JP5911293B2 - Topical skin preparation - Google Patents

Description

The present invention, cosmetics (including quasi-drugs) relates suitable skin external preparation etc., particularly, 1) a compound represented by the following general formula (1), its optical isomers and their drug and one or more selected from pharmacologically acceptable salts thereof, 2) Advanced Gurike Activation end Products (AGEs: about Advanced glycation end-products) decomposing agent containing a skin external preparation.

（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、炭素数１〜４の直鎖若しくは分岐のアルキル基、無置換若しくは置換基を有する芳香族基、又は無置換若しく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の直鎖若しくは分岐のアルキル基を表し、Ｒ _３ は、無置換又は置換基を有する芳香族基を表し、mは、０〜３の整数、ｎは、１又は２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
Hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an unsubstituted or an aromatic group having a substituent, or an unsubstituted or by straight having 1 to 4 carbon atoms substituted by an aromatic group having a substituent It represents a chain or branched alkyl group, R ₃ represents an unsubstituted or substituted aromatic group, m represents an integer of 0 to 3, and n represents an integer of 1 or 2. ]

  Changes in the physical shape of the skin, such as wrinkles and sagging, changes in the appearance, such as blotches and dullness, and skin texture deterioration such as a decrease in skin transparency and gloss are skin symptoms that manifest with aging and are independent. Rather, it is perceived as a skin aging phenomenon intricately intertwined. Such exacerbation of skin symptoms has a great influence on the impression that others have, so it is an important concern for people to keep the beauty of the skin beautiful. For this reason, various researches have been conducted to find a means for preventing or improving the skin aging phenomenon and regaining the youthful skin. However, at present, no satisfactory means have been obtained.

  As one of the action mechanisms for preventing or improving such a skin aging phenomenon, advanced glycation end-products (AGEs) are attracting attention. In 1912, L. C. AGEs discovered as a result of non-enzymatic condensation reactions of amino acids and reducing sugars, discovered by Mallard, include dozens of compounds with different characteristics (eg, crosslin, pyropyridine, pentosidine, pyralin, carboxymethyllysine, etc.) It exists and is known to exhibit various properties. Regarding AGEs, the relationship with various diseases such as diabetic vascular complications, arteriosclerosis, and Alzheimer's disease has been reported (for example, see Non-Patent Document 1). In addition, regarding AGEs of the skin, it is present in the epidermis (for example, see Patent Document 1) and the dermis, and further, it prevents or improves pigmentation such as dullness by suppressing the production of dermal AGEs (for example, , See Patent Document 2). On the other hand, the existence of AGEs in the stratum corneum and its biological activity have not yet been elucidated. Therefore, there is a possibility that the stratum corneum AGEs may exhibit biological activity through a mechanism of action different from that of conventional AGEs in the skin, and the ingredients that act on the stratum corneum AGEs prevent or prevent the aforementioned skin aging phenomenon. An improvement effect can be expected.

  Moreover, in most cases, a protein constituting a living body is composed of 20 kinds of α-amino acids having different side chains called essential amino acids. It is known that the α-amino acid is involved in various biological activities in a living body in addition to the function of constituting a biological component. Among the α-amino acids, cysteine and its derivatives contain sulfur atoms in the molecular structure, and therefore biological activity different from other α-amino acids is expected. Applications to cross-disciplinary fields have been made. However, α-amino acid derivatives containing sulfur atoms have poor stability in compositions such as amino acids themselves or topical skin preparations when blended in cosmetics and the like, and furthermore, a bad odor due to decomposition products is generated. In many cases, the use of such is limited. Furthermore, as for cysteic acid derivatives, cysteic acid and cysteic acid derivatives having an aliphatic acyl group on the nitrogen atom thereof are oil-soluble base materials (see, for example, Patent Document 3), surfactants (eg, It is known to have activities such as mucolytic activity and antioxidant activity (see, for example, Patent Literature 5). On the other hand, the compound represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof have an effect of preventing or improving wrinkle formation (see, for example, Patent Document 6). It has been reported that there is a preventive or ameliorating action against pigmentation due to ultraviolet exposure (see, for example, Patent Document 7). However, when both the compound represented by the general formula (1) and the AGEs decomposing agent are contained in a skin external preparation, the skin symptom is prevented or ameliorated, in particular, the pigmentation is prevented or ameliorated, and wrinkles are formed. As far as the inventor is aware, it has not been known that the preventive or ameliorating action against cerebral is enhanced.

JP 2009-008460 A JP 2003-261432 A JP 05-117295 A Japanese Patent Laid-Open No. 08-337563 JP 2003-095915 A WO2010-058730 WO2011-087006

Edited by Shoichi Yamagishi, forefront of AGEs research Current status of glycated protein-related diseases research (Medical Review, P231, (2004)

The present invention has been made under such circumstances, and is suitable for prevention or improvement of skin symptoms, particularly for prevention or improvement of pigmentation due to UV exposure, and prevention or improvement of wrinkle formation. It is an object to provide an external preparation for skin.

In view of such a situation, the present inventors have proposed a skin external preparation suitable for prevention or improvement of skin symptoms, particularly for prevention or improvement of pigmentation due to ultraviolet exposure, and prevention or improvement of wrinkle formation. And 1) one or more selected from the compounds represented by the general formula (1), optical isomers and pharmacologically acceptable salts thereof, and 2) It has been found that an external preparation for skin containing an AGEs degrading agent is excellent in such action, and has completed the present invention. The present invention is as follows.
<1> 1) The following compound of the formula (1), and one or more selected from optical isomers thereof and pharmaceutically acceptable salts thereof pharmacologically, 2) Advanced Gurike Activation End A topical skin preparation characterized by containing products (AGEs: Advanced glycation end-products) degradation agents.

（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、炭素数１〜４の直鎖若しくは分岐のアルキル基、無置換若しくは置換基を有する芳香族基、又は無置換若しく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の直鎖若しくは分岐のアルキル基を表し、Ｒ _３ は、無置換又は置換基を有する芳香族基を表し、mは、０〜３の整数、ｎは、１又は２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
Hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an unsubstituted or an aromatic group having a substituent, or an unsubstituted or by straight having 1 to 4 carbon atoms substituted by an aromatic group having a substituent It represents a chain or branched alkyl group, R ₃ represents an unsubstituted or substituted aromatic group, m represents an integer of 0 to 3, and n represents an integer of 1 or 2. ]

<2> The compound represented by the general formula (1), characterized in that a compound represented by the following general formula (2), the skin external preparation as described in <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、mは、０〜３の整数、nは、１又は２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, and R ₅ represents
It represents an unsubstituted or substituted aromatic group, m represents an integer of 0 to 3, and n represents an integer of 1 or 2. ]

<3> The compound represented by the general formula (2), characterized in Oh <br/> Rukoto compounds represented by the following general formula (3), the skin external preparation as described in <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, and R ₇ represents
It represents an unsubstituted or substituted aromatic group, and n represents an integer of 1 or 2. ]

<4> The compound represented by the general formula (3), characterized in that a compound represented by the following general formula (4), the skin external preparation as described in <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, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₉ represents
It represents an unsubstituted or substituted aromatic group. ]

<5> The compound represented by the general formula (1) to (4), N-(p-torr OIL) cysteic acid (Compound 1), N-(m-torr OIL) cysteic acid (Compound 2 ), N-(o-torr OIL) cysteic acid (compound 3), N-(p-methoxybenzoyl) cysteic acid (compound 4), it is N-(4-phenylbenzoyl) cysteic acid (compound 5) The external preparation for skin according to any one of <1> to <4>, wherein:
The compound represented in <6> above general formula (1) to (3), characterized in that it is N-(p-torr OIL) homocysteic acid (Compound 6), <1> to <3 > The skin external preparation in any one of>.

