylcarbonyl) -O-propionylserine, N- (methylbiphenylcarbonyl) -O-propionylserine, N- (ethylbiphenylcarbonyl) -O-propionylserine, N- (Methoxybiphenylcarbonyl) -O-propionylserine, N- ( Butoxy biphenylcarbonyl) -O- propionyl serine, its optical isomers and / or their pharmacologically acceptable salts are suitably be exemplified. Among the compounds represented by the general formula (2), more preferable compounds include N- (methylbenzoyl) serine, N- (ethylbenzoyl) serine, N- (methoxybenzoyl) serine, N- (fluorobenzoyl). ) Serine, N- (trifluoromethylbenzoyl) serine, N- (naphthoyl) serine, N- (phenylbenzoyl) serine, N- (benzoyl) serine, N-benzoyl-O-methylserine, N- (methylbenzoyl)- Preferable examples include O-methylserine, N- (methylbenzoyl) -O-acetylserine, N- (naphthoyl) -O-methylserine, optical isomers thereof and / or pharmacologically acceptable salts thereof. Preferably, N- (p-methylbenzoyl) serine (compound 1), N- (p-ethylbenzoyl) serine (compound 2), N- (p-methoxy) Benzoyl) serine (compound 3), N- (p-fluorobenzoyl) serine (compound 4), N- (p-trifluoromethylbenzoyl) serine (compound 5), N- (2-naphthoyl) serine (compound 6) N- (4-phenylbenzoyl) serine (compound 7), N- (benzoyl) serine (compound 8), N-benzoyl-O-methylserine (compound 11), N- (p-methylbenzoyl) -O-methylserine (Compound 12), N- (p-methylbenzoyl) -O-acetylserine (Compound 13), N- (2-naphthoyl) -O-methylserine (Compound 14), its optical isomers and / or their pharmacology A particularly acceptable salt can be suitably exemplified. Such a compound exhibits an excellent effect of preventing or improving pigmentation by being contained in a skin external preparation together with a whitening component described later.

Here, if it mentions about the compound represented by the said General formula (3), in formula, R6 represents the aromatic group which is unsubstituted or has a substituent, R7 is a hydrogen atom, C1-C4. Represents a linear or branched alkyl group. R6 represents an unsubstituted or substituted aromatic group, and examples thereof include the same substituents as the substituent R1 of the compound represented by the general formula (1). Among these, preferred are A methylphenyl group, an ethylphenyl group, a methoxyphenyl group, an ethoxyphenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a phenyl group, a naphthyl group, and a biphenyl group can be suitably exemplified, more preferably a 4-methylphenyl group, Preferred examples include 4-ethylphenyl group, 4-methoxyphenyl group, 4-fluorophenyl group, 4-trifluoromethylphenyl group, phenyl group, 2-naphthyl group, and 4-biphenyl group. Among the compounds represented by the general formula (3), R6 is a 4-methylphenyl group, a 4-ethylphenyl group, a 4-methoxyphenyl group, a 4-fluorophenyl group, a 4-trifluoromethylphenyl group, Compounds having a phenyl group, a 2-naphthyl group, and a 4-biphenyl group are particularly excellent in preventing or improving pigmentation. The number of substituents on the aromatic ring can be suitably exemplified by 0 to 3, more preferably 0 or 1, and the substituents on the aromatic ring can be present independently. Further, the substitution position of the substituent on the aromatic ring is not particularly limited, but the para position is more preferred.
R7 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and specific examples include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n- A butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group and the like can be preferably exemplified, and a hydrogen atom, a methyl group, an ethyl group and an acetyl group can be suitably exemplified. Among the compounds represented by the general formula (3), a compound in which R7 is a hydrogen atom, a methyl group, an ethyl group or an acetyl group is particularly excellent in preventing or improving pigmentation.

  Specific examples of the compound represented by the general formula (3) that are not included in the compound represented by the general formula (4) include N- (benzoyl) serine methyl ester, N- ( Methyl benzoyl) serine methyl ester, N- (ethylbenzoyl) serine methyl ester, N- (propylbenzoyl) serine methyl ester, N- (methoxybenzoyl) serine methyl ester, N- (ethoxybenzoyl) serine methyl ester, N- ( Propyloxybenzoyl) serine methyl ester, N- (hydroxybenzoyl) serine methyl ester, N- (aminobenzoyl) serine methyl ester, N- (chlorobenzoyl) serine methyl ester, N- (fluorobenzoyl) serine methyl ester, N- (Trifluoromethylbenzoyl) se Phosphorus methyl ester, N- (pyridinecarbonyl) serine methyl ester, N- (methylpyridinecarbonyl) serine methyl ester, N- (ethylpyridinecarbonyl) serine methyl ester, N- (methoxypyridinecarbonyl) serine methyl ester, N- ( Ethoxypyridinecarbonyl) serine methyl ester, N- (naphthoyl) serine methyl ester, N- (methylnaphthoyl) serine methyl ester, N- (ethylnaphthoyl) serine methyl ester, N- (methoxynaphthoyl) serine methyl ester, N- (ethoxynaphthoyl) serine methyl ester, N- (phenylbenzoyl) serine methyl ester, N- (methylphenylbenzoyl) serine methyl ester, N- (ethylphenylbenzoyl) serine methyl ester N- (methoxyphenylbenzoyl) serine methyl ester, N- (ethoxyphenylbenzoyl) serine methyl ester, N- (benzoyl) serine ethyl ester, N- (methylbenzoyl) serine ethyl ester, N- (ethylbenzoyl) serine Ethyl ester, N- (propylbenzoyl) serine ethyl ester, N- (methoxybenzoyl) serine ethyl ester, N- (ethoxybenzoyl) serine ethyl ester, N- (propyloxybenzoyl) serine ethyl ester, N- (hydroxybenzoyl) Serine ethyl ester, N- (aminobenzoyl) serine ethyl ester, N- (chlorobenzoyl) serine ethyl ester, N- (fluorobenzoyl) serine ethyl ester, N- (trifluoromethylbenzo L) serine ethyl ester, N- (pyridinecarbonyl) serine ethyl ester, N- (methylpyridinecarbonyl) serine ethyl ester, N- (ethylpyridinecarbonyl) serine ethyl ester, N- (methoxypyridinecarbonyl) serine ethyl ester, N -(Ethoxypyridinecarbonyl) serine ethyl ester, N- (naphthoyl) serine ethyl ester, N- (methylnaphthoyl) serine ethyl ester, N- (ethylnaphthoyl) serine ethyl ester, N- (methoxynaphthoyl) serine ethyl Esters, N- (ethoxynaphthoyl) serine ethyl ester, N- (phenylbenzoyl) serine ethyl ester, N- (methylphenylbenzoyl) serine ethyl ester, N- (ethylphenylbenzoyl) serine Ester, N- (methoxyphenylbenzoyl) serine ethyl ester, N- (ethoxyphenylbenzoyl) serine ethyl ester, N- (benzoyl) serine propyl ester, N- (methylbenzoyl) serine propyl ester, N- (ethylbenzoyl) serine Propyl ester, N- (propylbenzoyl) serine propyl ester, N- (methoxybenzoyl) serine propyl ester, N- (ethoxybenzoyl) serine propyl ester, N- (propyloxybenzoyl) serine propyl ester, N- (hydroxybenzoyl) Serine propyl ester, N- (aminobenzoyl) serine propyl ester, N- (chlorobenzoyl) serine propyl ester, N- (fluorobenzoyl) serine propyl ester, N- (trifluoromethylbenzoyl) serine propyl ester, N- (pyridinecarbonyl) serine propyl ester, N- (methylpyridinecarbonyl) serine propyl ester, N- (ethylpyridinecarbonyl) serine propyl ester, N- (methoxypyridinecarbonyl) ) Serine propyl ester, N- (ethoxypyridinecarbonyl) serine propyl ester, N- (naphthoyl) serine propyl ester, N- (methylnaphthoyl) serine propyl ester, N- (ethylnaphthoyl) serine propyl ester, N- ( Methoxynaphthoyl) serine propyl ester, N- (ethoxynaphthoyl) serine propyl ester, N- (phenylbenzoyl) serine propyl ester, N- (methylphenylbenzoyl) serine Pro Pill ester, N- (ethylphenylbenzoyl) serine propyl ester, N- (methoxyphenylbenzoyl) serine propyl ester, N- (ethoxyphenylbenzoyl) serine propyl ester, its optical isomers and / or their pharmacologically acceptable Suitable salts can be exemplified. Among these compounds represented by the general formula (3), N- (methylbenzoyl) serine, N- (ethylbenzoyl) serine, N- (methoxybenzoyl) serine, N- (fluoro Benzoyl) serine, N- (trifluoromethylbenzoyl) serine, N- (naphthoyl) serine, N- (phenylbenzoyl) serine, N- (benzoyl) serine, N- (methylbenzoyl) serine methyl ester, N- (naphthoyl) ) Serine methyl ester, its optical isomer and / or pharmacologically acceptable salt thereof can be preferably exemplified, and more preferably, N- (p-methylbenzoyl) serine (Compound 1), N- (p -Ethylbenzoyl) serine (compound 2), N- (p-methoxybenzoyl) serine (compound 3), N- (p-fluorobenzoyl) serine Compound 4), N- (p-trifluoromethylbenzoyl) serine (compound 5), N- (2-naphthoyl) serine (compound 6), N- (4-phenylbenzoyl) serine (compound 7), N- ( Benzoyl) serine (compound 8), N- (p-methylbenzoyl) serine methyl ester (compound 9), N- (2-naphthoyl) serine methyl ester (compound 10), its optical isomers and / or their pharmacology A particularly acceptable salt can be suitably exemplified.

