JP2013001656A - Skin care preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a skin care preparation suitable as a cosmetic (including quasi medicine), etc.SOLUTION: The skin care preparation comprises an acyl derivative of serine and a compound represented by the general formula [wherein Ris an unsubstituted or substituent-containing aromatic group or hydrogen atom; Rand Rare each independently an unsubstituted or substituent-containing aromatic group; X is a nitrogen atom or oxygen atom; Rand Rare each present in the number depending on X and are each independently 1-6C alkyl in which a hydrogen atom or carbon atom may be substituted with a heteroatom or hydrogen atom].

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 It relates to a skin external preparation characterized by containing a pharmacologically acceptable salt, 2) a compound represented by the following general formula (2), and / or a pharmacologically acceptable salt thereof.

（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）
[式中、Ｒ４は、無置換又は置換基を有する芳香族基、水素原子を表し、Ｒ５及びＲ６は、それぞれ独立に、無置換又は置換基を有する芳香族基を表し、Ｘは、窒素原子又は酸素原子を表し、Ｒ７及びＲ８は、Ｘに応じた数で存在し、それぞれ独立に、水素原子又は炭素原子が複素原子に置換されていても良い炭素数１〜６の直鎖又は分岐のアルキル基、水素原子を表す。]

(2)
[Wherein R4 represents an unsubstituted or substituted aromatic group or hydrogen atom, R5 and R6 each independently represents an unsubstituted or substituted aromatic group, and X represents a nitrogen atom. Or an oxygen atom, and R7 and R8 are present in a number corresponding to X, and each independently represents a straight or branched chain having 1 to 6 carbon atoms in which a hydrogen atom or a carbon atom may be substituted with a hetero atom. Represents an alkyl group or a hydrogen atom. ]

  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 pigmentation. 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.

  Pigmentation symptoms are regulated by complex intertwining of various information transmitters, cytokines, and the like, and are ultimately caused by enhanced production of melanin in pigment cells (melanocytes). In addition, many whitening agents have been developed and used in cosmetics and the like based on research results on the mechanism of action that causes pigmentation. As the whitening agent, whitening agents such as ascorbic acids, hydrogen peroxide, colloidal sulfur, glutathione, hydroquinone, catechol, ellagic acid, kojic acid and the like are well known (for example, Non-Patent Document 1 and Non-Patent Documents). Reference 2). Furthermore, in recent years, as a whitening agent having a new mechanism of action, a plant extract obtained from a leguminous clara (bitter) of α-MSH (MSH: Melanocyte stimulating hormone) inhibitor (see, for example, Patent Document 1) Whitening of plant extracts (for example, see Patent Document 2) obtained from honeysuckle, a melanocyte dendrite elongation inhibitor, and chayote fruit extract (for example, see Patent Document 3) of endothelin-1 production inhibitor A drug has been found. However, although these whitening agents have a certain whitening effect (pigmentation prevention or improvement effect), it is difficult to say that the whitening effect and sustainability desired by the user are sufficiently obtained. On the other hand, since extensive whitening material exploration research to date has made it difficult to create new whitening agents, combining multiple conventional whitening agents or combining ingredients that enhance the effects of whitening agents with whitening agents Attempts have been actively made to obtain a high whitening effect by improving the formulation technology. However, even in such an attempt, it cannot be said that a sufficiently satisfactory whitening effect is obtained.

  Widely known as an effective protecting group for hydroxyl groups or amino groups in the synthesis of sterically bulky aromatic groups or heteroaromatic groups, especially diphenylmethyl group or triphenylmethyl group, organic low molecular weight compounds, peptides and nucleic acids. (For example, refer nonpatent literature 3 and nonpatent literature 4.). In addition, research on the physiological activity of compounds having a sterically bulky substituent in the chemical structure such as a diphenylmethyl group and a triphenylmethyl group has been actively conducted. The physiological activity of such a compound includes antitumor activity (see, for example, Non-Patent Document 5), antifungal action (for example, see Patent Document 4), and antihistaminic action (for example, see Non-Patent Document 6). ), Biological activities such as dopamine uptake inhibitory action (see, for example, Non-Patent Document 7) and calsim antagonistic action (see, for example, Non-Patent Document 8) have been reported. In addition, the present applicant has already reported that the compound represented by the general formula (2) has an excellent melanin production inhibitory action (see, for example, Patent Document 5). However, since the compound represented by the general formula (2) has a bulky substituent, it cannot be said that the solubility in a versatile base material is necessarily good. For this reason, a technique for maintaining or enhancing the pigmentation prevention or improvement effect while reducing the content of the compound represented by the general formula (2) in the external preparation for skin has been desired.

On the other hand, various biological activities have been reported for amino acids having an amino group and a carboxyl group, especially about 20 kinds of α-amino acids constituting a protein of a biofunctional molecule. Furthermore, various amino acid derivatives obtained by structural conversion of the amino acids have been synthesized, and research on their physiological activity and safety has been actively conducted. Among the α-amino acids, serine is known to have a rough skin improving action (see, for example, Patent Document 6), a whitening effect (see, for example, Patent Document 7), and the like. Further, serine derivatives such as N-methyl-L-serine promote dermal hyaluronic acid production promoting action (for example, see Patent Document 8), O-acylserine deodorizing action (for example, refer to Patent Document 9), N- (Benzoyl) serine has been reported to have an anti-aging action (see, for example, Patent Document 10). However, as far as the inventors know, it is reported that the compound represented by the general formula (1) has a pigmentation prevention or improvement effect and an action effect that enhances the pigmentation prevention or improvement effect. Not. The skin external preparation of the present invention contains the compound represented by the general formula (1) and the compound represented by the general formula (2) in the skin external preparation, thereby expressing the general formula (2). When the compound represented by the general formula (2) effectively enhances the melanin production inhibitory action of the compound to be produced, it exhibits an excellent pigmentation prevention or improvement action.

JP 2009-0667804 A JP 2003-081747 A JP 2008-094737 A JP 09-255634 A WO2010-074052 Japanese Patent Laid-Open No. 11-060435 JP 11-049630 A Japanese Patent Laid-Open No. 06-189780 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 Theodora W. Green, Protective Groups in Organic Synthesis, A Wiley-Interscience Publication .: 1981, P173-176 and P273-274 Nobuo Izumiya, Tetsuo Kato, Tohiko Aoyagi, Michinori Waki, Basics and Experiments of Peptide Synthesis .: Maruzen Co., Ltd., 1985, P38 Naohisa Ogo et. Al., Bioorganic & Medicinal Chemistry, 17 (14), 3921-3924 (2007) Sasse A., et. Al., Bioorganic & Medicinal Chemistry, 8 (5), 1139-1149 (2000) Dutta AK. Et. Al., Bioorganic & Medicinal Chemistry, 11 (17), 2337-2340 (2001) Shanklin JR Jr., et al., J. Med. Chem., 34 (10), 3011-3022 (1991)

  This invention is made | formed under such a condition, and makes it a subject to provide the skin external preparation suitable for the pigmentation prevention or improvement.

In view of such circumstances, the present inventors have intensively sought for a skin external preparation suitable for preventing or improving pigmentation. As a result, 1) the compound represented by the general formula (1), its optical A skin external preparation containing an isomer and / or a pharmacologically acceptable salt thereof, and 2) a compound represented by the general formula (2) and / or a pharmacologically acceptable salt thereof. In addition, the present inventors have found that an excellent action for preventing or improving pigmentation exists and have completed the present invention. The present invention is as follows.
<1> 1) A compound represented by the following general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) a compound represented by the following general formula (2) and An external preparation for skin, comprising: / or a pharmacologically acceptable salt thereof.

（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）
[式中、Ｒ４は、無置換又は置換基を有する芳香族基、水素原子を表し、Ｒ５及びＲ６は、それぞれ独立に、無置換又は置換基を有する芳香族基を表し、Ｘは、窒素原子又は酸素原子を表し、Ｒ７及びＲ８は、Ｘに応じた数で存在し、それぞれ独立に、水素原子又は炭素原子が複素原子に置換されていても良い炭素数１〜６の直鎖又は分岐のアルキル基、水素原子を表す。]

(2)
[Wherein R4 represents an unsubstituted or substituted aromatic group or hydrogen atom, R5 and R6 each independently represents an unsubstituted or substituted aromatic group, and X represents a nitrogen atom. Or an oxygen atom, and R7 and R8 are present in a number corresponding to X, and each independently represents a straight or branched chain having 1 to 6 carbon atoms in which a hydrogen atom or a carbon atom may be substituted with a hetero atom. Represents an alkyl group or a hydrogen atom. ]

<2> 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、Ｒ９は、無置換又は置換基を有する芳香族基を表し、Ｒ１０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。]

(3)
[Wherein R9 represents an unsubstituted or substituted aromatic group, R10 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 (4), an optical isomer thereof and / or a pharmacologically acceptable salt thereof. The external preparation for skin according to <1>.