Ｎ−（ｐ−トルオイル）システイン酸（化合物１）

N-(p-torr OIL) cysteic acid (Compound 1)

Ｎ−（ｍ−トルオイル）システイン酸（化合物２）

N-(m-torr OIL) cysteic acid (Compound 2)

Ｎ−（ｏ−トルオイル）システイン酸（化合物３）

N-(o-torr OIL) 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−（４−フェニルベンゾイル）システイン酸（化合物５）

N- (4-Phenylbenzoyl) cysteic acid (Compound 5)

Ｎ−（ｐ−トルオイル）ホモシステイン酸（化合物６）

N-(p-torr OIL) homocysteic acid (Compound 6)

<7> One or more selected from the compound represented by the general formula (1), optical isomers thereof, and pharmacologically acceptable salts thereof is 0.0001 mass with respect to the total amount of the external preparation for skin. The external preparation for skin according to any one of <1> to <6>, which is contained in an amount of% to 20% by mass.
<8> The skin external preparation according to any one of <1> to <7>, wherein the AGEs decomposing agent is one or more selected from plant extracts obtained from the following plants.
Plants belonging to the (plant) legume Astragalus, a plant belonging to the Oleaceae Olive species, plants belonging to the Saxifragaceae Saxifraga, plant belonging to the Rosaceae Potenchira genus, plants belonging to the Demon Eyes Department of asparagus-to-scan genus in Rosaceae filipendula belongs to the plant, plant <9> said AGEs decomposition agent belonging to the Asteraceae Artemisia genus, legume Astragalus Rengesou, Oleaceae olive species olive, Saxifragaceae Saxifraga saxifrage, Rosaceae Potenchira genus Torumenchira, Rosaceae Potenchira genus Kawarasaiko, rose wherein the family Potenchira genus Miyamakinba Lee, leguminous asparagus toe scan genus rooibos is Rosaceae filipendula Shimotsukesou, one or more selected from a plant extract obtained from Asteraceae Artemisia Artemisia, <1> to <8> The external preparation for skin according to any one of the above.
<10> The external preparation for skin according to any one of <1> to <9>, wherein the AGEs degrading agent has a degrading action of AGEs present in the horny layer of the skin.
<11> The skin external preparation according to any one of <1> to <10>, wherein the AGEs decomposing agent is contained in an amount of 0.0001% by mass to 10% by mass with respect to the total amount of the external preparation for skin.
<12> The skin external preparation according to any one of <1> to <11>, which is a cosmetic.
<13> The external preparation for skin according to any one of <1> to <12>, which is used for prevention or improvement of skin symptoms.
<14> The external preparation for skin according to <13>, wherein the skin symptom is pigmentation by exposure to ultraviolet rays.
<15> The external preparation for skin according to <14>, wherein the pigmentation is caused by abnormal pigmentation involving cell inactivation of keratinocytes caused by melanin overtransport. <16> The external preparation for skin according to <13>, wherein the skin symptom is wrinkle formation.

According to the present invention, suitable for cosmetics (including quasi-drugs) and the like, preventive or ameliorating action on skin symptoms, especially, preventing or ameliorating pigmentation due to UV exposure, and preventing wrinkle formation Or the skin external preparation which is excellent in the improvement effect can be provided.

It is a figure which shows the production | generation suppression effect | action of AGEs in the human stratum corneum of the plant extract obtained from the leguminous genus Astragalus.

The skin external preparation of the present invention contains 1) a compound represented by the above general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) an AGE decomposition agent. It is characterized by that. The external preparation for skin of the present invention is excellent in a preventive or ameliorating action for skin symptoms, in particular, a prophylactic or ameliorating action for pigmentation due to UV exposure, and a prophylactic or improving action for wrinkle formation. The preventive or ameliorating effect on pigmentation due to UV exposure of the present invention is in addition to the preventive or improving effect on pigmentation such as normal sunburn caused by transient or reversible melanin production due to UV exposure, decrease in cellular functions keratinocytes by chronic melanin production promoting hardly heal due to te oleate over bar delay such stains, dullness, furthermore, are encompassed prevention or improvement effect on pigmentation with mild inflammation or rough skin symptoms The Ordinary pigmentation such as sunburn by exposure to ultraviolet rays occurs due to increased melanin production in melanocytes, and the melanin production enhancing action is a transient or reversible biological reaction. On the other hand, if the stimulation due to UV exposure etc. is excessive, melanin production in melanocytes becomes excessive and / or chronically enhanced, and finally it is incurable, dull, light due to abnormal pigmentation Abnormal pigmentation accompanied by inflammation and rough skin will occur. Excessive over-and / or chronic melanin production promoting state by stimulation of such melanocytes, excess transport of melanin to keratinocytes, causing a phenomena such as the storage or discharge delay, decrease cell function of keratinocytes, te oleate chromatography pigmentation abnormal due to the bar delay. In addition, in the process in which such pigmentation abnormality occurs, various information transfer factors represented by cytokines are involved, and pigmentation abnormality accompanied by rough skin symptoms such as inflammation and / or delamination may occur. Many are seen. The external preparation for skin of the present invention can be expected to have an excellent preventive or ameliorating effect against abnormal pigmentation that exhibits such skin symptoms. The skin external preparation of the present invention contains the compound represented by the general formula (1), its optical isomers and / or pharmacologically acceptable salts thereof, and the AGEs decomposing agent in the skin external preparation. Thus, it is possible to additively or synergistically enhance the preventive or ameliorating action against pigmentation due to UV exposure.

On the other hand, among the preventive or ameliorating action of the skin symptoms of the external preparation for skin of the present invention, the preventing or ameliorating action against wrinkle formation includes wrinkles in the formation stage in addition to the improving action against wrinkles already formed, and in the future A preventive or ameliorating action against the formation of wrinkles formed is included. In addition, the prevention or improvement action against wrinkle formation targeted by the external preparation for skin of the present invention can be applied without particular limitation as long as it is the above-described prevention or improvement action against wrinkle formation, but more preferably by ultraviolet exposure. It is preferably a preventive or ameliorating action against wrinkles that are formed. Wrinkles, the formation of slack is known to be closely related to Kola progestogen is an important extracellular matrix. That is, by Kola progestogen content in the skin decreased by an external stimulus, such as aging or UV exposure, network maintaining the skin structure formed by Kola progestogen fiber bundles and the elastic fibers to collapse, Wrinkles and sagging are formed. The compound represented by the general formula (1), acceptable salts thereof as optical isomers and / or manner their pharmacological of the present invention has excellent Kola progestogen production promoting action. Moreover, the skin external preparation of this invention makes the skin external preparation contain the compound represented by the said General formula (1), its optical isomer, and / or those pharmacologically acceptable salts with an AGEs decomposition agent. By this, the prevention or improvement action with respect to wrinkle formation which the compound represented by the general formula (1) has can be additively or synergistically enhanced.

  The following are essential components of the external preparation for skin of the present invention: 1) the compound represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof, and 2 ) AGEs decomposition agent will be explained.

<The compound represented by the general formula (1) of the present invention, its optical isomer and / or pharmacologically acceptable salt thereof>
The skin external preparation of the present invention contains 1) a compound represented by the above general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) an AGE decomposition agent. It is characterized by that. When the compound represented by the general formula (1) of the present invention, its optical isomer and / or pharmacologically acceptable salt thereof is contained in a skin external preparation together with the AGEs degrading agent described later, the skin Excellent preventive or ameliorating action on symptoms, preventing or ameliorating action on pigmentation due to exposure to ultraviolet rays, etc., and preventing or improving action on wrinkle formation. Further, the compound represented by the general formula (1) of the present invention, optical isomers thereof and / or pharmacologically acceptable salts thereof have a whitening action and a preventive or improving action against wrinkle formation. It is known. However, by including the compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof and an AGEs decomposing agent, such an effect is additive or synergistic. As far as the inventor knows, it has not been reported. In addition, since the compounds represented by the general formulas (1) to (4), optical isomers thereof and / or pharmacologically acceptable salts thereof have an asymmetric carbon in their chemical structures, Isomers, optically active isomers (D and L isomers), and racemic mixtures in which both optically active isomers are present in any ratio. The compounds represented by the general formulas (1) to (4) of the present invention exhibit a preventive or ameliorating action against high skin symptoms in any of the above-described embodiments relating to the optically active substance. From the surface, L-form (optically active substance) is particularly preferable.

