JP2011241164A5 - - Google Patents

Description

Composition

  The present invention relates to a composition suitable for cosmetics (including quasi-drugs), foods, and the like. Specifically, 1) a compound represented by the following general formula (1), its isomers and / or them And 2) a whitening component, and a composition.

（１）
[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た炭素数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)
[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 substituted by an aromatic group having R ₃ , R ₃ represents an unsubstituted or substituted aromatic group, n is an integer of 1 or 2, m Represents an integer of 0 to 3. ]

Skin aging phenomena such as wrinkles, stains and sagging become apparent with aging due to genetic factors in addition to accumulation of physicochemical stimuli over many years such as temperature changes, ultraviolet rays and chemical exposure. Such a skin aging phenomenon greatly affects the appearance of others, so it is an important concern for people to keep the beauty of the skin beautiful. Among the skin aging phenomena described above, it has been clarified that skin symptoms such as spots, freckles, and pigmentation after sunburn are caused by melanin production significantly increased by activation of pigment cells (melanocytes) present in the skin. ing. In addition, melanin overproduction in melanocytes is over-transported to keratinocytes (keratinocytes) in addition to normal pigmentation symptoms, inactivating keratinocytes due to accumulation and discharge delay, etc., and worsening skin symptoms such as delamination cause. As described above, since melanin enhancement is deeply involved in skin phenomena caused by various pigmentation, various active ingredients including whitening agents are used to prevent or improve the deterioration of skin symptoms including abnormal pigmentation. R & D has been done. For example, ascorbic acid, hydrogen peroxide, colloidal sulfur, glutathione, hydroquinone, and catechol are known as whitening agents found by such research, and external skin preparations containing these as active ingredients are also widely used. (See, for example, Non-Patent Document 1 and Non-Patent Document 2). Moreover, the action mechanism of the whitening agent created until now is wide-ranging, and melanin production inhibitor (for example, refer to Patent Document 1), tyrosinase enzyme inhibitor (for example, refer to Patent Document 2), tyrosinase enzyme Gene expression inhibitors, α-MSH inhibitors (see, for example, Patent Document 3), antioxidants, and the like have been reported.

Moreover, aiming at a composition having a high whitening effect, in addition to the creation of a novel whitening active ingredient (for example, see Patent Document 4), a combination of a plurality of whitening active ingredients (for example, see Patent Document 5), Studies that enhance skin permeability or storage properties (for example, see Patent Document 6) by combining with specific prescription ingredients have been attempted. However, a certain whitening effect is recognized in attempts to enhance the whitening effect by combining a plurality of whitening components, and further, a combination of a whitening component and a specific prescription component, but until a satisfactory whitening effect is obtained. Has not reached. Furthermore, some external preparations for skin containing the above-mentioned whitening components have problems in stability and safety. On the other hand, as a result of extensive research on the whitening ingredients so far, material resources such as natural products or synthetic compounds have been extensively investigated, and the creation of new active ingredients has become difficult year by year. Attention has been focused more than ever on techniques for effectively exerting the whitening action of ingredients. Further, the whitening agents, although effective in pigmentation abnormalities by conventional melanin production is expected, pigmentation abnormalities associated with skin irritation symptoms caused by such excessive accumulation and discharge delay of melanin definitive in Ke Rachinosai bets, or, Development of a means for improving the darkness that has almost no effect on pigmentation abnormalities such as incurable spots and dullness and that has such skin symptoms has been desired.

Various biological activities are known for 20 kinds of α-amino acids having different side chains including essential amino acids constituting a living body. Among the aforementioned α-amino acids, methionine, cysteine, and derivatives thereof are expected to have characteristic biological activities different from other α-amino acids due to the presence of a sulfur atom in the chemical structure, Attention has been paid. In fact, an acylated derivative of methionine is known to have an antioxidant effect (see, for example, Patent Document 7), and a dipeptide containing methionine has a whitening effect (see, for example, Patent Document 8). In addition, cysteic acid in which the sulfur atom of cysteine is oxidized and homocysteic acid, which is a derivative thereof, are attracting attention as metabolites in living bodies. (See, for example, Patent Document 9). Furthermore, as for cysteic acid and homocysteic acid derivatives, skin peeling or epidermal renewal action on derivatives having a hydrogen atom, linear or branched alkyl or alkenyl group on the nitrogen atom (see, for example, Patent Document 10) Etc. are known. 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 general, when organic compounds containing sulfur atoms in the molecular structure are applied to cosmetics, it is known that there are problems with the generation of off-flavors due to impurities and decomposition products, safety, and stability. ing. On the other hand, the compound represented by the general formula (1) can be stably blended in the composition together with the existing whitening component, and is excellent in the action of effectively enhancing the whitening action. Further, the compound represented by the general formula (1) has no off-flavor due to decomposition or the like even when blended in a composition such as a skin external preparation, and is soluble in a medium used for formulation, particularly a water-soluble medium. It is extremely good and is very stable in the compound and formulation form, so that it has excellent versatility for cosmetics and the like.

JP 2008-208073 A JP 2009-196895 A JP 2001-220347 A JP 2009-263258 A JP 2004-352630 A JP 2007-332115 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, FRAGRANCE JOURNAL Special Issue, No. 14, 1995, 118-126.

  The present invention has been made under such circumstances, abnormal pigmentation due to ultraviolet exposure, especially, abnormal pigmentation due to increased melanin production, more specifically, the amount of melanin present in the collected horny layer cells. It is an object of the present invention to provide a composition such as an external preparation for skin, which is suitable for people who have a large amount of skin.

In view of such a situation, the present inventors, for the prevention or improvement of pigmentation abnormality due to UV exposure, further suitable for the prevention or improvement of pigmentation abnormality due to increased melanin production, etc. And 1) a compound represented by the following general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) a whitening component. The present invention has been completed by finding that such a characteristic is provided in a composition containing a bismuth. That is, the present invention is as follows.
<1> 1) A composition comprising a compound represented by the following general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) a whitening component. .

（１）
[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た炭素数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)
[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 substituted by an aromatic group having R ₃ , R ₃ represents an unsubstituted or substituted aromatic group, n is an integer of 1 or 2, 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 (2), A composition according to <1>.

（２）
[式中、Ｒ ₄ 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 ₅ 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 ₄ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, R ₅ represents an unsubstituted or substituted aromatic group, and n represents 1 or 2 , M represents an integer of 0 to 3. ]

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

（３）
[式中、Ｒ ₆ 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 ₇ 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。]

(3)
[Wherein, R ₆ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, R ₇ represents an unsubstituted or substituted aromatic group, and n represents 1 or 2 Represents an integer. ]

<4> The composition according to <3>, wherein the compound represented by the general formula (3) is N- (p-toluyl) homocysteic acid (compound 6).

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

<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 <3>.

（４）
[式中、Ｒ ₈ 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 ₉ は、無置換又は置換基を有する芳香族基を表す。]

(4)
[Wherein R ₈ represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₉ represents an unsubstituted or substituted aromatic group. ]

<6> The compound represented by the general formula ( 4) is N- (o-toluyl) cysteic acid (compound 1), N- (m-toluyl) cysteic acid (compound 2), N- (p-toluyl). < 4 > characterized in that it is any one of cysteic acid (compound 3), N- (p-methoxybenzoyl) cysteic acid (compound 4), and N- (biphenylcarbonyl) cysteic acid (compound 5). The composition as described.