（４）
[式中、Ｒ１１は、無置換又は置換基を有する芳香族基を表し、Ｒ１２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。]

(4)
[Wherein, R11 represents an unsubstituted or substituted aromatic group, and R12 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 (5), an optical isomer thereof and / or a pharmacologically acceptable salt thereof. The skin external preparation according to any one of <1> to <3>.

（５）
[式中、Ｒ１３は、無置換又は置換基を有する芳香族基を表す。]

(5)
[Wherein, R13 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- (benzoyl) serine (compound 6), N -(2-naphthoyl) serine (compound 7), N- (4-phenylbenzoyl) 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> characterized by being cetylserine (compound 13), N- (2-naphthoyl) -O-methylserine (compound 14), an optical isomer thereof and / or a pharmacologically acceptable salt thereof. -The skin external preparation in any one of <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−（ベンゾイル）セリン（化合物６）

N- (benzoyl) serine (compound 6)

N−（２−ナフトイル）セリン（化合物７）

N- (2-naphthoyl) serine (Compound 7)

N−（４−フェニルベンゾイル）セリン（化合物８）

N- (4-Phenylbenzoyl) 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 (2) is a compound represented by the following general formula (6) and / or a pharmacologically acceptable salt thereof, <1 The external preparation for skin according to any one of> to <5>.

（６）
[式中、Ｒ１４は、無置換又は置換基を有する芳香族基、水素原子を表し、Ｒ１５及びＲ１６は、それぞれ独立に、無置換又は置換基を有する芳香族基を表し、Ｒ１７及びＲ１８は、それぞれ独立に、水素原子又は炭素原子が複素原子に置換されていても良い炭素数１〜６の直鎖又は分岐のアルキル基、水素原子を表す。]

(6)
[Wherein, R14 represents an unsubstituted or substituted aromatic group or a hydrogen atom, R15 and R16 each independently represents an unsubstituted or substituted aromatic group, and R17 and R18 represent Each independently represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms, in which a carbon atom may be substituted with a hetero atom, or a hydrogen atom. ]

<7> The compound represented by the general formula (2) is a compound represented by the following general formula (7) and / or a pharmacologically acceptable salt thereof, <1 The external preparation for skin according to any one of> to <5>.

（７）
[式中、Ｒ１９は、無置換又は置換基を有する芳香族基、水素原子を表し、Ｒ２０及びＲ２１は、それぞれ独立に、無置換又は置換基を有する芳香族基を表し、Ｒ２２は、水素原子又は炭素原子が複素原子に置換されていても良い炭素数１〜６の直鎖又は分岐のアルキル基、水素原子を表す。]

(7)
[Wherein R19 represents an unsubstituted or substituted aromatic group or a hydrogen atom, R20 and R21 each independently represents an unsubstituted or substituted aromatic group, and R22 represents a hydrogen atom. Alternatively, it represents a linear or branched alkyl group having 1 to 6 carbon atoms and a hydrogen atom, in which a carbon atom may be substituted with a hetero atom. ]

<8> The compound represented by the general formula (2) is 2-[(triphenylmethyl) oxy] ethanol (compound 15), 2-[(diphenylmethyl) oxy] ethanol (compound 16). 2-[(triphenylmethyl) amino] ethanol (compound 17), 2-[(diphenylmethyl) amino] ethanol (compound 18), 2-[(triphenylmethyl) oxy] ethylamine (compound 19) ), 2-[(diphenylmethyl) oxy] ethylamine (compound 20), triphenylmethylamine (compound 21), triphenylmethanol (compound 22), and / or pharmacologically acceptable salts thereof. The skin external preparation according to any one of <1> to <7>, which is characterized in that it exists.

２−[（トリフェニルメチル）オキシ]エタノ−ル（化合物１５）

2-[(Triphenylmethyl) oxy] ethanol (Compound 15)

２−[（ジフェニルメチル）オキシ]エタノ−ル（化合物１６）

2-[(Diphenylmethyl) oxy] ethanol (Compound 16)

２−[（トリフェニルメチル）アミノ]エタノ−ル（化合物１７）

2-[(Triphenylmethyl) amino] ethanol (Compound 17)

２−[（ジフェニルメチル）アミノ]エタノ−ル（化合物１８）

2-[(Diphenylmethyl) amino] ethanol (Compound 18)

２−[（トリフェニルメチル）オキシ]エチルアミン（化合物１９）

2-[(Triphenylmethyl) oxy] ethylamine (Compound 19)

２−[（ジフェニルメチル）オキシ]エチルアミン（化合物２０）

2-[(Diphenylmethyl) oxy] ethylamine (Compound 20)

トリフェニルメチルアミン（化合物２１）

Triphenylmethylamine (Compound 21)

トリフェニルメタノ−ル（化合物２２）

Triphenyl methanol (Compound 22)

<9> 0.0001% by mass to 20% by mass of the compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof with respect to the total amount of the external preparation for skin. The external preparation for skin according to any one of <1> to <8>, wherein
<10> 0.001% by mass to 10% by mass of the compound represented by the general formula (2) and / or a pharmacologically acceptable salt thereof with respect to the total amount of the external preparation for skin, The external preparation for skin according to any one of <1> to <9>.
<11> The skin external preparation according to any one of <1> to <10>, which is a cosmetic (however, including quasi-drugs).
<12> The external preparation for skin according to any one of <1> to <11>, which is for preventing or improving pigmentation.
<13> The external preparation for skin according to any one of <1> to <12>, further comprising a preferable formulation component.

ADVANTAGE OF THE INVENTION According to this invention, the skin external preparation suitable for the pigmentation prevention or improvement can be provided.

  The skin external preparation of the present invention includes 1) a compound represented by the general formula (1), an optical isomer thereof and / or a pharmaceutically acceptable salt thereof, and 2) a compound represented by the general formula (2). It contains the compound represented and / or those pharmacologically acceptable salts. The external preparation for skin of the present invention has an excellent effect of preventing or improving pigmentation. Such an effect is obtained by adding the compound represented by the general formula (1) and the skin external preparation together with the compound represented by the general formula (2) to the compound represented by the general formula (2). It is considered that the melanin production inhibitory action possessed by is enhanced and exhibits excellent pigmentation prevention or improvement action. 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.

<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 includes 1) a compound represented by the general formula (1), an optical isomer thereof and / or a pharmaceutically acceptable salt thereof, and 2) a compound represented by the general formula (2). It contains the compound represented and / or those pharmacologically acceptable salts. The external preparation for skin of the present invention is suitable for cosmetics (however, including quasi-drugs) and has an excellent effect of preventing or improving pigmentation. Such an effect is obtained by adding the compound represented by the general formula (1) and the compound represented by the general formula (2) to the skin external preparation, whereby the compound represented by the general formula (2) The compound represented by the general formula (1) effectively enhances the melanin production inhibitory action, and exhibits an excellent pigmentation prevention or improvement effect. For this reason, the content of the compound represented by the general formula (2) in the external preparation for skin is reduced while maintaining or enhancing the pigmentation prevention or improvement action of the compound represented by the general formula (2). I can do it. Reducing the content of the compound represented by the general formula (2) in the external preparation for skin is represented by the general formula (2) having a problem in solubility while having an excellent melanin production inhibitory action. This leads to widening the possibility of using such compounds. Among the compounds represented by the general formula (1) of the present invention and optical isomers thereof, preferred are the compounds represented by the general formula (3) or the compounds represented by the general formula (4). , Optical isomers thereof and / or pharmacologically acceptable salts thereof can be suitably exemplified, and more preferable examples include compounds represented by the general formula (5), optical isomers thereof and / or them. The pharmacologically acceptable salt of can be illustrated suitably. In addition, the compound represented by the general formula (1) has an asymmetric carbon in its chemical structure, so that it is an (L) isomer, a (D) isomer or a racemic isomer, and further an (L) isomer. And (D) various forms of existence such as a racemic mixture in which the isomer has an arbitrary mixing ratio can be considered. The compound represented by the general formula (1) of the present invention includes all possible forms such as (D) isomer, (L) isomer, racemate, racemic mixture and the like. Further, among the compounds represented by the general formula (1) and optical isomers thereof, the (L) isomer can be suitably 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 formula (1) of the present invention, optical isomers thereof and / or pharmacologically acceptable salts thereof are selected, and the skin external application of the present invention. It can be contained in the agent.