  Here, if it mentions about the compound represented by the said General formula (4), in formula, R8 represents the aromatic group which is unsubstituted or has a substituent. R8 represents an unsubstituted or substituted aromatic group, and includes the same substituent as the substituent R1 of the compound represented by the general formula (1). Among these, preferred are A methylphenyl group, an ethylphenyl group, a methoxyphenyl group, an ethoxyphenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a naphthyl group, and a biphenyl group can be suitably exemplified, more preferably a 4-methylphenyl group. , 4-ethylphenyl group, 4-methoxyphenyl group, 4-fluorophenyl group, 4-trifluoromethylphenyl group, phenyl group, 2-naphthyl group, and 4-biphenyl group. Among the compounds represented by the general formula (4), R8 is a 4-methylphenyl group, a 4-ethylphenyl group, a 4-methoxyphenyl group, a 4-fluorophenyl group, a 4-trifluoromethylphenyl group, Compounds having a phenyl group, a 2-naphthyl group, and a 4-biphenyl group are particularly excellent in preventing or improving pigmentation. The number of substituents on the aromatic ring can be suitably exemplified by 0 to 3, more preferably 0 or 1, and the substituents on the aromatic ring can be present independently. The substitution position of the substituent on the aromatic ring is not particularly limited, but more preferably, the para position is preferred with respect to the amide bond to which the serine structure on the aromatic ring is bonded.

Specific examples of preferred compounds among the compounds represented by the general formula (4) include N- (benzoyl) serine, N- (methylbenzoyl) serine, N- (ethylbenzoyl) serine, N- ( Propylbenzoyl) serine, N- (butylbenzoyl) serine, N- (methoxybenzoyl) serine, N- (ethoxybenzoyl) serine, N- (propyloxybenzoyl) serine, N- (butyloxybenzoyl) serine, N- ( Hydroxybenzoyl) serine, N- (aminobenzoyl) serine, N- (N′-methylaminobenzoyl) serine, N- (N′-ethylaminobenzoyl) serine, N- (N ′, N′-dimethylaminobenzoyl) Serine, N- (N ′, N′-diethylaminobenzoyl) serine, N- (chlorobenzoyl) serine, N- (fluorobenzoyl) serine, N- Trifluoromethylbenzoyl) serine, N- (pyridinecarbonyl) serine, N- (methylpyridinecarbonyl) serine, N- (ethylpyridinecarbonyl) serine, N- (propylpyridinecarbonyl) serine, N- (methoxypyridinecarbonyl) serine N- (ethoxypyridinecarbonyl) serine, N- (propyloxypyridinecarbonyl) serine, N- (hydroxypyridinecarbonyl) serine, N- (aminopyridinecarbonyl) serine, N- (chloropyridinecarbonyl) serine, N- ( Fluoropyridinecarbonyl) serine, N- (trifluoromethylpyridinecarbonyl) serine,
N- (naphthoyl) serine, N- (methylnaphthoyl) serine, N- (ethylnaphthoyl) serine, N- (propylnaphthoyl) serine, N- (methoxynaphthoyl) serine, N- (ethoxynaphthoyl) Serine, N- (propyloxynaphthoyl) serine, N- (hydroxynaphthoyl) serine, N- (aminonaphthoyl) serine, N- (chloronaphthoyl) serine, N- (fluoronaphthoyl) serine, N- (Trifluoromethylnaphthoyl) serine, N- (phenylbenzoyl) serine, N- (methylphenylbenzoyl) serine, N- (ethylphenylbenzoyl) serine, N- (propylphenylbenzoyl) serine, N- (methoxyphenylbenzoyl) ) Serine, N- (ethoxyphenylbenzoyl) serine, N- (propyloxyphenylbenzoyl) se Phosphorus, N- (hydroxyphenylbenzoyl) serine, N- (aminophenylbenzoyl) serine, N- (chlorophenylbenzoyl) serine, N- (fluorophenylbenzoyl) serine, N- (trifluoromethylphenylbenzoyl) serine, its optics The isomers and / or pharmacologically acceptable salts thereof can be suitably exemplified, and more preferably, N- (methylbenzoyl) serine, N- (ethylbenzoyl) serine, N- (methoxybenzoyl) serine, N -(Fluorobenzoyl) serine, N- (trifluoromethylbenzoyl) serine, N- (naphthoyl) serine, N- (phenylbenzoyl) serine, N- (benzoyl) serine, its optical isomers and / or their pharmacology Preferably acceptable salts, and more preferably N- (p-methylbenzo L) serine (compound 1), N- (p-ethylbenzoyl) serine (compound 2), N- (p-methoxybenzoyl) serine (compound 3), N- (p-fluorobenzoyl) serine (compound 4), N- (p-trifluoromethylbenzoyl) serine (compound 5), N- (2-naphthoyl) serine (compound 6), N- (4-phenylbenzoyl) serine (compound 7), N- (benzoyl) serine ( Preferred examples include compound 8), optical isomers thereof and / or pharmacologically acceptable salts thereof.

  The compounds represented by the general formulas (1) to (4), optical isomers thereof and / or pharmacologically acceptable salts thereof are obtained by using commercially available serine or serine derivatives as starting materials, and The peptide can be synthesized according to a production method, or can be produced according to the method described in “Basics and Experiments of Peptide Synthesis (Maruzen)”. Such a compound can be used as it is by adding it to the external preparation for skin of the present invention, but it can also be treated with a pharmacologically acceptable acid or base, converted into a salt form, and used as a salt. . For example, mineral salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, para Organic acid salts such as toluene sulfonate and benzene sulfonate, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, triethylamine salt, triethanolamine salt, ammonium salt, Preferred examples include organic amine salts such as monoethanolamine salts and piperidine salts, and basic amino acid salts such as lysine salts and alginates.

  The compounds represented by the general formulas (1) to (4) thus obtained, optical isomers thereof and / or pharmacologically acceptable salts thereof are contained in a skin external preparation together with a whitening component described later. By doing so, it exhibits an excellent effect of preventing or improving pigmentation. Moreover, the skin external preparation of this invention is 1 type selected from the compound represented by the said General formula (1)-(4), its optical isomer, and / or those pharmacologically acceptable salts, or Two or more kinds can be contained in the external preparation for skin. In order for the external preparation for skin of the present invention to exhibit the above-described action, the compound represented by the general formulas (1) to (4), optical isomers thereof and / or pharmacologically acceptable salts thereof are used. 1 type or 2 types or more selected from the total amount of 0.0001% by mass to 20% by mass, more preferably 0.001% by mass to 10% by mass, and still more preferably, based on the total amount of the external preparation for skin. It is preferable to contain 0.005-5 mass%. This is because the content of the compound represented by the general formulas (1) to (4), its optical isomer and / or pharmacologically acceptable salt thereof is 0.0001% by mass with respect to the total amount of the external preparation for skin. If the amount is less, the effect of preventing or improving pigmentation tends to be reduced, and even if an amount exceeding 20% by mass is added, the effect tends to reach its peak, which may reduce the degree of freedom of formulation. The content is preferably based on the total amount of the external preparation for skin.

N−（p−メチルベンゾイル）−Ｌ−セリン （化合物１のＬ体）

N- (p-methylbenzoyl) -L-serine (L-form of Compound 1)

<Production Example 1: Method for producing N- (p-methylbenzoyl) -L-serine (L-form of Compound 1)>
[Step 1] Synthesis of p-methylbenzoyl chloride p-toluic acid (100 g, 0.734 mol) (Tokyo Kasei Kogyo Co., Ltd.) and toluene (500 mL) (Wako Pure Chemical Industries, Ltd.) in a well-dried eggplant flask And p-toluic acid was dissolved. To this solution, thionyl chloride (132.4 mL, 1.84 mol) (Wako Pure Chemical Industries, Ltd.) was added dropwise over 1 hour. After dropping, the mixture was heated under reflux for 2 hours. After the reaction, the reaction mixture was cooled to room temperature, and then remaining thionyl chloride and toluene were distilled off with a rotary evaporator. Toluene (200 mL) was added to the concentrate, and concentration was repeated twice. The residue finally obtained was dissolved in tetrahydrofuran (200 mL) (Wako Pure Chemical Industries, Ltd.) and subjected to the next step.
[Step 2] Synthesis of N- (p-methylbenzoyl) -L-serine L-serine (100 g, 0.952 mol) (Wako Pure Chemical Industries, Ltd.), potassium carbonate (131.5 g, 0.952 mol) in an eggplant flask ) (Wako Pure Chemical Industries, Ltd.) and water (1 L) were added and stirred vigorously. To this solution, p-methylbenzoyl chloride prepared in Step 1 was dissolved in tetrahydrofuran (Wako Pure Chemical Industries, Ltd.) and added dropwise over 30 minutes. In the middle of the process, pH 8 was maintained while adding potassium carbonate. It stirred for 1 hour after completion | finish of dripping. The reaction solution was added to water (1 L) prepared in a separate container, adjusted to pH 3 or less with hydrochloric acid, and cooled to 4 ° C. The precipitated crystals were filtered and recrystallized with a mixed solvent of ethanol (Wako Pure Chemical Industries, Ltd.) / Water = 6/4 to obtain 106.0 g (yield 64.7%) of the desired product. It was.