N−（o−トルイル）システイン酸（化合物１）

N- (o-Toluyl) cysteic acid (Compound 1)

N−（m−トルイル）システイン酸（化合物２）

N- (m-Toluyl) cysteic acid (Compound 2)

N−（p−トルイル）システイン酸（化合物３）

N- (p-Toluyl) cysteic acid (Compound 3)

N−（p−メトキシベンゾイル）システイン酸（化合物４）

N- (p-methoxybenzoyl) cysteic acid (compound 4)

N−（ビフェニルカルボニル）システイン酸（化合物５）

N- (biphenylcarbonyl) cysteic acid (compound 5)

<7> The compound represented by the general formula (1), 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 < 6 >.
<8> the whitening component, melanin production inhibitors, alpha-MSH inhibitor, Dendorai preparative elongation inhibitor of melanocytes, and that it contains one or more members selected from the group consisting of a proton pump inhibitor The composition according to any one of <1> to < 7 >, which is characterized.
< 9 > The composition according to <8> , wherein the melanin production inhibitor is selected from any of the following.
(Melanin production inhibitor): 4- alkylresorcinol and / or salt thereof, ascorbic acid derivative and / or salt thereof, hydroquinone and / or salt thereof, tranexamic acid derivative and / or salt thereof, ursolic acid , Its derivatives and / or their salts, vitamin E and / or its derivatives, pantethein-S-sulfonic acid and / or its salts .
<10> The composition according to <8>, wherein the α-MSH inhibitor is a plant extract obtained from Clariaceae Clara.
<11> The composition according to <8>, wherein the melanocyte dendrite elongation inhibitor is selected from any of the following.
(Dendorai DOO elongation inhibitor for melanocytes): Methyl office opportunistic gona non B, source follower Rafura Bannon A, plant extract obtained from Asteraceae yarrow, a plant extract obtained from Liliaceae Bakumondou.
<12> The composition according to <8>, wherein the proton pump inhibitor is selected from any of the following.
(Proton pump inhibitors): Lamiaceae Thymus vulgaris plants of the genus Extraction obtained from thyme, plant extract obtained from leguminous genus Sophora Clara, plant extract obtained from Zingiberaceae ginger genus ginger, Araceae iris genus calamus From a plant extract obtained from the cucurbitaceae genus Acacha A plant extract obtained, a plant extract obtained from a leguminous genus Toxahahagi .
< 13 > The composition according to any one of <1> to < 12 >, wherein the whitening component is contained in an amount of 0.000001% by mass to 15% by mass with respect to the total amount of the composition .
<14 > The composition according to any one of <1> to <13>, wherein the composition is for whitening.
< 15 > An external preparation for skin , comprising the composition according to any one of <1> to <13> .
<16> The skin external agent characterized in that it is a water-in-oil emulsifier type external skin preparation according to <15>.
<17> The external skin preparation according to <15> or <16>, wherein the external skin preparation is a cosmetic.

<The compound represented by the general formula (1) of the present invention, its isomer and / or pharmacologically acceptable salt thereof>
The composition of the present invention comprises 1) a compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) a whitening component. To do. The compound represented by the general formula (1) of the present invention, its isomer and / or pharmacologically acceptable salt thereof is a whitening component of the present invention described later, specifically, a melanin production inhibitor. , Α-MSH inhibitor, melanocyte dendrite elongation inhibitor, and one or two or more whitening components selected from the group consisting of proton pump inhibitors are included in the composition to enhance the whitening effect. To do. The whitening action in the present invention specifically refers to the prevention or improvement of pigmentation due to UV exposure, as well as the enhancement of melanin production in melanocytes by stimulating UV exposure, excessive transport of melanin to keratinocytes, accumulation and discharge delay, etc. It means the effect of preventing or improving pigmentation abnormalities such as abnormal skin pigmentation accompanied by rough skin such as delamination caused by cell inactivation of keratinocytes, irreparable stains, dullness and the like. The compound represented by the general formula (1), its isomer and / or pharmacologically acceptable salt thereof is a component that enhances the whitening effect by being contained in the composition together with the whitening component described later. If possible, it can be applied without any particular limitation, more preferably a component that enhances the prevention or improvement action of pigmentation abnormality caused by UV exposure, more preferably due to excessive production of melanin by stimulation such as UV exposure A component that enhances the effect of preventing or improving pigmentation can be suitably exemplified. In fact, in people with pigmentation abnormalities caused by UV exposure, excessive UV exposure causes melanin to be produced in the pigment cells (melanocytes) of the skin, and keratinization occurs due to excessive transport of melanin to keratinocytes (keratinocytes). It is recognized as a rough skin phenomenon, causing damage such as cell inactivation and turnover delay. In those who have abnormal pigmentation due to UV exposure, when the stratum corneum is prepared, the appearance rate of nucleated cells is higher than the average, and skin symptoms such as delamination of the skin are observed. Is done. 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 (1) 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 substituted by an aromatic group having 1 to 4 carbon atoms, R ₃ represents an unsubstituted or substituted group N represents an integer of 1 or 2, and m represents an integer of 0 to 3. R ₁ 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, A propyl group, a butyl group, a pentyl group, 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 substituted with an aromatic group having 1 to 4 carbon atoms, and specific examples For example, 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 group, metho Cibenzyl group, ethoxybenzyl group, hydroxybenzyl group, aminobenzyl group, N-methylaminobenzyl group, N-ethylaminobenzyl group, chlorobenzyl group, fluorobenzyl group, trifluoromethylbenzyl group, naphthylmethyl group, biphenylmethyl group A phenylethyl group, a naphthylethyl group, a biphenylethyl group, a phenylpropyl group, a naphthylpropyl group, a biphenylpropyl group, a phenylbutyl group, a naphthylbutyl group, a biphenylbutyl group, and the like, more preferably a hydrogen atom, Preferred examples include a phenyl group and a benzyl group. 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 (1), preferred are the compounds represented by the general formula (2), isomers thereof and / or pharmacologically acceptable salts thereof. More preferably, a compound represented by the general formula (3), an isomer thereof and / or a pharmacologically acceptable salt thereof can be preferably exemplified, and more preferably, the general formula (4) is exemplified. ), Its isomers and / or their pharmacologically acceptable salts. Specific examples of preferable compounds among the compounds represented by the general formula (1) include N-benzoylcysteic acid, N- (o-toluyl) cysteic acid (compound 1), N- (m -Toluyl) cysteic acid (compound 2), N- (p-toluyl) cysteic acid (compound 3), N- (p-methoxybenzoyl) cysteic acid (compound 4), N- (biphenylcarbonyl) cysteic acid (compound 5) ), N- (p-toluyl) homocysteic acid (Compound 6), its isomers and / or their pharmacologically acceptable salts. When such a compound is contained in the composition together with a whitening component to be described later, it exhibits an excellent effect of enhancing the preventive or improving action against pigmentation abnormality caused by exposure to ultraviolet rays. 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 (2) will be described. In the formula, R ₄ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₅ 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 ₄ 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 ₅ 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, A bromophenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a pyridyl group, a naphthyl group, a biphenyl group and the like can be preferably exemplified, and a hydrogen atom, a phenyl group and a benzyl group can be suitably exemplified. R ₅ 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. 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 (2) that are not included in the compound represented by the general formula (3) or (4) 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'-methylaminobenzylcarbonyl) 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) cysteic acid et Chiruesuteru, 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 San'e chill 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 Chiruesu Le, 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- (butyl) Xylbenzylcarbonyl) 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 - (methylcarbamoyl Le benzylcarbonyl) homocysteine San'e Chiruesuteru, N - (ethyl benzylcarbonyl) homocysteine San'e Chiruesuteru, N - (propyl benzylcarbonyl) homocysteine San'e Chiruesuteru, N - (butyl benzyl carbonyl) homocysteic acid ethyl ester, 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'-methylamino 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. Among the compounds represented by the general formula (2), preferred are N-benzoylcysteic acid, N- (o-toluyl) cysteic acid (compound 1), N- (m-toluyl) cysteic acid (compound 2), N- (p-toluyl) cysteic acid (compound 3), N- (p-methoxybenzoyl) cysteic acid (compound 4) , N- ( biphenylcarbonyl) cysteic acid (compound 5), N- (p- Toluyl) homocysteic acid (compound 6), isomers thereof and / or pharmacologically acceptable salts thereof can be suitably exemplified. When such a compound is contained in the composition together with a whitening component to be described later, it exhibits an excellent effect of enhancing the preventive or improving action against pigmentation abnormality caused by exposure to ultraviolet rays. 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 (3) will be described. In the formula, R ₆ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₇ represents nothing. Represents a substituted or substituted aromatic group, and n represents an integer of 1 or 2. R ₆ 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 a propyl group. 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 ₇ 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, A bromophenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a pyridyl group, a naphthyl group, a biphenyl group and the like can be preferably exemplified, and a hydrogen atom, a phenyl group and a benzyl group can be suitably exemplified. R ₅ 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. 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 (3) that are not included in the compound represented by the general formula (4) 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) homosystem Acid, 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 Nzoyl) 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- (full Lobenzoyl) 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 Esters, N- (N ′, N′-diethylaminobenzoyl) homocysteine acid ethyl ester, N- (chlorobenzoyl) homocysteine acid ethyl ester, N- (fluorobenzoyl) homocysteine acid ethyl ester, N- (difluorobezoyl) ) Homocysteine acid ethyl ester Ter, N- (trifluoromethylbenzoyl) homocysteine acid ethyl ester, N- (naphthylcarbonyl) homocysteine acid ethyl ester, N- (biphenylcarbonyl) homocysteine acid ethyl ester, isomers thereof and / or their pharmacology A particularly acceptable salt can be suitably exemplified. Among the compounds represented by the general formula (3), N-benzoylcysteic acid, N- (o-toluyl) cysteic acid (compound 1), N- (m-toluyl) cysteic acid (compounds) are preferable. 2), N-(p-toluyl) cysteic acid (compound 3), N-(p-methoxybenzoyl) cysteic acid (compound 4), N-(biphenyl carbonyl) cysteine acid (compound 5), N-(p -Toluyl) homocysteic acid (compound 6), its isomers and / or pharmacologically acceptable salts thereof can be preferably exemplified. When such a compound is contained in the composition together with a whitening component to be described later, it exhibits an excellent effect of enhancing the preventive or improving action against pigmentation abnormality caused by exposure to ultraviolet rays. 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 (4) will be described. In the formula, R ₈ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₉ represents nothing. A substituted or substituted aromatic group is represented. R ₈ 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 ₉ 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 preferably exemplified, and a hydrogen atom, a phenyl group, and a benzyl group can be suitably exemplified. Specific examples of preferable compounds among the compounds represented by the general formula (5) 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′-diethylaminoben) Yl) 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 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) Stearic 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′- Tylaminobenzoyl) 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)
Cysteinic acid ethyl ester, N- (trifluoromethylbenzoyl) cysteic acid ethyl ester, N- (naphthylcarbonyl) cysteic acid ethyl ester, N- (biphenylcarbonyl) cysteic acid ethyl ester, isomers thereof and / or their pharmacology A particularly acceptable salt can be suitably exemplified. Among the compounds represented by the general formula (4), preferred are N-benzoylcysteic acid, N- (o-toluyl) cysteic acid (compound 1), N- (m-toluyl) cysteic acid (compound 2) N-(p-toluyl) cysteic acid (compound 3), N-(p-methoxybenzoyl) cysteic acid (compound 4), N-(biphenyl carbonyl) cysteine acid (compound 5), its isomers and Preferred examples thereof include pharmacologically acceptable salts thereof. Such a compound has an effect of enhancing the excellent pigmentation prevention or improvement action by being contained in the composition together with the whitening component described later. When such a compound is contained in the composition together with a whitening component to be described later, it exhibits an excellent effect of enhancing the preventive or improving action against pigmentation abnormality caused by exposure to ultraviolet rays. 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 (1), its isomer and / or pharmacologically acceptable salt thereof, together with the whitening component described later, is contained in the composition, thereby providing an excellent whitening effect. It has a potentiating effect, especially an excellent enhancing effect on the prevention or improvement of pigmentation abnormalities caused by UV exposure. Such enhancement effect of preventing or improving pigmentation is caused by abnormal pigmentation between the compound represented by the general formula (1), its isomer and / or pharmacologically acceptable salt, and a whitening component. In addition to the preventive or improving action against the substance or in addition to the synergistic action, the action of improving the delivery efficiency of the active ingredient to the target site, and the whitening action of the compound represented by the general formula (1) it is conceivable that. In addition to the racemic compound (DL form), the compounds represented by the general formulas (1) to (4) 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 formulas (1) to (4), isomers thereof and / or pharmacologically acceptable salts thereof are commercially available cysteic acid, homocysteic acid, and derivatives thereof. Can be produced by carrying out deprotection, coupling, and introduction of a protecting group according to the methods described in “Basics and Experiments of Peptide Synthesis (Maruzen)”, etc. It can also be produced by a method. When such a compound is contained in the composition together with a component having a whitening effect as described later, the effect of preventing or improving pigmentation due to UV exposure is enhanced, especially, due to excessive production of melanin due to stimulation such as UV exposure. It can also be used to enhance the effect of preventing or improving pigmentation, but it can also be treated with a pharmacologically acceptable acid or base, converted into a salt form, and used as a salt. For example, mineral salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, para Organic acid salts such as toluene sulfonate and benzene sulfonate, alkali metals such as sodium salt and potassium salt, alkaline earth metals such as calcium salt and magnesium salt, triethylamine salt, triethanolamine salt, ammonium salt, monoethanol amine salts, organic amine salts such as piperidine salts, lysine salts, and basic amino acid salts such as arginine salts suitably be exemplified.