Among the compounds represented by the above general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof contained in the external preparation for skin of the present invention, preferred are those represented by the general formula The compound represented by (2), its optical isomers and / or pharmacologically acceptable salts thereof can be suitably exemplified, more preferably, the compound represented by the general formula (3), its optical The isomers and / or pharmacologically acceptable salts thereof are preferably exemplified, and more preferably, the compound represented by the general formula (4), the optical isomers and / or the pharmacologically acceptable salts thereof. Suitable salts can be exemplified. Further, it relates to a compound represented by the general formula (1) to (4), if specifically exemplified preferred, N- (Torr OIL) cysteic acid, N- (methoxybenzoyl) cysteic acid, N- (4-phenylbenzoyl) cysteic acid, N- (torr OIL) homocysteic acid, its isomers and / or a pharmaceutically acceptable salt thereof pharmacologically can be preferably exemplified, more preferably, N- (p - torr OIL) cysteic acid (compound 1), N-(m-torr OIL) cysteic acid (compound 2), N-(o-torr OIL) cysteic acid (compound 3), N
- (p-methoxybenzoyl) cysteic acid (Compound 4), (N-4-phenyl-benzoyl) cysteic acid (Compound 5), N-(p-torr OIL) homocysteic acid (Compound 6), its optical isomers And / or pharmacologically acceptable salts thereof can be preferably exemplified.

  When the compound represented by the general formula (1) of the present invention, its optical isomer and / or pharmacologically acceptable salt thereof is contained in a skin external preparation together with the AGEs degrading agent described later, the skin It exhibits an excellent preventive or ameliorating effect on symptoms, in particular, a preventive or ameliorating effect on pigmentation due to UV exposure, and a preventive or improving effect on wrinkle formation. Such an action is obtained by adding a compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, and an AGEs decomposing agent to the external preparation for skin. It is thought that it is a physical additive or synergistic action, and further, an enhancement effect by improving the accumulation property or storage property of both components at the target site. Moreover, the skin external preparation containing the compound represented by the said General formula (1) and an AGEs decomposition agent has high safety in skin sensitization, irritation, etc. In addition, since such compounds have high solubility in general-purpose polar or non-polar media used in the manufacture of external preparations for skin, it is possible to manufacture various forms of external preparations for skin and easy to manufacture. It is.

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, a linear or branched alkyl group having 1 to 4 carbon atoms, an unsubstituted or substituted aromatic group, an unsubstituted or substituted aromatic group, or a straight chain having 1 to 4 carbon atoms or A branched alkyl group is represented, R ₃ represents an unsubstituted or substituted aromatic group, m represents an integer of 0 to 3, and n represents an integer of 1 or 2. 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, an ethyl group, a propyl group and a butyl group can be suitably exemplified, and further preferably Can be preferably exemplified by a hydrogen atom, a methyl group and an ethyl group. R ₂ is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an unsubstituted or substituted aromatic group, an unsubstituted or substituted aromatic group, and 1 carbon atom. Represents a linear or branched alkyl group of ˜4, and specific examples include hydrogen atom, phenyl group, methylphenyl group (toluyl group), ethylphenyl group, propylphenyl group, butylphenyl group, methoxyphenyl group, ethoxy Phenyl group, propyloxyphenyl group, butyloxyphenyl group, hydroxyphenyl group, aminophenyl group, N-methylphenyl group, N-ethylphenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, Chlorophenyl, bromophenyl, fluorophenyl, trifluoromethylphenyl, pyridyl, naphthyl, bif Nyl, benzyl, methylbenzyl, ethylbenzyl, methoxybenzyl, ethoxybenzyl, hydroxybenzyl, aminobenzyl, N-methylaminobenzyl, N-ethylaminobenzyl, chlorobenzyl, fluorobenzyl Group, trifluoromethylbenzyl group, naphthylmethyl group, biphenylmethyl group, phenylethyl group, naphthylethyl group, biphenylethyl group, phenylpropyl group, naphthylpropyl group, biphenylpropyl group, phenylbutyl group, naphthylbutyl group, biphenylbutyl A group etc. can be illustrated suitably, More preferably, a hydrogen atom, a phenyl group, and a benzyl group can be illustrated suitably. R ₃ represents an unsubstituted or substituted aromatic group, and specific examples include a phenyl group, a methylphenyl group (toluyl group), an ethylphenyl group, a propylphenyl group, a butylphenyl group, and a 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 and the like can be suitably exemplified, more preferably phenyl group, methylphenyl group (toluyl group), methoxy A phenyl group, a naphthyl group, and a biphenyl group can be suitably exemplified. . The m represents an integer of 0 to 3, particularly preferably m = 0. The n represents an integer of 1 or 2, and more preferably, n = 1 can be suitably exemplified.
Among the compounds represented by the general formula (1), preferred are the compounds represented by the general formula (2), optical isomers thereof and / or pharmacologically acceptable salts thereof. More preferably, a compound represented by the general formula (3), an optical isomer thereof and / or a pharmacologically acceptable salt thereof can be suitably exemplified, and more preferably, the general formula The compounds represented by (4), optical isomers thereof and / or pharmacologically acceptable salts thereof can be suitably exemplified. Among the compounds represented by the general formula (1), if Specific examples of the preferred compounds, N- benzoyl cysteic acid, N- (Torr OIL) cysteic acid, N- (
Methoxybenzoyl) cysteic acid, N- (phenylbenzoyl) cysteic acid, N- (Torr OIL) homocysteic acid, acceptable salt optical isomers thereof and / or their pharmacologically can be preferably exemplified, further preferably, N-(p-torr OIL) cysteic acid (compound 1), N-(m-torr OIL) cysteic acid (compound 2), N-(o-torr OIL) cysteic acid (compound 3) N- (p-methoxybenzoyl) cysteic acid (compound 4), N- (4-
Phenylbenzoyl) cysteic acid (Compound 5), N-(p-torr OIL) homocysteic acid (Compound 6), its optical isomers and / or their pharmacologically acceptable salts are suitably be exemplified.
Such a compound is contained in an external preparation for skin together with an AGEs degrading agent described later, thereby preventing or ameliorating excellent skin symptoms, especially, preventing or ameliorating pigmentation due to UV exposure, and preventing or improving wrinkle formation. Demonstrates an enhancing effect on action. Such an action is obtained by adding a compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, and an AGEs decomposing agent to the external preparation for skin. It is considered to be a physical additive or synergistic effect, and further an enhancement effect by improving the accumulation property or storage property of both components at the target site. Further, the compound represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof, and a skin external preparation containing an AGEs degrading agent are skin sensitization and High safety in terms of irritation. In addition, since such compounds have high solubility in general-purpose polar or non-polar media used in the manufacture of external preparations for skin, it is possible to manufacture various forms of external preparations for skin and easy to manufacture. It is.