<Physical constant of L-form of Compound 1>
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−メチルベンゾイル）−ＤＬ−セリン （化合物１のラセミ体）

N- (p-methylbenzoyl) -DL-serine (racemic compound 1)

<Production Example 2: Method for producing N- (p-methylbenzoyl) -DL-serine (racemic compound 1)>
The racemate of Compound 1 was synthesized according to the same method as the L-form of Compound 1 above using p-toluic acid (Tokyo Chemical Industry Co., Ltd.) and DL-serine (Peptide Institute Inc.).

<Physical constant of racemic 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−メチルベンゾイル）−Ｄ−セリン （化合物１のＤ体）

N- (p-methylbenzoyl) -D-serine (D-form of Compound 1)

<Production Example 3: Method for producing N- (p-methylbenzoyl) -D-serine (D-form of Compound 1)>
Using D-toluic acid (Tokyo Kasei Kogyo Co., Ltd.) and D-serine (Peptide Institute Inc.), the D-form of Compound 1 was synthesized in the same manner as the L-form of Compound 1 above.

<Physical constant of D-form of Compound 1>
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−（４−エチルベンゾイル）−Ｌ−セリン（化合物２のＬ体）

N- (4-ethylbenzoyl) -L-serine (L-form of Compound 2)

<Production Example 4: Method for producing L-form of Compound 2>
The L-form of Compound 2 was synthesized in the same manner as the L-form of Compound 1 above using p-ethylbenzoyl chloride (Wako Pure Chemical Industries, Ltd.) and L-serine (Peptide Laboratories).

<Physical constant of L-form of Compound 2>
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−（４−メトキシベンゾイル）−Ｌ−セリン（化合物３のＬ体）

N- (4-methoxybenzoyl) -L-serine (L-form of Compound 3)

<Production Example 5: Method for producing L-form of Compound 3>
The p-methoxybenzoyl chloride (Tokyo Kasei Kogyo Co., Ltd.) and L-serine (Peptide Institute, Inc.) were used to synthesize the L-form of Compound 3 according to the same method as the L-form of Compound 1 described above.

<Physical constant of L-form of compound 3>
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−（４−フルオロベンゾイル）−Ｌ−セリン（化合物４のＬ体）

N- (4-Fluorobenzoyl) -L-serine (L-form of Compound 4)

<Production Example 6: Method for producing L-form of Compound 4>
Using L-serine (Wako Pure Chemical Industries, Ltd.) and L-serine (Peptide Laboratories, Inc.) and p-fluorobenzoyl chloride (Wako Pure Chemical Industries, Ltd.), the L-form of Compound 4 was synthesized in the same manner as the L-form of Compound 1.

<Physical constant of L-form 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−（４−トリフルオロメチルベンゾイル）−Ｌ−セリン（化合物５のＬ体）

N- (4-trifluoromethylbenzoyl) -L-serine (L-form of Compound 5)

<Production Example 7: Method for producing L-form of Compound 5>
Using L-serine (Peptide Laboratories) and p- (trifluoromethyl) benzoyl chloride (Wako Pure Chemical Industries, Ltd.) did.

<Physical constant of L-form of compound 5>
¹ H-NMR (CD ₃ OD): δ 4.02 (2H, m), 4.74 (1H, m), 7.81 (2H, d), 8.07 (2H, d).

N−（２−ナフトイル）−Ｌ−セリン（化合物６のＬ体）

N- (2-naphthoyl) -L-serine (L-form of Compound 6)

<Production Example 8: Method for producing L-form of Compound 6>
L-serine (2.00 g, 19.0 mmol) (Peptide Institute, Inc.) was dispersed in tetrahydrofuran (19 mL) (Wako Pure Chemical Industries, Ltd.) and stirred under ice-cooling with 2N aqueous sodium hydroxide solution ( 19 mL) was added. Subsequently, 2-naphthoyl chloride (3.64 g, 19.1 mmol) (Tokyo Chemical Industry Co., Ltd.) was added. The water bath was removed, the temperature was returned to room temperature, and the mixture was stirred for 16 hours. Tetrahydrofuran was distilled off under reduced pressure. While stirring under ice cooling, hydrochloric acid (4 mL) (Wako Pure Chemical Industries, Ltd.) was added to adjust the pH to 2 or less. The solid was collected by filtration and washed thoroughly with water. tert-Butyl methyl ether (30 mL) (Tokyo Chemical Industry Co., Ltd.) was added, and insoluble matters were collected by filtration. This was thoroughly washed with tert-butyl methyl ether. Further, the mixture was washed successively with tert-butylmethyl ether: ethyl acetate (= 4: 1) and n-hexane to obtain 2.92 g (yield 59.2%) of Compound L.

<Physical constant of L-form of compound 6>
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−（４−フェニルベンゾイル）−Ｌ−セリン（化合物７のＬ体）

N- (4-Phenylbenzoyl) -L-serine (L-form of Compound 7)

<Production Example 9: Method for producing L-form of Compound 7>
Using L-serine (Peptide Institute Inc.) and 4-phenylbenzoyl chloride (Wako Pure Chemical Industries, Ltd.) and L-serine (Peptide Institute, Inc.), the L-form of Compound 7 was synthesized in the same manner as the L-form of Compound 1.

<Physical constant of L-form of compound 7>
¹ H-NMR (CD ₃ OD): δ 4.03 (2H, m), 4.75 (1H, m), 7.45 (3H, m), 7.73 (4H, m), 7.9 (2H, s), 8.37 (1H, d).

N−（４−メチルベンゾイル）−Ｌ−セリン メチルエステル（化合物９のＬ体）

N- (4-methylbenzoyl) -L-serine methyl ester (L-form of Compound 9)

<Production Example 10: Method for producing L-form of Compound 9>
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, Ltd.) and triethylamine (2.25 g, 22.2 mmol) (Wako Pure Chemical Industries, Ltd.) was added, and a solution of p-methoxybenzoyl chloride (1.78 g, 11.5 mmol) (Tokyo Chemical Industry Co., Ltd.) / Dichloromethane (5 mL) was added over 3 minutes with stirring under ice cooling. And dripped. After removing the water bath and returning to room temperature and stirring for 6 hours, the reaction solution was diluted with ethyl acetate (100 mL) (Wako Pure Chemical Industries, Ltd.), saturated sodium hydrogen carbonate solution (30 mL), 1N hydrochloric acid (50 mL) and Washed sequentially with saturated saline (30 mL, 60 mL × 2). The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.) and then filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1: 2), and fractions containing the desired product were collected and concentrated under reduced pressure to obtain 1.88 g (yield 79) of Compound 9 in L form. .5%).

<Physical constant of L-form of compound 9>
¹ H-NMR (CDCl ₃ ): δ 2.41 (3H, s), 2.58 (1H, brs), 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−（２−ナフトイル）−L−セリン メチルエステル（化合物１０のＬ体）

N- (2-naphthoyl) -L-serine methyl ester (L-form of Compound 10)

<Production Example 11: Method for producing L-form of Compound 10>
Using L-naphthoyl chloride (Tokyo Chemical Industry Co., Ltd.) and L-serine methyl ester hydrochloride (Tokyo Chemical Industry Co., Ltd.), the L-form of Compound 10 was synthesized in the same manner as the L-form of Compound 9 above. .

<Physical constant of L-form of compound 10>
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−ベンゾイル−ＤＬ−O−メチルセリン（化合物１１のラセミ体）

N-benzoyl-DL-O-methylserine (racemic compound 11)

<Production Example 12: Method for producing racemic compound 11>
A racemate of compound 11 was synthesized in the same manner as the L form of compound 1 using benzoyl chloride (Wako Pure Chemical Industries, Ltd.) and DL-O-methylserine (Tokyo Chemical Industry Co., Ltd.).

<Physical constant of racemic body of compound 11>
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−（４−メチルベンゾイル）−ＤＬ−O−メチルセリン（化合物１２のラセミ体）

N- (4-Methylbenzoyl) -DL-O-methylserine (racemic compound 12)

<Production Example 13: Method for producing racemic compound 12>
A racemate of compound 12 was synthesized in the same manner as the L form of compound 1 using p-methylbenzoyl chloride (Sigma Aldrich) and DL-O-methylserine (Tokyo Chemical Industry Co., Ltd.).