  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, a biphenyl group, a phenyl group and the like can be suitably exemplified, and more preferably a 4-methylphenyl group, Preferred examples include 4-ethylphenyl group, 4-methoxyphenyl group, 4-fluorophenyl group, 4-trifluoromethylphenyl group, 2-naphthyl group, 4-biphenyl group, and phenyl group. Among the compounds represented by the general formula (1), R1 is 4-methylphenyl group, 4-ethylphenyl group, 4-methoxyphenyl group, 4-fluorophenyl group, 4-trifluoromethylphenyl group, phenyl. The compounds which are a 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 of R1 can be suitably exemplified as 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 of R1 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. 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), a compound in which R2 is a hydrogen atom, a methyl group, an ethyl 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 compounds include N- (methylbenzoyl) serine and 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, its optical isomers and / or their pharmacologically acceptable salts are preferred. More preferable examples include 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-a Chiruserin (Compound 13), N-(2-naphthoyl) -O- methylserine (Compound 14), its optical isomers and / or their pharmacologically acceptable salts are suitably be exemplified. In addition, the compound represented by the general formula (1) and the compounds represented by the general formulas (3) to (5) are compounds represented by the general formula (2) and / or those described later. By containing it in a skin external preparation together with a pharmacologically acceptable salt of the above, it effectively enhances the melanin production inhibitory action of the compound represented by the general formula (2), and has an excellent pigmentation prevention or improvement effect Demonstrate. Further, such an action includes the pharmacological enhancement effect of the compound represented by the general formula (1) in the pigmentation prevention or improvement action of the compound represented by the general formula (2), and the general formula (2). It is considered that an excellent effect is exhibited by increasing the accumulation property or storage property of the compound represented by (2) at the target site. Thereby, the content of the compound represented by the general formula (2) in the external preparation for skin can be reduced while maintaining or enhancing the pharmacological effect of the compound represented by the general formula (2). I can do it. Further, the compound represented by the general formula (1), its optical isomer and / or pharmacologically acceptable salt thereof is a derivative of a natural amino acid, 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, it is possible to apply various forms of external preparations for skin, and the manufacture thereof is easy.

Here, the compound represented by the general formula (3) will be described. In the formula, R9 represents an unsubstituted or substituted aromatic group, and R10 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. R9 represents an unsubstituted or substituted aromatic group, and can be preferably exemplified by the same substituents as the substituent R1 in the general formula (1). Preferred examples thereof include a methylphenyl group and 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, and more preferably a 4-methylphenyl group, a 4-ethylphenyl group, 4 Preferred examples include -methoxyphenyl group, 4-fluorophenyl group, 4-trifluoromethylphenyl group, phenyl group, 2-naphthyl group, 4-biphenyl group, and phenyl group. Among the compounds represented by the general formula (3), R9 is 4-methylphenyl group, 4-ethylphenyl group, 4-methoxyphenyl group, 4-fluorophenyl group, 4-trifluoromethylphenyl group, phenyl. The compounds which are a 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 of R9 can be suitably exemplified as 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 of R9 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. R10 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 (3), a compound in which R10 is a hydrogen atom, a methyl group or an acetyl group is particularly excellent in preventing or improving pigmentation.
Further, among compounds represented by the general formula (3), specific examples of compounds not included in the compound represented by the general formula (5) include N-benzoyl-O-methylserine, N- (Methylbenzoyl) -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- (Chlorobenzoyl) -O-methylserine, N- (fluorobenzoyl) -O-methylserine, N- (trifluoromethylbenzoyl) -O-me L-serine, 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- (methoxynaphtho) Yl) -O-methylserine, N- (ethoxynaphthoyl) -O-methylserine, N- (biphenylcarbonyl) -O-methylserine, N- (methylbiphenylcarbonyl) -O-methylserine, N- (ethylbiphenylcarbonyl)- O-methylserine, N- (methoxybiphenylcarbonyl) -O-methylserine, N- ( Toxibiphenylcarbonyl) -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- (methylpyriline Carbonyl) -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-acetate Lucerin, 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- (d Tylpyridinecarbonyl) -O-acetylserine, N- (methoxypyridinecarbonyl) -O-acetylserine, N- (ethoxypyridinecarbonyl) -O-acetylserine, N- (naphthoyl) -O-acetylserine, N- ( Methylnaphthoyl) -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- (methylbenzoyl) -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- (methylpyridinyl) Carbonyl) -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-propionyl seri , N- (ethoxycarbonyl biphenylcarbonyl) -O- propionyl serine, its optical isomers and / or a pharmaceutically acceptable salt thereof pharmacologically be suitably be exemplified. Among the compounds represented by the general formula (3), more preferable compounds include N- (methylbenzoyl) serine, N- (ethylbenzoyl) serine, N- (methoxybenzoyl) serine, and 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.

  Here, the compound represented by the general formula (4) will be described. In the formula, R11 represents an unsubstituted or substituted aromatic group, and R12 represents a hydrogen atom having 1 to 4 carbon atoms. Represents a linear or branched alkyl group. R11 represents an unsubstituted or substituted aromatic group, and can be preferably exemplified by the same substituent as the substituent R1 in the general formula (1). Preferred examples thereof include a methylphenyl group and 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, and more preferably a 4-methylphenyl group, a 4-ethylphenyl group, 4 Preferred examples include -methoxyphenyl group, 4-fluorophenyl group, 4-trifluoromethylphenyl group, phenyl group, 2-naphthyl group, 4-biphenyl group, and phenyl group. Among the compounds represented by the general formula (4), R11 is 4-methylphenyl group, 4-ethylphenyl group, 4-methoxyphenyl group, 4-fluorophenyl group, 4-trifluoromethylphenyl group, phenyl. The compounds which are a 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 of R11 can be suitably exemplified as 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 of R11 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. R12 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 and a methyl group can be suitably exemplified. Among the compounds represented by the general formula (4), the compound in which R12 is a hydrogen atom or a methyl group is particularly excellent in preventing or improving pigmentation.

  Specific examples of the compound represented by the general formula (4) that are not included in the compound represented by the general formula (5) 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 the compounds represented by the general formula (4), 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 (5), in formula, R13 represents the aromatic group which is unsubstituted or has a substituent. R13 represents an unsubstituted or substituted aromatic group, and can be preferably exemplified by the same substituents as the substituent R1 in the general formula (1). Preferred examples thereof include a methylphenyl group and 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, and more preferably a 4-methylphenyl group, a 4-ethylphenyl group, 4 Preferred examples include -methoxyphenyl group, 4-fluorophenyl group, 4-trifluoromethylphenyl group, phenyl group, 2-naphthyl group, 4-biphenyl group, and phenyl group. Among the compounds represented by the general formula (5), R13 is 4-methylphenyl group, 4-ethylphenyl group, 4-methoxyphenyl group, 4-fluorophenyl group, 4-trifluoromethylphenyl group, phenyl. The compounds which are a 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 of R13 can be preferably 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 of R13 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.

Of the compounds represented by the general formula (5), specific examples of preferred compounds 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 formula (1), the general formulas (3) to (5), optical isomers thereof and / or pharmacologically acceptable salts thereof are commercially available serine or serine derivatives. Can be synthesized according to the following 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 formula (1) and the general formulas (3) to (5) thus obtained, optical isomers thereof and / or pharmacologically acceptable salts thereof are described above. By including the compound represented by the general formula (2) and / or a pharmacologically acceptable salt thereof in an external preparation for skin, an excellent effect of preventing or improving pigmentation is exhibited. The skin external preparation of the present invention is a skin external application comprising one or more selected from the compounds represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof. It can be contained in the agent. In order for the external preparation for skin of the present invention to exhibit the above pharmacological action, the compound represented by the general formula (1), the general formulas (3) to (5), its optical isomers and / or Alternatively, one or two or more kinds selected from pharmacologically acceptable salts in a total amount of 0.0001% to 20% by mass, more preferably 0. It is preferable to contain 001 mass%-10 mass%, More preferably, 0.005-5 mass%. This includes the compound represented by the general formula (1), the general formulas (3) to (5), optical isomers thereof and / or pharmacologically acceptable salts thereof with respect to the total amount of the external preparation for skin. If the amount is less than 0.0001% by mass, the effect of preventing or improving pigmentation tends to decrease, and even if the amount exceeds 20% by mass, the effect tends to reach its peak, so the degree of freedom of formulation The above content is preferable with respect to the total amount of the above-mentioned 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７のＬ体）

N- (2-naphthoyl) -L-serine (L form of compound 7)

<Production Example 8: Method for producing L-form of Compound 7>
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 product 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 7>
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８のＬ体）

N- (4-Phenylbenzoyl) -L-serine (L-form of Compound 8)

<Production Example 9: Method for producing L-form of Compound 8>
L-form of Compound 8 was synthesized according to the same method as L-form of Compound 1 above using 4-phenylbenzoyl chloride (Wako Pure Chemical Industries, Ltd.) and L-serine (Peptide Institute, Inc.).

<Physical constant of L-form of compound 8>
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).