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 a phenyl group, a methylphenyl group (toluyl group), an ethylphenyl group, a propylphenyl group, a butylphenyl group, and a 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 and the like can be suitably exemplified, more preferably phenyl group, methylphenyl group (toluyl group), methoxy A phenyl group, a naphthyl group, and 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.
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) cysteine Acid] methyl ester, [N- (methylbenzylcarbonyl) cysteic acid] methyl ester, [N- (ethylbenzylcarbonyl) cysteic acid] methyl ester, [N- (propylbenzylcarbonyl) cysteic acid] methyl ester, [N- (Butylbenzylcarbonyl) cysteic acid] Ester, [N- (methoxybenzylcarbonyl) cysteic acid] methyl ester, [N- (ethoxybenzylcarbonyl) cysteic acid] methyl ester, [N- (propyloxybezylcarbonyl) cysteic acid] methyl ester, [N- ( Butyloxybenzylcarbonyl) cysteic acid] methyl ester, [N- (hydroxybenzylcarbonyl) cysteic acid] methyl ester, [N- (aminobenzylcarbonyl) cysteic acid] methyl ester, [N- (N′-methylaminobenzylcarbonyl) ) Cysteinic acid] methyl ester, [N- (N′-ethylaminobenzylcarbonyl) cysteic acid] methyl ester, [N- (N
', N'-dimethylaminobenzylcarbonyl) cysteic acid] methyl ester, [N- (N
', N'-diethylaminobenzylcarbonyl) cysteic acid] methyl ester, [N- (chlorobenzylcarbonyl) cysteic acid] methyl ester, [N- (fluorobenzylcarbonyl) cysteic acid] methyl ester, [N- (difluorobenzylcarbonyl) ) Cysteic acid] methyl ester, [N- (trifluoromethylbenzylcarbonyl) cysteic acid] methyl ester, [N- (benzylcarbonyl) cysteic acid] ethyl ester, [N- (methylbenzylcarbonyl) cysteic acid] ethyl ester, [N- (ethylbenzylcarbonyl) cysteic acid] ethyl ester, [N- (propylbenzylcarbonyl) cysteic acid] ethyl ester, [N- (butylbenzylcarbonyl) cysteic acid] ethyl ester, [N- (methoxybenzylcarbonyl) Cysteine ] Ethyl ester, [N- (ethoxybenzylcarbonyl) cysteic acid] ethyl ester, [N- (propyloxybezylcarbonyl) cysteic acid] ethyl ester, [N- (butyloxybenzylcarbonyl) cysteic acid] ethyl ester, [ N- (hydroxybenzylcarbonyl) cysteic acid] ethyl ester, [N- (aminobenzylcarbonyl) cysteic acid] ethyl ester, [N- (N′-methylaminobenzylcarbonyl) cysteic acid] ethyl ester, [N- (N '-Ethylaminobenzylcarbonyl) cysteic acid] ethyl ester, [N- (N', N'-dimethylaminobenzylcarbonyl) cysteic acid] ethyl ester, [N- (N ', N'-diethylaminobenzylcarbonyl) cysteic acid ] Ethyl ester, [N- (chlorobenzylcarbonyl) cysteine ] Ethyl ester, [N- (fluorobenzylcarbonyl) cysteic acid] ethyl ester, [N- (difluorobenzylcarbonyl) cysteic acid] ethyl ester, [N- (trifluoromethylbenzylcarbonyl) cysteic acid] ethyl ester, N- (Phenylethylcarbonyl) cysteic acid, N- (methylphenylethylcarbonyl)
Cysteic acid, N- (ethylphenylethylcarbonyl) cysteic acid, N- (propylphenylethylcarbonyl) cysteic acid, N- (butylphenylethylcarbonyl) cysteic acid, N- (methoxyphenylethylcarbonyl) cysteic acid, N- ( Ethoxyphenylethylcarbonyl) cysteic acid, N- (propyloxyphenylethylcarbonyl) cysteic acid, N- (butyloxyphenylethylcarbonyl) cysteic acid, N- (hydroxyphenylethylcarbonyl) cysteic acid, N- (aminophenylethylcarbonyl) ) Cysteic acid, N- (N'-methylaminophenylethylcarbonyl) cysteic acid, N- (N'-ethylaminophenylethylcarbonyl) cysteic acid, N- (N ', N'-
Dimethylaminophenylethylcarbonyl) cysteic acid, N- (N ′, N′-diethylaminophenylethylcarbonyl) cysteic acid, N- (chlorophenylethylcarbonyl) cysteic acid, N- (fluorophenylethylcarbonyl) cysteic acid, N- ( Difluorophenylethylcarbonyl) cysteic acid, N- (trifluoromethylphenylethylcarbonyl) cysteic acid, N- (phenylpropylcarbonyl) cysteic acid, N- (methylphenylpropylcarbonyl) cysteic acid, N- (ethylphenylpropylcarbonyl) Cysteinic acid, N- (propylphenylpropylcarbonyl) cysteic acid, N- (butylphenylpropylcarbonyl) cysteic acid, N- (methoxyphenylpropylcarbonyl) cysteic acid, N- (ethoxy Phenylpropylcarbonyl) cysteic acid, N- (propyloxyphenylpropylcarbonyl) cysteic acid, N- (butyloxyphenylpropylcarbonyl) cysteic acid, N- (hydroxyphenylpropylcarbonyl) cysteic acid, N- (aminophenylpropylcarbonyl) Cysteinic acid, N- (N
'-Methylaminophenylpropylcarbonyl) cysteic acid, N- (N'-ethylaminophenylpropylcarbonyl) cysteic acid, N- (N', N'-dimethylaminophenylpropylcarbonyl) cysteic acid, N- (N ', N′-diethylaminophenylpropylcarbonyl) cysteic acid, N- (chlorophenylpropylcarbonyl) cysteic acid, N- (fluorophenylpropylcarbonyl) cysteic acid, N- (difluorophenylpropylcarbonyl) cysteic acid, N- (trifluoromethylphenylpropiate) Rucarbonyl) cysteic acid, N- (benzylcarbonyl) homocysteic acid, N- (methylbenzylcarbonyl) homocysteic acid, N- (ethylbenzylcarbonyl) homocysteic acid, N- (propylbenzylcarbonyl) homocysteine Acid, N- (butylbenzylcarbonyl) homocysteic acid, N- (methoxybenzylcarbonyl) homocysteic acid, N- (ethoxybenzylcarbonyl) homocysteic acid, N- (propyloxybezylcarbonyl)
Homocysteic acid, N- (butyloxybenzylcarbonyl) homocysteic acid, N- (hydroxybenzylcarbonyl) homocysteic acid, N- (aminobenzylcarbonyl) homocysteic acid, N- (N′-methylaminobenzylcarbonyl) homo Cysteinic acid, N-
(N′-ethylaminobenzylcarbonyl) homocysteic acid, N- (N ′, N′-dimethylaminobenzylcarbonyl) homocysteic acid, N- (N ′, N′-diethylaminobenzylcarbonyl) homocysteic acid, N— (Chlorobenzylcarbonyl) homocysteic acid, N- (fluorobenzylcarbonyl) homocysteic acid, N- (difluorobenzylcarbonyl) homocysteic acid, N- (trifluoromethylbenzylcarbonyl) homocysteic acid, [N- (benzylcarbonyl) ) Homocysteic acid] ethyl ester, [N- (methylbenzylcarbonyl) homocysteine acid] ethyl ester, [N- (ethylbenzylcarbonyl) homocysteine acid] ethyl ester, [N- (propylbenzylcarbonyl) homocysteic acid] Ethyl ester, [N- (butylbenzyl Rubonyl) homocysteic acid] ethyl ester, [N- (methoxybenzylcarbonyl) homocysteic acid] ethyl ester, [N- (ethoxybenzylcarbonyl) homocysteic acid] ethyl ester, [N- (propyloxybezylcarbonyl) homo Cysteinic acid] ethyl ester, [N- (butyloxybenzylcarbonyl) homocysteine acid] ethyl ester, [N- (hydroxybenzylcarbonyl) homocysteic acid] ethyl ester, [N- (aminobenzylcarbonyl) homocysteine acid] ethyl Ester, [N- (N′-methylaminobenzylcarbonyl) homocysteic acid] ethyl ester, [N- (N′-ethylaminobenzylcarbonyl) homocysteic acid] ethyl ester, [N- (N ′, N′- Dimethylaminobenzylcarbonyl) homocysteic acid] ethyl ester Ter, [N- (N ′, N′-diethylaminobenzylcarbonyl) homocysteine acid] ethyl ester, [N- (chlorobenzylcarbonyl) homocysteine acid] ethyl ester, [N- (fluorobenzylcarbonyl) homocysteine acid] Ethyl ester, [N
-(Difluorobenzylcarbonyl) homocysteic acid] ethyl ester, [N- (trifluoromethylbenzylcarbonyl) homocysteic acid] ethyl ester, its optical isomers and / or pharmacologically acceptable salts thereof are preferred. It can be illustrated. Among the compounds represented by the general formula (2), preferred are, N- benzoyl cysteic acid, N- (Torr OIL) cysteic acid, N- (methoxybenzoyl) cysteic acid, N- (phenylbenzoyl) cysteic acid, N- (torr OIL) homocysteic acid, its optical isomers and / or their pharmacologically acceptable salts can be preferably exemplified, more preferably, N- (p-torr OIL) cysteic acid (compound 1), N-(m-torr OIL) cysteic acid (compound 2), N-(o-torr OIL) cysteic acid (compound 3), N-(p-methoxybenzoyl) cysteic acid ( compound 4), N-(4-phenylbenzoyl) cysteic acid (compound 5), N-(p-preparative <br/> Le OIL) homocysteic acid (compound 6), its optical isomers and / or their Pharmacologically acceptable A suitable salt can be exemplified.
Such a compound is contained in an external preparation for skin together with an AGEs degrading agent described later, thereby preventing or ameliorating excellent skin symptoms, especially, preventing or ameliorating pigmentation due to UV exposure, and preventing or improving wrinkle formation. Demonstrates an enhancing effect on action. Such an action is obtained by adding a compound represented by the above general formula (2), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, and an AGEs degrading agent to the external preparation for skin. It is thought that the physical additive or synergistic effect is further enhanced by increasing the accumulation or storage of both components at the target site. The compound represented by the general formula (2), optical isomers thereof and / or pharmacologically acceptable salts thereof, and a skin external preparation containing an AGEs degrading agent are skin sensitization and High safety in terms of irritation. In addition, since such compounds have high solubility in general-purpose polar or non-polar media used in the manufacture of external preparations for skin, it is possible to manufacture various forms of external preparations for skin and easy to manufacture. It is.