<Physical constant of racemic body of compound 12>
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−メチルベンゾイル）−０−アセチル−Ｌ−セリン （化合物１３のＬ体）

N- (p-methylbenzoyl) -0-acetyl-L-serine (L-form of Compound 13)

<Production Example 14: Method for producing L-form of Compound 13>
The p-methylbenzoyl chloride (Sigma-Aldrich) and O-acetyl-L-serine hydrochloride (Sigma-Aldrich) were used and the L-form of Compound 13 was synthesized in the same manner as the L-form of Compound 1.

<Physical constant of L-form of compound 13>
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, q), 7.78 (2H, q), 8.68 (1H, d).

N−（２−ナフトイル）−DL−O−メチルセリン （化合物１４のラセミ体）

N- (2-naphthoyl) -DL-O-methylserine (racemic compound 14)

<Production Example 15: Method for producing racemic compound 14>
A racemic isomer of Compound 14 was synthesized according to the same method as the L isomer of Compound 1 using 2-naphthoyl chloride (Tokyo Chemical Industry Co., Ltd.) and DL-O-methylserine (Tokyo Chemical Industry Co., Ltd.).

<Physical constant of racemic compound 14>
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).

<Whitening component of the present invention>
The skin external preparation of the present invention contains 1) a compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) a whitening component. Features. The whitening component of the present invention is excellent in preventing pigmentation by containing it in a skin external preparation together with the compound represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof. Or it shows the improvement effect. Such an action is considered to be manifested by effectively enhancing the pigmentation preventing or improving action of the whitening agent by the compound represented by the general formula (1). Specific examples of the whitening component of the present invention include melanin production inhibitors, α-MSH inhibitors, melanocyte dendrite elongation inhibitors, proton pump inhibitors and the like. Moreover, as a whitening component of this invention, forms, such as a pure chemical substance and the extract derived from animals and plants, can be illustrated suitably. Here, the extracts derived from animals and plants are extracts themselves extracted from animals or plants, fractions obtained by fractionating and purifying animal or plant extracts, animals or plant extracts or fractions, solvents for purified products. It means the generic name of the removed material. When such a whitening component is contained in the external preparation for skin of the present invention, only one type of the following whitening components can be contained, or two or more types can be contained in combination.

  Among the whitening ingredients of the present invention, the melanin production inhibitor will be described. The melanin production inhibitor of the present invention can be applied without particular limitation as long as it is a component having a melanin production inhibitory action. If a thing preferable as a melanin production inhibitor of this invention is mentioned, for example, in the melanin production inhibitory action test of Unexamined-Japanese-Patent No. 2009-155236, in the test substance addition density | concentration which does not show cytotoxicity, 50% or more of melanin production A component showing an inhibitory action can be preferably exemplified. Specific examples of preferred melanin production inhibitors of the present invention include 4-alkylresorcinol derivatives and / or their pharmacologically acceptable salts, ascorbic acid derivatives and / or them. Pharmacologically acceptable salts, hydroquinone derivatives and / or their pharmacologically acceptable salts, tranexamic acid derivatives and / or their pharmacologically acceptable salts, vitamin E derivatives and / or their Pharmacologically acceptable salts thereof, pantethein-S-sulfonic acid and / or pharmacologically acceptable salts thereof, ursolic acid derivatives and / or pharmacologically acceptable salts thereof are preferred. Can be illustrated. In addition to the melanin production inhibitor, 4-alkoxysalicylic acid such as 4-methoxysalicylic acid and / or a pharmacologically acceptable salt thereof, 5,5′-dipropyl-biphenyl-2,2′-dio- Biphenyl derivatives such as ruthenium and / or pharmacologically acceptable salts thereof, nicotinic acid amide derivatives such as nicotinamide and / or pharmacologically acceptable salts thereof, unsaturated such as linoleic acid Fatty acids and / or pharmacologically acceptable salts thereof can also be suitably exemplified as the melanin production inhibitor of the present invention.

  Among the melanin production inhibitors of the present invention, 4-alkylresorcinol derivatives and / or pharmacologically acceptable salts thereof will be described. The 4-alkylresorcinol derivative which is the melanin production inhibitor of the present invention may be a 4-alkylresorcinol derivative exhibiting a melanin production inhibitory action and / or a pharmacologically acceptable salt thereof. For example, it can be applied without any particular limitation. The 4-position substituent of the 4-alkylresorcinol derivative has 3 to 10 carbon atoms, more preferably a cyclic alkyl group having 5 to 8 carbon atoms, and 1 to 8 carbon atoms, more preferably 2 carbon atoms. -6 linear or branched alkyl groups are preferred. Specific examples of the 4-alkylresorcinol derivative of the present invention include 4-cyclopentylresorcinol, 4-cyclohexylresorcinol, 4-cycloheptylresorcinol. 4-cyclooctyl resorcinol, 4-methyl resorcinol, 4-ethyl resorcinol, 4-n-propyl resorcinol, 4-isopropyl resorcinol, 4-n-butyl resorcinol 4-isobutyl resorcinol, 4-sec-butyl resorcinol, 4-tert-butyl resorcinol, 4-n-pentyl resorcinol, 4-n-hexyl resorcinol, 4- Preferred examples include n-heptyl resorcinol, 4-n-octyl resorcinol, and / or pharmacologically acceptable salts thereof. Of these compounds, 4-n-butylresorcinol and / or a pharmacologically acceptable salt thereof can be preferably exemplified as a particularly preferable compound.

  The 4-alkylresorcinol derivative of the melanin production inhibitor of the present invention and / or a pharmacologically acceptable salt thereof is a compound represented by the general formula (1), an optical isomer thereof and / or Or, by including in a skin external preparation together with a pharmacologically acceptable salt thereof, an excellent effect of preventing or improving pigmentation is exhibited. In order to exert such a pharmacological effect, the total amount of the 4-alkylresorcinol derivative and / or pharmacologically acceptable salt thereof is 0.0001% by mass to 5% by mass with respect to the total amount of the external preparation for skin. %, More preferably 0.001% by mass to 3% by mass, and still more preferably 0.01% by mass to 2% by mass. This is because if the amount is too small, the effect tends to decrease. If the amount is too large, the effect tends to reach its peak, and the degree of freedom of prescription may decrease.

  The 4-alkyl resorcinol derivative of the melanin production inhibitor of the present invention is a method in which a corresponding carboxylic acid having an alkyl group and resorcin are condensed in the presence of zinc chloride and reduced with zinc amalgam / hydrochloric acid, or Known synthesizing methods such as a method of condensing an alcohol having the corresponding alkyl group and resorcin at a high temperature of 200 to 400 ° C. (for example, Lille, J .; Bitter, LA; Peiner, V. Trudy-Nauchono- Issledovatel 'skii Institut Slantsev (1969), No. 18, 127-134, Japanese Patent Laid-Open No. 2006-124358, Japanese Patent Laid-Open No. 2006-124357), or purchased as a commercially available reagent You can also.

  Among the melanin production inhibitors of the present invention, ascorbic acid derivatives and / or pharmacologically acceptable salts thereof will be described. The ascorbic acid derivative and pharmacologically acceptable salt thereof of the melanin production inhibitor of the present invention are specially selected as long as it is an ascorbic acid derivative and / or a pharmacologically acceptable salt thereof showing a melanin production inhibitory action. It can be applied without limitation. Of these ascorbic acid derivatives, water-soluble ascorbic acid derivatives and / or pharmacologically acceptable salts thereof are more preferable. Specific examples of the ascorbic acid derivatives and / or pharmacologically acceptable salts thereof according to the present invention include ascorbic acid, ascorbic acid phosphate ester, ascorbic acid-2-glycoside (simply ascorbic acid In some cases, it may be expressed as glucoside), ethyl ascorbate and / or a pharmacologically acceptable salt thereof can be suitably exemplified, and more preferable examples include ascorbic acid, ascorbic acid-2-glucoside, and ascorbic acid. And ethyl and / or pharmacologically acceptable salts thereof. Alcorbic acid, ascorbic acid-2-glucoside, ethyl ascorbate, and / or their pharmacologically acceptable salts have a high water solubility in addition to having an excellent inhibitory action on melanin production. Rich in versatility.

  The ascorbic acid derivative and / or pharmacologically acceptable salt thereof of the melanin production inhibitor of the present invention is a compound represented by the general formula (1), its optical isomer and / or their pharmacological properties. When included in an external preparation for skin together with an acceptable salt, excellent pigmentation prevention or improvement effects are exhibited. In order to exert such a pharmacological effect, the total amount is preferably 0.01% by mass to 10% by mass, more preferably 0.05% by mass to 5% by mass with respect to the total amount of the external preparation for skin. This is because if the amount is too small, the effect tends to decrease, and if the amount is too large, the effect tends to reach a peak, and the degree of freedom of prescription may decrease.