<Compound represented by the general formula (2) of the present invention and / or a pharmacologically acceptable salt thereof>
The skin external preparation of the present invention includes 1) a compound represented by the general formula (1), an optical isomer thereof and / or a pharmaceutically acceptable salt thereof, and 2) a compound represented by the general formula (2). It contains the compound represented and / or those pharmacologically acceptable salts. The external preparation for skin of the present invention is an external preparation for skin suitable for cosmetics (including quasi-drugs), and has an excellent effect of preventing or improving pigmentation. The compound represented by the general formula (2) has an excellent inhibitory action on melanin production, but has a sterically bulky substituent in its chemical structure, and therefore is used for the preparation of a skin external preparation. Solubility in water is not necessarily high, which has been a limitation in formulation. When the compound represented by the general formula (2) is used as a skin external preparation, it is represented by the general formula (2) by being contained in the skin external preparation together with the compound represented by the general formula (1). The pigmentation prevention or improvement effect can be maintained or improved while reducing the compound content. Among the compounds represented by the general formula (2) of the present invention, preferred are the compounds represented by the general formula (6) and / or pharmacologically acceptable salts thereof, The compounds represented by the general formula (7) and / or their pharmacologically acceptable salts can be suitably exemplified, and among these compounds, particularly preferred ones are specifically exemplified by 2-[(triphenyl Methyl) oxy] ethanol (compound 15), 2-[(diphenylmethyl) oxy] ethanol (compound 16), 2-[(triphenylmethyl) amino] ethanol (compound 17), 2- [ (Diphenylmethyl) amino] ethanol (Compound 18), 2-[(Triphenylmethyl) oxy] ethylamine (Compound 19), 2-[(Diphenylmethyl) oxy] ethylamine (Compound 20), Triphenylmethyl Min (Compound 21), triphenyl methanolate - le (Compound 22), and / or their pharmacologically acceptable salts are suitably be exemplified.

Here, the compound represented by the general formula (2) will be described. In the formula, R4 represents an unsubstituted or substituted aromatic group or a hydrogen atom, and R5 and R6 each independently represent: Represents an unsubstituted or substituted aromatic group, X represents a nitrogen atom or an oxygen atom, R7 and R8 exist in a number corresponding to X, and each independently a hydrogen atom or a carbon atom is a heteroatom Represents a linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted with a hydrogen atom. R4 represents an unsubstituted or substituted aromatic group or a hydrogen atom, and specific examples of R4 include a hydrogen atom, a phenyl group, a methylphenyl group, an ethylphenyl group, a propylphenyl group, and a butylphenyl group. , Methoxyphenyl group, ethoxyphenyl group, propyloxyphenyl group, butyloxyphenyl group, hydroxyphenyl group, aminophenyl group, N-methylaminophenyl group, N-ethylaminophenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, chlorophenyl group, bromophenyl group, fluorophenyl group, trifluoromethylphenyl group, pyridyl group, methylpyridyl group, ethylpyridyl group, propylpyridyl group, butylpyridyl group, methoxypyridyl group, ethoxypyridyl group Group, propyloxypyridyl Butyloxypyridyl group, hydroxypyridyl group, aminopyridyl group, N-methylaminopyridyl group, N-ethylaminopyridyl group, N, N-dimethylaminopyridyl group, N, N-diethylaminopyridyl group, chloropyridyl group, bromo Pyridyl group, fluoropyridyl group, trifluoromethylpyridyl group, methylnaphthyl group, ethylnaphthyl group, propylnaphthyl group, butylnaphthyl group, methoxynaphthyl group, ethoxynaphthyl group, propyloxynaphthyl group, butyloxynaphthyl group, hydroxynaphthyl group Aminonaphthyl group, N-methylaminonaphthyl group, N-ethylaminonaphthyl group, N, N-dimethylaminonaphthyl group, N, N-diethylaminonaphthyl group, chloronaphthyl group, bromonaphthyl group, fluoronaphthyl group, trifluoro Methylna Til, methylbiphenyl, ethylbiphenyl, propylbiphenyl, butylbiphenyl, methoxybiphenyl, ethoxybiphenyl, propyloxybiphenyl, butyloxybiphenyl, hydroxybiphenyl, aminobiphenyl, N-methylaminobiphenyl Group, N-ethylaminobiphenyl group, N, N-dimethylaminobiphenyl group, N, N-diethylaminobiphenyl group, chlorobiphenyl group, bromobiphenyl group, fluorobiphenyl group, trifluoromethylbiphenyl group and the like can be suitably exemplified. More preferably, a hydrogen atom, a phenyl group, a methylphenyl group, a methoxyphenyl group, a chlorophenyl group, a fluorophenyl group, a pyridyl group, a naphthyl group, and a biphenyl group, and more preferably a phenyl group, a methylphenyl group Preferred examples include a group, a methoxyphenyl group and a 4-fluorophenyl group. Among the compounds represented by the general formula (2), the compound in which R4 is a phenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group or a 4-fluorophenyl group is particularly effective in preventing or improving pigmentation. Excellent. When the aromatic group of R4 is a phenyl group, the number of substituents on the phenyl group can be suitably exemplified by 0 to 3, more preferably 0 or 1, and the substituent on the phenyl group is , Each can exist independently. Further, the substitution position of the substituent on the phenyl group of R4 is not particularly limited, but more preferably the para position at the position bonded to the carbon atom on the phenyl group. R5 and R6 each independently represents an unsubstituted or substituted aromatic group. Of the R5 and R6, preferred are the same aromatic groups as the unsubstituted or substituted aromatic groups excluding the hydrogen atom described in R4, and more preferred are , Phenyl group, methylphenyl group, methoxyphenyl group, chlorophenyl group, fluorophenyl group, pyridyl group, naphthyl group, and biphenyl group. Among the compounds represented by the general formula (2), the compounds in which R5 and R6 are each independently a phenyl group, a methylphenyl group, a methoxyphenyl group, or a fluorophenyl group are particularly useful for preventing or improving pigmentation. Excellent effect. When the aromatic group of R5 and R6 is a phenyl group, the number of substituents on the phenyl group can be suitably exemplified by 0 to 3, more preferably 0 or 1, and the substitution on the phenyl group Each group can exist independently. The substitution position of the substituent on the phenyl group of R5 and R6 is not particularly limited, but more preferably the para position at the position bonded to the carbon atom on the phenyl group. X represents a nitrogen atom or an oxygen atom. Further, R7 and R8 are present in a number corresponding to X, and each independently represents a hydrogen atom or a carbon atom in which a carbon atom may be substituted with a hetero atom, more preferably, a carbon atom having 1 to 6 carbon atoms. 4 linear or branched alkyl groups and a hydrogen atom are represented. Specific examples of preferable R7 and R8 include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. N-pentyl group, n-hexyl group, hydroxymethyl group, hydroxyethyl group, hydroxypropyl group, hydroxybutyl group, hydroxypentyl group, hydroxyhexyl group, aminomethyl group, aminoethyl group, aminopropyl group, aminobutyl group An aminopentyl group, an aminohexyl group, a 2,3-dihydroxypropyl group and the like can be preferably exemplified, and a hydroxyethyl group, an aminoethyl group, an ethyl group and a hydrogen atom can be suitably exemplified as more preferable ones. Of the compounds represented by the general formula (2), the compounds in which R7 and R8 are hydroxyethyl group, aminoethyl group, ethyl group, and hydrogen atom are particularly excellent in preventing or improving pigmentation.
Among the compounds represented by the general formula (2), preferred are the compounds represented by the general formula (6) and / or pharmacologically acceptable salts thereof, and the general formula ( Preferred examples include the compounds represented by 7) and / or their pharmacologically acceptable salts. Further, among the compounds represented by the general formula (2), specific examples of preferred compounds include 2-[(triphenylmethyl) oxy] ethanol (compound 15), 2-[(diphenylmethyl). ) Oxy] ethanol (compound 16), 2-[(triphenylmethyl) amino] ethanol (compound 17), 2-[(diphenylmethyl) amino] ethanol (compound 18), 2-[( Triphenylmethyl) oxy] ethylamine (compound 19), 2-[(diphenylmethyl) oxy] ethylamine (compound 20), triphenylmethylamine (compound 21), triphenylmethanol (compound 22), diphenylmethanol , Diphenylmethylamine, [bis (4-methylphenyl)] methanol, [bis (4-methoxyphenyl)] methanol, [2-naphthyl (phenyl)] me Nord, [diphenyl (4-pyridyl)] methanol, [di- (2-pyridyl) phenyl] methanol, [diphenyl (4-methylphenyl)] methanol, [bis (4-methylphenyl) ) Phenyl] methanol, tris (4-methylphenyl) methanol, [diphenyl (4-methoxyphenyl)] methanol, [bis (4-methoxyphenyl) phenyl] methanol, 2-{[diphenyl (4-methoxyphenyl)] methyloxy} ethanol, 2-{[bis (4-methoxyphenyl) phenyl] methyloxy} ethanol, 2-{[diphenyl (4-methoxyphenyl) methylamino] ethanol 2-{[bis (4-methoxyphenyl) phenyl] methylamino} ethanol, 2-{[diphenyl (4-methoxyphenyl)] methyloxy} ethylamine, 2-{[bi (4-methoxyphenyl) methyloxy] ethylamine, N-triphenylmethyl-N-ethylamine, N, N- [bis (2-hydroxyethyl)]-N- (triphenylmethyl) amine, 1,2-hydroxy- 3- (Triphenylmethyloxy) propane, N- (triphenylmethyl) serine, and / or pharmacologically acceptable salts thereof can be suitably exemplified, and more preferable examples include 2-[(triphenyl Methyl) oxy] ethanol (compound 15), 2-[(diphenylmethyl) oxy] ethanol (compound 16), 2-[(triphenylmethyl) amino] ethanol (compound 17), 2- [ (Diphenylmethyl) amino] ethanol (compound 18), 2-[(triphenylmethyl) oxy] ethylamine (compound 19), 2-[(diphenylmethyl) oxy Preferred examples include ethylamine (Compound 20), triphenylmethylamine (Compound 21), triphenylmethanol (Compound 22), and / or their pharmacologically acceptable salts. The compound represented by the general formula (2), the compound represented by the general formula (6) or (7), and / or a pharmacologically acceptable salt thereof are represented by the general formula (1). ), An isomer thereof, and / or a pharmacologically acceptable salt thereof, together with a skin external preparation, exhibits an excellent effect of preventing or improving pigmentation. The compound represented by the general formula (2) and / or a pharmacologically acceptable salt thereof has an excellent melanin production inhibitory action, but when it is contained in an external preparation for skin, it is suitable for a base or the like. It is difficult to say that the solubility is necessarily high. However, the compound represented by the general formula (2) and / or a pharmacologically acceptable salt thereof is a compound represented by the general formula (1), an optical isomer thereof and / or a drug thereof. By containing in a skin external preparation together with a salt that is physically acceptable, the general formula (2) maintains or improves the pigmentation prevention or improvement effect of the compound represented by the general formula (2), and the general formula for the total amount of the skin external preparation The content of the compound represented by (2) can be effectively reduced. Such action is in addition to the pharmacological enhancement effect of the compound represented by the general formula (1) in the pigmentation prevention or improvement action of the compound represented by the general formula (2), and the general formula (2). It is considered that an excellent effect is exhibited by increasing the accumulation property or storage property of the compound represented by (1) to the target site.