The compound represented by the general formula (1) of the present invention, its isomer and / or pharmacologically acceptable salt thereof works together with the whitening component described later, whitening action, particularly, pigmentation by exposure to ultraviolet rays. In order to exert an enhancing effect on the prevention or improvement of abnormality, the total amount is 0.0001% by mass to 20% by mass, and more preferably 0.001% by mass to 10% by mass with respect to the total amount of the composition.
It is preferable to contain 0.01 mass%-5 mass% more preferably. This is because if the amount is too small, the above effect may not be achieved, and if the amount is too large, the effect may reach its peak and the degree of freedom of the system may be impaired.

N−（o−トルイル）−L−システイン酸（化合物１のL異性体）

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

<Production Example 1: Synthesis of L isomer of Compound 1>
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 20 ml of water 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 1 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 (1H, m), 7.24 (2H, m), 7.35 (2H, m).
FAB-MS (negative ion mode): M / z = 286 ([M−H] ⁻ )

N−（m−トルイル）−Ｌ−システイン酸（化合物２のＬ異性体）

N- (m-Toluyl) -L-cysteic acid (L isomer of compound 2)

<Production Example 2: Synthesis of L isomer of Compound 2>
3 g ( 17.7 mmol) of L-cysteic acid (Tokyo Chemical Industry Co., Ltd.), 18 mL of tetrahydrofuran ( Wako Pure Chemical Industries, Ltd.), and 18 mL of water were placed in a 100 mL eggplant-shaped flask, and then placed in an ice bath. And cooled. After cooling sufficiently, potassium carbonate 4.40 g ( 31.6 mmol) (Wako Pure Chemical Industries, Ltd.) and m-toluoyl chloride 2.19 g ( Tokyo Kasei Kogyo Co., Ltd.) should be kept from rising. Sequentially added. After reacting for 1 hour in an ice bath, 1.09 g of m-toluoyl 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 filtrate was concentrated and 18 mL of water 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 2 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 (negative ion mode): M / z = 286 ([M−H] ⁻ )

N−（p−トルイル）−Ｌ−システイン酸（化合物３のＬ異性体）

N- (p-Toluyl) -L-cysteic acid (L isomer of compound 3)

<Production Example 3: Synthesis of L isomer of Compound 3>
L- cysteic acid monohydrate 5 g (26.7 mmol) (Sigma-Aldrich), 1,4-dioxane 2 0 mL (Wako Pure Chemical Industries, Ltd.), and were placed water 1 0 mL to 10 0 mL eggplant type flask Then, it was cooled in an ice bath. After sufficiently cooling, 8 (N) 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 crystal collected by filtration was dried to obtain 9 g ( 20.2 mmol) of the L isomer of compound 3 having the above structure. 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 (negative ion 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４のＬ異性体）

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

<Production Example 4: Synthesis of L isomer of compound 4>
2 g ( 11.8 mmol) of L-cysteic acid (Tokyo Chemical Industry Co., Ltd.), 12 mL of tetrahydrofuran ( Wako Pure Chemical Industries, Ltd.) and 12 mL of water were placed in a 100 mL eggplant type flask and then placed in an ice bath. And cooled. After sufficiently cooling, the liquid temperature of potassium carbonate 2.9 4 g ( 21.3 mmol) (Wako Pure Chemical Industries, Ltd.) and 4-methoxybenzoyl chloride 1.6 1 g ( Tokyo Chemical Industry Co., Ltd.) is prevented from rising. Sequentially added. After reacting for 1 hour in an ice bath, 4-methoxybenzoyl chloride 0.8 1 g ( 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 4 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 (negative ion mode): 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５のＬ異性体）

N- (biphenylcarbonyl) -L-cysteic acid (L isomer of compound 5)

