JP2011241165A5 - - Google Patents

Description

Composition

  The present invention relates to a composition suitable for preventing or improving pigmentation. Specifically, the present invention relates to a compound represented by the following general formula (1) and / or a pharmaceutically acceptable salt thereof, and 2) The present invention relates to a skin external preparation characterized by containing a compound represented by the general formula (2), an isomer thereof and / or a pharmacologically acceptable salt thereof.

（１）
[式中、Aは、ジ芳香族メチル基又はトリ芳香族メチル基を表し、該芳香族は無置換又は置換基を有するアリール基及び無置換又は置換基を有する複素芳香族環よりなる群からそれぞれ独立に選ばれる。Bは、Aとの結合部位が複素原子である、水素原子、水素原子又は炭素原子が複素原子により置換されていてもよい環状又は非環状の脂肪族又は芳香族炭化水素基を表す。]

（２）
[式中、Ｒ ₁ は、水素原子、炭素数１〜８の直鎖又は分岐のアルキル基を表し、Ｒ ₂ は、水
素原子、無置換又は置換基を有する芳香族基、無置換又は置換基を有する芳香族基により置換されていてもよい炭素数１〜４の脂肪族炭化水素基を表し、Ｒ ₃ は、無置換又は置換
基を有する芳香族基を表し、ｎは、１又は２の整数、mは、０〜３の整数を表す。]

(1)
[In the formula, A represents a di-aromatic methyl group or tri aromatic methyl group, aromatic the group consisting of heteroaromatic ring having aryl Moto及beauty unsubstituted or substituted group having an unsubstituted or substituted group Are independently selected . B represents a cyclic or acyclic aliphatic or aromatic hydrocarbon group in which the bonding site to A is a hetero atom, and a hydrogen atom, a hydrogen atom, or a carbon atom may be substituted with a hetero atom. ]

(2)
[Wherein, R ₁ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₂ represents a hydrogen atom, an unsubstituted or substituted aromatic group, an unsubstituted or substituted group. Represents an aliphatic hydrocarbon group having 1 to 4 carbon atoms which may be substituted with an aromatic group having R ₃ , R ₃ represents an unsubstituted or substituted aromatic group, and n represents 1 or 2 An integer, m represents an integer of 0 to 3. ]

Skin symptoms such as wrinkles, stains and sagging become apparent with aging due to genetic factors in addition to accumulation of physicochemical stimuli such as temperature changes, ultraviolet rays and chemical exposure. Such skin symptoms greatly affect the visual impression of others, so it is an important concern for people to keep the beauty of the skin beautiful. Among these skin symptoms, it is clear that skin symptoms such as spots, dullness, freckles, and pigmentation after sunburn are caused by markedly increased melanin production due to activation of pigment cells (melanocytes) present in the skin. Has been. In addition, the chronic increase in melanin production in melanocytes causes phenomena such as excessive transport, accumulation, and discharge delay of melanin to keratinocytes, making it difficult to cure compared to normal spots, dullness, dullness formation, stratification, etc. Skin symptoms such as abnormal pigmentation accompanied by worsening of skin symptoms such as pigmentation accompanied by skin symptoms such as peeling occur. Various whitening ingredients have been researched and developed for the purpose of preventing or improving pigmentation abnormalities involving such melanin production. As such whitening ingredients, for example, ascorbic acid, hydrogen peroxide, colloidal sulfur, glutathione, hydroquinone, catechols and the like are known, and external preparations for skin containing these as active ingredients are also widely used (for example, non-patented). Reference 1 and Non-Patent Document 2). Moreover, the mechanism of action of these whitening components is diverse, including melanin production inhibitors (see, for example, Patent Document 1), tyrosinase enzyme inhibitors (see, for example, Patent Document 2), tyrosinase enzyme gene expression inhibitors. , Α-MSH inhibitors (see, for example, Patent Document 3), antioxidants, and the like have been reported.
However, some conventional whitening agents have problems in safety or stability. In addition, the above-mentioned whitening component has a desirable effect for prevention or improvement of pigmentation such as normal sunburn, but is caused by the above-described excessive transport, accumulation and discharge of melanin to keratinocytes. Since it is difficult to say that the effect of conventional whitening agents is sufficient for abnormal pigmentation accompanied by worsening of skin symptoms, incurable healing, dullness, etc., the appearance of new whitening agents is eagerly desired.

Steric bulky aromatic or heteroaromatic groups, especially diphenylmethyl or triphenylmethyl groups are widely known as effective protecting groups for hydroxyl or amino groups in organic low molecular weight compounds, peptides and nucleic acid synthesis. (For example, see Non-Patent Document 3 and Non-Patent Document 4). Reactions using these protecting groups and intermediate compounds (see, for example, Non-Patent Document 5 and Non-Patent Document 6) have been applied to organic synthesis on a wide scale from laboratory to industrial production. Moreover, about the compound which has the said three-dimensionally bulky substituent in the chemical structure, antitumor activity (for example, refer nonpatent literature 5), antifungal action (for example, refer patent document 4). Exhibit biological activities such as antihistamine action (see, for example, Non-Patent Document 6), dopamine uptake inhibitory action (see, for example, Non-Patent Document 7), calcium antagonism (see, for example, Non-Patent Document 8), etc. Has been reported. However, the compound represented by the general formula (1) has a melanin production inhibitory action and a whitening action, and further, the compound represented by the general formula (2), its isomers and / or their drugs. It has never been known that the prevention or amelioration action against pigmentation is enhanced by inclusion in the composition together with a salt that is physically acceptable.

  On the other hand, various biological activities are known for 20 kinds of α-amino acids having different side chains including an essential amino acid constituting a living body. In particular, among the above-mentioned α-amino acids, methionine, cysteine, and derivatives thereof have a characteristic biological activity different from other α-amino acids due to the presence of sulfur atoms in the chemical structure. Is expected and attracts attention. In fact, an acylated derivative of methionine is known to have an antioxidant effect (see, for example, Patent Document 5), and a dipeptide containing methionine has a whitening effect (see, for example, Patent Document 6). In addition, cysteic acid in which the sulfur atom of cysteine is oxidized and homocysteic acid, which is a derivative of cysteine, are attracting attention as metabolites in the living body. (See, for example, Patent Document 7) and the like. Furthermore, as for cysteic acid and homocysteic acid derivatives, skin peeling or epidermis renewal action on derivatives having a hydrogen atom, linear or branched alkyl or alkenyl group on the nitrogen atom (see, for example, Patent Document 8) Etc. are reported to exist. However, regarding compounds in which the nitrogen atom of cysteic acid and homocysteic acid is substituted by an aliphatic hydrocarbon group having an aromatic group, since the compound itself is a novel compound, its biological activity and structure-activity relationship are completely known. Not. In addition, the compound represented by the general formula (2), its isomer and / or pharmacologically acceptable salt thereof has a whitening action, and further, the compound represented by the general formula (1). It has not been known at all that the preventive or ameliorating action against pigmentation is enhanced by inclusion in a composition together with a compound to be produced and / or a pharmacologically acceptable salt thereof. The compound represented by the general formula (2) has no off-flavor due to decomposition or the like even when blended in a composition such as a skin external preparation, and has extremely high solubility in a medium used for formulation, especially in a water-soluble medium. In addition, since it is very stable in the compound and the preparation form, it is excellent in versatility for cosmetics and the like.

JP 2008-208073 A JP 2009-196895 A JP 2001-220347 A JP 09-255634 A JP 2006-052152 A Japanese Patent Laid-Open No. 1993-032533 JP 2006-143649 A JP 09-110627 A

Supervised by Katsuyuki Takeda et al., “Usefulness of cosmetics, evaluation technology and future prospects”, published by Yakuji Nippo (2001) Noriyuki Omori, FRAGRANCEJOURNAL extra edition, No. 14, 1995, 118-126 Theodora W. Green, ProtectiveGroupsinOrganicSynthesis, AWiley-IntersciencePublication .: 1981, P173-176 and P273-274 Nobuo Izumiya, Tetsuo Kato, Toshihiko Aoyagi, Michinori Waki, Basics and Experiments of Peptide Synthesis: Maruzen Co., Ltd., 1985, P38 NaohisaOgoet.al., Bioorganic & Medicinal Chemistry, 17 (4), 3921-3924 (2007) Sasse A., et.al., Bioorganic & Medicinal Chemistry, 8 (5), 1139-1149 (2000) DuttaAK. Et.al., Bioorganic & Medicinal Chemistry, 11 (17), 2337-2340 (2001) Shanklin JRJr., Etal., J. Med. Chem., 34 (10), 3011-3022 (1991)

  The present invention has been made under such circumstances, and is used for prevention or improvement of pigmentation due to ultraviolet exposure, etc., in particular, irrecoverable dullness, dullness caused by excessive transport, accumulation and excretion of melanin in keratinocytes. In addition, prevention of pigmentation accompanied by rough skin symptoms is to provide a composition such as an external preparation for skin suitable for improvement.

In view of such a situation, the present inventors have been able to prevent or ameliorate abnormal pigmentation due to exposure to ultraviolet rays, in particular, intractable itchiness, dullness, and rough skin symptoms caused by excessive transport, accumulation and discharge delay of melanin in keratinocytes. result of repeated prophylactic or seek compositions such as a suitable skin treatment composition for improving diligently for pigmentation with, 1) the compound and / or their pharmacologically represented by the general formula (1) And 2) the compound represented by the general formula (2), an isomer thereof and / or a pharmacologically acceptable salt thereof, have such characteristics. As a result, the present invention has been completed. Also, the stains, dullness, people exhibiting pigmentation with rough skin symptoms, although when taken corneocytes and abundance melanin is not multi-person, suitable for targeting such human It can be said that it is a simple composition. That is, the present invention is as follows.
<1> 1) A compound represented by the following general formula (1) and / or a pharmacologically acceptable salt thereof, and 2) a compound represented by the following general formula (2), its isomers and / or Or a pharmacologically acceptable salt thereof.

（１）
[式中、Aは、ジ芳香族メチル基又はトリ芳香族メチル基を表し、該芳香族は無置換又は置換基を有するアリール基及び無置換又は置換基を有する複素芳香族環よりなる群からそれぞれ独立に選ばれる。Bは、Aとの結合部位が複素原子である、水素原子、水素原子又は炭素原子が複素原子により置換されていてもよい環状又は非環状の脂肪族又は芳香族炭化水素基を表す。]

(1)
[In the formula, A represents a di-aromatic methyl group or tri aromatic methyl group, aromatic the group consisting of heteroaromatic ring having aryl Moto及beauty unsubstituted or substituted group having an unsubstituted or substituted group Are independently selected . B represents a cyclic or acyclic aliphatic or aromatic hydrocarbon group in which the bonding site to A is a hetero atom, and a hydrogen atom, a hydrogen atom, or a carbon atom may be substituted with a hetero atom. ]

（２）
[式中、Ｒ ₁ は、水素原子、炭素数１〜８の直鎖又は分岐のアルキル基を表し、Ｒ ₂ は、水
素原子、無置換又は置換基を有する芳香族基、無置換又は置換基を有する芳香族基により置換されていてもよい炭素数１〜４の脂肪族炭化水素基を表し、Ｒ ₃ は、無置換又は置換
基を有する芳香族基を表し、ｎは、１又は２の整数、mは、０〜３の整数を表す。]

(2)
[Wherein, R ₁ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₂ represents a hydrogen atom, an unsubstituted or substituted aromatic group, an unsubstituted or substituted group. Represents an aliphatic hydrocarbon group having 1 to 4 carbon atoms which may be substituted with an aromatic group having R ₃ , R ₃ represents an unsubstituted or substituted aromatic group, and n represents 1 or 2 An integer, m represents an integer of 0 to 3. ]

<2> The compound represented by the general formula (1), characterized in that a compound represented by the following general formula (3) The composition according to <1>.

（３）
[式中、Aは、ジアリールメチル基又はトリアリールメチル基を表し、該アリールは無置換又は置換基を有するアリール基よりなる群からそれぞれ独立に選ばれ、Bは、Aとの結合部位が複素原子である、水素原子、水素原子又は炭素原子が複素原子により置換されていてもよい環状又は非環状の脂肪族又は芳香族炭化水素基を表す。]

(3)
[In the formula, A represents a diarylmethyl group or a triarylmethyl group, and the aryl is independently selected from the group consisting of unsubstituted or substituted aryl groups , and B has a complex binding site with A. A hydrogen atom, a hydrogen atom, or a carbon atom, which is an atom, represents a cyclic or acyclic aliphatic or aromatic hydrocarbon group that may be substituted with a hetero atom. ]

<3> The composition according to <2>, wherein the compound represented by the general formula (3) is a compound represented by the following general formula (7).

(7)
[Wherein, A represents a diarylmethyl group or a triarylmethyl group, and each aryl is independently selected from the group consisting of unsubstituted or substituted aryl groups, and X is a nitrogen atom, R ₈ Is a hydrogen atom, a hydrogen atom or a carbon atom of 3 to 8 carbon atoms optionally substituted with a hetero atom
The aromatic hydrocarbon group includes a group in which X is present in the ring. ]

<4> The compound represented by the general formula (7) is one or more selected from 1- (diphenylmethyl) imidazole (compound 1) and 1- (triphenylmethyl) imidazole (compound 2). The composition according to <3>, which is characterized in that it exists.

1- (Diphenylmethyl) imidazole (Compound 1)

1- (Triphenylmethyl) imidazole (Compound 2)

<5> The compound represented by the general formula (3), characterized in that a compound represented by the following general formula (4) The composition according to <2>.

（４）
[式中、Aは、ジアリールメチル基又はトリアリールメチル基を表し、該アリールは無置換又は置換基を有するアリール基よりなる群からそれぞれ独立に選ばれ、Xは、窒素原子を
表し、R ₄ は、水素原子、水素原子又は炭素原子が複素原子で置換されていてもよい炭素数３〜８の環状脂肪族炭化水素基を表し、前記環状脂肪族炭化水素基の環は、Ｒ ₄ のもう一
方の末端がＸに再び結合して形成された環も包含する。]

(4)
[ Wherein , A represents a diarylmethyl group or a triarylmethyl group, and the aryl is independently selected from the group consisting of unsubstituted or substituted aryl groups , X represents a nitrogen atom, and R ₄ Represents a hydrogen atom, a hydrogen atom or a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms in which a carbon atom may be substituted with a hetero atom, and the ring of the cyclic aliphatic hydrocarbon group is a group other than R ₄ A ring formed by re-bonding one end to X is also included . ]

<6> The compound represented by the general formula (4) is 1- (diphenylmethyl) pyrrolidine (compound 9), 1- (triphenylmethyl) pyrrolidine (compound 10), 1- (diphenylmethyl) piperidine (compound 11) The composition according to <5>, which is one or more selected from 1- (triphenylmethyl) piperidine (Compound 12).

1- (Diphenylmethyl) pyrrolidine (Compound 9)

1- (Triphenylmethyl) pyrrolidine (Compound 10)

1- (Diphenylmethyl) piperidine (Compound 11)

1- (Triphenylmethyl) piperidine (Compound 12)

<7> The compound represented by the general formula (3), characterized in that a compound represented by the following general formula (5) A composition according to <2>.

（５）
[式中、Aは、ジアリールメチル基又はトリアリールメチル基を表し、該アリールは無置換又は置換基を有するアリール基よりなる群からそれぞれ独立に選ばれ、Ｘは、酸素原子、Ｒ ₅ は、水素原子、水素原子又は炭素原子が複素原子に置換されていてもよい炭素数１〜
８の脂肪族炭化水素を表す。]

(5)
[ Wherein , A represents a diarylmethyl group or a triarylmethyl group, and the aryl is independently selected from the group consisting of unsubstituted or substituted aryl groups , X is an oxygen atom, and R ₅ is A hydrogen atom, a hydrogen atom or a carbon atom may be substituted with a hetero atom, having 1 to 1 carbon atoms
8 represents an aliphatic hydrocarbon . ]

<8> The compound represented by the general formula (5) is 2-[(diphenylmethyl) oxy] ethanol (compound 3), 2-[(triphenylmethyl) oxy] ethanol (compound 4), 2- [ (Diphenylmethyl) oxy] ethylamine (Compound 7), 2-[(Triphenylmethyl)
L) Oxy] ethylamine (compound 8)
And the composition according to <7>.

2-[(Diphenylmethyl) oxy] ethanol (compound 3)

2-[(Triphenylmethyl) oxy] ethanol (compound 4)

2-[(Diphenylmethyl) oxy] ethylamine (Compound 7)

2-[(Triphenylmethyl) oxy] ethylamine (Compound 8)

<9> The compound represented by the general formula (3), characterized in that a compound represented by the following general formula (6) A composition according to <2>.

（６）
[式中、Aは、ジアリールメチル基又はトリアリールメチル基を表し、該アリールは無置換又は置換基を有するアリール基よりなる群からそれぞれ独立に選ばれ、Xは、窒素原子を
表し、Ｒ ₆ 及びＲ ₇ は、それぞれ独立に、水素原子、水素原子又は炭素原子が複素原子に置換されていてもよい炭素数１〜８の脂肪族炭化水素基を表す。]

(6)
[ Wherein , A represents a diarylmethyl group or a triarylmethyl group, and the aryl is independently selected from the group consisting of unsubstituted or substituted aryl groups , X represents a nitrogen atom, and R ₆ And R ₇ each independently represent a C 1-8 aliphatic hydrocarbon group in which a hydrogen atom, a hydrogen atom, or a carbon atom may be substituted with a hetero atom. ]

<10> The compound represented by the general formula (6) is selected from 2-[(diphenylmethyl) amino] ethanol (compound 5) and 2-[(triphenylmethyl) amino] ethanol (compound 6). <9> The composition according to <9>, wherein the composition is a seed or two or more kinds.