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 a phenyl group, a methylphenyl group (toluyl group), an ethylphenyl group, a propylphenyl group, a butylphenyl group, and a 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 and the like can be suitably exemplified, more preferably, more preferably phenyl group, methylphenyl group (toluyl). Group), methoxyphenyl group, naphthyl group, biphenyl group Suitably be 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) which 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) homocysteic acid, N- (N ', N'-dimethylaminobenzoyl) homocysteic acid, N- (N', N'-diethylaminobenzoyl) homocysteic acid, N- (chlorobenzoyl) ) Homocysteic acid, N- (fluorobenzoyl) homocysteic acid, N- (difluorobezoyl) homocysteic acid, N- (trifluoromethylbenzoyl) homocysteic acid, N- (naphthylcarbonyl) homocysteic acid, N- (Phenylbenzoyl) homocysteic acid, [N- (benzoyl) homocysteic acid] methyl ester, [N- (methylbenzoyl) homocysteic acid] methyl ester, [N- (ethylbenzoyl) homocysteine acid] methyl ester, [ N- (propylbenzoyl) homocysteic acid] methyl ester, [N- (butylbenzoyl) Mocysteic acid] methyl ester, [N- (methoxybenzoyl) homocysteic acid] methyl ester, [N- (ethoxybenzoyl) homocysteic acid] methyl ester, [N- (propyloxybenzoyl) homocysteine acid] methyl ester, [N- (Butyloxybenzoyl) homocysteic acid] methyl ester, [N- (hydroxybenzoyl) homocysteic acid] methyl ester, [N- (aminobenzoyl) homocysteic acid] methyl ester, [N- (N′- Methylaminobenzoyl) homocysteic acid] methyl ester, [N- (N′-ethylaminobenzoyl) homocysteic acid] methyl ester, [N- (N ′, N′-dimethylaminobenzoyl) homocysteine acid] methyl ester, [N- (N ′, N′-diethylaminobenzoyl) homocysteic acid] methyl ester, [N- ( Chlorobenzoyl) homocysteic acid] methyl ester, [N- (fluorobenzoyl) homocysteic acid] methyl ester, [N- (difluorobezoyl) homocysteic acid] methyl ester, [N- (trifluoromethylbenzoyl) homocysteine Acid] methyl ester, [N- (naphthylcarbonyl) homocysteine acid] methyl ester, [N- (phenylbenzoyl) homocysteine acid] methyl ester, [N- (benzoyl) homocysteine acid] ethyl ester, [N- ( Methylbenzoyl) homocysteic acid] ethyl ester, [N- (ethylbenzoyl) homocysteic acid] ethyl ester, [N- (propylbenzoyl) homocysteic acid] ethyl ester, [N- (butylbenzoyl) homocysteine acid] ethyl Esters, [N- (Methoxybenzoyl) homocysteine ] Ethyl ester, [N- (ethoxybenzoyl) homocysteine acid] ethyl ester, [N- (propyloxybenzoyl) homocysteine acid] ethyl ester, [N- (butyloxybenzoyl) homocysteine acid] ethyl ester, [N -(Hydroxybenzoyl) homocysteic acid] ethyl ester, [N- (aminobenzoyl) homocysteic acid] ethyl ester, [N- (N'-methylaminobenzoyl) homocysteic acid] ethyl ester, [N- (N ' -Ethylaminobenzoyl) homocysteine acid] ethyl ester, [N- (N ', N'-dimethylaminobenzoyl) homocysteine acid] ethyl ester, [N- (N', N'-diethylaminobenzoyl) homocysteine acid] Ethyl ester, [N- (chlorobenzoyl) homocysteic acid] ethyl ester, [N- (fluorobenzo L) Homocysteic acid] ethyl ester, [N- (difluorobezoyl) homocysteic acid] ethyl ester, [N- (trifluoromethylbenzoyl) homocysteic acid] ethyl ester, [N- (naphthylcarbonyl) homocysteine acid Preferred examples include ethyl ester, [N- (phenylbenzoyl) homocysteic acid] ethyl ester, optical isomers thereof and / or pharmacologically acceptable salts thereof. Among the compounds represented by the general formula (3), as is preferred, N- benzoyl cysteic acid, N- (Torr OIL) cysteic acid, N- (methoxybenzoyl) cysteic acid, N- (phenylbenzoyl) cysteic acid, N- (torr OIL) homocysteic acid, its optical isomers and / or their pharmacologically acceptable salts can preferably exemplified, more preferably, N
- (p-torr OIL) cysteic acid (Compound 1), N-(m-torr OIL) cysteic acid (
Compound 2), N-(o-torr OIL) cysteic acid (Compound 3), N-(p-methoxybenzoyl) cysteic acid (Compound 4), N-(4-phenylbenzoyl) cysteic acid (Compound 5), N-(p-torr OIL) homocysteic acid (compound 6), its optical isomers and / or their pharmacologically acceptable salts are suitably be exemplified.
Such a compound is contained in an external preparation for skin together with an AGEs degrading agent described later, thereby preventing or ameliorating excellent skin symptoms, especially, preventing or ameliorating pigmentation due to UV exposure, and preventing or improving wrinkle formation. Demonstrates an enhancing effect on action. Such an effect is obtained by adding a compound represented by the general formula (3), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, and an AGEs decomposing agent to the external preparation for skin. It is considered that the physical additive or synergistic effect is further enhanced by the increase in accumulation or storage of both components at the target site. Further, the compound represented by the general formula (3), its optical isomer and / or pharmacologically acceptable salt thereof, and a skin external preparation containing an AGEs degrading agent are skin sensitization and High safety in terms of irritation. In addition, since such compounds have high solubility in general-purpose polar or non-polar media used in the manufacture of external preparations for skin, it is possible to manufacture various forms of external preparations for skin and easy to manufacture. It is.