<Production Example 5: Synthesis of L isomer of compound 5>
2 g ( 11.8 mmol) of L-cysteic acid (Tokyo Chemical Industry Co., Ltd.), 12 mL of tetrahydrofuran ( Wako Pure Chemical Industries, Ltd.) and 12 mL of water were placed in a 100 mL eggplant type flask and then placed in an ice bath. And cooled. After sufficiently cooling, the liquid temperature of potassium carbonate 2.9 4 g ( 21.3 mmol) (Wako Pure Chemical Industries, Ltd.) and 4-phenylbenzoyl chloride 2.0 5 g ( Tokyo Chemical Industry Co., Ltd.) is prevented from rising. Sequentially added. 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 5 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 (negative ion mode): M / z = 348 ([M−H] ⁻ )

N−（p−トルイル）ホモシステイン酸（化合物６）

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

<Production Example 6: Synthesis of Compound 6>
DL-homocysteic acid 2 g ( 10.9 mmol) (Sigma Aldrich), tetrahydrofuran 12 mL ( Wako Pure Chemical Industries, Ltd.) and water 12 mL were placed in a 100 mL eggplant-shaped flask and then 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. 9 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 compound 61.9 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 (negative ion mode): M / z = 300 ([M−H] ⁻ )

<Whitening component which is an essential component of the composition of the present invention>
The composition of the present invention comprises 1) a compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) a whitening component. To do. The whitening component of the present invention can be applied without particular limitation as long as it has a whitening action, more preferably a melanin production inhibitor, an α-MSH inhibitor, a melanocyte dendrite elongation inhibitor, a proton pump. Inhibitors can be preferably exemplified. The whitening component of the present invention not only has a whitening effect in itself, but also in the composition together with the compound represented by the general formula (1), its isomer and / or pharmacologically acceptable salt thereof. By containing, it has the effect of enhancing the preventive or ameliorating action against abnormal pigmentation due to ultraviolet exposure, and in particular, the action of enhancing the preventive or improving action of pigmentation caused by excessive production of melanin by stimulation such as ultraviolet exposure. Suitable examples of the whitening component include simple chemical substances and plant-derived extracts containing the compound. Here, the extract derived from a plant, plant extracts themselves, fractionated plant extracts, purified fractions, also plant extracts fractionation means generic name for solvent removal of purified product. When the whitening component is contained in the composition together with the compound represented by the general formula (1), its isomer and / or pharmacologically acceptable salt thereof, it is selected from the group consisting of the whitening component. It is possible to contain only one kind of whitening component, or two or more kinds may be contained in combination.

Among the whitening components in the present invention, the melanin production inhibitor will be described. The melanin production inhibitor of the present invention can be applied without particular limitation as long as it has a melanin production inhibitory action, and more preferably, for example, a melanin production inhibitory action test described in JP-A-2009-155236. In the above, a component exhibiting a melanin production inhibitory effect of 50% or more at a test substance addition concentration that does not exhibit cytotoxicity can be suitably exemplified. Specific examples of preferred melanin production inhibitors include 4- alkylresorcinol and / or their pharmacologically acceptable salts, ascorbic acid derivatives and / or their pharmacologically acceptable. Salts, hydroquinone derivatives and / or their pharmacologically acceptable salts, tranexamic acid derivatives and / or their pharmacologically acceptable salts, vitamin E, their derivatives and / or their pharmacological properties Preferred examples include an acceptable salt, pantethein-S-sulfonic acid and / or a pharmacologically acceptable salt thereof. Other whitening components include 4-alkoxysalicylic acid such as 4-methoxysalicylic acid and / or pharmacologically acceptable salts thereof, 5,5′-dipropyl-biphenyl-2,2′- diol, etc. Biphenyl derivatives and / or their pharmacologically acceptable salts, nicotinic acid derivatives such as nicotinamide and / or their pharmacologically acceptable salts, unsaturated fatty acids such as linoleic acid and / or their A pharmacologically acceptable salt of

Among the melanin production inhibitors described above, 4- alkylresorcinol and / or pharmacologically acceptable salts thereof will be described. The 4- alkylresorcinol derivative of the present invention can be applied without particular limitation as long as it is a 4- alkylresorcinol and / or pharmacologically acceptable salt thereof having a melanin production inhibitory effect, and more preferably. The 4-position resorcinol 4-position alkyl group has a linear or branched alkyl group having 1 to 10 carbon atoms, more preferably a linear or branched alkyl group having 3 to 7 carbon atoms. Preferred examples include alkylresorcinol and / or pharmacologically acceptable salts thereof. Specific examples of preferred 4- alkylresorcinol and / or pharmaceutically acceptable salts thereof include 4- methylresorcinol , 4- ethylresorcinol , 4
- propyl resorcinol, 4- (1-methylethyl) resorcinol, 4-n-butyl resorcinol, 4- (2-methylpropyl resorcinol), 4- (1-methylethyl resorcinol), 1-ethylpropyl resorcinol, 1-ethyl 2-methylpropyl resorcinol , 1-isopropyl-2-methylpropyl resorcinol , 1-butylpentyl resorcinol , 1-isopropyl-2-methylpropyl resorcinol , 1-butylpentyl resorcinol , 1-isobutyl-3-methylbutyl resorcinol , 4- (1-methylpropyl) resorcinol, 4- (1-methylbutyl) resorcinol, 4-tert-butyl resorcinol and / or salts that are their pharmacologically acceptable can preferably exemplified, more preferably, 4 n- butyl resorcinol and / or a pharmacologically acceptable salt thereof suitably be exemplified.

The 4- alkylresorcinol and / or pharmacologically acceptable salt thereof together with the compound represented by the general formula (1), its isomer and / or pharmacologically acceptable salt thereof In order to exert the effect of enhancing the effect of preventing or improving pigmentation abnormality, the total amount of the compound is 0.0001% by mass to 5% by mass, more preferably 0.001% by mass with respect to the total amount of the composition. % To 3% by mass, more preferably 0.01% to 2% 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.

The 4- alkylresorcinol is a method in which a carboxylic acid having a corresponding alkyl group and resorcin are condensed in the presence of zinc chloride and reduced with zinc amalgam / hydrochloric acid, or an alcohol having a corresponding alkyl group and resorcin are 200. Known synthesis methods such as a method of condensation at a high temperature of ˜400 ° C. (for example, Lille, J .; Bitter, LA; Peiner, V. Trudy-Nauchono- Issledovatel 'skii Institut Slantsev (1969), No. 18, 127-134, Japanese Patent Application Laid-Open No. 2006-124358, and Japanese Patent Application Laid-Open No. 2006-124357), or commercially available reagents.

Among the melanin production inhibitors, ascorbic acid derivatives and / or pharmacologically acceptable salts thereof will be described. The ascorbic acid derivatives and their pharmacologically acceptable salts of the present invention are applicable without particular limitation as long as they are ascorbic acid derivatives having a melanin production inhibitory action and / or their pharmacologically acceptable salts. More preferably, water-soluble ascorbic acid derivatives and / or pharmacologically acceptable salts thereof can be preferably exemplified. Specific examples of the ascorbic acid derivatives and / or pharmacologically acceptable salts thereof include ascorbic acid, ascorbic acid phosphate, ascorbic acid-2-glycoside (simply referred to as ascorbic acid glucoside) And / or pharmacologically acceptable salts thereof can be suitably exemplified, and ascorbic acid, ascorbic acid-2-glucoside and / or pharmacologically acceptable salts thereof are more preferable. Can be illustrated.

The ascorbic acid, derivative thereof and / or pharmacologically acceptable salt thereof is a compound represented by the general formula (1), isomer thereof and / or pharmacologically acceptable salt thereof. In order to work together with the enhancement effect on the prevention or improvement of pigmentation abnormality, the total amount is 0.1% by mass to 10% by mass, more preferably 0.5% by mass to 5% by mass with respect to the total amount of the composition. % Content is preferable. 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.

Among the melanin production inhibitors, hydroquinone derivatives and / or pharmacologically acceptable salts thereof will be described. The hydroquinone derivatives and their pharmacologically acceptable salts of the present invention can be applied without particular limitation as long as they are hydroquinone derivatives having an inhibitory action on melanin production and their pharmacologically acceptable salt conductors. More preferably, a hydroquinone glycoside can be preferably exemplified. As the sugar chain portion of the hydroquinone glycoside, pentoses such as L- arabinose , D- xylose , D- ribose , D- xylulose , D- lyxose , D- ribulose , D- glucose , D- galactose , Preferred examples include hexoses such as D- mannose , D- tagalose , D- fructose , and L- sorbose , and amino acid sugars such as D-glucosamine, D-galactosamine, sialic acid, and muramic acid. Furthermore, as uronic acid or its methyl compound and acetyl compound, uronic acids such as D-glucuronic acid, D-galacturonic acid, D-mannuronic acid, and L-iduronic acid or their methyl compounds and acetyl compounds can be preferably exemplified. . Among these compounds, arbutin having a chemical structure in which hydroquinone and glucose are bonded and / or a pharmacologically acceptable salt thereof can be preferably exemplified.