2-[(Diphenylmethyl) amino] ethanol (Compound 5)

2-[(Triphenylmethyl) amino] ethanol (Compound 6)

<11> The compound represented by the general formula (2), characterized in that a compound represented by the following general formula (8), the composition of any crab described <1> to <10> object.

（８）
[式中、Ｒ ₉ は、水素原子、炭素数１〜８の直鎖又は分岐のアルキル基を表し、Ｒ ₁₀ は、無置換又は置換基を有する芳香族基を表し、nは、１又は２の整数、mは、０〜３の整数を表す。]

(8)
[Wherein R ₉ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, R ₁₀ represents an unsubstituted or substituted aromatic group, and n represents 1 or 2 , M represents an integer of 0 to 3. ]

<12> The compound represented by the general formula (8) is a compound represented by the following general formula (9), an isomer thereof and / or a pharmacologically acceptable salt thereof. The composition according to <11> .

（９）
[式中、Ｒ ₁₁ は、水素原子、炭素数１〜８の直鎖又は分岐のアルキル基を表し、Ｒ ₁₂ は、
無置換又は置換基を有する芳香族基を表し、nは、１又は２の整数を表す。]

(9)
[Wherein R ₁₁ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₁₂ represents
It represents an unsubstituted or substituted aromatic group, and n represents an integer of 1 or 2. ]

<13> The composition according to <12>, wherein the compound represented by the general formula (9) is N- (p-toluyl) homocysteic acid (compound 18).

N- (p-Toluyl) homocysteic acid (Compound 18)

<14> The compound represented by general formula (9), characterized in that a compound represented by the following general formula (10) The composition according to <12>.

（１０）
[式中、Ｒ ₁₃ は、水素原子、炭素数１〜８の直鎖又は分岐のアルキル基を表し、Ｒ ₁₄ は、
無置換又は置換基を有する芳香族基を表す。]

(10)
[Wherein R ₁₃ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₁₄ represents
It represents an unsubstituted or substituted aromatic group. ]

< 15 > The compound represented by the general formula ( 10) is N- (o-toluyl) cysteic acid (compound 13), N- (m-toluyl) cysteic acid (compound 14), N- (p-toluyl). ) cysteic acid (compound 15) N- (p-methoxybenzoyl) cysteic acid (compound 16), and characterized in that one or more selected from N- (biphenylcarbonyl) cysteic acid (compound 17) The composition according to <14> .

N−（o−トルイル）システイン酸（化合物１３）

N- (o-Toluyl) cysteic acid (Compound 13)

N−（m−トルイル）システイン酸（化合物１４）

N- (m-Toluyl) cysteic acid (Compound 14)

N−（p−トルイル）システイン酸（化合物１５）

N- (p-Toluyl) cysteic acid (Compound 15)

N−（p−メトキシベンゾイル）システイン酸（化合物１６）

N- (p-methoxybenzoyl) cysteic acid (Compound 16)

N−（ビフェニルカルボニル）システイン酸（化合物１７）

N- (biphenylcarbonyl) cysteic acid (Compound 17)

< 16 > The compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof is 0.001% by mass to 10% by mass with respect to the total amount of the composition. The composition according to any one of <1> to < 15 >.
< 17 > The compound represented by the general formula (2), its isomer and / or pharmacologically acceptable salt thereof is contained in an amount of 0.0001% by mass to 20% by mass with respect to the total amount of the composition. The composition according to any one of <1> to < 16 >.
< 18 > The composition according to any one of <1> to < 17 >, wherein the composition is for whitening .
<19 > A skin external preparation comprising the composition according to any one of <1> to <18> .
< 20 > The skin external preparation according to < 19 >, wherein the skin external preparation is a cosmetic (including quasi-drugs).

<Compound represented by the general formula (1) of the present invention>
The composition of the present invention comprises 1) a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, 2) a compound represented by the general formula (2), It contains isomers and / or pharmacologically acceptable salts thereof. The compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof is a compound represented by the general formula (2), an isomer thereof and / or a pharmacological compound thereof. When included in the composition together with an acceptable salt, it has excellent whitening action, more preferably, prevention or improvement of pigmentation due to UV exposure, and more preferably keratinocyte cells produced by increased melanin production. It exerts a preventive or ameliorating action against pigmentation involving inactivation. The compound represented by the general formula (1) of the present invention and / or a pharmacologically acceptable salt thereof can be applied without particular limitation as long as it has the above-described whitening action. In pigment cells (melanocytes), melanin production is enhanced by physical stimulation such as exposure to ultraviolet rays, and tanning, spots, dullness, etc. due to pigmentation are formed. Furthermore, when stimuli such as UV exposure are excessive or chronic, melanin production is increased in melanocytes, and further, melanin is excessively transported to keratinocytes, and accumulation and discharge delay occur, resulting in keratinocyte Damage such as inactivation of cell function and delay of turnover is caused, and pigmentation abnormality accompanied by rough skin symptoms such as incurable healing, dullness, or delamination occurs. In those who have abnormal pigmentation caused by excessive or chronic stimulation such as UV exposure, the incidence of nucleated cells is higher than average when preparing stratum corneum. Skin symptoms such as delamination of the skin are observed. For this reason, the composition of the present invention is particularly preferably used for a person exhibiting the above-mentioned skin symptoms, and observation of skin symptoms such as the appearance rate of nucleated cells by the preparation of a stratum corneum specimen, and delamination of the skin It is preferable to set a subject to be administered using the symptoms of

Here, the compound represented by the general formula (1) will be described. In the formula, A represents the aromatic group.
But it represents an unsubstituted or aryl groups and / or unsubstituted or di-aromatic methyl group or tri aromatic methyl groups each independently selected from the group consisting of heteroaromatic ring having a substituent having a substituent, B is , A represents a cyclic or acyclic aliphatic or aromatic hydrocarbon group in which the bonding site to A is a heteroatom, and a hydrogen atom or a carbon atom may be substituted with a heteroatom . As a specific example related to heteroaromatic ring having ants Lumpur group and / or an unsubstituted or substituted radical having an unsubstituted or substituted group of the previous SL A, a phenyl group, a naphthyl group, a biphenyl group, a pyridyl group, furyl Group, thienyl group, thiazolyl group, imidazolyl group , methylphenyl group, ethylphenyl group, propylphenyl group, methoxyphenyl group, ethoxyphenyl group, propyloxyphenyl group, hydroxyphenyl group, aminophenyl group, N-methylaminophenyl group N-ethylaminophenyl group, N-propylaminophenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, N, N-dipropylaminophenyl group, fluorophenyl group, difluorophenyl group, Trifluoromethylphenyl group, chlorophenyl group, bromophenyl group, methyl Pyridyl group, ethylpyridyl group, propylpyridyl group, methoxypyridyl group, ethoxypyridyl group, propyloxypyridyl group, hydroxypyridyl group, aminopyridyl group, N-methylaminopyridyl group, N-ethylaminopyridyl group, N-propylamino Pyridyl group, N, N-dimethylaminopyridyl group, N, N-diethylaminopyridyl group, N, N-dipropylaminopyridyl group, fluoropyridyl group, difluoropyridyl group, trifluoromethylpyridyl group, chloropyridyl group, bromopyridyl group Group, methylnaphthyl group, ethylnaphthyl group, propylnaphthyl group, methoxynaphthyl group, ethoxynaphthyl group, propyloxynaphthyl group, hydroxynaphthyl group, aminonaphthyl group, N-methylaminonaphthyl group, N-ethylaminonaphthyl group, N -Propi Aminonaphthyl group, N, N-dimethylaminonaphthyl group, N, N-diethylaminonaphthyl group, N, N-dipropylaminonaphthyl group, fluoronaphthyl group, difluoronaphthyl group, trifluoromethylnaphthyl group, chloronaphthyl group, bromo Naphthyl group, imidazolyl group , methylimidazolyl group , ethylimidazolyl group , propylimidazolyl group , methoxyimidazolyl group , ethoxyimidazolyl group , propyloxyimidazolyl group , hydroxyimidazolyl group , aminoimidazolyl group , N-methylaminoimidazolyl group , N-ethylamino imidazolyl group, N- propylamino-imidazolyl group, N, N- dimethylamino-imidazolyl group, N, N- diethylamino-imidazolyl group, N, N- dipropylamino imidazolyl group, fluoro imidazolyl group, difluoromethyl B imidazolyl group, a trifluoromethyl imidazolyl group, chloro imidazolyl group, bromo imidazolyl group and the like can be preferably exemplified, more preferably a phenyl group, methylphenyl group, methoxyphenyl group, naphthyl group, biphenyl group suitably be exemplified.
B represents a cyclic atom or a non-cyclic aliphatic or aromatic hydrocarbon group in which the bonding site to A is a hetero atom, a hydrogen atom, a hydrogen atom or a carbon atom optionally substituted with a hetero atom; For example, a mono- or di-substituted amino group, a hydrogen atom or a carbon having a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms in which a hydroxyl group, an amino group, a hydrogen atom or a carbon atom may be substituted by a hetero atom An alkyloxy group having a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms in which an atom may be substituted by a hetero atom, a hydrogen atom or a carbon atom having 1 to 8 carbon atoms in which the carbon atom may be substituted by a hetero atom, More preferably, a mono- or dialkyl-substituted amino group having an aliphatic hydrocarbon group having 1 to 4 carbon atoms, a hydrogen atom or a carbon atom having 1 to 8 carbon atoms in which the carbon atom may be substituted with a hetero atom, more preferably. Is a mono or di having an alkyloxy group having a C 1-4 aliphatic hydrocarbon group, a hydrogen atom or a C 3-8 aromatic hydrocarbon group in which the carbon atom may be substituted by a hetero atom. A substituted amino group, a hydrogen atom or an alkyloxy group having an aromatic hydrocarbon group having 3 to 8 carbon atoms which may be substituted with a hetero atom. The B is a hydrogen atom or a disubstituted amino group having a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms in which a carbon atom may be substituted with a heteroatom, or a hydrogen atom or a carbon atom is a heteroatom. In the case of representing a disubstituted amino group having an aromatic hydrocarbon group having 3 to 8 carbon atoms which may be substituted by, bonding of A and B to a ring of a cyclic aliphatic hydrocarbon group or an aromatic group The structure including the hetero atom of the site is also included.
Among the compounds represented by the general formula (1), more preferable examples include the compounds represented by the general formula (3) and / or pharmacologically acceptable salts thereof. More preferable examples include compounds represented by the general formulas (4) to (7) and / or pharmacologically acceptable salts thereof. Specific examples of compounds that are not included in the compounds represented by the general formulas (3) to (7) among the compounds represented by the general formula (1) include 1- [phenyl (pyridyl) methyl. ] Imidazole , 1- (dipyridylmethyl) imidazole , 1- [diphenyl (pyridyl) methyl] imidazole , 1-[(dipyridyl) phenylmethyl] imidazole , 1- (tripyridylmethyl) imidazole , 2-[[phenyl (pyridyl) Methyl] oxy] ethanol , 2-[(dipyridylmethyl) oxy] ethanol , 2-[[diphenyl (pyridyl) methyl] oxy] ethanol , 2-[[dipyridyl (phenyl) methyl] oxy] ethanol , 2-[(tri Pyridylmethyl) oxy] ethanol , 2-[[phenyl (pyridyl) methyl] amino] ethanol , 2-[(dipyridylmethyl) amino] eta Nord, 2 - [[diphenyl (pyridyl) methyl] amino] ethanol, 2 - [[dipyridyl (phenyl) methyl] amino] ethanol, 2 - [(tri-pyridyl methyl) amino] ethanol, 2 - [[phenyl (pyridyl) Methyl] oxy] ethylamine, 2-[(dipyridylmethyl) oxy] ethylamine, 2-[[diphenyl (pyridyl) methyl] oxy] ethylamine, 2-[[dipyridyl (phenyl) methyl] oxy] ethylamine, 2-[(tri Pyridylmethyl) oxy] ethylamine, 1- [phenyl (pyridyl) methyl] pyrrolidine, 1- (dipyridylmethyl) pyrrolidine, 1- [diphenyl (pyridyl) methyl] pyrrolidine, 1-[(dipyridyl) phenylmethyl] pyrrolidine, 1- (Tripyridylmethyl) pyrrolidine, 1- [phenyl (pyridyl) methyl] piperidine, 1 -(Dipyridylmethyl) piperidine, 1- [diphenyl (pyridyl) methyl] piperidine, 1-[(dipyridyl) phenylmethyl] piperidine, 1- (tripyridylmethyl) piperidine and / or their pharmaceutically acceptable salts Etc. can be suitably exemplified. Specific examples of preferred compounds among the compounds represented by the general formula (1) are 1- (diphenylmethyl) imidazole (compound 1), 1- (triphenylmethyl) imidazole (compound 2). 2-[(diphenylmethyl) oxy] ethanol (compound 3), 2-[(triphenylmethyl) oxy] ethanol (compound 4), 2-[(diphenylmethyl) amino] ethanol (compound 5), 2- [ (Triphenylmethyl) amino] ethanol (compound 6), 2-[(diphenylmethyl) oxy] ethylamine (compound 7), 2-[(triphenylmethyl) oxy] ethylamine (compound 8), 1- (diphenylmethyl) Pyrrolidine (Compound 9), 1- (Triphenylmethyl) pyrrolidine (Compound 10), 1- (Diphenylmethyl) piperidine (Compound 1) ), 1- (triphenylmethyl) piperidine (Compound 12) and / or their pharmacologically acceptable salts are suitably be exemplified. Such a compound exhibits an excellent whitening effect by being contained in the composition together with a compound represented by the general formula (2) described later, its isomer and / or a pharmacologically acceptable salt thereof. To do. Further, such compounds and / or pharmacologically acceptable salts thereof have excellent safety and stability, and can be contained stably and safely in the composition.

Here, the compound represented by the general formula (3) will be described. In the formula, A is the aryl.
Le is, represents di arylmethyl group or tri arylmethyl group selected independently from the group consisting of an aryl group having unsubstituted or substituted group, B is the binding site of A is a hetero atom, a hydrogen atom, It represents a cyclic or acyclic aliphatic or aromatic hydrocarbon group in which a hydrogen atom or a carbon atom may be substituted with a hetero atom. Relates to an aryl group, an unsubstituted or substituted group represented by the A, to name preferred compounds are specific examples, a phenyl group, a naphthyl group, a biphenyl group, methylphenyl group, ethylphenyl group, propylphenyl group, a methoxyphenyl group, Ethoxyphenyl group, propyloxyphenyl group, hydroxyphenyl group, aminophenyl group, N-methylaminophenyl group, N-ethylaminophenyl group, N-propylaminophenyl group, N, N-dimethylaminophenyl group, N, N -Diethylaminophenyl group, N, N-dipropylaminophenyl group, fluorophenyl group, difluorophenyl group, trifluoromethylphenyl group, chlorophenyl group, bromophenyl group, methylnaphthyl group, ethylnaphthyl group, propylnaphthyl group, methoxynaphthyl group Group, ethoxynaphthyl Group, propyloxynaphthyl group, hydroxynaphthyl group, aminonaphthyl group, N-methylaminonaphthyl group, N-ethylaminonaphthyl group, N-propylaminonaphthyl group, N, N-dimethylaminonaphthyl group, N, N-diethylamino A naphthyl group, an N, N-dipropylaminonaphthyl group, a fluoronaphthyl group, a difluoronaphthyl group, a trifluoromethylnaphthyl group, a chloronaphthyl group, a bromonaphthyl group, and the like can be preferably exemplified, and more preferably, a phenyl group, methylphenyl Preferred examples include a group, a methoxyphenyl group, and a naphthyl group. B represents a cyclic atom or a non-cyclic aliphatic or aromatic hydrocarbon group in which the bonding site to A is a hetero atom, a hydrogen atom, a hydrogen atom or a carbon atom optionally substituted with a hetero atom; For example, a mono- or di-substituted amino group, a hydrogen atom or a carbon having a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms in which a hydroxyl group, an amino group, a hydrogen atom or a carbon atom may be substituted by a hetero atom An alkyloxy group having a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms in which an atom may be substituted by a hetero atom, a hydrogen atom or a carbon atom having 1 to 8 carbon atoms in which the carbon atom may be substituted by a hetero atom, More preferably, a mono- or dialkyl-substituted amino group having an aliphatic hydrocarbon group having 1 to 4 carbon atoms, a hydrogen atom or a carbon atom having 1 to 8 carbon atoms in which the carbon atom may be substituted with a hetero atom, more preferably. Is a mono or di having an alkyloxy group having a C 1-4 aliphatic hydrocarbon group, a hydrogen atom or a C 3-8 aromatic hydrocarbon group in which the carbon atom may be substituted by a hetero atom. A substituted amino group, a hydrogen atom or an alkyloxy group having an aromatic hydrocarbon group having 3 to 8 carbon atoms which may be substituted with a hetero atom. The B is a hydrogen atom or a disubstituted amino group having a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms in which a carbon atom may be substituted with a heteroatom, or a hydrogen atom or a carbon atom is a heteroatom. In the case of representing a disubstituted amino group having an aromatic hydrocarbon group having 3 to 8 carbon atoms which may be substituted by, bonding of A and B to a ring of a cyclic aliphatic hydrocarbon group or an aromatic group The structure including the hetero atom of the site is also included.
Among the compounds represented by the general formula (3), more preferred are the compounds represented by the general formulas (4) to (7) and / or pharmacologically acceptable salts thereof. Specific examples of preferable compounds are 1- (diphenylmethyl) imidazole (compound 1), 1- (triphenylmethyl) imidazole (compound 2), 2-[(diphenylmethyl) oxy] ethanol. (Compound 3), 2-[(Triphenylmethyl) oxy] ethanol (Compound 4), 2-[(Diphenylmethyl) amino] ethanol (Compound 5), 2-[(Triphenylmethyl) amino] ethanol (Compound 6) ), 2-[(diphenylmethyl) oxy] ethylamine (compound 7), 2-[(triphenylmethyl) oxy] ethylamine (compound 8), 1- (diphenylmethyl) L) pyrrolidine (compound 9), 1- (triphenylmethyl) pyrrolidine (compound 10), 1- (diphenylmethyl) piperidine (compound 11), 1- (triphenylmethyl) piperidine (compound 12) and / or their Preferred examples include pharmacologically acceptable salts. Such a compound exhibits an excellent whitening effect by being contained in the composition together with a compound represented by the general formula (2) described later, its isomer and / or a pharmacologically acceptable salt thereof. To do. Further, such compounds and / or pharmacologically acceptable salts thereof have excellent safety and stability, and can be contained stably and safely in the composition.