  The hydroquinone derivative of the melanin production inhibitor of the present invention and / or a pharmacologically acceptable salt thereof will be described. The hydroquinone derivative and / or pharmacologically acceptable salt thereof of the melanin production inhibitor of the present invention is special if it is a hydroquinone derivative showing melanin production inhibitory action and / or a pharmacologically acceptable salt thereof. It can be applied without limitation. Of the hydroquinone derivatives of the present invention and / or pharmacologically acceptable salts thereof, preferred examples include hydroquinone glycosides. Examples of the sugar chain portion of the hydroquinone glycoside include L-arabinose, D-xylos, D-ribose, D-xylose, D-lyxose, D-ribose and the like. Carbon sugar, D-glucose, D-galactose, D-mannose, D-tagalose, D-fructose, L-sorbose and other hexoses, D-glucosamine, D- Amino acid sugars such as galactosamine, sialic acid, and muramic acid can be preferably exemplified. In addition, as other hydroquinone derivatives and / or pharmacologically acceptable salts thereof, uronic acid or a methyl compound thereof, and acetyl compounds include D-glucuronic acid, D-galacturonic acid, D-mannuronic acid, L -Uronic acids such as iduronic acid or their methyl compounds and acetyl compounds can be preferably exemplified. Of these hydroquinone derivatives, arbutin having a chemical structure in which hydroquinone and glucose are combined and / or a pharmacologically acceptable salt thereof can be preferably exemplified.

  The hydroquinone derivative of the melanin production inhibitor of the present invention can be obtained by a conventional method from a sugar corresponding to hydroquinone. For example, arbutin can be synthesized by enzymatic reaction using β-glucosidase in a solution composed of hydroquinone and glucose described in JP-A No. 05-176785.

  The hydroquinone derivative of the melanin production inhibitor of the present invention and / or a pharmacologically acceptable salt thereof is a compound represented by the general formula (1), an optical isomer thereof and / or a pharmacology thereof. When included in a skin external preparation together with a chemically acceptable salt, it exhibits an excellent effect of preventing or improving pigmentation. In order to achieve the above pharmacological effects, the hydroquinone derivatives and / or pharmacologically acceptable salts thereof in a total amount of 0.001% by mass to 5% by mass, more preferably 0%, based on the total amount of the external preparation for skin. It is preferable to contain 1 mass%-3 mass%. This is because if the amount is too small, the effect tends to decrease. If the amount is too large, the effect tends to reach its peak, and the degree of freedom of prescription may decrease.

  The melanin production inhibitor tranexamic acid of the present invention, its derivative and / or pharmacologically acceptable salt thereof will be described. The tranexamic acid derivative and / or pharmacologically acceptable salt thereof of the present invention is not particularly limited as long as it is a tranexamic acid derivative and / or pharmacologically acceptable salt thereof exhibiting a melanin production inhibitory action. It can be applied. Specific examples of the tranexamic acid derivatives and pharmacologically acceptable salts thereof according to the present invention include tranexamic acid, tranexamic acid methylamide, and / or pharmacologically acceptable salts thereof. Can be preferably exemplified, and more preferably, tranexamic acid and / or a pharmacologically acceptable salt thereof can be suitably exemplified.

  The tranexamic acid derivative of the present invention and / or a pharmacologically acceptable salt thereof is a compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof. In addition, when contained in an external preparation for skin, an excellent effect of preventing or improving pigmentation is exhibited. In order for the tranexamic acid derivative of the present invention and / or pharmacologically acceptable salt thereof to exhibit the above pharmacological effects, the total amount is 0.01% by mass to 10% by mass with respect to the total amount of the external preparation for skin, More preferably, it is 0.05 mass%-5 mass%, More preferably, it is preferable to contain 0.1 mass%-3 mass%. This is because if the amount is too small, the pharmacological effect tends to decrease, and if the amount is too large, the effect tends to reach its peak, which may reduce the degree of freedom of prescription.

  The vitamin E derivatives and / or pharmacologically acceptable salts thereof that are melanin production inhibitors of the present invention will be described. The vitamin E derivative of the present invention and / or pharmacologically acceptable salt thereof is not particularly limited as long as it is a vitamin E derivative showing a melanin production inhibitory action and / or a pharmacologically acceptable salt thereof. It can be applied without. Specific examples of preferred vitamin E derivatives and / or pharmacologically acceptable salts thereof according to the present invention include vitamin E, vitamin E acetate, vitamin E nicotine, vitamin E oroate. And / or pharmacologically acceptable salts thereof can be preferably exemplified, and more preferably, vitamin E and / or pharmacologically acceptable salts thereof can be suitably exemplified.

  The vitamin E derivative of the present invention and / or a pharmacologically acceptable salt thereof is a compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof. By containing it in a skin external preparation together with salt, it exhibits an excellent effect of preventing or improving pigmentation. In addition, in order for the vitamin E derivative of the present invention and / or pharmacologically acceptable salt thereof to exhibit the above-described effects, the total amount is 0.05% by mass to 10% by mass with respect to the total amount of the external preparation for skin. More preferably, the content is from 0.2% by mass to 5% by mass, and more preferably from 0.5% by mass to 3% by mass. This is because if the amount is too small, the pharmacological effect tends to decrease. If the amount is too large, the effect tends to reach its peak, and the degree of freedom of prescription may decrease.

  The melanin production inhibitor pantethein-S-sulfonic acid and / or pharmacologically acceptable salt thereof of the present invention will be described. The pantethein-S-sulfonic acid of the present invention can be used not only in a free acid form but also in a salt form. The salt of pantethein-S-sulfonic acid of the present invention can be applied without particular limitation as long as it is a pharmacologically acceptable salt. For example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, organic amine salts such as ammonium salt, triethylamine salt, triethanolamine salt, monoethanolamine salt, lysine salt, Preferred examples include basic amino acid salts such as alginates. Of these, alkaline earth metal salts are preferable, and calcium salts are particularly preferable. This is because bioavailability is high when used in the form of an external preparation for skin. In addition, pantethein-S-sulfonic acid has an optical isomer, and any of D-form, L-form and DL-form can be used in the present invention, but it is preferable to use D-form. Panthetin-S-sulfonic acid and its salt are known compounds, and there are those already marketed as cosmetic raw materials, and such commercial products can be purchased and used. As such a commercially available product, “pantethine S sulfonic acid CA-70” (Mutaku Pharmaceutical Co., Ltd.), which is a calcium salt of pantethine-S-sulfonic acid, can be preferably exemplified.

  The pantethein-S-sulfonic acid and / or pharmacologically acceptable salt thereof of the present invention is a compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof. When included in an external preparation for skin together with a salt to be produced, it exhibits an excellent effect of preventing or improving pigmentation. In order for the pantethein-S-sulfonic acid and / or pharmacologically acceptable salt thereof of the present invention to exert the above pharmacological effects, the total amount of the external preparation for skin is 0.001% by mass to It is preferable to contain 1.0 mass%, More preferably, 0.005 mass%-0.8 mass%, More preferably, it contains 0.01 mass%-0.3 mass%. This is because if the amount is too small, the pharmacological effect tends to decrease. If the amount is too large, the effect tends to reach its peak, and the degree of freedom of prescription may decrease.

  The ursolic acid derivative and / or pharmacologically acceptable salt thereof of the melanin production inhibitor of the present invention will be described. The ursolic acid derivative and / or pharmacologically acceptable salt thereof of the present invention is an ursolic acid derivative and / or pharmacologically acceptable salt thereof exhibiting a melanin production inhibitory action. It can be applied without any particular limitation. Specific examples of preferred ursolic acid derivatives and / or pharmacologically acceptable salts thereof according to the present invention include ursolic acid and ursolic acid having 1 to 20 carbon atoms. A hydrocarbon ester, a hydrocarbon ester having 1 to 4 carbon atoms substituted by an aromatic group of ursolic acid, a phosphoric ester of ursolic acid, and / or a pharmaceutically acceptable salt thereof. It can illustrate suitably. Examples of the aliphatic hydrocarbon ester of ursolic acid having 1 to 20 carbon atoms include methyl ester, ethyl ester, hexyl ester, cyclohexyl ester, octyl ester, isooctyl ester, lauryl ester, cetyl ester, stearyl ester, Suitable examples include aliphatic esters such as stearyl esters and oleyl esters. Examples of the C1-C4 hydrocarbon ester substituted with the aromatic group of ursolic acid include benzyl ester, phenylethyl ester, phenylpropyl ester, and phenylbutyl ester. Esters are particularly preferred. Of the ursolic acid derivatives of the present invention and / or their pharmacologically acceptable salts, preferred compounds are specifically exemplified by ursolic acid, ursolic acid benzyl (for example, JP-A 2000 -302659), ursolic acid phosphate (see, for example, WO2006132033), and / or pharmacologically acceptable salts thereof.