The hydroquinone derivative can be obtained by a conventional method from hydroquinone and a corresponding sugar. For example, arbutin can be synthesized in a solution composed of hydroquinone and glucose by an enzymatic reaction using β- glucosidase (for example, Japanese Patent Laid-Open No. 05-176785).

The hydroquinone derivative and / or a pharmacologically acceptable salt thereof together with the compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof. In order to exert a potentiating effect on the action or prevention or improvement of pigmentation abnormality, the total amount is 0.001% by mass to 5% by mass, and more preferably 0.1% by mass to 3% by mass with respect to the total amount of the composition. It is preferable to contain. 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.

  Among the melanin production inhibitors, tranexamic acid, its derivatives and / or pharmacologically acceptable salts thereof will be described. The tranexamic acid derivative and / or pharmacologically acceptable salt thereof of the present invention is not particularly limited as long as it is a tranexamic acid derivative having a melanin production inhibitory action and / or a pharmacologically acceptable salt thereof. Can adapt. Specific examples of preferable tranexamic acid derivatives and pharmacologically acceptable salts thereof include tranexamic acid, tranexamic acid methylamide, and / or pharmacologically acceptable salts thereof. More preferable examples include tranexamic acid and / or a pharmacologically acceptable salt thereof.

The tranexamic acid derivative and / or pharmacologically acceptable salt thereof is a compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof. In order to work together and to enhance the effect of preventing or improving pigmentation abnormality due to UV exposure, the total amount is 0.01% by mass to 10% by mass, more preferably 0.05% by mass with respect to the total amount of the composition. -5% by mass, more preferably 0.1% by mass to 3% 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.

Among the above melanin production inhibitors, ursolic acid, derivatives thereof and / or pharmacologically acceptable salts thereof will be described. The ursolic acid, derivative thereof and pharmacologically acceptable salt thereof of the present invention are not particularly limited as long as it is ursolic acid having a melanin production inhibitory effect, derivative thereof and pharmacologically acceptable salt thereof. Can adapt without any problem. Specific examples of preferable ursolic acid, its derivatives and pharmacologically acceptable salts thereof include ursolic acid , ursolic acid phosphate ester (see, for example, WO2006132033), ursolic acid benzyl ester. (For example, refer to Table 2007-148474) and / or pharmacologically acceptable salts thereof can be suitably exemplified.

In addition, the ursolic acid, its derivative and / or pharmacologically acceptable salt thereof is the compound represented by the general formula (1), its isomer and / or their pharmacologically acceptable. In order to work together with the salt and exert an enhancement effect on the prevention or improvement of pigmentation abnormality, the total amount is 0.001% by mass to 10% by mass, more preferably 0.01% by mass to It is preferable to contain 5 mass%, More preferably, 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.

Of the aforementioned melanin production inhibitors, vitamin E, its derivatives and / or pharmacologically acceptable salts thereof will be described. Vitamin E of the present invention, its derivatives and / or pharmacologically acceptable salts thereof are special if it is vitamin E having a melanin production inhibitory action, its derivatives and pharmacologically acceptable salts thereof. It can be applied without limitation. Specific examples of preferred vitamin E, derivatives thereof and pharmacologically acceptable salts thereof include vitamin E, vitamin E acetate , vitamin E nicotinate , vitamin E orotate and / or their pharmacological properties. Suitable salts can be preferably exemplified, and more preferably, vitamin E and / or pharmacologically acceptable salts thereof can be suitably exemplified.

  In addition, the vitamin E, derivative thereof and / or pharmacologically acceptable salt thereof is a compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof. In order to work together with the salt and exert an enhancement effect on the prevention or improvement of pigmentation abnormality, the total amount is 0.05% by mass to 10% by mass, more preferably 0.2% by mass to 5 mass%, More preferably, it is preferable to contain 0.5 mass%-3 mass%. This is because if the amount is too small, the above effect may not be achieved, and if the amount is too large, the effect may reach a limit and the degree of freedom of the system may be impaired.

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

In addition, the pantethein-S-sulfonic acid and / or a pharmacologically acceptable salt thereof is a compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof. In order to work together with the added salt and exert an enhancement effect on the prevention or improvement of abnormal pigmentation, the total amount is 0.001% by mass to 1.0% by mass, and more preferably 0.005%. It is preferable to contain from 0.01% by mass to 0.3% by mass, more preferably from 0.01% by mass to 0.8% 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.

The α-MSH production inhibitor will be described. The α-MSH production inhibitor of the present invention can be applied without particular limitation as long as it is a component having an α-MSH production inhibitory action. Examples of the component having an α-MSH production inhibitory action include a component having an action of reducing the amount of c-AMP produced in cultured cells in the α-MSH production inhibitory action evaluation system described in JP-A-2009-0667804. Can be suitably exemplified. As such a component, a plant extract obtained from a plant belonging to the leguminous family Claraaceae can be preferably exemplified, and more preferably, a plant extract obtained from a leguminous family Clara genus Clara can be suitably exemplified. α-MSH production suppressor suppresses intracellular c-AMP production by inhibiting α-MSH production of an important signaling substance involved in melanin production in vivo, or inhibiting intercellular communication. And suppress melanin production.

The α-MSH production inhibitor works together with the compound represented by the general formula (1), isomers thereof and / or pharmacologically acceptable salts thereof, and prevents or improves pigmentation abnormality. In order to exert an enhancing effect, the total amount is 0.00001% by mass to 15% by mass, more preferably 0.0001% by mass to 10% by mass, and more preferably 0.01% by mass to the total amount of the composition. It is preferable to contain 5 mass%. This is because if the amount is too small, the above effect may not be achieved, and if the amount is too large, the effect may reach a limit and the degree of freedom of the system may be impaired.

  The melanocyte dendrite elongation inhibitor will be described. The melanocyte dendrite elongation inhibitor of the present invention can be applied without particular limitation as long as it is a component having a melanocyte elongation inhibitory action. As a component which has the dendrite extension inhibitory action of the melanocyte of this invention, the component which has a dendrite extension inhibitory action in the evaluation of the dendrite extension inhibitory action of the melanocyte of Unexamined-Japanese-Patent No. 2009-0465503 can be illustrated suitably. Specific examples of such ingredients include methyl ophiopogononone B, sophoraflavanone A, plant extracts obtained from Asteraceae Achillea millefolium, plant extracts obtained from Lily family Bakumondo, and the like. In addition to abnormal pigmentation due to increased melanin production, the melanocyte dendrite elongation inhibitor is also effective against abnormal pigmentation caused by increased migration of melanin granules from melanocyte dendrite, which does not contribute much to melanin production.

The melanocyte dendrite elongation inhibitor works together with the compound represented by the general formula (1), isomers thereof and / or pharmacologically acceptable salts thereof to prevent or improve the pigmentation abnormality. In order to exert the enhancing effect, the total amount is preferably 0.01% by mass to 10% by mass, and more preferably 0.05% 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.