Here, the compound represented by the general formula (6) will be described. In the formula, R14 represents an unsubstituted or substituted aromatic group or a hydrogen atom, and R15 and R16 each independently represent: Represents an unsubstituted or substituted aromatic group, and R17 and R18 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms in which a carbon atom may be substituted with a hetero atom. Represents a hydrogen atom. R14 represents an unsubstituted or substituted aromatic group, a hydrogen atom, and preferred examples include the same substituents as R4 of the compound represented by the general formula (2), More preferred examples include a phenyl group, a methylphenyl group, a methoxyphenyl group, a chlorophenyl group, a fluorophenyl group, a pyridyl group, a naphthyl group, a biphenyl group, and a hydrogen atom. Among the compounds represented by the general formula (6), a compound in which R14 is a phenyl group, a methylphenyl group, a methoxyphenyl group or a fluorophenyl group is particularly excellent in preventing or improving pigmentation. When the aromatic group of R14 is a phenyl group, the number of substituents on the phenyl group can be suitably exemplified by 0 to 3, more preferably 0 or 1, and the substituent on the phenyl group is , Each can exist independently. Further, the substitution position of the substituent on the phenyl group of R14 is not particularly limited, but more preferably the para position at the position bonded to the carbon atom on the phenyl group. R15 and R16 each independently represents an aromatic group having no substituent or a substituent, and when specific examples thereof are specifically exemplified, they are the same as R5 and R6 of the compound represented by the general formula (2). And more preferable examples include phenyl group, methylphenyl group, methoxyphenyl group, chlorophenyl group, fluorophenyl group, pyridyl group, naphthyl group, and biphenyl group. Among the compounds represented by the general formula (6), the compounds in which R15 and R16 are a phenyl group, a methylphenyl group, a methoxyphenyl group, and a fluorophenyl group are particularly excellent in preventing or improving pigmentation. When the aromatic group of R15 and R16 is a phenyl group, the number of substituents on the phenyl group can be suitably exemplified by 0 to 3, more preferably 0 or 1, and the substitution on the phenyl group Each group can exist independently. The substitution position of the substituent on the phenyl group of R15 and R16 is not particularly limited, but more preferably the para position at the position bonded to the carbon atom on the phenyl group. R17 and R18 are each independently a hydrogen atom or a carbon atom having 1 to 6 carbon atoms in which a hetero atom may be substituted, more preferably a linear or branched alkyl group having 1 to 4 carbon atoms, hydrogen If a preferable thing is specifically mentioned as an atom, the substituent similar to R7 and R8 of the compound represented by the said General formula (2) can be illustrated suitably, As a more preferable thing, a hydroxyethyl group, amino Preferred examples include an ethyl group, an ethyl group, and a hydrogen atom. Among the compounds represented by the general formula (6), the compounds in which R17 and R18 are a hydroxyethyl group, an aminoethyl group, an ethyl group, or a hydrogen atom are particularly excellent in preventing or improving pigmentation.
Specific examples of preferable compounds among the compounds represented by the general formula (6) include 2-[(diphenylmethyl) amino] ethanol, 2-[(methylphenyl) phenylmethylamino] ethanol- 2- [bis (methylphenyl) methylamino] ethanol, 2-[(ethylphenyl) phenylmethylamino] ethanol, 2-[(bis (ethylphenyl) methylamino] ethanol, 2- [(Methoxyphenyl) phenylmethylamino] ethanol, 2-[(bis (methoxyphenyl) methylamino] ethanol, 2-[(ethoxyphenyl) phenylmethylamino] ethanol, 2-[(bis ( Ethoxyphenyl) methylamino] ethanol, 2-[(hydroxyphenyl) phenylmethylamino] ethanol, 2-[(bis (hydroxyphenyl) methylamino] ethanol 2-[(aminophenyl) phenylmethylamino] ethanol, 2-[(bis (aminophenyl) methylamino] ethanol, 2-[(fluorophenyl) phenylmethylamino] ethanol, -[(Bis (fluorophenyl) methylamino] ethanol, 2-[(triphenylmethyl) amino] ethanol, 2- [diphenyl (methylphenyl) methylamino] ethanol, 2- [bis (methyl Phenyl) phenylmethylamino] ethanol, 2- [tris (methylphenyl) methylamino] ethanol, 2- [diphenyl (ethylphenyl) methylamino] ethanol, 2- [bis (ethylphenyl) phenylmethyl Amino] ethanol, 2- [tris (ethylphenyl) methylamino] ethanol, 2- [diphenyl (methoxyphenyl) methylamino] ethanol 2- [bis (methoxyphenyl) phenylmethylamino] ethanol, 2- [tris (methoxyphenyl) methylamino] ethanol, 2- [diphenyl (ethoxyphenyl) methylamino] ethanol, 2- [Bis (ethoxyphenyl) phenylmethylamino] ethanol, 2- [tris (ethoxyphenyl) methylamino] ethanol, 2- [diphenyl (hydroxyphenyl) methylamino] ethanol, 2- [bis (hydroxy Phenyl) phenylmethylamino] ethanol, 2- [tris (hydroxyphenyl) methylamino] ethanol, 2-[(aminophenyl) diphenylmethylamino] ethanol, 2- [bis (aminophenyl) phenylmethyl Amino] ethanol, 2- [tris (aminophenyl) methylamino] ethanol, 2- [diphenyl ( Fluorophenyl) methylamino] ethanol, 2- [bis (fluorophenyl) phenylmethylamino] ethanol, 2- [tris (fluorophenyl) methylamino] ethanol, triphenylmethylamine, and / or The pharmacologically acceptable salt and the like can be suitably exemplified, and more preferably 2-[(triphenylmethyl) amino] ethanol (Compound 17), 2-[(diphenylmethyl) amino] ethanol (Compound 18), triphenylmethylamine (Compound 21) and / or pharmacologically acceptable salts thereof can be suitably exemplified.