Here, the compound represented by the general formula (4) will be described. In the formula, A represents the aryl.
Le is, represents di arylmethyl group or triaryl over Rumechiru groups each independently selected from the group consisting of an aryl group having unsubstituted or substituted group, X represents a nitrogen atom, R ₄ is a hydrogen atom, a hydrogen atom Or a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms in which a carbon atom may be substituted with a hetero atom, and the ring of the cyclic aliphatic hydrocarbon group is again connected to X at the other end of R ₄ A ring formed by bonding is also included. An unsubstituted or substituted aryl group in A
If specifically exemplified relates, preferably those in, a phenyl group, a naphthyl group, a biphenyl group, methylphenyl group, ethylphenyl group, propylphenyl group, methoxyphenyl group, ethoxyphenyl group, propyloxyphenyl group, hydroxyphenyl group Aminophenyl group, N-methylaminophenyl group, N-ethylaminophenyl group, N-propylaminophenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, N, N-dipropylamino Phenyl group, fluorophenyl group, difluorophenyl group, trifluoromethylphenyl group, chlorophenyl group, bromophenyl group, methylnaphthyl group, ethylnaphthyl group, propylnaphthyl group, methoxynaphthyl group, ethoxynaphthyl group, propyloxynaphthyl group, hydroxy Nafti Group, aminonaphthyl group, N-methylaminonaphthyl group, N-ethylaminonaphthyl group, N-propylaminonaphthyl group, N, N-dimethylaminonaphthyl group, N, N-diethylaminonaphthyl group, N, N-dipropyl Amino naphthyl group, fluoro naphthyl group, difluoro naphthyl group, trifluoromethyl naphthyl group, chloro naphthyl group, bromo naphthyl group and the like can be preferably exemplified, more preferably phenyl group, methyl phenyl group, methoxyphenyl group, naphthyl group, etc. Can be suitably exemplified. X represents a nitrogen atom.
R ₄ represents a C 3-8 cyclic aliphatic hydrocarbon group in which a hydrogen atom, a hydrogen atom, or a carbon atom may be substituted with a hetero atom, and the ring of the cyclic aliphatic hydrocarbon group is R Also included is a ring formed by bonding the other end of ₁ to X again. Specific examples of preferred R ₄ include N-cyclopropyl group, N-cyclobutyl group, N-cyclopentyl group, N-cyclohexyl group, N-cycloheptyl group, N-cyclooctyl group, and succinimide group. Etc. can be suitably exemplified. Examples of the substituent having a ring structure in which the ring of the cyclic aliphatic hydrocarbon group is formed by rebonding the other end of R ₄ to X (including the X moiety) include a pyrrolidino group, methylpyrrolidino Group, ethylpyrrolidino group, propylpyrrolidino group, methoxypyrrolidino group, ethoxypyrrolidino group, propyloxypyrrolidino group, hydroxypyrrolidino group, aminopyrrolidino group, N-methylpyrrolidino group, N-ethylpyrrolidino group Group, N-propylpyrrolidino group, N, N-dimethylpyrrolidino group, N, N-diethylpyrrolidino group, N, N-dipropylpyrrolidino group, fluoropyrrolidino group, difluoropyrrolidino group, trifluoromethyl Pyrrolidino, chloropyrrolidino, piperidyl, methylpiperidyl, ethylpiperidyl, propylpiperidyl, methoxypiperidyl Group, ethoxy piperidyl group, propyloxy piperidyl group, hydroxy-piperidyl group, an amino piperidyl group, N-
Methylpiperidyl group, N-ethylpiperidyl group, N-propylpiperidyl group, N, N-dimethylpiperidyl group, N, N-diethylpiperidyl group, N, N-dipropylpiperidyl group, fluoropiperidyl group, difluoropiperidyl group, tri Fluoromethylpiperidyl group, chloropiperidyl group, piperazyl group, methylpiperazyl group, ethylpiperazyl group, propylpiperazyl group, methoxypiperazyl group, ethoxypiperazyl group, propyloxypiperazyl group, hydroxypiperazyl group, aminopiperazyl group, N-methylpiperazyl group Group, N-ethylpiperazyl group, N-propylpiperazyl group, N, N-dimethylpiperazyl group, N, N-diethylpiperazyl group, N, N-dipropylpiperazyl group, fluoropiperazyl group, difluoropiperazyl group Group, trifluoromethylpipera Group, chloropiperazyl group, morpholino group, methylmorpholino group, ethylmorpholino group, propylmorpholino group, methoxymorpholino group, ethoxymorpholino group, propyloxymorpholino group, hydroxymorpholino group, aminomorpholino group, N-methylmorpholino group, N- Ethylmorpholino group, N-propylmorpholino group, N, N-dimethylmorpholino group, N, N-diethylmorpholino group, N, N-dipropylmorpholino group, fluoromorpholino group, difluoromorpholino group, trifluoromethylmorpholino group, chloro morpholino group and the like can be preferably exemplified, and more preferably, pyrrolidino, piperidyl group, piperazyl group, a morpholino group and the like can be preferably exemplified, and more preferably, pyrrolidino, piperidyl group, model Ruhorino group suitably be exemplified.
Specific examples of preferable compounds among the compounds represented by the general formula (4) are N- (
Diphenylmethyl) succinimide, N-[(methylphenyl) phenylmethyl] succinimide, N- [bis (methylphenyl) methyl] succinimide, N-[(ethylphenyl)
Phenylmethyl] succinimide, N- [bis (ethylphenyl) methyl] succinimide, N-[(methoxyphenyl) phenylmethyl] succinimide, N- [bis (methoxyphenyl) methyl] succinimide, N-[(ethoxyphenyl) phenylmethyl ] Succinimide, N- [bis (ethoxyphenyl) methyl] succinimide, N-[(fluorophenyl) phenylmethyl] succinimide, N- [bis (fluorophenyl) methyl] succinimide, N- (triphenylmethyl) succinimide, N- [Diphenyl (methylphenyl) methyl] succinimide, N- [bis (methylphenyl) phenylmethyl] succinimide, N- [tris (methylphenyl) methyl] succinimide, N- [diphenyl (ethylphenyl) methyl] succinimide, N- [ Bis (ethylpheny L) phenylmethyl] succinimide, N- [tris (ethylphenyl) methyl] succinimide, N- [diphenyl (methoxyphenyl) methyl] succinimide, N- [bis (methoxyphenyl) phenylmethyl] succinimide, N- [tris (methoxy) Phenyl) methyl] succinimide, N- [diphenyl (ethoxyphenyl) methyl] succinimide, N- [bis (ethoxyphenyl) phenylmethyl] succinimide, N- [tris (ethoxyphenyl) methyl] succinimide, N- [diphenyl (fluorophenyl) ) Methyl] succinimide, N- [bis (fluorophenyl) phenylmethyl] succinimide, N- [tris (fluorophenyl) methyl] succinimide, 1- (diphenylmethyl) pyrrolidine (compound 9), 1-[(methylphenyl) phenylmeth ] Pyrrolidine, 1- [bis (methylphenyl) methyl] pyrrolidine, 1-[(ethylphenyl) phenylmethyl] pyrrolidine, 1- [bis (ethylphenyl) methyl] pyrrolidine, 1-[(methoxyphenyl) phenylmethyl] pyrrolidine 1- [bis (methoxyphenyl) methyl] pyrrolidine, 1-[(ethylphenyl) phenylmethyl] pyrrolidine, 1- [bis (ethylphenyl) methyl] pyrrolidine, 1-[(hydroxyphenyl) phenylmethyl] pyrrolidine, 1 -[Bis (hydroxyphenyl) methyl] pyrrolidine, 1-[(aminophenyl) phenylmethyl] pyrrolidine, 1- [bis (aminophenyl) methyl] pyrrolidine, 1-[(fluorophenyl) phenylmethyl] pyrrolidine, 1- [ Bis (fluorophenyl) methyl] pyrrolidine, 1-[(chlorophenyl) Enylmethyl] pyrrolidine, 1- [bis (chlorophenyl) methyl] pyrrolidine, 1- (triphenylmethyl) pyrrolidine (compound 10), 1- [diphenyl (methylphenyl) methyl] pyrrolidine, 1- [bis (methylphenyl) phenylmethyl ] Pyrrolidine, 1- [tris (methylphenyl) methyl] pyrrolidine, 1- [diphenyl (ethylphenyl) methyl] pyrrolidine, 1- [bis (ethylphenyl) phenylmethyl] pyrrolidine, 1- [tris (ethylphenyl) methyl] Pyrrolidine, 1- [diphenyl (methoxyphenyl) methyl] pyrrolidine, 1- [bis (methoxyphenyl) phenylmethyl] pyrrolidine, 1- [tris (methoxyphenyl) methyl] pyrrolidine, 1- [diphenyl (ethoxyphenyl) methyl] pyrrolidine , 1- [bis (ethoxyphenyl) Phenylmethyl] pyrrolidine, 1- [tris (ethoxyphenyl) methyl] pyrrolidine, 1- [diphenyl (hydroxyphenyl) methyl] pyrrolidine, 1- [bis (hydroxyphenyl) phenylmethyl] pyrrolidine, 1- [tris (hydroxyphenyl) Methyl] pyrrolidine, 1-[(aminophenyl) diphenylmethyl] pyrrolidine, 1- [bis (aminophenyl) phenylmethyl] pyrrolidine, 1- [tris (aminophenyl) methyl] pyrrolidine, 1- [diphenyl (fluorophenyl) methyl ] Pyrrolidine, 1- [bis (fluorophenyl) phenylmethyl] pyrrolidine, 1- [tris (fluorophenyl) methyl] pyrrolidine, 1- (diphenylmethyl) piperidine (compound 11), 1-[(methylphenyl) phenylmethyl] Piperidine, 1- [bis (methyl Phenyl) methyl] piperidine, 1-[(ethylphenyl) phenylmethyl] piperidine, 1- [bis (ethylphenyl) methyl] piperidine, 1-[(methoxyphenyl) phenylmethyl] piperidine, 1- [bis (methoxyphenyl) methyl] piperidine, 1-[(ethylphenyl) phenylmethyl] piperidine, 1- [bis (ethylphenyl) methyl] piperidine, 1-[(hydroxyphenyl) phenyl Methyl] piperidine, 1- [bis (hydroxyphenyl) methyl] piperidine, 1-[(aminophenyl) phenylmethyl] piperidine, 1- [bis (aminophenyl) methyl] piperidine, 1-[(fluorophenyl) phenylmethyl] Piperidine, 1- [bis (fluorophenyl) methyl] piperidine, 1-[(chlorophenyl) phenylmethyl] piperidine, 1- [ (Chlorophenyl) methyl] piperidine, 1- (triphenylmethyl) piperidine (compound 12), 1- [diphenyl (methylphenyl) methyl] piperidine, 1- [bis (methylphenyl) phenylmethyl] piperidine, 1- [tris (Methylphenyl) methyl] piperidine, 1- [diphenyl (ethylphenyl) methyl] piperidine, 1- [bis (ethylphenyl) phenylmethyl] piperidine, 1- [tris (ethylphenyl) methyl] piperidine, 1- [diphenyl ( Methoxyphenyl) methyl] piperidine, 1- [bis (methoxyphenyl) phenylmethyl] piperidine, 1- [tris (methoxyphenyl) methyl] piperidine, 1- [diphenyl (ethoxyphenyl) methyl] piperidine, 1- [bis (ethoxy) Phenyl) phenylmethyl] piperidine, 1- [Tris (ethoxyphenyl) methyl] piperidine, 1- [diphenyl (hydroxyphenyl) methyl] piperidine, 1- [bis (hydroxyphenyl) phenylmethyl] piperidine, 1- [tris (hydroxyphenyl) methyl] piperidine, 1- [ (Aminophenyl) diphenylmethyl] piperidine, 1- [bis (aminophenyl) phenylmethyl] piperidine, 1- [tris (aminophenyl) methyl] piperidine, 1- [diphenyl (fluorophenyl) methyl] piperidine, 1- [bis (Fluorophenyl) phenylmethyl] piperidine, 1- [tris (fluorophenyl) methyl] piperidine, 1- (diphenylmethyl) morpholine, 1-[(methylphenyl) phenylmethyl] morpholine, 1- [bis (methylphenyl) methyl ] Morpholine, 1-[(ethyl phen Nyl) phenylmethyl] morpholine, 1- [bis (ethylphenyl) methyl] morpholine, 1-[(methoxyphenyl) phenylmethyl] morpholine, 1- [bis (methoxyphenyl) methyl] morpholine, 1-[(ethylphenyl) Phenylmethyl] morpholine, 1- [bis (ethylphenyl) methyl] morpholine, 1-[(hydroxyphenyl) phenylmethyl] morpholine, 1- [bis (hydroxyphenyl) methyl] morpholine, 1-[(aminophenyl) phenylmethyl ] Morpholine, 1- [bis (aminophenyl) methyl] morpholine, 1-[(fluorophenyl) phenylmethyl] morpholine, 1- [bis (fluorophenyl) methyl] morpholine, 1-[(chlorophenyl) phenylmethyl] morpholine, 1- [bis (chlorophenyl) methyl] morpholine, 1- Triphenylmethyl) morpholine, 1- [diphenyl (methylphenyl) methyl] morpholine, 1- [bis (methylphenyl) phenylmethyl] morpholine, 1- [tris (methylphenyl) methyl] morpholine, 1- [diphenyl (ethylphenyl) ) Methyl] morpholine, 1- [bis (ethylphenyl) phenylmethyl] morpholine, 1- [tris (ethylphenyl) methyl] morpholine, 1- [diphenyl (methoxyphenyl) methyl] morpholine, 1- [bis (methoxyphenyl) Phenylmethyl] morpholine, 1- [tris (methoxyphenyl) methyl] morpholine, 1- [diphenyl (ethoxyphenyl) methyl] morpholine, 1- [bis (ethoxyphenyl) phenylmethyl] morpholine, 1- [tris (ethoxyphenyl) Methyl] morpholine, 1- [diphenyl] (Hydroxyphenyl) methyl] morpholine, 1- [bis (hydroxyphenyl) phenylmethyl] morpholine, 1- [tris (hydroxyphenyl) methyl] morpholine, 1-[(aminophenyl) diphenylmethyl] morpholine, 1- [bis ( Aminophenyl) phenylmethyl] morpholine, 1- [tris (aminophenyl) methyl] morpholine, 1- [diphenyl (fluorophenyl) methyl] morpholine, 1- [bis (fluorophenyl) phenylmethyl] morpholine, 1- [tris ( Fluorophenyl) methyl] morpholine and / or a pharmacologically acceptable salt thereof can be suitably exemplified, and more preferable examples include 1- (diphenylmethyl) pyrrolidine (Compound 9), 1- (triphenylmethyl) Pyrrolidine (compound 10), 1- (diphenylmethyl) Preferred examples include piperidine (compound 11), 1- (triphenylmethyl) piperidine (compound 12) and / or pharmacologically acceptable salts thereof. Such a compound exhibits an excellent whitening effect by being contained in the composition together with a compound represented by the general formula (2) described later, its isomer and / or a pharmacologically acceptable salt thereof. To do. Further, such compounds and / or pharmacologically acceptable salts thereof have excellent safety and stability, and can be contained stably and safely in the composition.