The proton pump inhibitor will be described. The proton pump inhibitor of the present invention can be applied without particular limitation as long as it is a component having a proton pump inhibitory action. The proton pump inhibitor is a membrane H ⁺ -ATPase that exists in a biological membrane and actively transports protons and / or Na ⁺ / H that works in conjunction with Na ⁺ / K ⁺ -ATPase of an ion pump and passively transports protons. ⁺ Acts on exchange transport systems, etc., acts on biological functional molecules that regulate proton concentration in cells or organelles, and excels in acidification in cells or organelles by inhibiting proton transport . Acidification in a cell or organelle has a great influence on the biological activity or function of a biofunctional molecule such as an ion channel or enzyme (for example, tyrosinase ) that works in a pH-dependent manner. Tyrosinase, a key enzyme in melanin production, since Ru greatly affected by the pH variation, it inhibits melanin production reduces tyrosinase activity by acidification. As a component which has the proton pump inhibitory action of this invention, the component which shows a proton pump inhibitory action in the proton pump inhibitory action evaluation of Japanese Patent Application No. 2009-219292 can be illustrated suitably, for example. Of the components having proton pump inhibitory activity of the present invention, preferred examples are specifically exemplified: plants belonging to the genus Lamiaceae, genus Clara, plants belonging to the genus Clariaceae, cucurbitaceae A plant extract obtained from a plant belonging to the genus Hetchima, a plant belonging to the genus Hydrangeaceae, a plant belonging to the genus Sarcophagus matsuhodo, a plant belonging to the genus Leguminosae can be suitably exemplified, more preferably from the genus Thymus Obtained plant extract, plant extract obtained from leguminous clara genus clara, plant extract obtained from ginger family ginger genus ginger, plant extract obtained from taro family ginger genus ginger, obtained from cucurbitaceae Plant extract, plant extract obtained from Hydrangeaceae Hydrangea amacha, Sarnokoshika Plant extracts obtained from family Wolfiporia Extensa sclerotia Bukuryou, plant extract obtained from leguminous clover genus Kihagi, plant extract obtained from leguminous gores genus Toukusahagi be suitably be exemplified.

The component having the proton pump inhibitory action works together with the compound represented by the general formula (1), isomers thereof and / or pharmacologically acceptable salts thereof, and prevents or improves the pigmentation abnormality. In order to exert an enhancing effect on the total amount of the composition, the total amount is 0.000001% by mass to 10% by mass, more preferably 0.00001% by mass to 5% by mass, and still more preferably 0.0001% by mass. It is preferable to contain -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.

In addition, among simple whitening agents such as melanin production inhibitors, α-MSH inhibitors, melanocyte dendrite elongation inhibitors, proton pump inhibitors and the like, which are essential components of the present invention, the compounds may be used as they are. It can be used as a pharmacologically acceptable salt form. These salts can be used without any particular limitation as long as they are used in skin external preparations, for example, alkali salts such as sodium salts and potassium salts, calcium salts, magnesium salts, etc. Preferred examples include organic earth salts such as alkaline earth metal salts, ammonium salts, triethylamine salts, triethanolamine salts and monoethanolamine salts , and basic amino acid salts such as lysine salts and arginine salts . Moreover, as long as it is a salt with an acid, mineral acid salts, such as hydrochloride, phosphate, sulfate, and nitrate, organic acid salts, such as carbonate, citrate, and tartrate, etc. can be illustrated suitably.

  Such a whitening component is included in the composition together with the compound represented by the general formula (1), its isomer and / or a pharmacologically acceptable salt thereof, thereby allowing excellent pigmentation by exposure to ultraviolet rays. This shows the effect of enhancing the prevention or improvement of pigmentation caused by excessive production of melanin by stimulation such as exposure to ultraviolet rays, and particularly, the prevention or improvement of prevention. Such an enhancement effect of preventing or improving pigmentation is caused by the pharmacological effect of the compound represented by the general formula (1), its isomer and / or pharmacologically acceptable salt, and a whitening component. This is considered to be due to the effect of improving the delivery efficiency of the whitening component to the target site, as well as the pharmacological activity of the compound represented by the general formula (1), in addition to the additive or synergistic effect.

<Composition of the present invention>
The composition of the present invention comprises 1) a compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) a whitening component. To do. The compound represented by the general formula (1) of the present invention, its isomers and / or pharmacologically acceptable salts thereof are contained in the composition together with the above-described whitening component, whereby a whitening action, specifically Specifically, it shows the effect of enhancing the effect of preventing or improving pigmentation by exposure to ultraviolet rays, particularly the effect of enhancing the effect of preventing or improving pigmentation caused by excessive production of melanin by stimulation such as exposure to ultraviolet rays. Such an enhancement effect of preventing or improving pigmentation is caused by the pharmacological effect of the compound represented by the general formula (1), its isomer and / or pharmacologically acceptable salt, and a whitening component. In addition to an additive or synergistic effect, the effect of improving the delivery efficiency of the whitening component to the target site, and further, the compound represented by the general formula (1), its isomer and / or their pharmacological properties It is thought to be due to pharmacological activity such as whitening effect of the acceptable salt. In addition, the above-mentioned ultraviolet ray exposure causes abnormal pigmentation, and at the same time, overproduction of melanin in melanocytes, and cell inactivation of keratinocytes such as excessive transport, accumulation and elimination of melanin to keratinocytes, It is observed that the deterioration of skin symptoms due to damage such as turnover delay occurs. The composition of the present invention is preferably used for a person who exhibits rough skin symptoms caused by excessive production and transport of melanin in addition to preventing or ameliorating abnormal pigmentation. When a person with such skin symptoms is observed, phenomena such as an increase in nucleated cells and delamination are observed. Therefore, it is also effective to narrow down the target to be used using these as an index.

In addition, a preparation of a composition comprising 1) a compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) a whitening component. In preparation, it can contain optional components used in the preparation of ordinary foods, pharmaceuticals, cosmetics and the like. 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. The cosmetics are not particularly limited as long as the water-in-oil emulsifier form can be applied. For example, basic cosmetics such as essences, emulsions, creams , under-makeups , foundations , cheek colors , mascaras, eyeliners. makeup cosmetics such as, such as hair cosmetics such as hair cream can be preferably exemplified.

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. Oils such as hardened oil, mole, castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba wax, waxes , liquid paraffin, squalane, pristane, ozokerite, paraffin, ceresin, petrolatum , 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 , di-2-ethylhexanoic acid ethylene glycol , dicaprate neopentyl glycol , di-2-heptylundecanoic acid glycerin, tri-2-ethylhexanoic acid glycerin, tri-2-ethylhexanoic acid trimethylolpropane , tri isostearate 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, Oil agents such as silicone oil such as modified polysiloxane such as fluorine-modified polysiloxane, anionic surfactants such as fatty acid soap (sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, triethanolamine ether of alkyl sulfate , chloride Cationic surfactants such as stearyltrimethylammonium, benzalkonium chloride, laurylamine oxide , imidazoline-based amphoteric surfactants (2-cocoyl-2-imida Zolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), betaine surfactants (alkyl betaine, amide betaine, sulfobetaine, etc.), amphoteric surfactants such as acylmethyltaurine , sorbitan fatty acid esters ( sorbitan) monostearate, sorbitan sesquioleate etc.), ethers of glycerin fatty acid (glycerol monostearate and the like), propylene glycol fatty acid esters (propylene glycol monostearate, etc.), hardened castor oil derivatives, glycerin alkyl ether, POE sorbitan fatty acid esters (POE sorbitan monooleate, monostearate polyoxyethylated sorbitan, etc.), POE sorbitol fatty acid esters (POE- sorbit monolaurate), POE glycerol fatty acid Ester compounds (POE- glyceryl monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate and the like), POE alkyl ether - ethers (POE2- octyldodecyl ether), POE alkylphenyl ethers (POE nonyl Phenyl ether, etc.), Pluronic type, POE / POP alkyl ethers ( POE / POP2-decyltetradecyl ether, etc.), Tetronics , POE castor oil / hardened castor oil derivatives (POE castor oil, POE hardened castor oil, etc.) , 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 Mother, calcium carbonate, magnesium carbonate, silicic anhydride (silica), 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, an inorganic pigment such as titanium oxide, zinc oxide may be surface treated mica titanium, Sakanarinhaku, pearl agent such as bismuth oxychloride, good red No. 202 be laked red 228, Red 226, Yellow 4, Blue 404, Yellow 5, Red 505, Red 230, Red 223, Orange 201, Red 213, Yellow 204, Yellow 203, Blue 1 Organic powders such as green 201, purple 201, red 204 , polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane elastomer, etc. S, p-aminobenzoic acid UV absorbers, anthranilic acid UV absorbers, salicylic acid ultraviolet absorbers, Katsura peel acid UV absorbers, Baie benzophenone-based ultraviolet absorbents, sugar-based ultraviolet absorber, 2- (2' UV absorbers such as hydroxy-5′-t-octylphenyl) benzotriazole , 4-methoxy-4′-t-butyldibenzoylmethane, lower alcohols such as ethanol and isopropanol , vitamin A or a derivative thereof, vitamin B ₆ hydrochloride, vitamin B ₆ tripalmitate , vitamin B ₆ dioctanoate, vitamin B ₂ or its derivative, vitamin B ₁₂ such as vitamin B ₁₂ , vitamin B ₁₅ or its derivative , α-tocopherol , β-tocopherol , γ-tocopherol , Vitamin E acetate , vitamin E, vitamin D, vitamin H, bread Toten acid, pantethine, vitamins pyrroloquinoline quinone such like, antibacterial agents such as phenoxyethanol, hectorite, organic modified clay minerals such as dimethyl distearyl ammonium modified hectorite may be preferably exemplified.