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 is a hydrogen atom having 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms.
A straight-chain or branched alkyl group, 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, and an octyl group. More preferably, a hydrogen atom, a methyl group, and an ethyl group can be illustrated suitably. R ₉ represents an unsubstituted or substituted aromatic group. Specific examples include a phenyl group, a methylphenyl group (toluyl group), an ethylphenyl group, a propylphenyl group, a butylphenyl group, and a 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 and the like can be suitably exemplified, more preferably, more preferably phenyl group, methylphenyl group (toluyl). Group), methoxyphenyl group, naphthyl group, biphenyl group Suitably be exemplified.
Specific examples of preferable compounds among the compounds represented by the general formula (4) are N- (
Benzoyl) cysteic acid, N- (Torr OIL) cysteic acid, N- (ethylbenzoyl) cysteic acid, N- (propyl-benzoyl) cysteic acid, N- (butylbenzoyl) cysteic acid, N- (methoxybenzoyl) cysteic acid N- (ethoxybenzoyl) cysteic acid, N- (propyloxybenzoyl) cysteic acid, N- (butyloxybenzoyl) 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'-diethylamino) Benzoyl) cysteic acid, N- (chlorobenzoyl) cysteic acid, N- (fluorobenzoyl) Cysteic acid, N- (difluorobezoyl) cysteic acid, N- (trifluoromethylbenzoyl) cysteic acid, N- (naphthylcarbonyl) cysteic acid, N- (phenylbenzoyl) cysteic acid, [N- (benzoyl) cysteic acid ] methyl ester, [N-(torr OIL) cysteic acid] methyl ester, [N-(ethylbenzoyl) cysteic acid] methyl ester, [N-(propyl-benzoyl) cysteic acid] methyl ester, [N-(butylbenzoyl ) Cysteinic acid] methyl ester, [N- (methoxybenzoyl) cysteic acid] methyl ester, [N- (ethoxybenzoyl) cysteic acid] methyl ester, [N- (propyloxybenzoyl) cysteic acid] methyl ester, [N- (Butyloxybenzoyl) cysteic acid] methyl ester, [N- (hydro Cibenzoyl) cysteic acid] methyl ester, [N- (aminobenzoyl) cysteic acid] methyl ester, [N- (N′-methylaminobenzoyl) cysteic acid] methyl ester, [N- (N′-ethylaminobenzoyl) Cysteinic acid] methyl ester, [N- (N
', N'-dimethylaminobenzoyl) cysteic acid] methyl ester, [N- (N', N'-diethylaminobenzoyl) cysteic acid] methyl ester, [N- (chlorobenzoyl)
Cysteinic acid] methyl ester, [N- (fluorobenzoyl) cysteic acid] methyl ester, [N- (difluorobezoyl) cysteic acid] methyl ester, [N- (trifluoromethylbenzoyl) cysteic acid] methyl ester, [N - (naphthylcarbonyl) cysteic acid] methyl ester, [N-(phenylbenzoyl) cysteic acid] methyl ester, [N-(benzoyl) cysteic acid] ethyl ester, [N-(torr OIL) 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) cysteic acid] ethyl ester, [N- (butyloxybenzoyl) cysteic acid] ethyl ester, [N- (hydroxybenzoyl) cysteic acid] ethyl ester, [N- (aminobenzoyl) cysteic acid ] Ethyl ester, [N- (N′-methylaminobenzoyl) cysteic acid] ethyl ester, [N- (N′-ethylaminobenzoyl) cysteic acid] ethyl ester, [N- (N ′, N′-dimethylamino) Benzoyl) 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- (phenylbenzoyl) cysteic acid] ethyl ester, its optical isomerism The body and / or pharmacologically acceptable salts thereof can be preferably exemplified. Among the compounds represented by the general formula (4), as is preferred, N- benzoyl cysteic acid, N- (Torr OIL) cysteic acid, N- (methoxybenzoyl) cysteic acid, N- (phenylbenzoyl) cysteic acid, N- (torr OIL) homocysteic acid, its optical isomers and / or their pharmacologically acceptable salts can be preferably exemplified, more preferably, N- (p-torr OIL) cysteic acid (compound 1), N-(m-torr OIL) cysteic acid (compound 2), N-(o-torr OIL) cysteic acid (compound 3), N-(p-methoxybenzoyl) cysteic acid ( Compound 4), N- (4-phenylbenzoyl) cysteic acid (
Preferred examples include compound 5), optical isomers thereof and / or pharmacologically acceptable salts thereof.
Such a compound is contained in an external preparation for skin together with an AGEs degrading agent described later, thereby preventing or ameliorating excellent skin symptoms, especially, preventing or ameliorating pigmentation due to UV exposure, and preventing or improving wrinkle formation. Demonstrates an enhancing effect on action. Such an action is obtained by adding a compound represented by the general formula (4), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, and an AGEs decomposing agent to the external preparation for skin. It is thought that the physical additive or synergistic effect is further enhanced by increasing the accumulation or storage of both components at the target site. The compound represented by the general formula (4), optical isomers thereof and / or pharmacologically acceptable salts thereof, and a skin external preparation containing an AGEs degrading agent are skin sensitization and High safety in terms of irritation. In addition, since such compounds have high solubility in general-purpose polar or non-polar media used in the manufacture of external preparations for skin, it is possible to manufacture various forms of external preparations for skin and easy to manufacture. It is.

The compounds represented by the general formulas (1) to (4), optical isomers thereof and / or pharmacologically acceptable salts thereof are commercially available cysteic acid, homocysteic acid, and their A derivative can be used as a starting material, and can be produced, for example, by deprotection, coupling, and introduction of a protecting group according to the methods described in “Basics and Experiments for Peptide Synthesis (Maruzen)”. It can also be manufactured by a manufacturing method. Such a compound can be used as it is by adding it to the external preparation for skin of the present invention, but it can also be treated with a pharmacologically acceptable acid or base, converted into a salt form, and used as a salt. . For example, mineral salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, para toluenesulfonate, organic acid salts such as benzenesulfonate, sodium salt, alkali metal, calcium salts, alkaline earth metals such as magnesium salt metal, triethylamine salt and potassium salt, triethanolamine over triethanolamine salts, ammonium salts, monoethanolamine over Preferred examples include organic amine salts such as ruamine salt and piperidine salt, and basic amino acid salts such as lysine salt and alginate.

  The thus obtained compounds represented by the above general formulas (1) to (4), optical isomers thereof and / or pharmacologically acceptable salts thereof are an external preparation for skin together with an AGEs degrading agent described later. By containing it, it exhibits an excellent preventive or ameliorating effect on skin symptoms, in particular, a preventive or ameliorating effect on pigmentation due to UV exposure, and an additive or synergistic enhancing effect on preventing or improving wrinkle formation. In order to achieve such an action, one or more selected from the compounds represented by the general formulas (1) to (4), optical isomers thereof and / or pharmacologically acceptable salts thereof. Two or more kinds in a total amount of 0.0001% by mass to 20% by mass, more preferably 0.001% by mass to 10% by mass, and still more preferably 0.01% by mass to 3% by mass with respect to the total amount of the external preparation for skin. It is preferable to contain. This is because the content of the compound represented by the general formulas (1) to (4), its optical isomer and / or pharmacologically acceptable salt thereof is 0.0001% by mass with respect to the total amount of the external preparation for skin. If the amount is less, the effect of beautifying skin is lowered, and even if an amount exceeding 20% by mass is blended, the effect reaches a peak, so the content described above relative to the total amount of the external preparation for skin is preferable.