Here, the compound represented by the general formula (5) will be described. In the formula, A is the aryl.
Le is, represents di arylmethyl group or tri arylmethyl group each independently selected from the group consisting of an aryl group having unsubstituted or substituted group, X represents an oxygen atom, R ₅ is a hydrogen atom or a carbon atom Represents an aliphatic hydrocarbon having 1 to 8 carbon atoms which may be substituted with a hetero atom. Relates to an aryl group, an unsubstituted or substituted group of the A, if specifically exemplified preferred, a phenyl group, a naphthyl group, a biphenyl group, methylphenyl group, ethylphenyl group, propylphenyl group, a methoxyphenyl group ethoxy Phenyl group, propyloxyphenyl group, hydroxyphenyl group, aminophenyl group, N-methylaminophenyl group, N-ethylaminophenyl group, N-propylaminophenyl group, N, N-dimethylaminophenyl group, N, N- Diethylaminophenyl group, N, N-dipropylaminophenyl group, fluorophenyl group, difluorophenyl group, trifluoromethylphenyl group, chlorophenyl group, bromophenyl group, methylnaphthyl group, ethylnaphthyl group, propylnaphthyl group, methoxynaphthyl group Ethoxynaphthyl group, pro Pyroxynaphthyl group, hydroxynaphthyl group, aminonaphthyl group, N-methylaminonaphthyl group, N-ethylaminonaphthyl group, N-propylaminonaphthyl group, N, N-dimethylaminonaphthyl group, N, N-diethylaminonaphthyl group N, N-dipropylaminonaphthyl group, fluoronaphthyl group, difluoronaphthyl group, trifluoromethylnaphthyl group, chloronaphthyl group, bromonaphthyl group and the like can be suitably exemplified, more preferably phenyl group, naphthyl group, methyl Preferred examples include a phenyl group and a methoxyphenyl group.
X represents an oxygen atom. R ₅ represents an aliphatic hydrocarbon having 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms in which a hydrogen atom or a carbon atom may be substituted with a hetero atom. Methyl group, hydroxyethyl group, hydroxypropyl group, hydroxybutyl group, hydroxypentyl group, hydroxyhexyl group, hydroxyheptyl group, hydroxyoctyl group, methoxymethyl group, methoxyethyl group, methoxypropyl group, methoxybutyl group, methoxypentyl group Methoxyhexyl group, methoxyheptyl group, methoxyoctyl group, dihydroxymethyl group, dihydroxyethyl group, dihydroxypropyl group, dihydroxybutyl group, dihydroxypentyl group, dihydroxyhexyl group, dihydroxyheptyl group, dihydroxyoctyl group, amino Methyl, aminoethyl group, aminopropyl group, aminobutyl group, aminopentyl group, an aminohexyl group, an amino heptyl group, an amino octyl be preferably exemplified, yo RiYoshimi Mashiku is hydroxyethyl group, aminoethyl Preferred examples include a group and a methoxyethyl group.
Specific examples of preferable compounds among the compounds represented by the general formula (5) include 1- (diphenylmethyloxy) methanol , 3- (diphenylmethyloxy) propanol and 4- (diphenylmethyloxy) 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 -(Trifeni Methyloxy) octanol, 1- (diphenylmethyl) methyl amine, 3- (diphenylmethyl) propyl amine amine, 4- (diphenylmethyl oxy) butylamine, 5- (diphenylmethyl oxy) pentylamine, 6- (diphenylmethyl Oxy) 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- (diphenylmethyl amino) methanol, 3- (diphenylmethylamino) propanol, 4- (diphenylmethyl amino) butanol, 5- (diphenylmethyl amino) pentanol, 6- (diphenylmethyl amino) hexanol, 7- (diphenylmethylamino) heptanol , 8- (diphenylmethylamino) octanol , 1- (triphenylmethylamino) methanol , 3- (triphenylmethylamino) propanol , 4- (triphenylmethylamino) butanol , 5- (triphenylmethyl amino) pentanol, 6- (triphenylmethyl amino) hexanol, 7- (triphenylmethyl amino) heptanol, 8- (triphenylmethyl amino) octanol, 2 - [(diphenylmethyl) Carboxymethyl] ethanol (Compound 3), 2 - [(methylphenyl) phenyl methyloxy] ethanol, 2- [bis (methylphenyl) methyl oxy] ethanol, 2 - [(ethylphenyl) phenyl methyloxy] 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) phenyl Methyloxy] ethanol , 2-[(bis (aminopheny L) methyloxy] ethanol , 2-[(fluorophenyl) phenylmethyloxy] ethanol , 2-[(bis (fluorophenyl) methyloxy] ethanol , 2-[(triphenylmethyl) oxy] ethanol (compound 4), 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) ) phenylmethyl oxy] ethanol, 2- [DOO Scan (Methoxyphenyl) methyloxy] ethanol, 2- [diphenyl (ethoxy) methyl oxy] ethanol, 2- [bis (ethoxy) phenylmethyl oxy] 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 (fluorophenyl) methyloxy] ethanol , 2- [bis (fluorophenyl) ) Sulfonyl methyloxy] ethanol, 2- [tris (fluorophenyl) methyloxy] ethanol, 2 - [(diphenylmethyl) oxy] ethylamine (Compound 7), 2 - [(methylphenyl) phenyl methyloxy] ethylamine, 2- [ Bis (methylphenyl) methyloxy] 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) phenylmethyl Oxy] 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 (compound 8), 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 (methoxyphenyl) 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) phenyl Phenylmethyloxy] ethylamine, 2- [tris (aminophenyl) methyloxy] ethylamine, 2- [diphenyl (fluorophenyl) methyloxy] ethylamine, 2- [bis (fluorophenyl) phenylmethyloxy] ethylamine, 2- [tris (Fluorophenyl) methyloxy] ethylamine and / or a pharmacologically acceptable salt thereof can be suitably exemplified, and more preferably 2-[(diphenylmethyl) oxy] ethanol (Compound 3), 2-[( Triphenylmethyl) oxy] ethanol (compound 4), 2-[(diphenylmethyl) oxy] ethylamine (compound 7), 2-[(triphenylmethyl) oxy] ethylamine (compound 8) and / or their pharmacological properties Suitable examples of the salts are acceptable. Such a compound exhibits an excellent whitening effect by being contained in the composition together with a compound represented by the general formula (2) described later, its isomer and / or a pharmacologically acceptable salt thereof. To do. Further, such compounds and / or pharmacologically acceptable salts thereof have excellent safety and stability, and can be contained stably and safely in the composition.

Here, the compound represented by the general formula (6) will be described. In the formula, A is the aryl.
Le is, represents di arylmethyl group or tri arylmethyl group selected independently from the group consisting of an aryl group having unsubstituted or substituted group, X represents a nitrogen atom, R ₆ and R ₇ are each independently Represents a C 1-8 aliphatic hydrocarbon in which a hydrogen atom, a hydrogen atom or a carbon atom may be substituted with a hetero atom. Relates to an aryl group, an unsubstituted or substituted group in the A, if specifically exemplified preferred, a phenyl group, a naphthyl group, a biphenyl group, methylphenyl group, ethylphenyl group, propylphenyl group, a methoxyphenyl group, Ethoxyphenyl group, propyloxyphenyl group, hydroxyphenyl group, aminophenyl group, N-methylaminophenyl group, N-ethylaminophenyl group, N-propylaminophenyl group, N, N-dimethylaminophenyl group, N, N -Diethylaminophenyl group, N, N-dipropylaminophenyl group, fluorophenyl group, difluorophenyl group, trifluoromethylphenyl group, chlorophenyl group, bromophenyl group, methylnaphthyl group, ethylnaphthyl group, propylnaphthyl group, methoxynaphthyl group Group, ethoxynaphthyl Group, propyloxynaphthyl group, hydroxynaphthyl group, aminonaphthyl group, N-methylaminonaphthyl group, N-ethylaminonaphthyl group, N-propylaminonaphthyl group, N, N-dimethylaminonaphthyl group, N, N-diethylamino A naphthyl group, an N, N-dipropylaminonaphthyl group, a fluoronaphthyl group, a difluoronaphthyl group, a trifluoromethylnaphthyl group, a chloronaphthyl group, a bromonaphthyl group, and the like can be suitably exemplified, and more preferably a phenyl group, a naphthyl group , Methylphenyl group, methoxyphenyl group and the like can be preferably exemplified. X represents a nitrogen atom. R ₆ and R ₇ each independently represent a hydrogen atom, a hydrogen atom or an aliphatic hydrocarbon group having 1 to 8 carbon atoms in which a carbon atom may be substituted with a hetero atom, and R ₆ and R ₇ are preferred. Specific examples are hydrogen atom, hydroxymethyl group, hydroxyethyl group, hydroxypropyl group, hydroxybutyl group, hydroxypentyl group, hydroxyhexyl group, hydroxyheptyl group, hydroxyoctyl group, methoxymethyl group, methoxyethyl. Group, methoxypropyl group, methoxybutyl group, methoxypentyl group, methoxyhexyl group, methoxyheptyl group, methoxyoctyl group, dihydroxymethyl group, dihydroxyethyl group, dihydroxypropyl group, dihydroxybutyl group, dihydroxypentyl group, dihydroxyhexyl group, Dihydroxy Heptyl group, dihydroxy-octyl group, aminomethyl group, aminoethyl group, aminopropyl group, aminobutyl group, aminopentyl group, an aminohexyl group, an amino heptyl group, an amino octyl be preferably exemplified, yo RiYoshimi Mashiku Suitable examples include hydroxyethyl group, aminoethyl group, and methoxyethyl group.
Of the compounds represented by the general formula (6), specific examples of preferred compounds include 2-[(diphenylmethyl) amino] ethanol (compound 5), 2-[(methylphenyl) phenylmethylamino]. Ethanol , 2- [bis (methylphenyl) methylamino] ethanol
Le, 2 - [(ethylphenyl) phenyl methylamino] ethanol, 2 - [(bis (ethylphenyl) methylamino] ethanol, 2 - [(methoxyphenyl) phenylmethyl amino] 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
Le, 2 - [(bis (fluorophenyl) methylamino] ethanol, 2 - [(triphenylmethyl) amino] ethanol (Compound 6), 2- [diphenyl (methyl phenyl) methylamino] ethanol, 2- [bis ( Methylphenyl) phenylmethylamino] ethanol , 2- [tris (methylphenyl) methylamino] ethanol , 2- [diphenyl (ethylphenyl) methylamino] ethanol , 2- [bis (ethylphenyl) phenylmethylamino] 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 (hydroxyphenyl) phenylmethylamino ] Eta
Nord, 2- [tris (hydroxymethyl) methyl amino] ethanol, 2 - [(aminophenyl) diphenylmethyl amino] ethanol, 2- [bis (aminophenyl) phenyl methyl amino] ethanol, 2- [tris (aminophenyl) Methylamino] ethanol
Le, 2- [diphenyl (fluorophenyl) methylamino] ethanol, 2- [bis (fluorophenyl) phenyl methylamino] ethanol, 2- [tris (fluorophenyl)
Methylamino] ethanol and / or a pharmacologically acceptable salt thereof can be suitably exemplified. More preferably, 2-[(diphenylmethyl) amino] ethanol (compound 5), 2-[(triphenylmethyl) Amino] ethanol (compound 6) and / or a pharmacologically acceptable salt thereof can be preferably exemplified. Such a compound exhibits an excellent whitening effect by being contained in the composition together with a compound represented by the general formula (2) described later, its isomer and / or a pharmacologically acceptable salt thereof. To do. Further, such compounds and / or pharmacologically acceptable salts thereof have excellent safety and stability, and can be contained stably and safely in the composition.

Here, the compound represented by the general formula (7) will be described. In the formula, A represents the aryl.
Le is, diallyl each independently selected from the group consisting of an aryl group having a substituted or unsubstituted group - represents a Rumechiru group or tri arylmethyl group, X represents a nitrogen atom, R ₈ represents a hydrogen atom or a carbon atom Represents an aromatic hydrocarbon group having 3 to 8 carbon atoms which may be substituted with a hetero atom, and the aromatic hydrocarbon group also includes a group in which X is present in the ring. As a specific example relates to an aryl group, an unsubstituted or substituted group in the A, a phenyl group, a naphthyl group, a biphenyl group, methylphenyl group, ethylphenyl group, propylphenyl group, methoxyphenyl group, ethoxyphenyl group, propyl Oxyphenyl group, hydroxyphenyl group, aminophenyl group, N-methylaminophenyl group, N-ethylaminophenyl group, N-propylaminophenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, N, N-dipropylaminophenyl group, fluorophenyl group, difluorophenyl group, trifluoromethylphenyl group, chlorophenyl group, bromophenyl group, methylnaphthyl group, ethylnaphthyl group, propylnaphthyl group, methoxynaphthyl group, ethoxynaphthyl group , Propyloxy Naphthyl group, hydroxynaphthyl group, aminonaphthyl group, N-methylaminonaphthyl group, N-ethylaminonaphthyl group, N-propylaminonaphthyl group, N, N-dimethylaminonaphthyl group, N, N-diethylaminonaphthyl group, N , N-dipropylaminonaphthyl group, fluoronaphthyl group, difluoronaphthyl group, trifluoromethylnaphthyl group, chloronaphthyl group, bromonaphthyl group and the like can be suitably exemplified, more preferably phenyl group, naphthyl group, methylphenyl group A methoxyphenyl group can be preferably exemplified. X represents a nitrogen atom. R ₈ represents a hydrogen atom or an aromatic hydrocarbon group having 3 to 8 carbon atoms in which a carbon atom may be substituted with a hetero atom, and the aromatic hydrocarbon group is a group in which X is present in the ring. Represents a group which also includes Specific examples of the aromatic hydrocarbon group include a phenyl group, a pyridyl group, an imidazolyl group, a furyl group, a thienyl group, and the like, and more preferably an imidazolyl group. Specific examples of the compound represented by the general formula (7) include 1- (diphenylmethyl) imidazole (compound 1), 1-[(methylphenyl) methyl] imidazole , 1- [bis (methylphenyl) methyl. ] Imidazole , 1-[(ethylphenyl) methyl] imidazole , 1- [bis (ethylphenyl) methyl] imidazole , 1-[(methoxyphenyl) methyl] imidazole , 1- [bis (methoxyphenyl) methyl] imidazole , 1 -[(Ethoxyphenyl) methyl] imidazole , 1- [bis (ethoxyphenyl) methyl] imidazole , 1-[(hydroxyphenyl) methyl] imidazole , 1- [bis (hydroxyphenyl) methyl] imidazole , 1-[(amino phenyl) methyl] imidazole, 1- [bis (aminophenyl) methyl] imidazole, - [(fluorophenyl) -methyl] imidazole, 1- [bis (fluorophenyl) -methyl] imidazole, 1- (triphenylmethyl) imidazole (Compound 2), 1- [diphenyl (methyl phenyl) methyl] imidazole, l- [ Bis (methylphenyl) phenylmethyl] imidazole , 1- [tris (methylphenyl) methyl] imidazole , 1- [diphenyl (ethylphenyl) methyl] imidazole , 1- [bis (ethylphenyl) phenylmethyl] imidazole , 1- [ Tris (ethylphenyl) methyl] imidazole , 1- [diphenyl (methoxyphenyl) methyl] imidazole , 1- [bis (methoxyphenyl) phenylmethyl] imidazole , 1- [tris (methoxyphenyl) methyl] imidazole , 1- [diphenyl (Ethoxyphenyl) methyl ] Imidazole , 1- [bis (methoxyphenyl) phenylmethyl] imidazole , 1- [tris (ethoxyphenyl) methyl] imidazole , 1- [diphenyl (hydroxyphenyl) methyl] imidazole , 1- [bis (hydroxyphenyl) phenylmethyl ] Imidazole , 1- [tris (hydroxyphenyl) methyl] imidazole , 1-[(aminophenyl) diphenylmethyl] imidazole , 1- [bis (aminophenyl) phenylmethyl] imidazole , 1- [tris (aminophenyl) methyl] Imidazole , 1- [diphenyl (fluorophenyl) methyl] imidazole , 1- [bis (fluorophenyl) phenylmethyl] imidazole , 1- [tris (fluorophenyl) methyl] imidazole and / or their pharmacologically acceptable Salt is a good example Years, more preferably, 1- (diphenylmethyl) imidazole (Compound 1), 1- (triphenylmethyl) imidazole (Compound 2) and / or their pharmacologically acceptable salts are suitably be exemplified. Such a compound exhibits an excellent whitening effect by being contained in the composition together with a compound represented by the general formula (2) described later, its isomer and / or a pharmacologically acceptable salt thereof. To do. Further, such compounds and / or pharmacologically acceptable salts thereof have excellent safety and stability, and can be contained stably and safely in the composition.

  In addition, the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof is a compound represented by the general formula (2) described below, an isomer thereof and / or a compound thereof. When included in the composition together with a pharmacologically acceptable salt, it has an excellent whitening effect, in particular, a preventive or ameliorating effect on pigmentation abnormalities caused by UV exposure, and also cell function inactivation of keratinocytes caused by melanin overproduction It is effective for the prevention or improvement of pigmentation involving crystallization. Such a pigmentation preventing or ameliorating action is a preventive or ameliorating action against pigmentation due to a melanin production inhibitory action of the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof. An additive or synergistic effect in preventing or ameliorating the pigmentation of the compound represented by the general formula (2) described later, its isomer and / or their pharmacologically acceptable salt, to the target site It is considered that the whitening action and the prevention or improvement action of pigmentation are enhanced by the pharmacokinetics such as the improvement of the delivery efficiency of the drug, the additive or synergistic action of the preparation.

The compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof can be synthesized according to the method shown below or with reference, using commercially available corresponding reagents as starting materials. Regarding the synthesis method of the compound represented by the general formula (1), it can be produced according to the synthesis method described in PCT / JP2009 / 071279 filed by the present applicant.
Such a compound can be used as it is in a composition together with a compound represented by the general formula (2) described later, its isomer and / or a pharmacologically acceptable salt thereof, thereby whitening, exposure to ultraviolet rays. It can also be used to enhance the effect of preventing or improving the pigmentation caused by glycine, 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 toluenesulfonate, organic acid salts such as benzenesulfonate, sodium salt, alkali metal, calcium salts, alkaline earth metals such as magnesium salt metal, triethylamine salt or potassium salt, triethanolamine salt, an ammonium salt, monoethanolamine Preferred examples include organic amine salts such as amine salts and piperidine salts, and basic amino acid salts such as lysine salts and arginine salts .

The compound represented by the general formula (1) of the present invention and / or a pharmacologically acceptable salt thereof is a compound represented by the general formula (2) described below, its isomers and / or them. It works with pharmacologically acceptable salts, prevents or ameliorates pigmentation due to UV exposure, etc., especially, pigmentation with irritable blemishes, dullness, and rough skin that involves keratinocyte cell function decline due to increased melanin production In order to exert an enhancement effect in the prevention or improvement action against abnormality, the total amount is 0.001% to 10% by mass, more preferably 0.01% to 5% by mass, and still more preferably, with respect to the total amount of the composition. It is preferable to contain 0.1 mass%-3 mass%. This resides may not exhibited the effect is too small or too large, the effect becomes plateau is because resides may impair the flexibility of the system.

<Production Example 1: Method for producing Compound 1 and Compound 2>
Compound 1 and Compound 2 were synthesized according to the method described in JP-A-53-16879. Compound 2 can also be purchased as a reagent from Wako Pure Chemical Industries, Ltd.