Among such optional components, organically modified clay minerals are particularly preferable. Here, the organic modified, also covalently bond a portion of the organic compound in a part of the clay mineral firmly via ionic bonds
Or give rise to a loose coupling, method No part or of the nature of the organic compound means that is imparted to the clay minerals, As such modified coupling the anion moiety of the quaternary amine groups and clay minerals A method of binding a carboxyl group and a cation part of a clay mineral can be exemplified, and a method of binding a quaternary amine group and an anion part of a clay mineral can be particularly preferably exemplified. Although it does not necessarily limit as a compound which has a quaternary amino group which modifies a clay mineral, The compound called quaternium is illustrated. Quotanium is a low molecular weight substituted quaternary ammonium salt, and is preferably a cosmetic raw material registered in International Standard Cosmetic Ingredients (INCI). Furthermore, the compound having a quaternary amino group that modifies the clay mineral is preferably a quaternium compound contained in a conventional external skin preparation among quaternium compounds. Preferred examples of the quaternium compound used in conventional external preparations for skin include stearyl trimethyl ammonium chloride and dimethyl distearyl ammonium chloride. Among them, dimethyl distearyl ammonium chloride is particularly preferable. This is because two long-chain alkyl groups are contained in one molecule, so that it is easy to make a structure that sterically holds the oil phase. Stearyl trimethyl ammonium chloride, dimethyl distearyl ammonium chloride, and the like are preferable because they can form a stable aqueous oil-in-water component emulsion structure together with clay minerals. In particular, when the aqueous component is an oil-in-water emulsion, an emulsion having a continuous phase as an oil phase can be formed without significantly affecting the oil-in-water emulsion. preferable. On the other hand, as a clay mineral (unmodified clay mineral) modified with a compound having a quaternary amino group, any clay mineral contained in a conventional external preparation for skin can be used without particular limitation. Preferred clay minerals contained in conventional skin external preparations include smectite-type hectorite, bentonite, montmorillonite , kaolinite , illite , marine clay mineral (sea mud) , desert rose clay mineral, and pascalite. Among these, bentonite, hectorite, montmorillonite or kaolinite which can stabilize the water-in-oil emulsion structure is preferably exemplified. Among them, hectorite and montmorillonite are particularly preferable because they have a firm layer structure in minerals and can easily orient cation molecules. An example of a method for producing a clay mineral modified with a compound having a quaternary amino group contained in the external preparation for skin of the present invention will be described below. The unmodified clay mineral is dispersed in a dispersion medium. The dispersant is preferably an aqueous solvent, and may be water. A compound having a quaternary amino group is further added to the dispersion containing the dispersed unmodified clay mineral and stirred well. The compound having a quaternary amino group may be added after being dissolved in water. The amount of the compound having a quaternary amino group to be added is preferably 0.1 to 20% by mass, and more preferably 0.5 to 15% by mass with respect to the amount of the dispersed unmodified clay mineral. This is because by taking such a configuration, a preferable feeling of use is exhibited in the emulsification system. After stirring, the dispersoid is filtered, dehydrated and dried to obtain the modified clay mineral in the present invention. Or the modified clay mineral in this invention can also be obtained by removing a dispersing agent by concentrating under reduced pressure without filtering a dispersoid, and making it dry. The obtained modified clay mineral is preferably pulverized to a desired size (preferably having a particle size of 1 to 1000 μm) and contained in the skin external preparation of the present invention. The modified clay mineral in the present invention can be prepared and used as described above, but a commercially available one can also be used. Some modified clay minerals on the market are used as external preparations for skin such as cosmetics. Preferable examples of commercially available modified clay minerals include dimethyl distearyl ammonium modified hectorite sold under the name “Benton 38V” by Elementis. In the skin external preparation of this invention, this component is contained preferably 0.5 mass%-10 mass%, More preferably, 1 mass%-5 mass% are contained. In such a range, the compound represented by the general formula (1) or the whitening component can be stabilized and formulated into a water-in-oil emulsifier form. Here, the water-in-oil emulsifier form described in the present invention is a general term for an emulsifier form in which an oil phase is present in the outermost phase, a form in which water phase drops are dispersed in the oil phase, and an oil-in-water emulsified drop in the oil phase. Any form in which the is dispersed can be employed. In addition, when employ | adopting such a water-in-oil emulsifier form, it is preferable to contain 0.1-5 mass% of polyether modified methyl polysiloxane as an auxiliary | assistant surfactant. Such polyether- modified methylpolysiloxanes are commercially available, and such commercial products can be purchased and used. Preferred commercially available products, manufactured by Shin-Etsu Chemical Co., Ltd. of "Silicone KF6017" can be suitably exemplified.

When diglycerin monooleate and / or triglycerin diisostearate is contained as an emulsifier, 0.5 to 2 times the mass of the emulsifier may be included together with a polyhydric alcohol such as maltitol or sorbitol . preferable. As the raw material for cosmetics of diglycerin monooleate, to be mentioned "Nikkol DGMO-C" (manufactured by Nihon Surfactant Co., Ltd.) is preferred, as a raw material for cosmetics of triglycerol diisostearate is "Emeresuto “2452” (manufactured by Emery Co., Ltd.) is preferable. The preferable content of this component is 1 to 10% by mass, more preferably 2 to 7% by mass, based on the total amount of the external preparation for skin. This is because if the amount is out of this range, emulsification may not be possible or the stability of the solution may be impaired.

In the external preparation for skin of the present invention, in addition to the above-mentioned components, both oily components and aqueous components are difficult to dissolve, especially, hardly soluble in nonpolar components such as silicones such as dimethicone and hydrocarbons such as liquid paraffin. Examples of such components that preferably contain such components and are difficult to dissolve include phytosterol glycosides and glycosphingolipids. Such an ingredient is an active ingredient having preferable functions such as a photoaging prevention effect, a turnover adjusting effect, and a moisturizing effect on the skin, and the phytosterol is a general term for plant sterols , the sterols, stigmastanol, campesterol, such as sitosterol is resides, collectively these, are collectively referred to as phytosterols. Phytosterol glycosides, in which sugar chain is bonded to the phytosterols. As the phytosterol glycosides from plant material such as wheat germ, remove the sterol glycoside fraction containing a plurality of phytosterol glycosides In many cases, cosmetic raw materials obtained by purifying only such fractions are also commercially available, and such commercial raw materials of the present invention can be purchased and used. Usually, such components often contain glycosphingolipids extracted at the same time. Examples of such commercially available materials include “Phytosteside” sold by Okayasu Shoten Co., Ltd. About 85% by mass of such “phytosteside” is a glycoside of phytosterol , and about 15% by mass is a glycosphingolipid. The preferable content of such an insoluble active ingredient, especially a solid component, is 0.05 to 0.5% by mass.

Since the external preparation for skin of the present invention takes the form of a water-in-oil emulsifier, silicone , particularly preferably, cyclomethicone and / or a viscosity of 1 mPa -It is preferable to contain the dimethicone below s, and as content of this silicone , it is preferable to contain 10-50 mass% with respect to cosmetics whole quantity, More preferably, it is 20-40 mass% The sum of the contents of cyclomethicone and dimethicone having a viscosity of 1 mPa · s or less is preferably 50% by mass or more, more preferably 55% by mass or more based on the total amount of the oil phase.

When the organically modified clay mineral is used as an emulsifier, a preferable optional component other than the above components is exemplified by a polyhydric alcohol that can stabilize the emulsified state. Particularly preferred are glycerin, diglycerin and dipropylene glycol . Such a component may contain only one species or may contain two or more species in combination. A preferable content is 5-30 mass% with respect to the total amount of skin external preparations in total, More preferably, it is 10-25 mass%. In addition, the addition of 3 to 7% by mass of one or more selected from 1,2 -pentanediol , 1,2-hexanediol and 1,2-octanediol also improves antiseptic power. From the viewpoint of making it.