Here, the compound represented by the general formula (7) will be described. In the formula, R19 represents an unsubstituted or substituted aromatic group or a hydrogen atom, and R20 and R21 each independently represent: An unsubstituted or substituted aromatic group is represented, and R22 represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms in which a carbon atom may be substituted with a hetero atom, or a hydrogen atom. R19 represents an unsubstituted or substituted aromatic group, a hydrogen atom, and preferable examples include the same substituents as R4 of the compound represented by the general formula (2), More preferred examples include a phenyl group, a methylphenyl group, a methoxyphenyl group, a chlorophenyl group, a fluorophenyl group, a pyridyl group, a naphthyl group, a biphenyl group, and a hydrogen atom. Among the compounds represented by the general formula (7), the compound in which R19 is a phenyl group, a methylphenyl group, a methoxyphenyl group, or a fluorophenyl group is particularly excellent in preventing or improving pigmentation. When the aromatic group of R19 is a phenyl group, the number of substituents on the phenyl group can be suitably exemplified by 0 to 3, more preferably 0 or 1, and the substituent on the phenyl group is , Each can exist independently. The substitution position of the substituent on the phenyl group of R19 is not particularly limited, but more preferably the para position at the position bonded to the carbon atom on the phenyl group. R20 and R21 each independently represents an unsubstituted or substituted aromatic group, and the specific examples thereof are the same as R5 and R6 of the compound represented by the general formula (2). And more preferable examples include phenyl group, methylphenyl group, methoxyphenyl group, chlorophenyl group, fluorophenyl group, pyridyl group, naphthyl group, and biphenyl group. When the aromatic group of R20 and R21 is a phenyl group, the number of substituents on the phenyl group can be suitably exemplified by 0 to 3, more preferably 0 or 1, and the substitution on the phenyl group Each group can exist independently. Among the compounds represented by the general formula (7), compounds in which R20 and R21 are a phenyl group, a methylphenyl group, a methoxyphenyl group, and a fluorophenyl group are particularly excellent in preventing or improving pigmentation. The substitution position of the substituent on the phenyl group of R20 and R21 is not particularly limited, but more preferably the para position at the position bonded to the carbon atom on the phenyl group. R22 represents a hydrogen atom or a carbon atom in which a carbon atom may be substituted with a hetero atom, more preferably a linear or branched alkyl group having 1 to 4 carbon atoms, or a hydrogen atom, which is preferable. Specifically, the same substituent as R7 or R8 of the compound represented by the general formula (2) can be preferably exemplified, and more preferable examples include hydroxyethyl group, aminoethyl group, ethyl group, A hydrogen atom can be preferably exemplified. Among the compounds represented by the general formula (7), the compound in which R22 is a hydroxyethyl group, an aminoethyl group, an ethyl group, or a hydrogen atom is particularly excellent in preventing or improving pigmentation.
Specific examples of preferred compounds among the compounds represented by the general formula (7) include 1- (diphenylmethyloxy) methanol, 3- (diphenylmethyloxy) propanol, 4- (diphenyl). Methyloxy) butanol, 5- (diphenylmethyloxy) pentanol, 6- (diphenylmethyloxy) hexanol, 7- (diphenylmethyloxy) heptanol, 8- (diphenylmethyloxy) octanol 1- (triphenylmethyloxy) methanol, 3- (triphenylmethyloxy) propanol, 4- (triphenylmethyloxy) butanol, 5- (triphenylmethyloxy) pentanol, 6 -(Triphenylmethyloxy) hexanol, 7- (triphenylmethyloxy) heptanol, 8- (triphenyl) Tiloxy) octanol, 1- (diphenylmethyloxy) methylamine, 3- (diphenylmethyloxy) propylamineamine, 4- (diphenylmethyloxy) butylamine, 5- (diphenylmethyloxy) pentylamine, 6- (diphenyl) Methyloxy) hexylamine, 7- (diphenylmethyloxy) heptylamine, 8- (diphenylmethyloxy) octylamine, 1- (triphenylmethyloxy) methylamine, 3- (triphenylmethyloxy) propylamine, 4- (Triphenylmethyloxy) butylamine, 5- (triphenylmethyloxy) pentylamine, 6- (triphenylmethyloxy) hexylamine, 7- (triphenylmethyloxy) heptylamine, 8- (triphenylmethyloxy) Octylamine, 1- (diphenylmethylamino) methanol, 3- (diphenylmethylamino) propanol, 4- (diphenylmethylamino) butanol, 5- (diphenylmethylamino) pentanol, 6- ( Diphenylmethylamino) hexanol, 7- (diphenylmethylamino) heptanol, 8- (diphenylmethylamino) octanol, 1- (triphenylmethylamino) methanol, 3- (triphenylmethylamino) Propanol, 4- (triphenylmethylamino) butanol, 5- (triphenylmethylamino) pentanol, 6- (triphenylmethylamino) hexanol, 7- (triphenylmethylamino) heptanol , 8- (triphenylmethylamino) octanol, 2-[(diphenylmethyl) o C] ethanol, 2-[(methylphenyl) phenylmethyloxy] ethanol, 2- [bis (methylphenyl) methyloxy] ethanol, 2-[(ethylphenyl) phenylmethyloxy] ethanol 2-[(bis (ethylphenyl) methyloxy] ethanol, 2-[(methoxyphenyl) phenylmethyloxy] ethanol, 2-[(bis (methoxyphenyl) methyloxy] ethanol, 2- [(Ethoxyphenyl) phenylmethyloxy] ethanol, 2-[(bis (ethoxyphenyl) methyloxy] ethanol, 2-[(hydroxyphenyl) phenylmethyloxy] ethanol, 2-[(bis ( Hydroxyphenyl) methyloxy] ethanol, 2-[(aminophenyl) phenylmethyloxy] ethanol, 2-[(bis (aminophenyl) methyloxy C] ethanol, 2-[(fluorophenyl) phenylmethyloxy] ethanol, 2-[(bis (fluorophenyl) methyloxy] ethanol, 2-[(triphenylmethyl) oxy] ethanol 2- [diphenyl (methylphenyl) methyloxy] ethanol, 2- [bis (methylphenyl) phenylmethyloxy] ethanol, 2- [tris (methylphenyl) methyloxy] ethanol, 2- [ Diphenyl (ethylphenyl) methyloxy] ethanol, 2- [bis (ethylphenyl) phenylmethyloxy] ethanol, 2- [tris (ethylphenyl) methyloxy] ethanol, 2- [diphenyl (methoxyphenyl) ) Methyloxy] ethanol, 2- [bis (methoxyphenyl) phenylmethyloxy] ethanol, 2- [tris (methoxyphenyl) methyl Ruoxy] ethanol, 2- [diphenyl (ethoxyphenyl) methyloxy] ethanol, 2- [bis (ethoxyphenyl) phenylmethyloxy] ethanol, 2- [tris (ethoxyphenyl) methyloxy] ethanol 2- [diphenyl (hydroxyphenyl) methyloxy] ethanol, 2- [bis (hydroxyphenyl) phenylmethyloxy] ethanol, 2- [tris (hydroxyphenyl) methyloxy] ethanol, 2- [(Aminophenyl) diphenylmethyloxy] ethanol, 2- [bis (aminophenyl) phenylmethyloxy] ethanol, 2- [tris (aminophenyl) methyloxy] ethanol, 2- [diphenyl (fluoro Phenyl) methyloxy] ethanol, 2- [bis (fluorophenyl) phenylmethyloxy] ethanol 2- [tris (fluorophenyl) methyloxy] ethanol, 2-[(diphenylmethyl) oxy] ethylamine, 2-[(methylphenyl) phenylmethyloxy] ethylamine, 2- [bis (methylphenyl) methyl Oxy] ethylamine, 2-[(ethylphenyl) phenylmethyloxy] ethylamine, 2-[(bis (ethylphenyl) methyloxy] ethylamine, 2-[(methoxyphenyl) phenylmethyloxy] ethylamine, 2-[(bis ( Methoxyphenyl) methyloxy] ethylamine, 2-[(ethoxyphenyl) phenylmethyloxy] ethylamine, 2-[(bis (ethoxyphenyl) methyloxy] ethylamine, 2-[(hydroxyphenyl) phenylmethyloxy] ethylamine, 2- [(Bis (hydroxyphenyl) methyloxy ] Ethylamine, 2-[(aminophenyl) phenylmethyloxy] ethylamine, 2-[(bis (aminophenyl) methyloxy] ethylamine, 2-[(fluorophenyl) phenylmethyloxyethylamine, 2-[(bis (fluorophenyl) ) Methyloxy] ethylamine, 2-[(triphenylmethyl) oxy] ethylamine, 2- [diphenyl (methylphenyl) methyloxy] ethylamine, 2- [bis (methylphenyl) phenylmethyloxy] ethylamine, 2- [tris ( Methylphenyl) methyloxy] ethylamine, 2- [diphenyl (ethylphenyl) methyloxy] ethylamine, 2- [bis (ethylphenyl) phenylmethyloxy] ethylamine, 2- [tris (ethylphenyl) methyloxy] ethylamine, 2- [Diphenyl (Methoxy Phenyl) methyloxy] ethylamine, 2- [bis (methoxyphenyl) phenylmethyloxy] ethylamine, 2- [tris (methoxyphenyl) methyloxy] ethylamine, 2- [diphenyl (ethoxyphenyl) methyloxy] ethylamine, 2- [ Bis (ethoxyphenyl) phenylmethyloxy] ethylamine, 2- [tris (ethoxyphenyl) methyloxy] ethylamine, 2- [diphenyl (hydroxyphenyl) methyloxy] ethylamine, 2- [bis (hydroxyphenyl) phenylmethyloxy] ethylamine 2- [tris (hydroxyphenyl) methyloxy] ethylamine, 2-[(aminophenyl) diphenylmethyloxy] ethylamine, 2- [bis (aminophenyl) phenylmethyloxy] ethylamine, 2- [tris (ami Phenyl) methyloxy] ethylamine, 2- [diphenyl (fluorophenyl) methyloxy] ethylamine, 2- [bis (fluorophenyl) phenylmethyloxy] ethylamine, 2- [tris (fluorophenyl) methyloxy] ethylamine and / or And a pharmacologically acceptable salt thereof can be suitably exemplified. More preferably, 2- (triphenylmethyloxy) ethanol (Compound 15), 2- (diphenylmethyloxy) ethanol (Compound 16), 2- (triphenylmethyloxy) ethylamine (compound 19), 2- (diphenylmethyloxy) ethylamine (compound 20), triphenylmethanol (compound 22), and / or pharmacologically acceptable salts thereof Can be suitably exemplified.