１−（ジフェニルメチル）イミダゾ−ル（化合物１）

1- (Diphenylmethyl) imidazole (Compound 1)

１−（トリフェニルメチル）イミダゾ−ル（化合物２）

1- (Triphenylmethyl) imidazole (Compound 2)

<Production Example 2: Production Method of Compound 3 and Compound 4>
Ethylene glycol (3.10 g, 49.9 mmol) (Wako Pure Chemical Industries, Ltd.) and triphenyl chloromethane (1.39 g, 49.9 mmol) (Wako Pure Chemical Industries, Ltd.) in pyridine (6 mL) (Wako Pure Chemical Dissolved in Kogyo Co., Ltd. ), heated to 45 ° C., and stirred for 2 hours. To the reaction mixture was poured the water (50mL), 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 evaporated under reduced pressure. The resulting crude was purified by silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.): methanol (Wako Pure Chemical Industries, Ltd.) = 9: 1) to give compound 4 (yield 0.37g
Yield 24%). Moreover, the compound 3 can be obtained by performing the same operation using diphenyl chloromethane instead of triphenyl chloromethane.

<Physical constant of compound 4>
mp. 103-106 ° C
¹ H-HMR (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] エタノール（化合物３）

2-[(Diphenylmethyl) oxy] ethanol (compound 3)

２−[（トリフェニルメチル）オキシ] エタノール（化合物４）

2-[(Triphenylmethyl) oxy] ethanol (compound 4)

<Production Example 3: Production Method of Compound 5 and Compound 6>
Triphenylchloromethane (1.00 g, 3.58 mmol) (Wako Pure Chemical Industries, Ltd.) and aminoethanol (2.00 g, 32.7 mmol) was dissolved in acetonitrile (5 mL),
Stir at room temperature overnight. Water (100 mL) was poured into the reaction solution, and the precipitate was suction filtered and dried. The solid was obtained ethanol (Wako Pure Chemical Industries, Ltd.) and Compound 6 by recrystallization with water mixed solvent system (Yield 0.43 g, 39% yield). Moreover, the compound 5 can be obtained by performing the same operation using diphenylchloromethane instead of triphenylchloromethane.

<Physical constant of compound 6>
mp. 94-97 ° C
¹ H-NMR ( DMSO-d ₆ ): 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] エタノール（化合物５）

2-[(Diphenylmethyl) amino] ethanol (Compound 5)

２−[（トリフェニルメチル）アミノ] エタノール（化合物６）

2-[(Triphenylmethyl) amino] ethanol (Compound 6)

<Production Example 4: Production Method of Compound 7 and Compound 8>
Triphenylchloromethane (1.00 g, 3.58 mmol) was dissolved in (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, 3N hydrochloric acid (Wako Pure Chemical Industries shares Association
Inc.) was added and stirred at room temperature for 15 minutes, filtered off with suction insolubles. Insoluble material was dissolved in a mixed solution of ethyl acetate (Wako Pure Chemical Industries, Ltd.) and saturated sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) aqueous solution, after shaking the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), suction filtered, and concentrated under reduced pressure, Compound 8 (Yield 0.31g
Yield 28%). Moreover, the compound 7 can be obtained by performing the same operation using diphenyl chloromethane instead of triphenyl chloromethane.

<Physical constant of compound 8>
mp. 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７）

2-[(Diphenylmethyl) oxy] ethylamine (Compound 7)

２−[（トリフェニルメチル）オキシ]エチルアミン（化合物８）

2-[(Triphenylmethyl) oxy] ethylamine (Compound 8)

<Production Example 5: Method for producing Compound 9>
Chlorodiphenylmethane (0.50 g, 2.47 mmol) (Wako Pure Chemical Industries, Ltd.), pyrrolidine (0.53 g, 7.45 mmol) (Tokyo Kasei) and potassium iodide (0.10 g, 0.60 mmol) (Wako Pure in addition the Chemical Industries, Ltd.) in acetonitrile (20mL) (Wako pure Chemical Industries, Ltd.), and the mixture was refluxed for 2 hours. After Ho却to room temperature, saturated sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) solution was added to the reaction solution, followed by extraction with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform (Wako Pure Chemical Industries, Ltd.): methanol (Wako Pure Chemical Industries, Ltd.) = 99: 1) to give Compound 9 (yield 0.36 g, yield 61% )

<Physical constant of compound 9>
mp . 6 9-72 ℃.
¹ H-NMR (CDCl ₃ ): δ 1.73-1.79 (m, 4H), 2.40-2.44 (m, 4H)
4.15 (s, 1H), 7.12-7.47 (m, 10H).
IR (cm ⁻¹ ): 2793, 1452, 703.

１−（ジフェニルメチル）ピロリジン（化合物９）

1- (Diphenylmethyl) pyrrolidine (Compound 9)

<Production Example 6: Method for producing Compound 10>
Pyrrolidine (0.26 g, 3.66 mmol) (Wako Pure Chemical Industries, Ltd.), triphenylchloromethane (1.02 g, 3.66 mmol) (Wako Pure Chemical Industries, Ltd.) and potassium carbonate (
0.51 g, 3.66 mmol) (Wako Pure Chemical Industries, Ltd.) was added in acetonitrile (30 mL) (Wako Pure Chemical Industries, Ltd.), and refluxed for 5 hours. To the reaction solution, a saturated sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) aqueous solution was added, and extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent n- hexane (Wako Pure Chemical Industries, Ltd.): ethyl acetate (Wako Pure Chemical Industries, Ltd.) = 9: 1) to give Compound 10 (Yield 0.45 g, yield 80%).

<Physical constant of compound 10>
mp. 127-129 ° C
¹ H-NMR (CDCl ₃ ): δ 1.53-1.65 (m, 4H), 2.00-2.30 (m, 4H)
7.11-7.28 (m, 5H), 7.48-7.52 (m, 10H).
IR (cm ^-1 ): 2961, 2819, 1486, 1448, 711.

１−（トリフェニルメチル）ピロリジン（化合物１０）

1- (Triphenylmethyl) pyrrolidine (Compound 10)

<Production Example 7: Production Method of Compound 11 and Compound 12>
Piperidine (1.50 g, 17.6 mmol) (Wako Pure Chemical Industries, Ltd.), triphenylchloromethane (5.40 g, 19.4 mmol) (Wako Pure Chemical Industries, Ltd.) and potassium carbonate (2.68 g, 19. 4mmol) (Wako pure Chemical Industries, Ltd.) was dissolved in acetonitrile (30mL) (
In addition to the Wako Pure Chemical Industries, Ltd.), and the mixture was refluxed for 5 hours. To the reaction solution, a saturated sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) aqueous solution was added, and extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was evaporated under reduced pressure. The resulting crude product was recrystallized with a mixed solvent of chloroform (Wako Pure Chemical Industries, Ltd.) and n- hexane (Wako Pure Chemical Industries, Ltd.), Compound 12 (Yield 1.80 g, yield 31% ) Moreover, the compound 11 can be obtained by performing the same operation using diphenyl chloromethane instead of triphenyl chloromethane.

<Physical constant of compound 12>
mp. 156-158 ° C
¹ H-NMR (CDCl ₃ ): δ 0.70-3.50 (m, ¹⁰ H), 7.14-7.80 (m, 1
5H).
IR (cm < ^-1 >): 2923, 1485, 1448, 708.

１−（ジフェニルメチル）ピペリジン（化合物１１）

1- (Diphenylmethyl) piperidine (Compound 11)

１−（トリフェニルメチル）ピペリジン（化合物１２）

1- (Triphenylmethyl) piperidine (Compound 12)

<Compound represented by the general formula (2) of the present invention>
The composition of the present invention comprises 1) a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, 2) a compound represented by the general formula (2), It contains isomers and / or pharmacologically acceptable salts thereof. The compound represented by the general formula (2), its isomers and / or pharmacologically acceptable salts thereof are the compounds represented by the general formula (1) and / or their pharmacologically. Inclusion in the composition together with an acceptable salt prevents or improves pigmentation due to excellent UV exposure, especially, prevents or improves pigmentation involving cell function inactivation of keratinocytes caused by increased melanin production Indicates. The compound represented by the general formula (2) of the present invention and / or a pharmacologically acceptable salt thereof can be used without particular limitation as long as it is a component that exerts a preventive or ameliorating action on the pigmentation. I can do it. Melanin production is increased in melanocytes by physical stimulation such as exposure to ultraviolet rays. In addition, if melanin production in melanocytes is excessive or chronic, phenomena such as melanin production in melanocytes, excessive transport of melanin to keratinocytes, accumulation and discharge delay occur, and cell function in keratinocytes is impaired. Damages such as activation and delay of turnover are given, and skin symptoms such as incurable pigmentation, dullness, and abnormal pigmentation accompanied by rough skin symptoms occur. In those people who have skin symptoms due to abnormal pigmentation due to decreased cell function in keratinocytes, when the stratum corneum is prepared, the appearance rate of nucleated cells is higher than the average, and the delamination of the skin Skin symptoms such as are observed. Since the composition of the present invention is particularly preferably used for a person who exhibits the above-mentioned skin symptoms, symptoms due to observation of skin symptoms such as the appearance rate of nucleated cells by the preparation of a stratum corneum and skin delamination It is preferable to set a subject to be administered using as an index.

Here, the compound represented by the general formula (2) will be described. In the formula, R ₁ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₂ represents hydrogen. An atom, an unsubstituted or substituted aromatic group, an unsubstituted or substituted aromatic group optionally substituted by an aromatic group having 1 to 4 carbon atoms, R ₃ is unsubstituted Or the aromatic group which has a substituent is represented, n represents the integer of 1 or 2, and m represents the integer of 0-3. R ₁ is a hydrogen atom having 1 carbon atom.
To 8, more preferably, 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, a propyl group, a butyl group, a pentyl group, and a hexyl group. , A heptyl group, an octyl group and the like can be preferably exemplified, and more preferably, a hydrogen atom, a methyl group and an ethyl group can be suitably exemplified. R ₂ represents a hydrogen atom, an unsubstituted or substituted aromatic group, an unsubstituted or substituted aromatic group optionally substituted with an aromatic group having 1 to 4 carbon atoms, Specific examples include hydrogen atom, phenyl group, methylphenyl group, ethylphenyl group, propylphenyl group, butylphenyl group, methoxyphenyl group, ethoxyphenyl group, propyloxyphenyl group, butyloxyphenyl group, hydroxyphenyl group, Aminophenyl group, N-methylphenyl group, N-ethylphenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, chlorophenyl group, bromophenyl group, fluorophenyl group, trifluoromethylphenyl group, Pyridyl group, naphthyl group, biphenyl group, benzyl group, methylbenzyl group, ethylbenzyl , Methoxybenzyl group, ethoxybenzyl group, hydroxybenzyl group, aminobenzyl group, N-methylaminobenzyl group, N-ethylaminobenzyl group, chlorobenzyl group, fluorobenzyl group, trifluoromethylbenzyl group, naphthylmethyl group, biphenyl Methyl group, phenylethyl group, naphthylethyl group, biphenylethyl group, phenylpropyl group, naphthylpropyl group, biphenylpropyl group, phenylbutyl group, naphthylbutyl group, biphenylbutyl group, methyl group, ethyl group, propyl group, butyl group Can be preferably exemplified, and more preferably, a hydrogen atom, a phenyl group, a benzyl group, a methyl group, and an ethyl group can be suitably exemplified. R ₃ represents an unsubstituted or substituted aromatic group. Specific examples include a phenyl group, a methylphenyl group, an ethylphenyl group, a propylphenyl group, a butylphenyl group, a methoxyphenyl group, and an ethoxyphenyl group. Propyloxyphenyl group, butyloxyphenyl group, hydroxyphenyl group, aminophenyl group, N-methylphenyl group, N-ethylphenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, chlorophenyl group , A bromophenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a pyridyl group, a naphthyl group, a biphenyl group and the like can be suitably exemplified, and more preferably, a phenyl group, a methylphenyl group, a methoxyphenyl group, a naphthyl group, a biphenyl group Can be suitably exemplified. The n represents an integer of 1 or 2, and more preferably, n = 1 can be suitably exemplified. The m represents an integer of 0 to 3, and more preferably m = 0. Among the compounds represented by the general formula (2), preferred are the compounds represented by the general formula (8), isomers thereof and / or pharmacologically acceptable salts thereof. More preferably, a compound represented by the general formula (9), an isomer thereof and / or a pharmacologically acceptable salt thereof can be preferably exemplified, and more preferably, the general formula (10) is exemplified. ), Its isomers and / or their pharmacologically acceptable salts. Specific examples of preferable compounds among the compounds represented by the general formula (2) include N-benzoylcysteic acid, N- (o-toluyl) cysteic acid (compound 13 ), N- (m -Toluyl) cysteic acid (compound 14 ), N- (p-toluyl) cysteic acid (compound 15 ), N- (p-methoxybenzoyl) cysteic acid (compound 16 ), N- (biphenylcarbonyl) cysteic acid (compound 17) ), N- (p-toluyl) homocysteic acid (compound 18 ), isomers thereof and / or pharmacologically acceptable salts thereof. When such a compound is contained in the composition together with the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, it has a preventive or ameliorating action against abnormal pigmentation due to exposure to ultraviolet rays. Demonstrate the excellent effect. Further, such compounds and / or pharmacologically acceptable salts thereof have excellent safety and stability, and can be contained stably and safely in the composition. Further, such a compound is excellent in solubility in a medium used for formulation, in particular, in a polar medium, easily formulated into a skin external preparation, etc., and further excellent in stability and skin retention in the formulation, Excellent effect in preventing or improving pigmentation.

Here, the compound represented by the general formula (8) will be described. In the formula, R ₉ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₁₀ represents nothing. Represents a substituted or substituted aromatic group, n represents an integer of 1 or 2, and m represents an integer of 0 to 3. R ₉ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms, and specific examples include a hydrogen atom, a methyl group, an ethyl group, and propyl. A group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, and the like can be preferably exemplified, and a hydrogen atom, a methyl group, and an ethyl group can be suitably exemplified. R ₁₀ 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, hydroxyphenyl group, aminophenyl group, N-methylphenyl group, N-ethylphenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, chlorophenyl group, Preferred examples include a bromophenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a pyridyl group, a naphthyl group, and a biphenyl group, and more preferably a phenyl group, a methylphenyl group, a methoxyphenyl group, a naphthyl group, and a biphenyl group. It can illustrate suitably. The n represents an integer of 1 or 2, and more preferably, n = 1 can be suitably exemplified. The m represents an integer of 0 to 3, and more preferably m = 0. Specific examples of the compound represented by the general formula (8) that are not included in the compounds represented by the general formulas (9) and (10) include N- (benzylcarbonyl) cysteic acid. N- (methylbenzylcarbonyl) cysteic acid, N- (ethylbenzylcarbonyl) cysteic acid, N- (propylbenzylcarbonyl) cysteic acid, N- (butylbenzylcarbonyl) cysteic acid, N- (methoxybenzylcarbonyl) cysteic acid N- (ethoxybenzylcarbonyl) cysteic acid, N- (propyloxybezylcarbonyl) cysteic acid, N- (butyloxybenzylcarbonyl) cysteic acid, N- (hydroxybenzylcarbonyl) cysteic acid, N- (aminobenzylcarbonyl) ) Cysteinic acid, N- (N'-methylaminobenzylcarboni) ) Cysteic acid, N- (N′-ethylaminobenzylcarbonyl) cysteic acid, N- (N ′, N′-dimethylaminobenzylcarbonyl) cysteic acid, N- (N ′, N′-diethylaminobenzylcarbonyl) cysteic acid N- (chlorobenzylcarbonyl) cysteic acid, N- (fluorobenzylcarbonyl) cysteic acid, N- (difluorobenzylcarbonyl) cysteic acid, N- (trifluoromethylbenzylcarbonyl) cysteic acid , N- (benzylcarbonyl) cysteine San'e Chiruesute Le, N - (methyl benzylcarbonyl) cysteine San'e Chiruesuteru, N - (ethyl benzylcarbonyl) cysteine San'e Chiruesuteru, N - (propyl benzylcarbonyl) cysteine San'e Chiruesuteru, N - (butyl benzyl carbonyl) cysteine acid d switch Glycol ester, N - (methoxybenzyl carbonyl) cysteine San'e Chiruesuteru, N - (ethoxycarbonyl benzylcarbonyl) cysteine San'e Chiruesuteru, N - (propyloxy Veggie ylcarbonyl) cysteine San'e Chiruesuteru, N - (butyloxy benzylcarbonyl) cysteic acid et Chiruesuteru, N - (hydroxy benzylcarbonyl) cysteine San'e Chiruesuteru, N - (amino benzylcarbonyl) cysteine San'e Chiruesuteru, N - (N'-methyl-amino benzyl carbonyl) cysteine San'e Chiruesuteru, N-(N'-ethyl aminobenzyl carbonyl) cysteine San'e Chiruesuteru, N - (N ', N'- dimethylamino benzyl carbonyl) cysteine San'e Chiruesueru, N - (N', N'- diethylamino benzylcarbonyl) cysteine San'e Chirue Ether, N - (chlorobenzyl carbonyl) cysteine San'e Chiruesuteru, N - (fluoro benzylcarbonyl) cysteine San'e Chiruesuteru, N - (difluorobenzyl carbonyl) cysteine San'e Chiruesuteru, N - (trifluoromethyl benzylcarbonyl) cysteine San'e Tyl ester, N- (benzylcarbonyl) homocysteic acid, N- (methylbenzylcarbonyl) homocysteic acid, N- (ethylbenzylcarbonyl) homocysteic acid, N- (propylbenzylcarbonyl) homocysteic acid, N- (butylbenzyl) Carbonyl) homocysteic acid, N- (methoxybenzylcarbonyl) homocysteic acid, N- (ethoxybenzylcarbonyl) homocysteic acid, N- (propyloxybezylcarbonyl) homocysteic acid, N- (butyrate) Oxybenzylcarbonyl) homocysteic acid, N- (hydroxybenzylcarbonyl) homocysteic acid, N- (aminobenzylcarbonyl) homocysteic acid, N- (N′-methylaminobenzylcarbonyl) homocysteic acid, N- (N ′ -Ethylaminobenzylcarbonyl) homocysteic acid, N- (N ', N'-dimethylaminobenzylcarbonyl) homocysteic acid, N- (N', N'-diethylaminobenzylcarbonyl) homocysteic acid, N- (chlorobenzyl) Carbonyl) homocysteic acid, N- (fluorobenzylcarbonyl) homocysteic acid, N- (difluorobenzylcarbonyl) homocysteic acid, N- (trifluoromethylbenzylcarbonyl) homocysteic acid , N- (benzylcarbonyl) homocysteic acid d Chiruesuteru, N - (menu Chill benzylcarbonyl) homocysteine San'e Chiruesuteru, N - (ethyl benzylcarbonyl) homocysteine San'e Chiruesuteru, N - (propyl benzylcarbonyl) homocysteine San'e Chiruesuteru, N - (butyl benzyl carbonyl) homocysteine San'e Chiruesuteru, N - (methoxybenzyl carbonyl) homocysteine San'e Chiruesuteru, N - (ethoxycarbonyl benzylcarbonyl) homocysteine San'e Chiruesuteru, N - (propyloxy Veggie ylcarbonyl) homocysteine San'e Chiruesuteru, N- (butyloxy benzylcarbonyl) homocysteine San'e Chiruesuteru, N - (hydroxy benzylcarbonyl) homocysteine San'e Chiruesuteru, N - (amino benzylcarbonyl) homocysteine San'e Chiruesuteru, N - (N'Mechiruami Benzylcarbonyl) homocysteine San'e Chiruesuteru, N - (N'-ethylamino benzylcarbonyl) homocysteine San'e Chiruesuteru, N - (N ', N'- dimethylamino benzyl carbonyl) homocysteine San'e Chiruesuteru, N - (N ', N'- diethylamino benzylcarbonyl) homocysteine San'e Chiruesuteru, N - (chlorobenzyl carbonyl) homocysteine San'e Chiruesuteru, N - (fluoro benzylcarbonyl) homocysteine San'e Chiruesuteru, N - (difluorobenzyl carbonyl) homocysteine San'e Chiruesuteru, N - (trifluoromethyl benzylcarbonyl) homocysteine San'e Chiruesuteru, its isomers and / or salts thereof pharmacologically acceptable suitably be exemplified. Of the compounds represented by the general formula (8), N-benzoylcysteic acid, N- (o-toluyl) cysteic acid (compound 13 ), N- (m-toluyl) cysteic acid (compound) 14 ), N- (p-toluyl) cysteic acid (compound 15 ), N- (p-methoxybenzoyl) cysteic acid (compound 16 ), N- (biphenylcarbonyl) cysteic acid (compound 17 ), N- (p- Toluyl) homocysteic acid (compound 18 ), isomers thereof and / or pharmacologically acceptable salts thereof can be suitably exemplified. When such a compound is contained in the composition together with the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, it has a preventive or ameliorating action against abnormal pigmentation due to exposure to ultraviolet rays. Demonstrate the excellent effect. Such a compound exhibits an excellent whitening effect by being contained in the composition together with the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof. Further, such compounds and / or pharmacologically acceptable salts thereof have excellent safety and stability, and can be contained stably and safely in the composition. Further, such a compound is excellent in solubility in a medium used for formulation, in particular, in a polar medium, easily formulated into a skin external preparation, etc., and further excellent in stability and skin retention in the formulation, Excellent effect in preventing or improving pigmentation.