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 Example 7: Method 1 for producing skin external preparation of the present invention>
According to the formulations described in Tables 1 and 2, water-in-oil emulsifier type cosmetics ( creams ) were prepared. That is, each of the components (a), (b), and (c) is heated to 80 ° C., and (d) is added and dissolved in (b), kneaded to form a gel, and then added to (b) and diluted. The mixture was emulsified with water, stirred and cooled to prepare cosmetics 1 to 11 in the form of a water-in-oil emulsifier, which is a skin external preparation of the present invention. 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” in the formulation component of the cosmetic 1, and “the whitening component of the present invention” was replaced with “water”. A comparative example 2 in which “the compound represented by the general formula (1) of the present invention” and “a whitening component of the present invention” were both replaced with “water” was prepared.

<Test Example 1: Evaluation 1 of pigmentation inhibitory effect of the external preparation for skin of the present invention>
The pigmentation inhibitory effect was investigated using the water-in-oil emulsifier type cosmetics (cosmetics 1-11) and the cosmetics of Comparative Examples 1-3. A test site of 1.5 cm × 1.5 cm was provided on the first day (1st day) on the back of the panelists who participated voluntarily, and the skin lightness (L * value) of the test site was measured using a color difference meter (CR-300, Konica Minolta Co., Ltd.). After the skin brightness was measured on the first day of the test, the test site was irradiated with ultraviolet rays twice the minimum erythema amount (2 MED) once. Each specimen (Cosmetics 1-11 or Comparative Example 1) was applied to each test site three times a day for 14 consecutive days immediately after the end of ultraviolet irradiation.
~ 3 cosmetics) was applied. 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 1-11 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 the cosmetics 1-11. Thereby, it turns out that the cosmetics 1-11 which are the skin external preparations of this invention show the outstanding pigmentation inhibitory effect.

<Production Example 8: Method 2 for producing external preparation for skin of the present invention>
A cosmetic composition in which the contents of the “compound represented by the general formula (1) of the present invention” and the “whitening component of the present invention” contained in the cosmetic compositions 1 to 3 are changed is described in Production Example 7 . The pigmentation inhibitory effect by ultraviolet exposure was examined. The content of the components is as described 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.

<Test Example 2: Evaluation 2 of pigmentation inhibitory effect of the external preparation for skin of the present invention>
The water-in-oil emulsifier type cosmetics 12 to 17 produced by the method described in Production Example 8 , and further, Comparative Example 3 produced according to the method described in Production Example 7, and the pigment according to the test method described in Test Example 1 The deposition inhibitory action was evaluated. The results are shown in Table 5. From the results in Table 5, it can be seen that the cosmetics 12 to 17 which are the external preparation for skin of the present invention show an excellent pigmentation inhibitory effect.

<Test Example 3: Evaluation of pigmentation inhibitory effect 3 of the external preparation for skin of the present invention>
Cosmetics 19 in which “Benton 38V” is replaced with “ Silicone KF6017” in the prescription ingredients of Cosmetic 1 described in Production Example 7 , and “19,2- pentanediol ” is replaced with “polyethylene glycol 400” Was made. Furthermore, regarding the cosmetic 18, the cosmetic 19, and the comparative example 3, when the pigmentation inhibitory action by ultraviolet exposure was evaluated according to the method described in Test Example 1 , the ΔL * value of the cosmetic 18 was −4.01, △ L * value of the cosmetic 19, -4.03, △ L * value of comparative example 3, was shown the value of -4.11.

<Test Example 4: Evaluation of inhibitory effect on pigmentation of skin external preparation of the present invention 4>
For cosmetics 1 to 3 and Comparative Examples 1 to 3 produced according to the method described in Production Example 7 , the pigmentation inhibitory action was evaluated 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. Divided into portions the upper and lower two stages of 1.5 cm × 1.5 cm on both the upper inner arm of the panelists who participated voluntarily having the characteristics, provided a total of four locations, one day UV irradiation minimal erythema dose (1 MED) Irradiated once 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 1-3 which are the skin external preparations of this invention show the outstanding pigmentation inhibitory effect.

<Production Example 9: Production of health food of the present invention>
According to the prescription shown in Table 7 and Table 8, health foods (health foods 1 to 11) were prepared. That is, the formulation components rolling phase granulated with 10 parts by weight of water (manufactured by Fuji Paudal Co., Ltd., "New Marumerizer") to obtain a tablet-shaped health food and then pressed into tablets. In addition, the unit of the numerical value in a table | surface represents a weight part. This health food had excellent pigmentation prevention or improvement action.

  The present invention can be applied to whitening cosmetics, foods and the like.

Claims (17)

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

(1)
[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 substituted by an aromatic group having R ₃ , R ₃ represents an unsubstituted or substituted aromatic group, n is an integer of 1 or 2, 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 (2), A composition according to claim 1.

(2)
[Wherein, R ₄ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, R ₅ 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 the general formula (2), characterized in that a compound represented by the following general formula (3) A composition according to claim 2.

(3)
[Wherein, R ₆ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, R ₇ represents an unsubstituted or substituted aromatic group, and n represents 1 or 2 Represents an integer. ] 4. The composition according to claim 3, wherein the compound represented by the general formula (3) is N- (p-toluyl) homocysteic acid (compound 6).

  N- (p-Toluyl) homocysteic acid (Compound 6) The compound represented by the general formula (3), characterized in that a compound represented by the following general formula (4) The composition of claim 3.

(4)
[Wherein R ₈ represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₉ represents an unsubstituted or substituted aromatic group. ] The compound represented by the general formula ( 4) is N- (o-toluyl) cysteic acid (compound 1), N- (m-toluyl) cysteic acid (compound 2), N- (p-toluyl) cysteic acid. 6. The composition according to claim 5 , which is any one of (Compound 3), N- (p-methoxybenzoyl) cysteic acid (Compound 4), and N- (biphenylcarbonyl) cysteic acid (Compound 5). object.

N- (o-Toluyl) cysteic acid (Compound 1)

N- (m-Toluyl) cysteic acid (Compound 2)

N- (p-Toluyl) cysteic acid (Compound 3)

N- (p-methoxybenzoyl) cysteic acid (compound 4)

N- (biphenylcarbonyl) cysteic acid (compound 5) 0.0001% by mass to 20% by mass of the compound represented by the general formula (1), 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 6 . The whitening component contains one or more selected from the group consisting of a melanin production inhibitor, an α-MSH inhibitor, a melanocyte dendrite elongation inhibitor, and a proton pump inhibitor. The composition according to any one of claims 1 to 7 . The composition according to claim 8 , wherein the melanin production inhibitor is selected from any of the following.
(Melanin production inhibitor): 4-alkylresorcinol and / or their salts, ascorbic acid derivatives and / or their salts, hydroquinone and / or their salts, tranexamic acid derivatives and / or their salts, ursolic acid, their derivative conductors and / or their salts, vitamin E and / or derivatives thereof, pantetheine -S- sulfonic acid and / or salts thereof. The composition according to claim 8, wherein the α-MSH inhibitor is a plant extract obtained from a legume Clara genus Clara. The composition according to claim 8, wherein the dendrite elongation inhibitor of melanocytes is selected from any of the following.
(Dendrite extension inhibitor of melanocytes): Methyl ophiopogononone B, Sophoraf
A plant extract obtained from Labanon A, Asteraceae Achillea millefolium, or a plant extract obtained from Lilyaceae Bakumondo. The composition according to claim 8, wherein the proton pump inhibitor is selected from any of the following.
(Proton pump inhibitor): Plant extract obtained from Lamiaceae genus Thymus, plant extract obtained from Leguminous clara genus Clara, plant extract obtained from Ginger ginger genus Ginger, taro family Ginger genus Obtained plant extract, plant extract obtained from Cucurbitaceae genus Hachima, plant extract obtained from Hydrangeaceae hydrangea Achacha, plant extract obtained from Sarcophagaceae Plant extract obtained from leguminous hagi spruce spruce. The whitening component, relative to the total amount of the composition, characterized in that it contains 0.000001% by weight to 15% by weight, the composition according to any one of claims 1 to 12. It said composition characterized in that it is used for whitening composition according to any one of claims 1 to 13. A skin external preparation comprising the composition according to any one of claims 1 to 13. The skin external preparation according to claim 15 , wherein the skin external preparation is in the form of a water- in- oil emulsifier. The external preparation for skin according to claim 15 or 16, wherein the external preparation for skin is a cosmetic.