  The ursolic acid derivative and / or pharmacologically acceptable salt thereof of the present invention is a compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof. In combination with a salt, the skin external preparation exhibits an excellent effect of preventing or improving pigmentation. In order for the ursolic acid derivative and / or pharmacologically acceptable salt thereof of the present invention to exhibit the pharmacological effect, the total amount is 0.0001% by mass to 15% with respect to the total amount of the external preparation for skin. It is preferable to contain 0.001 mass%-10 mass%, More preferably, it contains 0.01 mass%-5 mass% more preferably. This is because if the amount is too small, the pharmacological effect tends to decrease, and if the amount is too large, the effect tends to reach its peak, which may reduce the degree of freedom of prescription.

  Among the whitening components of the present invention, the α-MSH production inhibitor will be described. The α-MSH production inhibitor of the present invention can be applied without particular limitation as long as it is a component that exhibits an α-MSH production inhibitory action. As the α-MSH production inhibitor of the present invention, for example, a component having an action of reducing the amount of c-AMP produced in cultured cells in the α-MSH production inhibitory action evaluation system described in JP-A-2009-067804 is preferable. Can be illustrated. As the α-MSH production inhibitor of the present invention, a plant extract obtained from a plant belonging to the leguminous family Clara can be preferably exemplified, more preferably a plant extract obtained from the leguminous family Clara genus is suitably exemplified. I can do it. The α-MSH production inhibitor of the present invention prevents pigmentation by inhibiting the production and information transmission of α-MSH, which is a signal transmitter involved in melanin production in the living body, in particular, melanin production in skin melanocytes. Or it shows the improvement effect.

  By containing the α-MSH production inhibitor of the present invention in a skin external preparation together with the compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, Exhibits excellent pigmentation prevention or improvement effect. In order for the α-MSH production inhibitor of the present invention to exert the above-described effects, the total amount is 0.00001% by mass to 15% by mass, and more preferably 0.0001% by mass to 10% by mass with respect to the total amount of the external preparation for skin. %, More preferably 0.01% by mass to 5% by mass. If the amount is too small, the pharmacological effect tends to decrease. If the amount is too large, the effect tends to reach its peak, and the degree of freedom of prescription may decrease.

  Among the whitening components of the present invention, the melanocyte dendrite elongation inhibitor will be described. The dendritic extension inhibitor for melanocytes of the present invention can be applied without particular limitation as long as it is a component exhibiting a melanocyte extension inhibitory action. As a component which has the dendrite extension inhibitory action of the melanocyte of this invention, the component which has a dendrite extension inhibitory action in the evaluation of the dendrite extension inhibitory action of the melanocyte of Unexamined-Japanese-Patent No. 2009-0465503 can be illustrated suitably. Specific examples of preferred dendrite elongation inhibitors of the present invention include methylophiopogononone B, sophoraflavanone A, plant extract obtained from Asteraceae yarrow, plant extract obtained from lily family Bakumondo Can be suitably exemplified. The melanocyte dendrite elongation inhibitor of the present invention is effective not only for pigmentation caused by increased melanin production, but also for pigmentation caused by increased migration of melanin granules from melanocyte dendrite, which does not contribute much to melanin production. It has been known.

  The melanocyte dendrite elongation inhibitor of the present invention is contained in a skin external preparation together with the compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof. Excellent pigmentation prevention or improvement effect. In order for the dendrite elongation inhibitor of melanocytes of the present invention to exert the pharmacological effect, the total amount is 0.01% by mass to 10% by mass, and more preferably 0.05% by mass to 5% by mass with respect to the total amount of the external preparation for skin. % Content is preferable. This is because if the amount is too small, the pharmacological effect tends to decrease. If the amount is too large, the effect tends to reach its peak, and the degree of freedom of prescription may decrease.

Among the whitening components of the present invention, the proton pump inhibitor will be described. The proton pump inhibitor of the present invention can be applied without particular limitation as long as it is a component that exhibits pigment prevention or improvement by proton pump inhibition. The proton pump inhibitor is a membrane H ⁺ -ATPase that is present in a biological membrane and actively transports protons, and / or Na ⁺ / H that works in conjunction with Na ⁺ / K ⁺ -ATPase of an ion pump and passively transports protons. ⁺ Acts on the exchange transport system and the like, and inhibits proton transport, thereby being excellent in the action of inducing acidification in cells or organelles. Acidification in a cell or organelle has a great influence on the biological activity or function of a biologically functional molecule such as an ion channel or enzyme (for example, tyrosinase) that works in a pH-dependent manner. The tyrosinase enzyme is greatly affected by pH fluctuations, and when tyrosinase activity is lowered by intracellular acidification by a proton pump inhibitor, melanin production is suppressed. As a component which shows the proton pump inhibitory action of this invention, the component which shows a proton pump inhibitory action in the proton pump inhibitory action evaluation of Japanese Patent Application No. 2009-219292 can be illustrated suitably, for example. Of the components having proton pump inhibitory activity of the present invention, preferred examples are specifically exemplified: plants belonging to the genus Lamiaceae, genus Clara, plants belonging to the genus Clariaceae, cucurbitaceae A plant extract obtained from a plant belonging to the genus Hechima, a plant belonging to the genus Hydrangeaceae, a plant belonging to the genus Sarcophagus matsuhodo, a plant belonging to the genus Leguminosae, can be preferably exemplified, more preferably, Obtained plant extract, plant extract obtained from leguminous clara genus clara, plant extract obtained from ginger family ginger genus ginger, plant extract obtained from taro family ginger genus ginger, obtained from cucurbitaceae Plant extract, plant extract obtained from Hydrangea hydrangea amacha, Sarnokoshika Plant extracts obtained from family Wolfiporia Extensa sclerotia Bukuryou, plant extract obtained from leguminous clover genus Kihagi, plant extract obtained from leguminous gores genus Toukusahagi be suitably be exemplified.

  The proton pump inhibitor of the present invention is excellent when contained in a skin external preparation together with the compound represented by the general formula (1), its optical isomer and / or pharmacologically acceptable salt thereof. Demonstrate or improve pigmentation. In order for the proton pump inhibitor of the present invention to exert the pharmacological effect, the total amount is 0.000001 mass% to 10 mass%, more preferably 0.00001 mass% to 5 mass%, based on the total amount of the external preparation for skin. More preferably, the content is 0.0001% by mass to 3% by mass. This is because if the amount is too small, the pharmacological effect tends to decrease. If the amount is too large, the effect tends to reach its peak, and the degree of freedom of prescription may decrease.

  When the skin whitening component of the present invention is contained in the external preparation for skin, one or more kinds from the group consisting of the above-mentioned whitening ingredients melanin production inhibitor, α-MSH inhibitor, melanocyte dendrite elongation inhibitor, proton pump inhibitor Two or more types can be selected and contained in the external preparation for skin. In addition to the pure chemical substances, the whitening ingredients include extracts from animals or plants. Here, the extract of the present invention means a general term for the extract itself, the fraction of the extract, the purified fraction, the extract or fraction, and the solvent-removed product of the purified product.

  Among the whitening components of the present invention, for a pure chemical substance, the compound can be used as it is, or can be used as a pharmacologically acceptable salt form. These salts can be used without particular limitation as long as they are used in cosmetics (external preparations for skin), pharmaceuticals, and the like. For example, alkali salts such as sodium salts and potassium salts are used as alkali salts. Preferred are alkaline earth metal salts such as calcium salts and magnesium salts, organic amine salts such as ammonium salts, triethylamine salts, triethanolamine salts and monoethanolamine salts, and basic amino acid salts such as lysine salts and alginates. It can be illustrated. Moreover, as long as it is a salt with an acid, mineral acid salts, such as hydrochloride, phosphate, sulfate, and nitrate, organic acid salts, such as carbonate, citrate, and tartrate, etc. can be illustrated suitably.

The whitening component of the present invention contains a compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof in an external preparation for skin, whereby excellent pigmentation is achieved. Demonstrate the prevention or improvement effect. The pharmacological effect can be achieved by including in the skin external preparation both the whitening component of the present invention and the compound represented by the general formula (1), optical isomers and / or pharmacologically acceptable salts thereof. It is considered that the pigmentation preventing or improving effect of the whitening component is enhanced additively or synergistically, and further, the effect of improving the delivery efficiency of the whitening component to the target site.

<Skin external preparation of the present invention>
The skin external preparation of the present invention contains 1) the compound represented by the above general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof, and 2) a whitening component. It is characterized by the fact that both components are contained in an external preparation for skin, thereby having an excellent pigmentation preventing or improving action. As far as the inventor knows, the compound represented by the general formula (1) of the present invention has an effect of preventing or improving pigmentation, and further enhancing the effect of preventing or improving pigmentation of the whitening component. Not. For this reason, the pigmentation prevention or improvement effect which the skin external preparation of this invention has is because the compound represented by the said General formula (1) efficiently enhances the pigmentation prevention or improvement effect which a whitening component has. It is thought that it is demonstrated. In addition, the effect of preventing or improving the pigmentation of the external preparation for skin of the present invention includes an action of preventing pigmentation in addition to the action of thinning or returning the pigmentation already formed. The pigmentation prevention or improvement action in the present invention can be applied without particular limitation as long as it is a pigmentation prevention or improvement action. Among these actions, the action of preventing or improving pigmentation in “Evaluation of pigmentation inhibitory effect of topical skin preparation in humans” in Example 2 described later can be preferably exemplified. In Example 2, “Evaluation of pigmentation inhibitory effect of topical skin preparations in humans”, as a component having a pigmentation inhibitory action, a formulation containing an evaluation substance as compared with a control group (a formulation group containing no evaluation substance) Ingredients that have an effect of preventing or improving pigmentation in the group (components having a smaller ΔL * value in the evaluation substance combination preparation group than in the control group) can be preferably exemplified, and more preferably, prevention or improvement of pigmentation is preferred. A component having a statistically significant difference in the effect can be suitably exemplified.