  The compounds represented by the general formula (2), the general formulas (7) and (8) and / or their pharmacologically acceptable salts are obtained by using commercially available compounds as starting materials. Can be synthesized in accordance with the production method described in WO20150074052 filed by, or a part of the compounds can be purchased and used as a reagent. 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 Preferable examples include organic acid salts such as toluene sulfonate and benzene sulfonate, alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt and magnesium salt.

  The compounds represented by the general formula (2), the general formulas (6) and (7) and / or their pharmacologically acceptable salts thus obtained are the above-mentioned general formula (1). ), An optical isomer thereof, and / or a pharmacologically acceptable salt thereof, together with a skin external preparation, exhibits an excellent effect of preventing or improving pigmentation. The skin external preparation of the present invention is selected from the compounds represented by the general formula (2), the general formulas (6) and (7) and / or pharmacologically acceptable salts thereof. Species 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 exert the above pharmacological action, the compound represented by the general formula (2), the general formula (6) and (7) and / or their pharmacology. 1 type or 2 types or more selected from pharmaceutically acceptable salts in a total amount of 0.001% to 10% by mass, more preferably 0.01% to 5%, based on the total amount of the external preparation for skin. It is preferable to contain 0.05 mass%, More preferably, it is 0.05-3 mass%. This is because when the content of the compound represented by the general formula (2), the general formulas (6) and (7) is less than 0.001% by mass relative to the total amount of the external preparation for skin, the effect of preventing or improving pigmentation decreases. Even if an amount exceeding 10% by mass is added, the effect tends to reach its peak, so the degree of freedom of formulation may be reduced, and the content of the above-mentioned total amount of the above-mentioned external preparation for skin Is preferred.

２−（トリフェニルメチルオキシ）エタノ−ル（化合物１５）

2- (Triphenylmethyloxy) ethanol (Compound 15)

<Production Example 16: Method for producing Compound 15>
Ethylene glycol (3.10 g, 49.9 mmol) (Wako Pure Chemical Industries, Ltd.) and triphenylchloromethane (1.39 g, 49.9 mmol) (Wako Pure Chemical Industries, Ltd.) were mixed with pyridine (6 mL) (Wako Pure Chemical Industries, Ltd.). The solution was dissolved in Kojunkaku Kogyo Co., Ltd.), heated to 45 ° C., and stirred for 2 hours. Water (50 mL) was poured into the reaction solution and extracted with toluene (Wako Pure Chemical Industries, Ltd.). The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.): methanol (Wako Pure Chemical Industries, Ltd.) = 9: 1), and the title compound (yield 0.37 g, Yield 24%).
m. p. 103-106 ° C
¹ H-NMR (CDCl ₃ ): δ 3.26 (t, J = 4.5 Hz, 2H), 3.75 (t, J = 4.5 Hz, 2H), 7.23-7.54 (m, 15H ).
IR (cm ⁻¹ ): 3337, 1448, 1093, 1061.

２−（ジフェニルメチルオキシ）エタノ−ル（化合物１６）

2- (Diphenylmethyloxy) ethanol (Compound 16)

<Production Example 17: Method for producing Compound 16>
Compound 16 was synthesized according to the same method as Compound 15 using ethylene glycol (Wako Pure Chemical Industries, Ltd.) and diphenylchloromethane (Wako Pure Chemical Industries, Ltd.).

２−（トリフェニルメチルアミノ）エタノ−ル（化合物１７）

2- (Triphenylmethylamino) ethanol (Compound 17)

<Production Example 18: Method for producing Compound 17>
Triphenylchloromethane (1.00 g, 3.58 mmol) (Wako Pure Chemical Industries, Ltd.) and aminoethanol (2.00 g, 32.7 mmol) were dissolved in acetonitrile (5 mL) and stirred overnight at room temperature. . Water (100 mL) was poured into the reaction solution, and the precipitate was suction filtered and dried. The title compound (yield 0.43 g, yield 39%) was obtained by recrystallizing the solid with ethanol (Wako Pure Chemical Industries, Ltd.) and water mixed solvent system.
m. p. 94-97 ° C
¹ H-NMR (DMSO): δ 2.07 (t, J = 6.0 Hz, 2H), 3.51 (t, J = 6.0 Hz, 2H), 7.15-7.42 (m, 15H) .
IR (cm ^-1 ): 3244, 1488, 1442, 1025.

２−（ジフェニルメチルアミノ）エタノ−ル（化合物１８）

2- (Diphenylmethylamino) ethanol (Compound 18)

<Production Example 19: Method for producing compound 18>
Compound 18 was synthesized in the same manner as Compound 17 using ethylene glycol (Wako Pure Chemical Industries, Ltd.) and diphenylchloromethane (Wako Pure Chemical Industries, Ltd.).

２−（トリフェニルメチルオキシ）エチルアミン（化合物１９）

2- (Triphenylmethyloxy) ethylamine (Compound 19)

<Production Example 20: Method for producing Compound 19>
Dissolve triphenylchloromethane (1.00 g, 3.58 mmol) (Wako Pure Chemical Industries, Ltd.) and ethanolamine hydrochloride (1.00 g, 10.3 mmol) (Wako Pure Chemical Industries, Ltd.) in pyridine (4 mL). And stirred at room temperature for 3 days. Water (200 mL) was poured into the reaction solution, and the precipitate was filtered with suction. The solid was suspended in diethyl ether, 3 (N) hydrochloric acid (Wako Pure Chemical Industries, Ltd.) was added, and the mixture was stirred at room temperature for 15 minutes. The insoluble material was dissolved in a mixed solution of an aqueous solution of ethyl acetate (Wako Pure Chemical Industries, Ltd.) and saturated sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.), and after shaking, the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), then suction filtered and concentrated under reduced pressure to obtain the title compound (yield 0.31 g, yield 28%).
m. p. 87-89 ° C.
¹ H-NMR (CDCl ₃ ): δ 2.88 (t, J = 5.1 Hz, 2H), 3.14 (t, J = 5.1 Hz, 2H), 7.24-7.51 (m, 15H ).
IR (cm ⁻¹ ): 3378, 1594, 1448, 1054.

２−（ジフェニルメチルオキシ）エチルアミン（化合物２０）

2- (Diphenylmethyloxy) ethylamine (Compound 20)

<Production Example 21: Method for producing compound 20>
Compound 20 was synthesized in the same manner as Compound 19 using ethanolamine hydrochloride (Wako Pure Chemical Industries, Ltd.) and diphenylchloromethane (Wako Pure Chemical Industries, Ltd.).

Triphenylmethylamine (compound 21), triphenylmethanol (compound 22), diphenylmethanol (compound 23), and diphenylmethylamine (compound 24) are available from reagent manufacturers such as Tokyo Chemical Industry Co., Ltd. It can be purchased as a commercially available reagent.

<Skin external preparation of the present invention>
The skin external preparation of the present invention includes 1) a compound represented by the general formula (1), an optical isomer thereof and / or a pharmaceutically acceptable salt thereof, and 2) a compound represented by the general formula (2). It contains the compound represented and / or those pharmacologically acceptable salts. The external preparation for skin of the present invention has an excellent effect of preventing or improving pigmentation. This action is the same as that of the compound represented by the general formula (1), the melanin production inhibitory action of the compound represented by the general formula (2) and / or pharmacologically acceptable salts thereof, and its It is exerted by effectively enhancing isomers and / or pharmacologically acceptable salts thereof. 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. Further, the dosage form of the external preparation for skin of the present invention is not particularly limited as long as it is known in the cosmetics field, and is a lotion preparation, an oil-in-water emulsion preparation, a water-in-oil emulsion preparation, a composite. Emulsified emulsion formulations and the like can be suitably exemplified, but particularly emulsifier forms such as an oil-in-water emulsifier form, a water-in-oil emulsifier form, and a composite emulsion emulsifier form are preferred. 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 of the present invention can contain a non-surfactant used in skin external preparations such as ordinary cosmetics. Furthermore, it is also preferable to contain an alkyl-modified carboxyvinyl polymer and / or a salt thereof in the sense of keeping the emulsified state stable. The preferable content of such components is 0.01 to 0.5 mass%, more preferably 0.05 to 0.3 mass%, based on the total amount of the external preparation for skin. Such alkyl-modified carboxyvinyl polymers include commercially available products, which can be purchased and used. Preferable commercial products are “Pemuren (registered trademark) TR-1” and “Pemuren (registered trademark)” which are commercially available from Nippon Surfactant Kogyo Co., Ltd. and are alkyl-modified with an alkyl group having 10 to 30 carbon atoms. (Trademark) TR-2 "," Carbopol (registered trademark) 1382 "commercially available from BF Goodrich (USA), and the like. There are “Carbopol (registered trademark) Ultrez 10”, “Carbopol (registered trademark) 940”, and the like, which are commercially available from BF Goodrich (USA). Such hydrophilic polymers may be used alone or in combination of two or more. The oil-in-water emulsified skin external preparation of the present invention preferably contains 0.05 to 1% by mass of such hydrophilic polymer, more preferably 0.08 to 0.5% by mass. When less than this, an emulsification system will become unstable, and when more than this, the viscosity of a system will become high too much and applicability | paintability will worsen.