Ｎ−（ｐ−トルオイル）−Ｌ−システイン酸（化合物１のＬ異性体）

N-(p-torr OIL) -L- cysteic acid (L-isomer of Compound 1)

<Production Example 1: Synthesis of L isomer of Compound 1>
L-cysteic acid monohydrate 5 (g) (26.7 mmol) (Sigma Aldrich), 1
1,4-Dioxane 20 (mL) (Wako Pure Chemical Industries, Ltd.) and water 10 (mL) were placed in a 100 (mL) eggplant-shaped flask, and then cooled in an ice bath. After sufficiently cooling, 10.7 (mL) of 8 (N) sodium hydroxide aqueous solution and 3.36 (mL) of p-toluoyl chloride (Sigma Aldrich) were successively 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, it was distilled off under reduced pressure 1,4-dioxane. The obtained residue was washed with ethyl acetate (Wako Pure Chemical Industries, Ltd.), and the pH was adjusted to 2 or less with hydrochloric acid. The resulting aqueous solution was lyophilized, and the objective product was extracted with methanol (Wako Pure Chemical Industries, Ltd.). After the methanol was distilled off under reduced pressure, crystallized and filtered. The crystals collected by filtration were dried, and the L isomer of compound 1 having the above structure 5.79 (g) (20
. 2 mmol) was obtained.

<Physical constant of L isomer of Compound 1>
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, dd).
FAB-MS (negative ion mode): M / z = 286 ([M−H] ⁻ ), 308 ([M + Na−H] ⁻ ).

Ｎ−（ｍ−トルオイル）−Ｌ−システイン酸（化合物２のＬ異性体）

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

<Production Example 2: Synthesis of L isomer of Compound 2>
100 (mL) eggplant-shaped flask containing L-cysteic acid 3 (g) (17.7 mmol) (Tokyo Chemical Industry Co., Ltd.), tetrahydrofuran 18 (mL) (Wako Pure Chemical Industries, Ltd.), and water 18 (mL) And then cooled in an ice bath. After cooling sufficiently, potassium carbonate 4.4
0 (g) (31.6 mmol) (Wako Pure Chemical Industries, Ltd.), m-toluoyl chloride 2.19
(G) (Tokyo Chemical Industry Co., Ltd.) was sequentially added so that the liquid temperature did not rise. After reacting in an ice bath for 1 hour, m-toluoyl chloride 1.09 (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, it was distilled off under reduced pressure and tetrahydrofuran. The obtained residue was washed with ethyl acetate (Wako Pure Chemical Industries, Ltd.), and the pH was adjusted to 2 or less with hydrochloric acid. Concentrate the filtrate and water
18 (mL) was added. After aging at 4 ° C., the precipitated crystals were separated by filtration. The obtained crystal was washed with acetone (Wako Pure Chemical Industries, Ltd.) 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.

<Physical constant of L isomer of compound 2>
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, brs).
FAB-MS (negatove ion mode): M / z = 286 ([M−H] ⁻ )

Ｎ−（ｏ−トルオイル）−Ｌ−システイン酸（化合物３のＬ異性体）

N-(o-torr OIL) -L- cysteic acid (L-isomer of Compound 3)

<Production Example 3: Synthesis of L isomer of Compound 3>
L-cysteic acid 3 (g) (17.7 mmol) (Tokyo Chemical Industry Co., Ltd.), tetrahydrofuran 18 (mL) (Wako Pure Chemical Industries, Ltd.) and water 18 (mL) are placed in a 100 (mL) eggplant type flask. Then, it was cooled in an ice bath. After sufficiently cooling, potassium carbonate 4.40 (g) (31.6 mmol) (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 increase. 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, it was distilled off under reduced pressure and tetrahydrofuran. The obtained residue was washed with ethyl acetate (Wako Pure Chemical Industries, Ltd.), and the pH was adjusted to 2 or less with hydrochloric acid. The filtrate was concentrated and water 20 (mL) was added. The precipitated crystals were collected by filtration and washed with acetone (Wako Pure Chemical Industries, Ltd.). The crystals collected by filtration were dried at 60 ° C., and the L isomer of compound 3 having the above structure 0.78 (g) (2
. 72 mmol) was obtained.

<Physical constant of L isomer of compound 3>
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−（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)

<Production Example 4: Synthesis of L isomer of compound 4>
L-cysteic acid 2 (g) (11.8 mmol) (Tokyo Chemical Industry Co., Ltd.), tetrahydrofuran 12 (mL) (Wako Pure Chemical Industries, Ltd.), and water 12 (mL) in 100 (mL) eggplant type flask And then cooled in an ice bath. After cooling sufficiently, potassium carbonate 2.9
4 (g) (21.3 mmol) (Wako Pure Chemical Industries, Ltd.) and 4-methoxybenzoyl chloride 1.61 (g) (Tokyo Chemical Industry Co., Ltd.) were sequentially added so as not to increase the liquid temperature. After reacting for 1 hour in an ice bath, 4-methoxybenzoyl chloride 0.81 (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, it was distilled off under reduced pressure and tetrahydrofuran. The obtained residue was washed with ethyl acetate (Wako Pure Chemical Industries, Ltd.), and then adjusted to pH 2 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 (Wako Pure Chemical Industries, Ltd.). After filtering the crystals, the collected crystals were dried at 60 ° C. to obtain L isomer 2.47 (g) (8.14 mmol) of Compound 4 having the above structure.

<Physical constant of L isomer of compound 4>
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−（４−フェニルベンゾイル）−L−システイン酸（化合物５のL異性体）

N- (4-Phenylbenzoyl) -L-cysteic acid (L isomer of compound 5)

<Production Example 5: Synthesis of L isomer of compound 5>
L-cysteic acid 2 (g) (11.8 mmol) (Tokyo Chemical Industry Co., Ltd.), tetrahydrofuran 12 (mL) (Wako Pure Chemical Industries, Ltd.), and water 12 (mL) in 100 (mL) eggplant type flask And then cooled in an ice bath. After cooling sufficiently, potassium carbonate 2.9
4 (g) (21.3 mmol) (Wako Pure Chemical Industries, Ltd.) and 4-phenylbenzoyl chloride 2.05 (g) (Tokyo Chemical Industry Co., Ltd.) were sequentially added so as not to increase the liquid temperature. After reacting for 1.5 hours in an ice bath, 4-phenylbenzoyl chloride 1.02 (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, it was distilled off under reduced pressure and tetrahydrofuran. The obtained residue was washed with ethyl acetate (Wako Pure Chemical Industries, Ltd.), and the pH was adjusted to 2 or less with hydrochloric acid (Wako Pure Chemical Industries, Ltd.). The precipitated crystals were filtered and washed with water. The obtained crystals were washed with acetone (Wako Pure Chemical Industries, Ltd.) and then filtered. The crystal collected by filtration was dried at 60 ° C. to obtain the L isomer 2.37 (g) (6.78 mmol) of the compound 5 having the above structure.