  Moreover, as a skin external preparation of this invention, since a pharmaceutical, a quasi-drug, cosmetics, etc. can be illustrated suitably and can be ingested on a daily basis, it is preferable to apply to cosmetics, a quasi-drug, etc. The administration route is preferably such that these components are administered continuously, or transdermally in consideration of safety. The external skin preparation of the present invention can be used without particular limitation as long as it is applied externally to the skin, for example, cosmetics, skin external medicine, skin external goods and the like can be suitably exemplified, It is particularly preferable to apply to cosmetics. This is because the external preparation for skin of the present invention has an unparalleled feeling of use and is particularly suitable for cosmetics where the feeling of use is important. The external preparation for skin (cosmetics) of the present invention can be applied without particular limitation as long as it can be used in the form of external preparation for skin. Examples of such forms include lotion preparations, oil-in-water emulsion preparations, A water-in-oil emulsion preparation, a composite emulsion emulsion preparation and the like can be suitably exemplified. Examples of the external preparation for skin of the present invention preferably include lotions such as cosmetics, emulsions, essences, creams, pack cosmetics, facial cleansing cosmetics, and cleansing cosmetics. Further, the water-in-oil emulsifier type preparations include, for example, basic cosmetics such as essence, milky lotion, cream, etc., under-make-up, foundation, teak color, mascara, eyeliner, etc. Suitable examples include makeup cosmetics and hair cosmetics such as hair creams.

  In the external preparation for skin of the present invention, in addition to the essential components described above, optional components that are usually used in external preparations for skin can be contained. Such optional ingredients include, for example, macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, palm oil, palm oil, liquid Lanolin, hydrogenated coconut oil, hydrogenated oil, molasses, hydrogenated castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba wax, oils, waxes; liquid paraffin, squalane, pristane, ozokerite, Hydrocarbons such as paraffin, ceresin, petrolatum, microcrystalline wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid; cetyl alcohol, stearyl alcohol -Le, Isosteari Higher alcohols such as alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol, cetostearyl alcohol; cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, diisopropyl adipate, sebacic acid Di-2-ethylhexyl, cetyl lactate, diisostearyl malate, ethylene glycol di-2-ethylhexanoate, neopentyl glycol dicaprate, glycerin di-2-heptylundecanoate, glycerin tri-2-ethylhexanoate Synthetic ester oils such as trimethylolpropane tri-2-ethylhexanoate, trimethylolpropane triisostearate, pentane erythritol tetra-2-ethylhexanoate; dimethylpolysiloxane, methylphenylpoly Chain polysiloxanes such as Loxane and diphenylpolysiloxane; Cyclic polysiloxanes such as octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, and dodecamethylcyclohexanesiloxane; Amino-modified polysiloxane, polyether-modified polysiloxane, and alkyl-modified polysiloxane , Oil agents such as silicone oil such as modified polysiloxane such as fluorine-modified polysiloxane; anionic surface activity such as fatty acid soap (sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, triethanolamine alkyl sulfate Agents; cationic surfactants such as stearyltrimethylammonium chloride, benzalkonium chloride, laurylamine oxide; imidazoline-based amphoteric surfactants (2-cocoyl-2-imida) Zolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), betaine surfactants (alkyl betaine, amide betaine, sulfobetaine, etc.), and amphoteric surfactants such as acylmethyltaurine; sorbitan fatty acid esters (sorbitan) Monostearate, sorbitan sesquioleate, etc.), glycerin fatty acids (such as glyceryl monostearate), propylene glycol fatty acid esters (such as propylene glycol monostearate), hardened castor oil derivatives, glycerin alkyl ether POE sorbitan fatty acid esters (POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbite fatty acid esters (POE-sorbitol monolaurate, etc.), POE glycerin fatty acid ester Tells (POE-glycerol monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE alkylphenyl ethers (POE nonylphenyl ether, etc.), Pluronic types, POE / POP alkyl ethers (POE / POP2-decyltetradecyl ether, etc.), Tetronics, POE castor oil, Hardened castor oil derivatives (POE castor oil, POE hardened castor oil, etc.), nonionic surfactants such as sucrose fatty acid ester, alkyl glucoside; moisturizing ingredients such as sodium pyrrolidone carboxylate, lactic acid, sodium lactate; surface treatment May be mica, talc, kaolin, synthetic mica, Powders such as calcium oxide, magnesium carbonate, anhydrous silicic acid (silica), aluminum oxide, barium sulfate; surface may be treated, bengara, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, bitumen Inorganic pigments such as titanium oxide and zinc oxide; surfaces may be treated; pearling agents such as titanium mica, fish phosphorus foil, bismuth oxychloride; red 202 which may be laked , Red 228, Red 226, Yellow 4, Blue 404, Yellow 5, Red 505, Red 230, Red 223, Orange 201, Red 213, Yellow 204, Yellow 203, Blue Organic dyes such as No. 1, Green No. 201, Purple No. 201, Red No. 204; Organic powders such as polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane elastomer; Paraaminobenzoic acid UV absorbers; Anthranilic acid UV absorbers; Salicylic acid UV absorbers; Cinnamic acid UV absorbers; Benzophenone UV absorbers; Sugar UV absorbers; 2- (2'-hydroxy-5 ' UV absorbers such as -t-octylphenyl) benzotriazole and 4-methoxy-4'-t-butyldibenzoylmethane, lower alcohols such as ethanol and isopropanol; vitamin A or a derivative thereof, vitamin Vitamin Bs such as B6 hydrochloride, vitamin B6 tripalmitate, vitamin B6 dioctanoate, vitamin B2 or derivatives thereof, vitamin B12, vitamin B15 or derivatives thereof; α-tocopherol, β-tocopherol, γ- Vitamin E such as tocopherol, vitamin E acetate, vitamin D, vitamin H, Preferable examples include vitamins such as pantothenic acid, panthetin and pyrroloquinoline quinone; antibacterial agents such as phenoxyethanol; and organic modified clay minerals such as hectorite and dimethyl distearyl ammonium modified hectorite.

  The skin external preparation containing 1) the compound represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof, and 2) a whitening component of the present invention, Some of them have effects other than pigmentation prevention or improvement. Even when the external preparation for skin of the present invention is used for the purpose of expressing such an action, the effect of the present invention is utilized when the above effect is exhibited. It belongs to the technical scope. Examples of the action other than the pigmentation prevention or improvement action of the present invention include actions such as rough skin prevention or improvement action, anti-aging action, wrinkle formation prevention or improvement action, anti-inflammatory action, moisturizing action and the like.

  The external preparation for skin of the present invention can be produced by treating the above-mentioned optional components and essential components according to a conventional method.

Hereinafter, the present invention will be described in more detail with reference to examples, but it is needless to say that the present invention is not limited to such examples.

<Production Example 16: Method 1 for producing skin external preparation of the present invention>
According to the formulations shown in Tables 1 and 2 below, external preparations for the skin of the present invention (lotion type, cosmetics 1 to 11) were prepared. That is, the prescription ingredients were heated to 80 ° C., stirred, dissolved, stirred and cooled, and then an appropriate amount of 10% (mass%) potassium hydroxide aqueous solution was added to adjust the pH to 6.5. Finally, water was added to make the total weight 1000 g to obtain a skin external preparation (lotion preparation, cosmetics 1 to 11). Similarly, Comparative Example 1 in which the “whitening component of the present invention” contained in the cosmetic 1 is replaced with “the compound represented by the general formula (1) of the present invention” and “the present invention” Comparative Example 2 in which “the compound represented by the general formula (1)” is replaced by “the whitening component of the present invention”, “the compound represented by the above general formula (1) of the present invention” and “the whitening component of the present invention” Comparative Example 3 was prepared by substituting “water” with “water”.