Here, the compound represented by the general formula (9) will be described. In the formula, R ₁₁ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₁₂ represents nothing. Represents a substituted or substituted aromatic group, and n represents an integer of 1 or 2. R ₁₁ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms. Specific examples include a hydrogen atom, a methyl group, an ethyl group, and propyl. A group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, and the like can be preferably exemplified, and a hydrogen atom, a methyl group, and an ethyl group can be suitably exemplified. R ₁₂ represents an unsubstituted or substituted aromatic group, and specific examples include a phenyl group, a methylphenyl group, an ethylphenyl group, a propylphenyl group, a butylphenyl group, a methoxyphenyl group, and an ethoxyphenyl group. Propyloxyphenyl group, butyloxyphenyl group, hydroxyphenyl group, aminophenyl group, N-methylphenyl group, N-ethylphenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, chlorophenyl group , A bromophenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a pyridyl group, a naphthyl group, a biphenyl group and the like can be suitably exemplified, and more preferably, a phenyl group, a methylphenyl group, a methoxyphenyl group, a naphthyl group, a biphenyl group Can be suitably exemplified. The n represents an integer of 1 or 2, and more preferably, n = 1 can be suitably exemplified. Specific examples of the compound represented by the general formula (9) that are not included in the compound represented by the general formula (10) include N- (benzoyl) homocysteic acid, N- (methyl Benzoyl) homocysteic acid, N- (ethylbenzoyl) homocysteic acid, N- (propylbenzoyl) homocysteic acid, N- (butylbenzoyl) homocysteic acid, N- (methoxybenzoyl) homocysteic acid, N- (ethoxy Benzoyl) homocysteic acid, N- (propyloxybenzoyl) homocysteic acid, N- (butyloxybenzoyl) homocysteic acid, N- (hydroxybenzoyl) homocysteic acid, N- (aminobenzoyl) homocysteic acid, N- (N'-methylaminobenzoyl) homocysteic acid, N- (N'-ethylaminobenzoyl) homosis Inacid, N- (N ′, N′-dimethylaminobenzoyl) homocysteic acid, N- (N ′, N′-diethylaminobenzoyl) homocysteic acid, N- (chlorobenzoyl) homocysteic acid, N- (fluoro Benzoyl) homocysteic acid, N- (difluorobezoyl) homocysteic acid, N- (trifluoromethylbenzoyl) homocysteic acid, N- (naphthylcarbonyl) homocysteic acid, N- (biphenylcarbonyl) homocysteic acid, N -(Benzoyl) homocysteic acid methyl ester, N- (methylbenzoyl) homocysteic acid methyl ester, N- (ethylbenzoyl) homocysteic acid methyl ester, N- (propylbenzoyl) homocysteic acid methyl ester, N- (butyl Benzoyl) homocysteine acid methyl ester, N- (methoxy) Benzoyl) homocysteine acid methyl ester, N- (ethoxybenzoyl) homocysteine acid methyl ester, N- (propyloxybenzoyl) homocysteine acid methyl ester, N- (butyloxybenzoyl) homocysteine acid methyl ester, N- (hydroxy Benzoyl) homocysteic acid methyl ester, N- (aminobenzoyl) homocysteic acid methyl ester, N- (N′-methylaminobenzoyl) homocysteic acid methyl ester, N- (N′-ethylaminobenzoyl) homocysteine acid methyl Ester, N- (N ′, N′-Dimethylaminobenzoyl) homocysteine acid methyl ester, N- (N ′, N′-diethylaminobenzoyl) homocysteine acid methyl ester, N- (chlorobenzoyl) homocysteine acid methyl ester , N- (F Orobenzoyl) homocysteic acid methyl ester, N- (difluorobezoyl) homocysteic acid methyl ester, N- (trifluoromethylbenzoyl) homocysteic acid methyl ester, N- (naphthylcarbonyl) homocysteic acid methyl ester, N- (Biphenylcarbonyl) homocysteine acid methyl ester, N- (benzoyl) homocysteine acid ethyl ester, N- (methylbenzoyl) homocysteine acid ethyl ester, N- (ethylbenzoyl) homocysteine acid ethyl ester, N- (propylbenzoyl) ) Homocysteine acid ethyl ester, N- (butylbenzoyl) homocysteine acid ethyl ester, N- (methoxybenzoyl) homocysteine acid ethyl ester, N- (ethoxybenzoyl) homocysteine acid ethyl ester N- (propyloxybenzoyl) homocysteine acid ethyl ester, N- (butyloxybenzoyl) homocysteine acid ethyl ester, N- (hydroxybenzoyl) homocysteine acid ethyl ester, N- (aminobenzoyl) homocysteine acid ethyl Ester, N- (N′-methylaminobenzoyl) homocysteine acid ethyl ester, N- (N′-ethylaminobenzoyl) homocysteine acid ethyl ester, N- (N ′, N′-dimethylaminobenzoyl) homocysteine acid Ethyl ester, N- (N ′, N′-diethylaminobenzoyl) homocysteine acid ethyl ester, N- (chlorobenzoyl) homocysteine acid ethyl ester, N- (fluorobenzoyl) homocysteine acid ethyl ester, N- (difluorobenzoic acid Zoyl) ethyl homocysteine Steal, N- (trifluoromethylbenzoyl) homocysteine acid ethyl ester, N- (naphthylcarbonyl) homocysteine acid ethyl ester, N- (biphenylcarbonyl) homocysteine acid ethyl ester, its isomers and / or their pharmacology A particularly acceptable salt can be suitably exemplified. Of the compounds represented by the general formula (9), preferred are N-benzoylcysteic acid, N- (o-toluyl) cysteic acid (compound 13 ), N- (m-toluyl) cysteic acid (compound 14 ), N- (p-toluyl) cysteic acid (compound 15 ), N- (p-methoxybenzoyl) cysteic acid (compound 16 ), N- (biphenylcarbonyl) cysteic acid (compound 17 ), N- (p- Toluyl) homocysteic acid (compound 18 ), isomers thereof and / or pharmacologically acceptable salts thereof can be suitably exemplified. When such a compound is contained in the composition together with the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, it has a preventive or ameliorating action against abnormal pigmentation due to exposure to ultraviolet rays. Demonstrate the excellent effect. Further, such compounds and / or pharmacologically acceptable salts thereof have excellent safety and stability, and can be contained stably and safely in the composition. Further, such a compound is excellent in solubility in a medium used for formulation, in particular, in a polar medium, easily formulated into a skin external preparation, etc., and further excellent in stability and skin retention in the formulation, Excellent effect in preventing or improving pigmentation.

Here, the compound represented by the general formula (10) will be described. In the formula, R ₁₃ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₁₄ represents nothing. A substituted or substituted aromatic group is represented. R ₁₃ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms, and specific examples include a hydrogen atom, a methyl group, an ethyl group, and propyl. A group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, and the like can be preferably exemplified, and a hydrogen atom, a methyl group, and an ethyl group can be suitably exemplified. R ₁₄ represents an unsubstituted or substituted aromatic group, and specific examples include a phenyl group, a methylphenyl group, an ethylphenyl group, a propylphenyl group, a butylphenyl group, a methoxyphenyl group, and an ethoxyphenyl group. Propyloxyphenyl group, butyloxyphenyl group, hydroxyphenyl group, aminophenyl group, N-methylphenyl group, N-ethylphenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, chlorophenyl group , A bromophenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a pyridyl group, a naphthyl group, a biphenyl group, etc. Can be suitably exemplified. Specific examples of preferable compounds among the compounds represented by the general formula (10) include N- (benzoyl) cysteic acid, N- (methylbenzoyl) cysteic acid, N- (ethylbenzoyl) cysteic acid, N- (propylbenzoyl) cysteic acid, N- (butylbenzoyl) cysteic acid, N- (methoxybenzoyl) cysteic acid, N- (ethoxybenzoyl) cysteic acid, N- (propyloxybenzoyl) cysteic acid, N- (butyl Oxybenzoyl) cysteic acid, N- (hydroxybenzoyl) cysteic acid, N- (aminobenzoyl) cysteic acid, N- (N′-methylaminobenzoyl) cysteic acid, N- (N′-ethylaminobenzoyl) cysteic acid, N- (N ′, N′-dimethylaminobenzoyl) cysteic acid, N- (N ′, N′-diethylaminobenzene) Zoyl) cysteic acid, N- (chlorobenzoyl) cysteic acid, N- (fluorobenzoyl) cysteic acid, N- (difluorobezoyl) cysteic acid, N- (trifluoromethylbenzoyl) cysteic acid, N- (naphthylcarbonyl) Cysteine acid, N- (biphenylcarbonyl) cysteic acid, N- (benzoyl) cysteic acid methyl ester, N- (methylbenzoyl) cysteic acid methyl ester, N- (ethylbenzoyl) cysteic acid methyl ester, N- (propylbenzoyl) Cysteinic acid methyl ester, N- (butylbenzoyl) cysteic acid methyl ester, N- (methoxybenzoyl) cysteic acid methyl ester, N- (ethoxybenzoyl) cysteic acid methyl ester, N- (propyloxybenzoyl) cysteic acid methyl Ester, N- (butyloxybenzoyl) cysteic acid methyl ester, N- (hydroxybenzoyl) cysteic acid methyl ester, N- (aminobenzoyl) cysteic acid methyl ester, N- (N′-methylaminobenzoyl) cysteic acid methyl ester N- (N′-ethylaminobenzoyl) cysteic acid methyl ester, N- (N ′, N′-dimethylaminobenzoyl) cysteic acid methyl ester, N- (N ′, N′-diethylaminobenzoyl) cysteic acid methyl ester N- (chlorobenzoyl) cysteic acid methyl ester, N- (fluorobenzoyl) cysteic acid methyl ester, N- (difluorobezoyl) cysteic acid methyl ester, N- (trifluoromethylbenzoyl) cysteic acid methyl ester, N- (Naphthylcarbonyl Cysteine acid methyl ester, N- (biphenylcarbonyl) cysteic acid methyl ester, N- (benzoyl) cysteic acid ethyl ester, N- (methylbenzoyl) cysteic acid ethyl ester, N- (ethylbenzoyl) cysteic acid ethyl ester, N- (Propylbenzoyl) cysteic acid ethyl ester, N- (butylbenzoyl) cysteic acid ethyl ester, N- (methoxybenzoyl) cysteic acid ethyl ester, N- (ethoxybenzoyl) cysteic acid ethyl ester, N- (propyloxybenzoyl) cysteine Acid ethyl ester, N- (butyloxybenzoyl) cysteic acid ethyl ester, N- (hydroxybenzoyl) cysteic acid ethyl ester, N- (aminobenzoyl) cysteic acid ethyl ester, N- (N ′ Methylaminobenzoyl) cysteic acid ethyl ester, N- (N'-ethylaminobenzoyl) cysteic acid ethyl ester, N- (N ', N'-dimethylaminobenzoyl) cysteic acid ethyl ester, N- (N', N ' -Diethylaminobenzoyl) cysteic acid ethyl ester, N- (chlorobenzoyl) cysteic acid ethyl ester, N- (fluorobenzoyl) cysteic acid ethyl ester, N- (difluorobezoyl) cysteic acid ethyl ester, N- (trifluoromethylbenzoyl) Preferred examples include cysteic acid ethyl ester, N- (naphthylcarbonyl) cysteic acid ethyl ester, N- (biphenylcarbonyl) cysteic acid ethyl ester, isomers thereof and / or pharmacologically acceptable salts thereof. Among the compounds represented by the general formula (10), preferred are N-benzoylcysteic acid, N- (o-toluyl) cysteic acid (compound 13 ), N- (m-toluyl) cysteic acid (compound 14 ), N- (p-toluyl) cysteic acid (compound 15 ), N- (p-methoxybenzoyl) cysteic acid (compound 16 ), N- (biphenylcarbonyl) cysteic acid (compound 17 ), its isomers and / or Alternatively, pharmacologically acceptable salts thereof can be preferably exemplified. Such a compound, when contained in the composition together with the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, enhances the excellent pigmentation prevention or improvement effect. Have Further, such a compound is excellent in solubility in a medium used for formulation, in particular, in a polar medium, easily formulated into a skin external preparation, etc., and further excellent in stability and skin retention in the formulation, Excellent effect in preventing or improving pigmentation.

  In addition, the compound represented by the general formula (2), its isomers and / or pharmacologically acceptable salts thereof are the compound represented by the general formula (1) and / or their pharmacology. Incorporated into the composition together with a chemically acceptable salt prevents or improves the pigmentation abnormality caused by excellent UV exposure, in particular, excessive melanin transport to keratinocytes, accumulation and elimination of keratinocyte cellular functions It has an excellent effect on pigmentation abnormality involving reduction. Such an action of preventing or improving pigmentation is represented by the general formula (1) possessed by the compound represented by the general formula (2), its isomer and / or a pharmacologically acceptable salt thereof. An additive or synergistic effect in preventing or ameliorating the pigmentation abnormality with the compound and / or pharmacologically acceptable salt thereof, and further the compound represented by the general formula (2), its isomerism Preventive or ameliorating the pigmentation of the body and / or pharmacologically acceptable salts thereof, and further whitening effect by pharmacokinetics such as improved delivery efficiency to the target site, pharmaceutical additive or synergistic effect It is considered that the effect of preventing or improving pigmentation is enhanced. In addition to the racemic compound (DL form), the compounds represented by the general formula (2) and general formulas (8) to (10) include D and L isomers. These isomers, when included in the composition together with the whitening component described later, all exhibit an excellent enhancing effect on the prevention or improvement of pigmentation abnormality, but are safe for the living body and stable in the preparation. The L form can be suitably exemplified by the nature and the like.

The compounds represented by the general formula (2) and the general formulas (8) to (10), their isomers and / or pharmacologically acceptable salts thereof are commercially available cysteic acid and homocysteine. Production using acids and their derivatives as starting materials, for example, by deprotection, coupling, and introduction of protecting groups according to the methods described in “Basics and Experiments for Peptide Synthesis (Maruzen)” It can also be manufactured by the following manufacturing method. Such a compound is contained in the composition together with the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, thereby preventing whitening effect, prevention of pigmentation due to exposure to ultraviolet rays, or Although it can be used to enhance the effect of the improving action, it can 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 toluenesulfonate, organic acid salts such as benzenesulfonate, sodium salt, alkali metal, calcium salts, alkaline earth metals such as magnesium salt metal, triethylamine salt or potassium salt, triethanolamine salt, an ammonium salt, monoethanolamine Preferred examples include organic amine salts such as amine salts and piperidine salts, and basic amino acid salts such as lysine salts and arginine salts .