  Further, among the above optional components, nonionic surfactants are particularly preferable, and among them, lipophilic surfactants that are excellent in structure formation in an emulsified state are preferable. As the activator, sorbitan stearate, glycerin monostearate and the like can be particularly preferably exemplified. The preferable content of such components is 0.1 to 5% by mass, and more preferably 0.2 to 3% by mass. By adding such a component, the adhesiveness with the skin becomes excellent.

  The skin external preparation of the present invention comprises 1) a compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) the general formula ( 2) and / or a pharmacologically acceptable salt thereof. Some of the external preparations for skin of the present invention exhibit 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.

<Manufacture example 22: Manufacturing method 1 of skin external preparation (milky lotion) of this invention>
According to the formulations shown in Tables 1 and 2, the external preparation for skin of the present invention (emulsion type, cosmetics 1-2) was prepared. That is, after the components (a) and (b) were heated to 80 ° C. and dissolved, the component (a) was added to the component (b) while stirring and emulsified, and the particles were homogenized with a homogenizer. An appropriate amount of 10% (mass%) potassium hydroxide aqueous solution was added thereto to adjust the pH to 6.5. Finally, water was added so that the total weight became 1000 g, and the mixture was stirred and cooled to prepare an external preparation for skin (emulsion formulation, cosmetics 1-2). Similarly, the “compound represented by the general formula (2) of the present invention” contained in the cosmetic 1 is replaced with “water” and the “compound represented by the general formula (1) of the present invention” In Comparative Example 1 in which the blending amount was changed from 2.5 g to 12.5 g, “the compound represented by the general formula (1) of the present invention” contained in the cosmetic 1 was replaced with “water”. Comparative Example 2 in which the compounding amount of “compound represented by (2)” was changed from 10 g to 12.5 g, “compound represented by the general formula (1) of the present invention” and “general formula (2)” Comparative Example 3 was prepared by substituting “represented compounds” with “water”.

<Test Example 1: Evaluation 1 of pigmentation inhibitory effect in human of topical skin preparation of the present invention>
Using the external preparation for skin (emulsion formulation, cosmetics 1-2) prepared according to the method described in Example 1 and the external preparation for skin (emulsion formulation) of Comparative Examples 1-3, the pigmentation inhibitory effect was examined. 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 to 4 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 and 2 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 cosmetics 1-2. Thereby, it turns out that the cosmetics 1-2 which are the skin external preparation of this invention show the prevention or improvement effect with respect to the outstanding pigmentation.

<Production Example 23: Method 2 for producing skin external preparation of the present invention>
Content of “compound represented by the general formula (1) of the present invention” and “compound represented by the general formula (2) of the present invention” in the formulation components of the cosmetic 1 described in Example 1 A skin external preparation (emulsion type, cosmetics 3 to 4) with the content changed to the content shown in Table 4 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 preparations (Cosmetics 1, Cosmetics 3, Cosmetics 4) described in Examples 1 and 3 and Comparative Example 3, the effect of inhibiting pigmentation by ultraviolet rays in humans was evaluated according to the method described in Example 2. did. The results are shown in Table 5. Similarly to the cosmetic 1, the cosmetics 3 to 4 which are external preparations of the present invention have a smaller ΔL * value compared to the comparative example 3, and it can be seen that they have an excellent preventive or improving effect on pigmentation.

<Production Example 24: Method 3 for producing skin external preparation of the present invention>
Preparation of external preparation for skin (milky lotion, cosmetic 5) by replacing “Pemlen TR-2” with POE (25) stearic acid in the prescription components of external preparation for skin (cosmetic 1) shown in Table 1 and Table 2. As a result, cosmetic 5 was separated immediately after production, and an emulsion was not obtained.

  The present invention can be applied to cosmetics for whitening (including quasi-drugs).

Claims (13)

1) a compound represented by the following general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) a compound represented by the following general formula (2) and / or them. An external preparation for skin, comprising a pharmacologically acceptable salt of

(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)
[Wherein R4 represents an unsubstituted or substituted aromatic group or hydrogen atom, R5 and R6 each independently represents an unsubstituted or substituted aromatic group, and X represents a nitrogen atom. Or an oxygen atom, and R7 and R8 are present in a number corresponding to X, and each independently represents a straight or branched chain having 1 to 6 carbon atoms in which a hydrogen atom or a carbon atom may be substituted with a hetero atom. Represents an alkyl group or a hydrogen atom. ] 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 R9 represents an unsubstituted or substituted aromatic group, R10 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 (4), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, The external preparation for skin according to claim 1.

(4)
[Wherein, R11 represents an unsubstituted or substituted aromatic group, and R12 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 (5), an optical isomer thereof and / or a pharmaceutically acceptable salt thereof. The skin external preparation of any one of Claims 1-3.

(5)
[Wherein, R13 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- (benzoyl) serine (Compound 6), N- (2 -Naphthoyl) serine (compound 7), N- (4-phenylbenzoyl) 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-acetylse 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- (benzoyl) serine (compound 6)

N- (2-naphthoyl) serine (Compound 7)

N- (4-Phenylbenzoyl) 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) 6. The compound represented by the general formula (2) is a compound represented by the following general formula (6) and / or a pharmacologically acceptable salt thereof. The external preparation for skin according to any one of the above.

(6)
[Wherein, R14 represents an unsubstituted or substituted aromatic group or a hydrogen atom, R15 and R16 each independently represents an unsubstituted or substituted aromatic group, and R17 and R18 represent Each independently represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms, in which a carbon atom may be substituted with a hetero atom, or a hydrogen atom. ] The compound represented by the general formula (2) is a compound represented by the following general formula (7) and / or a pharmaceutically acceptable salt thereof. The external preparation for skin according to any one of the above.

(7)
[Wherein R19 represents an unsubstituted or substituted aromatic group or a hydrogen atom, R20 and R21 each independently represents an unsubstituted or substituted aromatic group, and R22 represents a hydrogen atom. Alternatively, it represents a linear or branched alkyl group having 1 to 6 carbon atoms and a hydrogen atom, in which a carbon atom may be substituted with a hetero atom. ] The compound represented by the general formula (2) is 2-[(triphenylmethyl) oxy] ethanol (compound 15), 2-[(diphenylmethyl) oxy] ethanol (compound 16), 2- [(Triphenylmethyl) amino] ethanol (Compound 17), 2-[(Diphenylmethyl) amino] ethanol (Compound 18), 2-[(Triphenylmethyl) oxy] ethylamine (Compound 19), 2 -[(Diphenylmethyl) oxy] ethylamine (compound 20), triphenylmethylamine (compound 21), triphenylmethanol (compound 22), and / or a pharmaceutically acceptable salt thereof. The external preparation for skin according to any one of claims 1 to 7, characterized in that it is characterized by the following.

2-[(Triphenylmethyl) oxy] ethanol (Compound 15)

2-[(Diphenylmethyl) oxy] ethanol (Compound 16)

2-[(Triphenylmethyl) amino] ethanol (Compound 17)

2-[(Diphenylmethyl) amino] ethanol (Compound 18)

2-[(Triphenylmethyl) oxy] ethylamine (Compound 19)

2-[(Diphenylmethyl) oxy] ethylamine (Compound 20)

Triphenylmethylamine (Compound 21)

Triphenyl methanol (Compound 22) Containing 0.0001% by mass to 20% by mass of the compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof 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 8, which is characterized by the following. The compound represented by the general formula (2) and / or a pharmacologically acceptable salt thereof is contained in an amount of 0.001% by mass to 10% by mass with respect to the total amount of the external preparation for skin. Item 10. The skin external preparation according to any one of Items 1 to 9. The skin external preparation according to any one of claims 1 to 10, wherein the preparation is a cosmetic (however, including quasi-drugs). The skin external preparation according to any one of claims 1 to 11, which is used for preventing or improving pigmentation. Furthermore, the preferable preparation component is contained, The skin external preparation in any one of Claims 1-12 characterized by the above-mentioned.