<Test Example 1: Human skin pigmentation inhibitory effect 1 in humans>
Using the skin external preparation (lotion preparation, cosmetics 1 to 11) produced according to the method described in Example 1 and the skin external preparation (lotion preparation) of Comparative Examples 1 to 3, the pigmentation inhibitory effect I investigated. A test site of 1.5 cm × 1.5 cm was provided on the first day (1st day) on the back of the panel that participated voluntarily, and the skin lightness (L * value) of the test site was measured using a color difference meter (CR-300 , Konica Minolta Co., Ltd.). After the skin brightness was measured on the first day of the test, the test site was irradiated with ultraviolet rays twice the minimum erythema amount (2 MED) once. 50 μL of each specimen (cosmetics 1-11 or cosmetics of Comparative Examples 1 to 3) was applied to each test site three times a day for 14 consecutive days immediately after the end of ultraviolet irradiation. 24 hours after application (15th day), the skin brightness (L * value) of each test site was measured with a color difference meter (CR-300, Konica Minolta Co., Ltd.), and 15 days from the L * value on the first day of the test. The ΔL * value was calculated by subtracting the L * value of the eye. A larger L * value indicates higher skin brightness. Therefore, the smaller the ΔL * value, the smaller the difference between the L * value on the first day of the test and the L * value on the 15th day, and it can be determined that pigmentation has been suppressed. The results are shown in Table 3. It can be seen that cosmetics 1 to 11 which are external preparations for skin of the present invention have a small ΔL * value as compared with Comparative Example 3, and have an excellent pigmentation inhibitory effect. Moreover, although the comparative example 1 and the comparative example 2 also had (DELTA) L * value small compared with the comparative example 3, and the pigmentation inhibitory action was recognized, the effect was weak compared with the cosmetics 1-11. Thereby, it turns out that the cosmetics 1-11 which are the skin external preparations of this invention show the prevention or improvement effect with respect to the outstanding pigmentation.

<Production Example 17: Method 2 for producing skin external preparation of the present invention>
Skin in which “the compound represented by the general formula (1) of the present invention” and “the whitening component of the present invention” in the prescription components of the cosmetic 1 described in Example 1 are changed to the contents described in Table 4. An external preparation (lotion type, cosmetics 12 to 13) was prepared in the same manner as cosmetic 1.

<Test Example 2: Evaluation 2 of pigmentation inhibitory effect in humans of the external preparation for skin of the present invention>
Using the skin external preparation (lotion preparation type, cosmetics 12 to 13) of the present invention prepared by the method described in Example 3 and Comparative Example 3, the pigmentation inhibitory effect was achieved according to the method described in Example 2. evaluated. The results are shown in Table 5. It can be seen that the cosmetic preparations 12 to 13 which are the external preparation for skin of the present invention have a small ΔL * value as compared with Comparative Example 3, and have an excellent prevention or improvement effect on pigmentation.

<Production Example 18: Method 3 for producing skin external preparation of the present invention>
According to the formulation shown in Table 6 below, the external preparation for skin of the present invention (cream formulation, cosmetic 14) was prepared. That is, the component B was heated to 80 ° C., stirred and dissolved, and then an appropriate amount of 10% (mass%) potassium hydroxide aqueous solution was added to adjust the pH to 6.5. Finally, water was added so that the total weight was 524.5 g (referred to as mixture A). In addition, component (a) was heated to 80 ° C., stirred, and dissolved (referred to as mixture B). Mixing mixture A heated to 80 ° C. is gradually added to mixture B with emulsification, emulsified, and the particles are homogenized with a homogenizer, followed by stirring and cooling to prepare a skin external preparation (cream formulation, cosmetic 14). did. In the same manner, Comparative Example 4 in which “the compound represented by the general formula (1) of the present invention” and “the whitening component of the present invention” in Table 6 were both replaced with “water” was prepared.

<Test Example 1: Pigmentation inhibitory effect 3 by ultraviolet irradiation in human of topical skin preparation of the present invention>
With respect to the external preparation for skin (cream formulation, cosmetic 14) produced according to the production method of Example 5 and Comparative Example 4, the pigmentation inhibitory action in humans was evaluated according to the method described in Example 2. The results are shown in Table 7. From the results shown in Table 7, the skin external preparation of the present invention (cream preparation type, cosmetic 14) showed an excellent preventive or improving action against pigmentation.

  The present invention can be applied to cosmetics (however, including quasi drugs).

Claims (11)

A skin external preparation characterized by comprising 1) a compound represented by the following general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) a whitening component.

(1)
[Wherein, R1 represents an unsubstituted or substituted aromatic group, R2 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched group having 1 to 4 carbon atoms. R3 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. ] The compound represented by the general formula (1) is a compound represented by the following general formula (2), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, The external preparation for skin according to claim 1.

(2)
[Wherein, R4 represents an unsubstituted or substituted aromatic group, R5 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched group having 1 to 4 carbon atoms. Represents an acyl group having an alkyl chain. ] The compound represented by the general formula (1) is a compound represented by the following general formula (3), an optical isomer thereof and / or a pharmaceutically acceptable salt thereof. The external preparation for skin according to claim 1.

(3)
[Wherein, R6 represents an unsubstituted or substituted aromatic group, and R7 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. ] The compound represented by the general formula (1) is a compound represented by the following general formula (4), an optical isomer thereof and / or a pharmaceutically acceptable salt thereof. The skin external preparation of any one of Claims 1-3.

(4)
[Wherein R8 represents an unsubstituted or substituted aromatic group. ] The compound represented by the general formula (1) is N- (p-methylbenzoyl) serine (compound 1), N- (p-ethylbenzoyl) serine (compound 2), N- (p-methoxybenzoyl) serine. (Compound 3), N- (p-fluorobenzoyl) serine (Compound 4), N- (p-trifluoromethylbenzoyl) serine (Compound 5), N- (2-naphthoyl) serine (Compound 6), N- (4-phenylbenzoyl) serine (compound 7), N- (benzoyl) serine (compound 8), N- (p-methylbenzoyl) serine methyl ester (compound 9), N- (2-naphthoyl) serine methyl ester ( Compound 10), N-benzoyl-O-methylserine (compound 11), N- (p-methylbenzoyl) -O-methylserine (compound 12), N- (p-methylbenzoyl) -O-acetyl 2. Phosphorus (compound 13), N- (2-naphthoyl) -O-methylserine (compound 14), optical isomers thereof and / or pharmacologically acceptable salts thereof, The skin external preparation of any one of -4.

N- (p-methylbenzoyl) serine (Compound 1)

N- (p-ethylbenzoyl) serine (compound 2)

N- (p-methoxybenzoyl) serine (compound 3)

N- (p-fluorobenzoyl) serine (compound 4)

N- (p-trifluoromethylbenzoyl) serine (compound 5)

N- (2-naphthoyl) serine (Compound 6)

N- (4-Phenylbenzoyl) serine (Compound 7)

N- (benzoyl) serine (compound 8)

N- (p-methylbenzoyl) serine methyl ester (compound 9)

N- (2-naphthoyl) serine methyl ester (compound 10)

N-benzoyl-O-methylserine (compound 11)

N- (p-methylbenzoyl) -O-methylserine (compound 12)

N- (p-methylbenzoyl) -O-acetylserine (compound 13)

N- (2-naphthoyl) -O-methylserine (Compound 14) The compound represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof are contained in an amount of 0.0001% by mass to 20% by mass with respect to the total amount of the external preparation for skin. The external preparation for skin according to any one of claims 1 to 5, wherein: The whitening component contains one or more selected from the group consisting of a melanin production inhibitor, an α-MSH (MSH: Melanocyte stiumulating hormone) inhibitor, a melanocyte dendrite elongation inhibitor, and a proton pump inhibitor. The skin external preparation according to any one of claims 1 to 6, wherein the preparation is externally applied. The one selected from the group consisting of the melanin production inhibitor, α-MSH inhibitor, melanocyte dendrite elongation inhibitor and proton pump inhibitor is any of the following: The external preparation for skin according to any one of the above.
(Melanin production inhibitor): 4-alkylresorcinol and / or salt thereof, ascorbic acid derivative and / or salt thereof, hydroquinone and / or salt thereof, tranexamic acid derivative and / or salt thereof, Vitamin E and / or its derivative, pantethein-S-sulfonic acid and / or its salt, ursolic acid derivative and / or their salt (α-MSH inhibitor): plant extract obtained from legume Clara (Melanosite dendriide elongation inhibitor): Methyl ophiopogononone B, Sophoraflavanone A, Plant extract obtained from Asteraceae Achillea millefolium, Plant extract obtained from Liliaceae saccharum (proton pump inhibitor) Plant extract obtained from Musk genus Thyme, plant extract obtained from Clariaceae Clara , Plant extract obtained from ginger ginger genus ginger, plant extract obtained from taro family ginger genus ginger, plant extract obtained from cucurbitaceae genus gneiss, plant extract obtained from saxifragae hydrangea amacha, A plant extract obtained from the sorghum pine fungus nuclei, a plant extract obtained from the leguminous genus kihagi, a plant extract obtained from the leguminous sage The skin external preparation according to any one of claims 1 to 8, wherein the whitening component is contained in an amount of 0.000001 to 15 mass% with respect to the total amount of the external preparation for skin. The external preparation for skin according to any one of claims 1 to 9, which is a cosmetic (however, including quasi-drugs). The skin external preparation according to any one of claims 1 to 10, which is used for preventing or improving pigmentation.