The compound represented by the general formula (2) of the present invention, its isomer and / or pharmacologically acceptable salt thereof works together with the whitening component described later, and prevents or improves pigmentation abnormality due to ultraviolet exposure. In order to exert a preventive or ameliorating effect on pigmentation abnormalities involving a decrease in cellular function of keratinocytes caused by phenomena such as enhancement effect on action, especially, excessive transport of melanin to keratinocytes, accumulation and delayed discharge, etc. On the other hand, the total amount is preferably 0.0001% by mass to 20% by mass, more preferably 0.001% by mass to 10% by mass, and still more preferably 0.01% by mass to 5% by mass. This resides may not exhibited the effect is too small or too large, the effect becomes plateau is because resides may impair the flexibility of the system.

N−（o−トルイル）−L−システイン酸（化合物１３のL異性体）

N- (o-toluyl) -L-cysteic acid (L isomer of compound 13)

<Production Example 8: Synthesis of L isomer of compound 13>
3 g ( 17.7 mmol) of L-cysteic acid (Tokyo Chemical Industry Co., Ltd.), 18 mL of tetrahydrofuran ( Wako Pure Chemical Industries, Ltd.), and 8 mL of water were placed in a 100 mL eggplant-shaped flask and cooled in an ice bath. did. After sufficiently cooling, 4.40 g ( 31.6 mmol) of potassium carbonate (Wako Pure Chemical Industries, Ltd.) was added. o-Toluoyl chloride 3.2 8 g ( Tokyo Chemical Industry Co., Ltd.) was sequentially added so that the liquid temperature did not rise. After the addition, the ice bath was removed and the mixture was stirred at room temperature. After confirming the progress of the reaction by thin layer chromatography , tetrahydrofuran was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate, and the pH was adjusted to 2 or less with hydrochloric acid. The filtrate was concentrated and water (20 ml) was added. The precipitated crystals were collected by filtration, and the crystals were washed with acetone. The crystal collected by filtration was dried at 60 ° C. to obtain 0.78 g ( 2,72 mmol) of the L isomer of Compound 13 having the above structure. Shown below are the values of the indications.
¹ H-NMR (D ₂ O): δ 2.31 (3H, s), 3.42 (2H, m), 4.86 (1
H, m), 7.24 (2H, m), 7.35 (2H, m).
FAB-MS (negativeion mode): M / z = 286 ([M−H] ⁻ )

N−（m−トルイル）−Ｌ−システイン酸（化合物１４のＬ異性体）

N- (m-Toluyl) -L-cysteic acid (L isomer of compound 14)

<Production Example 9: Synthesis of L isomer of compound 14>
L- cysteine acid 3g (17.7mmol) (Tokyo Kasei Kogyo Co., Ltd.), tetrahydrofuran 1 8mL (Wako Pure Chemical Industries, Ltd.), and, after putting water 1 8mL to 10 0mL na scan type flask, to an ice bath And cooled. After cooling sufficiently, potassium carbonate 4.40 g ( 3
1.6 mmol) (Wako Pure Chemical Industries, Ltd.) and m-toluoyl chloride 2.19 g ( Tokyo Chemical Industry Co., Ltd.) were sequentially added so that the liquid temperature did not rise. After reacting for 1 hour in an ice bath, m
-Toluoyl chloride 1.09g ( Tokyo Chemical Industry Co., Ltd.) was added again. After the addition, the ice bath was removed and the mixture was stirred at room temperature. After confirming the progress of the reaction by thin layer chromatography , tetrahydrofuran was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate, and the pH was adjusted to 2 or less with hydrochloric acid. The filtrate was concentrated and water (18 mL) was added. After aging at 4 ° C., the precipitated crystals were separated by filtration. The obtained crystals were washed with acetone and collected by filtration. The crystals collected by filtration were dried at 60 ° C. to obtain 1.65 g ( 5.74 mmol) of the L isomer of compound 14 having the above structure. Shown below are the values of the indications.
¹ H-NMR (DMSO-d ₆ ): δ 2.36 (3H, s), 2.94 (2H, m), 4.41 (1H, m), 7.36 (2H, d), 7. 58 (2H, t), 8.84 (1H, d), 12.5 (1H, bs).
FAB-MS (negativeion mode): M / z = 286 ([M−H] ⁻ )

N−（p−トルイル）−Ｌ−システイン酸（化合物１５のＬ異性体）

N- (p-Toluyl) -L-cysteic acid (L isomer of compound 15)

<Production Example 10: Synthesis of L isomer of compound 15>
L-cysteic acid monohydrate 5 g ( 26.7 mmol) (Sigma Aldrich), 1, 4
- dioxane 20mL (Wako Pure Chemical Industries, Ltd.), and, after putting the water 10mL to 10 0mL na scan type flask, and cooled in an ice bath. After cooling sufficiently, 8N aqueous sodium hydroxide solution10. 7 mL, p-toluoyl chloride 3.3 6 mL ( Sigma-Aldrich) was sequentially added dropwise so that the liquid temperature did not increase. After completion of dropping, the ice bath was removed and the mixture was stirred at room temperature. After confirming the progress of the reaction by thin layer chromatography , 1,4-dioxane was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate, and the pH was adjusted to 2 or less with hydrochloric acid. The obtained aqueous solution was freeze-dried and the target product was extracted with methanol . Methanol was distilled off under reduced pressure, then crystallized and filtered. The crystals collected by filtration are dried, and the L isomer of compound 15 having the above structure 5.7 9 g
( 20.2 mmol) was obtained. Indicative values are shown below. ¹ H-NMR (D ₂ O): δ 2.32 (3H, s), 3.46 (2H, m), 4.87 (1H, m), 7.25 (2H, d), 7.64 (2H, d).
FAB-MS (negativeion mode): M / z = 286 ([M−H] ⁻ ), 308 ([M + Na−H] ⁻ )

N−（p−メトキシベンゾイル）−Ｌ−システイン酸（化合物１６のＬ異性体）

N- (p-methoxybenzoyl) -L-cysteic acid (L isomer of compound 16)

<Production Example 11: Synthesis of L isomer of compound 16>
L- cysteine acid 2g (11.8mmol) (Tokyo Kasei Kogyo Co., Ltd.), tetrahydrofuran 1 2mL (Wako Pure Chemical Industries, Ltd.), and, after putting water 1 2mL to 10 0mL na scan type flask, to an ice bath And cooled. After cooling sufficiently, potassium carbonate 2.9 4 g ( 21
. 3 mmol) (Wako Pure Chemical Industries, Ltd.), 4-methoxybenzoyl chloride 1.6 1 g (
Tokyo Chemical Industry Co., Ltd.) was sequentially added so that the liquid temperature did not rise. After reacting for 1 hour in an ice bath, 0.81 g of 4-methoxybenzoyl chloride ( Tokyo Chemical Industry Co., Ltd.) was added again. After the addition, the ice bath was removed and the mixture was stirred at room temperature. After confirming the progress of the reaction by thin layer chromatography , tetrahydrofuran was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate, and the pH was adjusted to 2 or less with hydrochloric acid. The precipitated crystals were filtered and washed with water. The filtrate was concentrated and the precipitated crystals were filtered again. The obtained crystals were combined and then washed with acetone. After filtering the crystals, the collected crystals were dried at 60 ° C. to obtain 2.47 g ( 8.14 mmol) of L isomer of compound 16 having the above structure. Indicative values are shown below.
¹ H-NMR (D ₂ O): δ 3.45 (2H, m), 3.81 (3H, s), 4.85 (1H, m), 7.00 (2H, d), 7.72 (2H, d).
FAB-MS (negativeionmode): M / z = 302 ([M−H] ⁻ )

Ｎ−(ビフェニルカルボニル）−Ｌ−システイン酸（化合物１７のＬ異性体）

N- (biphenylcarbonyl) -L-cysteic acid (L isomer of compound 17)

<Production Example 12: Synthesis of L isomer of compound 17>
L- cysteine acid 2g (11.8mmol) (Tokyo Kasei Kogyo Co., Ltd.), tetrahydrofuran 1 2mL (Wako Pure Chemical Industries, Ltd.), and, after putting water 1 2mL to 10 0mL na scan type flask, to an ice bath And cooled. After cooling sufficiently, potassium carbonate 2.9 4g ( 2
1.3 mmol) (Wako Pure Chemical Industries, Ltd.), 4-phenylbenzoyl chloride 2.05 g (
Tokyo Chemical Industry Co., Ltd.) was sequentially added so that the liquid temperature did not rise. After reacting in an ice bath for 1.5 hours, 1.02 g of 4-phenylbenzoyl chloride ( Tokyo Chemical Industry Co., Ltd.) was added again. After the addition, the ice bath was removed and the mixture was stirred at room temperature. After confirming the progress of the reaction by thin layer chromatography , tetrahydrofuran was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate, and the pH was adjusted to 2 or less with hydrochloric acid. The precipitated crystals were filtered and washed with water. The obtained crystals were washed with acetone and then filtered. The crystals collected by filtration were dried at 60 ° C. to obtain 2.37 g ( 6.78 mmol) of the L isomer of compound 17 having the above structure. Indicative values are shown below.
¹ H-NMR (DMSO-d ₆ ): δ 2.96 (2H, m), 4.54 (1H, q), 7.42 (1H, m), 7.51 (2H, m), 7. 74 (2H, d), 7.80 (2H, d), 7.90 (2H, d), 8.94 (1H, d).
FAB-MS (negativeionmode): M / z = 348 ([M−H] ⁻ )

N−（p−トルイル）ホモシステイン酸（化合物１８）

N- (p-Toluyl) homocysteic acid (Compound 18)

<Production Example 13: Synthesis of Compound 18>
DL- homocysteine acid 2 g (10.9 mmol) (Sigma-Aldrich), tetrahydrofuran 1 2 mL (Wako Pure Chemical Industries, Ltd.), and, after putting water 1 2 mL of a 10 0 mL Na scan type flask in an ice bath Cooled down. After cooling sufficiently, 1 g ( 19.6 mmol) of potassium carbonate 2.7 (Wako Pure Chemical Industries, Ltd.) was added. 1.49 g of p-toluoyl chloride ( Sigma Aldrich) was sequentially added so that the liquid temperature did not increase. After reacting for 1 hour in an ice bath, 0.76 g of p-toluoyl chloride ( Sigma Aldrich) was added again. After the addition, the ice bath was removed and the mixture was stirred at room temperature. After confirming the progress of the reaction by thin layer chromatography , tetrahydrofuran was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate, and the pH was adjusted to 2 or less with hydrochloric acid. After filtration of the solution, the filtrate was concentrated and methanol was added. The precipitated crystals were separated by filtration and washed with water. The crystals were filtered, and the collected crystals were dried at 60 ° C. to obtain 51.9 g ( 6.47 mmol) of the compound 18 having the above structure. Indicative values are shown below.
¹ H-NMR (DMSO-d ₆ ): δ 2.12 (2H, m), 2.35 (3H, s), 2.57 (2H, t), 4.37 (1H, m ), 7. 26 (2H, d), 7.79 (2H, d), 9.02 (1H, d).
FAB-MS (negativeionmode): M / z = 300 ([M−H] ⁻ )

<Composition of the present invention>
The composition of the present invention comprises 1) a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, 2) a compound represented by the general formula (2), It contains isomers and / or pharmacologically acceptable salts thereof. Such a composition has an excellent whitening effect, more preferably, an effect of preventing or improving pigmentation by exposure to ultraviolet rays, particularly, an effect of preventing or improving pigmentation involving cell function inactivation of keratinocytes caused by melanin overproduction. Show. Melanin production is increased in melanocytes by physical stimulation such as exposure to ultraviolet rays. In addition, if melanin production in melanocytes is excessive or chronic, phenomena such as melanin production in melanocytes, excessive transport of melanin to keratinocytes, accumulation and discharge delay occur, and cell function in keratinocytes is impaired. Damages such as activation and delay of turnover are given, and skin symptoms such as incurable pigmentation, dullness, and abnormal pigmentation accompanied by rough skin symptoms occur. In those people who have skin symptoms due to abnormal pigmentation due to decreased cell function in keratinocytes, when the stratum corneum is prepared, the appearance rate of nucleated cells is higher than the average, and the delamination of the skin Skin symptoms such as are observed. Since the composition of the present invention is particularly preferably used for a person who exhibits the above-mentioned skin symptoms, symptoms due to observation of skin symptoms such as the appearance rate of nucleated cells by the preparation of a stratum corneum and skin delamination It is preferable to set a subject to be administered using as an index.

In addition, 1) a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, and 2) a compound represented by the general formula (2), an isomer thereof and / or In formulating a composition containing such a pharmacologically acceptable salt, optional components used in formulating normal foods, pharmaceuticals, cosmetics and the like can be contained. Examples of such optional ingredients, if oral dosage composition, for example, excipients such as lactose, white sugar, starch, cellulose, gum arabic, binders such as hydroxypropylcellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose Disintegrants such as calcium, surfactants such as soybean lecithin and sucrose fatty acid esters, sweeteners such as maltitol and sorbitol , sour agents such as citric acid, buffering agents such as phosphate, and film formation such as shellac and zein Agents, lubricants such as talc, waxes, glidants such as light anhydrous silicic acid, dry aluminum hydroxide gel, diluents such as physiological saline and aqueous glucose solution, flavoring agents, coloring agents, bactericides, antiseptics agents, perfumes, etc. can suitably be exemplified.

As the composition of the present invention, pharmaceuticals, cosmetics, foods, beverages and the like can be suitably exemplified, and since they can be taken on a daily basis, it is preferable to adapt to foods, cosmetics and the like. The administration route can be either oral administration or transdermal administration. For the purpose of detoxification (detox), oral administration with high efficiency in reaching the relevant organ is adopted, and forms of oral administration compositions such as foods Is preferably adopted. Moreover, when such a component is continuously administered, and further considering safety, it is preferably administered transdermally . 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. As a cosmetic, there is no limitation of the special stage, for example, essence, emulsion, chestnut - basic cosmetics such as arm, under make-up, foundation, blush, mascara, make-up cosmetics such as eyeliner, hair cream, etc. Examples of hair cosmetics are suitable.

The external preparation for skin of the present invention can contain, in addition to such components, optional components that are usually used in external preparations for skin. Examples of such optional ingredients include macadamia nut oil, avocado oil , corn oil, olive oil , rapeseed oil, sesame oil, castor oil, safflower oil , cottonseed oil, jojoba oil, coconut oil, palm oil , liquid lanolin, and hardened coconut oil. Oil, wax , liquid paraffin, squalane, pristane, ozokerite, paraffin, ceresin, petrolatum, oil, wax , liquid wax , liquid paraffin, squalane, bean wax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin , hydrocarbons such as microcrystalline wax, oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, higher fatty acids such as undecylenic acid, cetyl alcohol, stearyl alcohol, Isosuteari Alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol, higher alcohols such as cetostearyl alcohol, cetyl isooctanoate, isopropyl myristate, isostearate hexyl decyl, diisopropyl adipate, sebacic di-2-ethylhexyl, cetyl lactate, malate Diisostearyl acid, ethylene glycol di-2-ethylhexanoate, neopentyl glycol dicaprate, glycerin di-2-heptylundecanoate, glycerin tri-2-ethylhexanoate, trimethylolpropane tri-2-ethylhexanoate, tri isostearic acid trimethylol over trimethylolpropane, synthetic ester oils such as tetra-2-ethylhexanoate pentane pentaerythritol, dimethyl polysiloxane, methylphenyl Rokisan, linear polysiloxanes such as diphenyl polysiloxane, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, cyclic polysiloxanes such as dodeca methylcyclohexane siloxane, amino-modified polysiloxane, polyether-modified polysiloxane, alkyl-modified polysiloxanes, fluorine-modified polysiloxane-modified polysiloxane silicone in - oil such emissions oils, fatty soaps (sodium laurate, sodium palmitate), potassium lauryl sulfate, alkyl sulfate triethanol Amin'e - anionic surfactants such as ether s, stearyl trimethyl ammonium chloride, benzalkonium chloride, cationic surfactants such as lauryl amine oxide, imidazoline amphoteric surface active agent (2 cocoyl-2-Imida Zolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), betaine surfactants (alkyl betaine, amide betaine, sulfobetaine, etc.), amphoteric surfactants such as acylmethyltaurine , sorbitan fatty acid esters (sorbitan) Monosuteare over DOO, sorbitan sesquioleate etc.), glycerol fatty acids (glycerol monostearate, etc.), propylene glycol fatty acid esters (propylene glycol monostearate, etc.), hardened castor oil derivatives, glycerin alkyl ether, POE sorbitan fatty acid esters (POE sorbitan monooleate over preparative monostearate polyoxyethylated sorbitan, etc.), POE sorbitol fatty acid esters (POE- sorbit monolaurate over preparative etc.), POE glycerin fatty et Ethers (POE- glyceryl monoisostearyl array over preparative etc.), POE fatty acid esters (polyethylene glycol Monoore over preparative, POE Jisuteare over preparative etc.), POE alkyl ethers (POE2- octyldodecyl ether), POE alkyl phenyl ether (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 cured) castor oil, etc.), sucrose fatty acid esters, nonionic surfactants such as alkyl glucosides, sodium pyrrolidone carboxylic acid, lactic acid, moisturizing ingredients, such as sodium lactate, may be surface treated, mica, talc, kaolin , Synthetic mica, Calcium, magnesium carbonate, silicate (silica) anhydrous aluminum oxide powder such as barium sulfate, may be processed to the front surface, red iron oxide, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, iron blue , titanium oxide, inorganic pigments zinc oxide may be surface treated mica titanium, Sakanarinhaku, pearl agent such as bismuth oxychloride, good red No. 202 be laked red No. 228 , Red No. 226, Yellow No. 4, Blue No. 404, Yellow No. 5, Red No. 505, Red No. 230, Red No. 223, Orange No. 201, Red No. 213, Yellow No. 204, Yellow No. 203, Blue No. 1, Green No. 201, purple No. 201, organic dyes red No. 204, etc., polyethylene powder, polymethyl methacrylate, nylon powder, organic powders such as organopolysiloxane elastomers, Pas Raamino benzoic acid UV absorbers, anthranilic acid UV absorbers, salicylic acid ultraviolet absorbers; cinnamic acid-based ultraviolet absorbents, Baie benzophenone-based ultraviolet absorbents, sugar-based ultraviolet absorber, 2- (2'-hydroxy-5 UV absorbers such as' -t-octylphenyl) benzotriazole, 4-methoxy-4'-t-butyldibenzoylmethane, lower alcohols such as ethanol and isopropanol , vitamin A or a derivative thereof, vitamin B6 hydrochloride, vitamin B6 Toriparumite over preparative, vitamin B6 Jiokutanoe over preparative, vitamin B2 or derivatives thereof, vitamin B12, vitamin B such as vitamin B15 or a derivative thereof, alpha-tocopherol Lumpur, beta-tocopherol Lumpur, .gamma. tocopherol Lumpur, vitamin E such as vitamin E Asete over preparative, vitamin D, vitamin H, pantothenic acid, Ntechin, vitamins pyrroloquinoline quinone such like, antibacterial agents such as phenoxyethanol Lumpur, hectorite, organic modified clay minerals such dimethyl distearyl ammonium modified hectorite may be preferably exemplified.

  The skin external preparation of the present invention contains the above essential components and is in the form of an emulsifier. The form of the emulsifier form may be either the water-in-oil emulsifier form or the oil-in-water emulsifier form, but the oil-in-water emulsifier form is particularly preferred. Here, the water-in-oil emulsifier form is a term collectively referred to as an emulsifier form having an oil phase in the outer phase, and may contain an aqueous phase in the inner phase or may have an emulsion such as an oil-in-water emulsion. You may do it. Similarly, the oil-in-water emulsifier form is a general term for an emulsion having an aqueous phase in the outer phase, and may have an oil phase in the inner phase or an emulsion such as a water-in-oil emulsion. good.

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 . The or mow alkyl-modified carboxyvinyl polymer is commercially resides, it can be used to purchase such commercially. Preferred commercially available from Nippon support over Fakutanto Industrial Co., are alkyl-modified with an alkyl group having 10 to 30 carbon atoms "Pemulen (PEMUREN, R) TR-1", "Pemulen (PEMUREN, registration R) TR-2 ", BF Goodrich (commercially available from US)" Carbopol (CARBOPOL, registered trademark) 1382 "include, as a carboxyvinyl polymer which is not an alkyl-modified, BF Goodrich ( which is commercially available from the US), "Carbopol (CARBOPOL, registered trademark) Ultrez10", there is such as "Carbopol (CARBOPOL, registered trademark) 940". Such hydrophilic polymers may be used alone or in combination of two or more. The oil-in-water emulsion composition of the present invention preferably contains 0.05 to 1% by mass of such a hydrophilic polymer, and 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-forming properties in an emulsified state are preferable. As the nonionic surfactant, sorbitan stearate, glycerol 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 includes 1) a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, 2) a compound represented by the general formula (2), By containing the isomers and / or pharmacologically acceptable salts thereof, for prevention or improvement of pigment-related abnormalities such as “for pigmentation improvement”, “for whitening”, “for stain improvement”, etc. Demonstrate the effect. In addition, 1) a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, and 2) a compound represented by the general formula (2), an isomer thereof and / or Among the compositions containing such pharmacologically acceptable salts, there are those that exhibit an action other than the preventive or ameliorating action against abnormal pigmentation due to ultraviolet exposure or the like. For the purpose of expressing such action, the compound represented by the general formula (1) of the present invention and / or a pharmacologically acceptable salt thereof, and 2) represented by the general formula (2) Even if the composition contains a compound, its isomer and / or a pharmacologically acceptable salt thereof, if the effect of preventing or ameliorating pigmentation due to UV exposure is exerted, Since the effect is utilized, it belongs to the technical scope of the present invention. Examples of actions other than prevention or improvement against pigmentation abnormality due to ultraviolet exposure and the like include moisturizing action, prevention or improvement action against wrinkle formation, rough skin prevention or improvement action, anti-aging improvement 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.

< Production 1 of Composition of the Invention (External Preparation for Skin) 1>
According to the formulations shown in Tables 1 and 2, the composition of the present invention (external preparation for skin) was prepared. That is, the components of A, B, and C are heated to 80 ° C., and are gradually added and neutralized with stirring to B, then A is added with stirring, and the emulsion particles are homogenized with a homomixer. Cosmetics 1 to 4) were obtained. In the same manner, Comparative Example 1 in which “the compound represented by the general formula (1) of the present invention” was replaced with “water” and “the compound represented by the general formula (2) of the present invention” were “ Comparative Example 2 substituted with “water”, “compound represented by the general formula (1) of the present invention” and “compound represented by the general formula (2) of the present invention” were both replaced with “water”. Comparative Example 3 was produced.

< Evaluation 1 for inhibiting pigmentation of composition of the present invention (external preparation for skin) 1>
The pigmentation inhibitory effect was investigated using the oil-in-water emulsifier type cosmetics (cosmetics 1 to 4) and the cosmetics of Comparative Examples 1 to 3. On the inner side of the upper arm of the panelists who participated freely, a test site of 1.5 cm x 1.5 cm was provided on the first day of the test (Day 1), 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. The skin lightness (L * value) of each test site was measured with a color difference meter (CR-300, Konica Minolta Co., Ltd.) 24 hours after the application was finished (15th day), and ΔL * value relative to the L value on the first day of the test. Was calculated. The results are shown in Table 3. Since the ΔL * value decreases as the degree of pigmentation increases, it can be determined that the pigmentation is suppressed as the ΔL * value increases. Thereby, it turns out that the cosmetics 1-6 which are the skin external preparations of this invention have the outstanding pigmentation inhibitory effect. Moreover, although the pigmentation inhibitory action was recognized also in the comparative example 1 and the comparative example 2, the effect was weak compared with cosmetics 1-4. Thereby, it turns out that the cosmetics 1-4 which are the skin external preparations of this invention show the outstanding pigmentation inhibitory effect.

< Manufacture 2 of the composition of the present invention (external preparation for skin)>
“Compound represented by the general formula (1) of the present invention” (compound 12) and “compound represented by the general formula (2) of the present invention” (L of compound 15) contained in the cosmetic 3 Cosmetics (cosmetics 5 to 9) in which the content of isomers was changed were produced according to the production method described in Production 1, and the pigmentation inhibitory action by exposure to ultraviolet rays was examined. The contents of the components are as shown in Table 4. Moreover, the change of the mass% by the increase / decrease in the said component was adjusted by increasing / decreasing the mass% of water.

< Evaluation 2 for inhibiting pigmentation of composition of the present invention (external preparation for skin) 2>
The oil-in-water emulsifier type cosmetics 5 to 9 produced by the method described in Production 2 and Comparative Example 3 produced according to the method described in Production 1 were applied in accordance with the test method described in Evaluation 1 for pigmentation inhibitory action. The pigmentation inhibitory effect of Samples 5 to 9 and Comparative Example 3 was evaluated. The results are shown in Table 5. Thereby, it turns out that the cosmetics 5-9 which are the skin external preparations of this invention show the outstanding pigmentation inhibitory effect.

< Evaluation 3 for inhibiting pigmentation of composition of the present invention (external preparation for skin) 3>
The cosmetics 1-4 produced according to the method described in Production 1 and Comparative Examples 1 to 3 were evaluated for pigmentation inhibitory action according to the following procedure. When selecting panelists with more than the average melanin, the sample of stratum corneum cells collected from the skin by adhesive tape stripping was visualized by melanin staining using an aqueous silver nitrate solution, and this was determined by observing under a microscope. did. In the determination, the determination was made by scoring around the average existence situation. Furthermore, among the panelists, higher than average incidence of nucleated cells with the stratum corneum sample, also the degree of overlay peeling was selected panelists by observing the human more than the average. The measurement site divided portions of 1.5 cm × 1.5 cm in upper and lower stages on both the upper inner arm of the panelists who participated voluntarily having the properties provided, minimal erythemal dose (1 MED) 1 UV irradiation of day 1 Irradiated 3 times for 3 consecutive days. From 1 day after the completion of irradiation, 50 μL of sample was applied once a day for 28 consecutive days. One site was an untreated site. 24 hours after the completion of application, the skin lightness (L * value) of each test site was measured with a color difference meter (CR-300, Konica Minolta Co., Ltd.), and the ΔL * value relative to the L value of the untreated site was calculated. The L * value decreases as the degree of pigmentation increases. Therefore, it can be determined that the greater the ΔL * value, the more pigmentation is suppressed. The results are shown in Table 6. Thereby, it turns out that the cosmetics 1-4 which are the skin external preparations of this invention show the outstanding pigmentation inhibitory effect.

< Production 3 of Composition of the Present Invention (External Preparation for Skin) 3>
An attempt was made to prepare cosmetic 10 in which “Pemlen TR-2” was replaced with POE (25) stearic acid in the prescription ingredients of cosmetic 3 described in Production 1 , and the cosmetic 10 was separated immediately after production. Thus, an emulsion was not obtained.

< Production of Composition (Health Food) of the Present Invention>
According to the prescription shown in Table 7 and Table 8, health foods (health foods 1 to 4) were prepared. That is, formulation components rolling phase granulated with 10 parts by weight of water (manufactured by Fuji Paudal Co., Ltd., "New Malmo riser
- ") And tableted to obtain a tablet-like health food. In addition, the unit of the numerical value in a table | surface represents a weight part. This health food was found to have an excellent pigmentation prevention or improvement effect.

  The present invention can be applied to cosmetics, foods and the like for preventing or improving pigmentation.

Claims (20)

1) a compound represented by the following general formula (1) and / or a pharmacologically acceptable salt thereof, and 2) a compound represented by the following general formula (2), its isomers and / or their A composition comprising a pharmacologically acceptable salt.

(1)
[In the formula, A represents a di-aromatic methyl group or tri aromatic methyl group, aromatic the group consisting of heteroaromatic ring having aryl Moto及beauty unsubstituted or substituted group having an unsubstituted or substituted group Are independently selected . B represents a cyclic or acyclic aliphatic or aromatic hydrocarbon group in which the bonding site to A is a hetero atom, and a hydrogen atom, a hydrogen atom, or a carbon atom may be substituted with a hetero atom. ]

(2)
[Wherein, R ₁ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₂ represents a hydrogen atom, an unsubstituted or substituted aromatic group, an unsubstituted or substituted group. Represents an aliphatic hydrocarbon group having 1 to 4 carbon atoms which may be substituted with an aromatic group having R ₃ , R ₃ represents an unsubstituted or substituted aromatic group, and n represents 1 or 2 An integer, m represents an integer of 0 to 3. ] The compound represented the general formula (1), characterized in that a compound represented by the following general formula (3) A composition according to claim 1.

(3)
[In the formula, A represents a diarylmethyl group or a triarylmethyl group, and the aryl is independently selected from the group consisting of unsubstituted or substituted aryl groups , and B has a complex binding site with A. A hydrogen atom, a hydrogen atom, or a carbon atom, which is an atom, represents a cyclic or acyclic aliphatic or aromatic hydrocarbon group that may be substituted with a hetero atom. ] 3. The composition according to claim 2, wherein the compound represented by the general formula (3) is a compound represented by the following general formula (7).

(7)
[Wherein, A represents a diarylmethyl group or a triarylmethyl group, and each aryl is independently selected from the group consisting of unsubstituted or substituted aryl groups, and X is a nitrogen atom, R ₈ Is a hydrogen atom, a hydrogen atom or a carbon atom of 3 to 8 carbon atoms optionally substituted with a hetero atom
The aromatic hydrocarbon group includes a group in which X is present in the ring. ] The compound represented by the general formula (7) is one or more selected from 1- (diphenylmethyl) imidazole (compound 1) and 1- (triphenylmethyl) imidazole (compound 2). A composition according to claim 3, characterized.

1- (Diphenylmethyl) imidazole (Compound 1)

1- (Triphenylmethyl) imidazole (Compound 2) The compound represented by the general formula (3), characterized in that a compound represented by the following general formula (4) The composition of claim 2.

(4)
[ Wherein , A represents a diarylmethyl group or a triarylmethyl group, and the aryl is independently selected from the group consisting of unsubstituted or substituted aryl groups , X represents a nitrogen atom, and R ₄ Represents a hydrogen atom, a hydrogen atom or a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms in which a carbon atom may be substituted with a hetero atom, and the ring of the cyclic aliphatic hydrocarbon group is a group other than R ₄ A ring formed by re-bonding one end to X is also included . ] The compound represented by the general formula (4) is 1- (diphenylmethyl) pyrrolidine (compound 9), 1- (triphenylmethyl) pyrrolidine (compound 10), 1- (diphenylmethyl) piperidine (compound 11), 6. The composition according to claim 5, wherein the composition is one or more selected from 1- (triphenylmethyl) piperidine (compound 12).

1- (Diphenylmethyl) pyrrolidine (Compound 9)

1- (Triphenylmethyl) pyrrolidine (Compound 10)

1- (Diphenylmethyl) piperidine (Compound 11)

1- (Triphenylmethyl) piperidine (Compound 12) The compound represented by the general formula (3), characterized in that a compound represented by the following general formula (5) A composition according to claim 2.

(5)
[ Wherein , A represents a diarylmethyl group or a triarylmethyl group, and the aryl is independently selected from the group consisting of unsubstituted or substituted aryl groups , X is an oxygen atom, and R ₅ is A hydrogen atom, a hydrogen atom or a carbon atom may be substituted with a hetero atom, having 1 to 1 carbon atoms
8 represents an aliphatic hydrocarbon . ] The compound represented by the general formula (5) is 2-[(diphenylmethyl) oxy] ethanol (compound 3), 2-[(triphenylmethyl) oxy] ethanol (compound 4), 2-[(diphenylmethyl). The composition according to claim 7, wherein the composition is one or more selected from) oxy] ethylamine (compound 7) and 2-[(triphenylmethyl) oxy] ethylamine (compound 8).

2-[(Diphenylmethyl) oxy] ethanol (compound 3)

2-[(Triphenylmethyl) oxy] ethanol (compound 4)

2-[(Diphenylmethyl) oxy] ethylamine (Compound 7)

2-[(Triphenylmethyl) oxy] ethylamine (Compound 8) The compound represented by the general formula (3), characterized in that a compound represented by the following general formula (6) A composition according to claim 2.

(6)
[ Wherein , A represents a diarylmethyl group or a triarylmethyl group, and the aryl is independently selected from the group consisting of unsubstituted or substituted aryl groups , X represents a nitrogen atom, and R ₆ And R ₇ each independently represent a C 1-8 aliphatic hydrocarbon group in which a hydrogen atom, a hydrogen atom, or a carbon atom may be substituted with a hetero atom. ] The compound represented by the general formula (6) is one or two selected from 2-[(diphenylmethyl) amino] ethanol (compound 5) and 2-[(triphenylmethyl) amino] ethanol (compound 6). Composition according to claim 9, characterized in that it is more than a seed.

2-[(Diphenylmethyl) amino] ethanol (Compound 5)

2-[(Triphenylmethyl) amino] ethanol (Compound 6) The compound represented by the general formula (2), characterized in that a compound represented by the following general formula (8) A composition according to any one of claims 1-10.

(8)
[Wherein R ₉ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, R ₁₀ represents an unsubstituted or substituted aromatic group, and n represents 1 or 2 , M represents an integer of 0 to 3. ] The compound represented by general formula (8), characterized in that a compound represented by the following general formula (9) A composition according to claim 11.

(9)
[Wherein R ₁₁ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₁₂ represents
It represents an unsubstituted or substituted aromatic group, and n represents an integer of 1 or 2. ] 13. The composition according to claim 12, wherein the compound represented by the general formula (9) is N- (p-toluyl) homocysteic acid (compound 18).

N- (p-Toluyl) homocysteic acid (Compound 18) The compound represented by general formula (9), characterized in that a compound represented by the following general formula (10) A composition according to claim 12.

(10)
[Wherein R ₁₃ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₁₄ represents
It represents an unsubstituted or substituted aromatic group. ] The compound represented by the general formula ( 10) is N- (o-toluyl) cysteic acid (compound 13), N- (m-toluyl) cysteic acid (compound 14), N- (p-toluyl) cysteic acid. One or more selected from (Compound 15), N- (p-methoxybenzoyl) cysteic acid (Compound 16) and N- (biphenylcarbonyl) cysteic acid (Compound 17) Item 15. The composition according to Item 14 .

N- (o-Toluyl) cysteic acid (Compound 13)

N- (m-Toluyl) cysteic acid (Compound 14)

N- (p-Toluyl) cysteic acid (Compound 15)

N- (p-methoxybenzoyl) cysteic acid (Compound 16)

N- (biphenylcarbonyl) cysteic acid (Compound 17) The compound represented by the general formula (1) 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 composition. Item 16. The composition according to any one of Items 1 to 15 . 0.0001% by mass to 20% by mass of the compound represented by the general formula (2), an isomer thereof and / or a pharmacologically acceptable salt thereof with respect to the total amount of the composition The composition according to any one of claims 1 to 16 . It said composition characterized in that it is used for whitening composition according to any one of claims 1 to 17. A skin external preparation comprising the composition according to any one of claims 1 to 18 . The skin external preparation according to claim 19, wherein the external preparation for skin is a cosmetic (including quasi-drugs).