<Physical constant of L isomer of compound 5>
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−トルオイル）ホモシステイン酸（化合物６）

N-(p-torr OIL) 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) in a 100 (mL) eggplant type flask After putting, it was cooled in an ice bath. After cooling sufficiently, potassium carbonate
2.71 (g) (19.6 mmol) (Wako Pure Chemical Industries, Ltd.) was added. p-Toluoyl chloride 1.49 (g) (Sigma Aldrich) was sequentially added so that the liquid temperature did not increase. After reacting for 1 hour in an ice bath, p-toluoyl chloride 0.76 (g) (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, it was distilled off under reduced pressure and tetrahydrofuran. The obtained residue was washed with ethyl acetate (Wako Pure Chemical Industries, Ltd.), and then adjusted to pH 2 with hydrochloric acid. After filtering the solution, the filtrate was concentrated and added methanol (Wako Pure Chemical Industries, Ltd.). 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 compound 61.95 (g) (6.47 mmol) having the above structure.

<Physical constant of compound 6>
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] ⁻ )

<AGEs decomposition agent of the present invention>
Meira over de reaction is a reaction for amino acids and reducing sugars to produce a brown pigment by heating. Glycation, the amino group of the carbonyl group and the amino acid of reducing sugars after the formation of the Schiff base, via the enamino Lumpur, an initial step of generating a stable Amadori compound Amadori rearrangement, later, dehydration, hydrolysis Decomposition and cleavage between carbons produce α-dicarbonyl compounds, followed by degradation of α-dicarbonyl compounds, Schiff bases and Amadori compounds, aldehydes derived from lipid peroxidation, auto-oxidation and decomposition of sugars, etc. Can be classified into later stages. AGEs is a general term for products generated as a result of the saccharification reaction, and does not mean a single compound. In addition, the saccharification reaction causes physical or physiological changes in the process leading to the generation of AGEs of the final product by forming a disordered cross-linked structure between the protein in the body and between the molecules, and the skin tone. It is known to be deeply involved in factors such as dullness, elasticity, skin beautification such as skin texture, and whitening factors. For this reason, it is known that a component having an action of degrading dermis AGEs has an effect of preventing or improving skin symptoms involving pigmentation such as dullness by suppressing a saccharification reaction. However, even with said AGEs decomposing agent, preventing or ameliorating effect against pigmentation due to ultraviolet rays exposure, especially, reduction cell function keratinocytes caused by excessive and / or chronic melanin production promoting, te oleate over bar The preventive or ameliorating effect on incurable pigments and dullness caused by the delay, as well as abnormal pigmentation presenting symptoms of inflammation and rough skin, was not satisfactory. The external preparation for skin of the present invention comprises an AGEs decomposing agent, in particular, an AGEs decomposing agent having a stratum corneum AGEs decomposing action, a compound represented by the general formula (1), an optical isomer thereof and / or a pharmacological thereof. When included in a skin external preparation together with an acceptable salt, it exhibits excellent preventive or ameliorating action on skin symptoms, especially, prevention or ameliorating action against pigmentation due to UV exposure, and preventing or improving wrinkle formation. .

As the AGEs decomposing agent of the present invention, any component having an action to reduce the amount of AGEs can be applied without particular limitation. Among such AGEs decomposing agents, AGEs present in the stratum corneum are preferable. The component which has the effect | action which reduces the quantity can illustrate suitably. In addition to the component which has the effect | action which decomposes | disassembles the produced | generated AGEs, the component which has the effect | action which suppresses AGE production produced | generated by saccharification reaction is also included by the AGEs decomposition agent of this invention. In addition, as the AGEs decomposing agent of the present invention, for example, AGEs decomposing action evaluation described in JP-A-2007-161662 (measurement of CC bond cleaving action of α-diketone, measurement of glucose-bovine serum albumin AGEs degrading action) The component which shows AGEs decomposition | disassembly action in) etc. can illustrate suitably. The component having AGEs decomposing action in the AGEs decomposing action evaluation is calculated from the amount of 1-phenyl-1,2-propanedione in the measurement evaluation of CC bond cleaving action of α-diketone in the AGEs degrading action evaluation. In the measurement evaluation of a substance in which the amount of benzoic acid actually produced is 20% or more or the glucose-bovine serum albumin AGEs decomposition action relative to the theoretical amount of benzoic acid, the AGE decomposition rate is 15% or more Means a substance. According to the applicant, as the component having AGEs decomposing action in such evaluation systems, Oleaceae olea, Saxifragaceae Saxifraga, Rosaceae Potenchira genus Leguminosae asparagus toe scan genus Rosaceae filipendula, key click Department Artemisia genus plant extract obtained from leguminous Astragalus belongs plants can preferably exemplified, more preferably, Oleaceae olea olive, Saxifragaceae Saxifraga saxifrage, Rosaceae Potenchira genus Torumenchira, Rosaceae Potenchira genus Kawarasaiko, Rosaceae Potenchira Preferable examples are plant extracts obtained from the genus Miyamakinbai, leguminous aspartus rooibos, rosaceae spruce spruce spruce, chrysanthemum spruce wormwood, legume spruce spider. Further, among the components having the AGEs decomposition action, a horny layer AGEs decomposition agent can be preferably exemplified as a more preferable one. As the stratum corneum AGEs decomposing agent, for example, a component having an AGEs decomposing action in the human stratum corneum or a component having an action of suppressing AGEs production in the human stratum corneum can be suitably exemplified. In addition, as a component having AGEs decomposing action present in the human stratum corneum, in the evaluation of AGEs decomposing action in the human stratum corneum, an anti-AGE antibody is reacted to a stratum corneum sample collected from a panel, and the reaction site When the number of reaction sites is clearly fewer in the coexistence with the AGEs decomposing agent than in the non-coexistence, it can be said to be a component having an action of decomposing AGEs present in the stratum corneum. In addition, as a component having an action of suppressing the generation of AGEs in the human stratum corneum, in the evaluation of inhibition of AGEs generation in the human stratum corneum, the stratum corneum specimen is immersed in a glucose solution and left at 37 ° C. for AGEs. When it is produced, a component having an action of suppressing the production of AGEs in the stratum corneum can be suitably exemplified in the presence of the AGEs decomposing agent when there are clearly fewer reactive sites than in the non-coexistence. According to the inventors of the present application, the component having an action of degrading AGEs in the human stratum corneum or the component having an action of suppressing the production of AGEs in the human stratum corneum is obtained from a plant belonging to the genus Leguminous genus. A plant extract can be preferably exemplified, and more preferably, a plant extract obtained from leguminous genus Astragalus can be suitably exemplified.

The AGEs degrading agent of the present invention means a simple chemical substance or an extract obtained from an animal or a plant, and the composition of the present invention can contain only one such component, or two kinds. The above can also be contained in combination. Here, the plant extract in the present invention means a general term for the extract itself, the fraction of the extract, the purified fraction, the extract or fraction, and the solvent-removed product of the purified product. As such AGEs-degrading agents, according to the study by the present inventors, leguminous genus genus, oleaceae olive genus, saxifrage family yukinoshita genus, rose family potentia genus, legume aspartus genus, rosaceae shimokeso, asteraceae plant extract obtained from plants belonging to the Artemisia is possible preferably exemplified, more preferably, Leguminosae Astragalus Rengesou, Oleaceae olea olive, Saxifragaceae Saxifraga saxifrage, Rosaceae Potenchira genus Torumenchira, Rosaceae Potenchira genus Kawarasaiko , Plant extracts obtained from leguminous potentia spruce, peas aspartus rooibos, rosaceae spruce spruce, chrysanthemum spp., More preferably a plant extract obtained from legumes It can be illustrated. The plant extract obtained from the leguminous genus Astragalus is superior in AGEs degrading action, in particular, epidermal AGEs degrading action.

Among the plant extracts having the above-mentioned AGEs-decomposing action, the olive genus Olive is an evergreen tree native to North Africa, and the fruit is used as olive oil or pickles. In Japan, it is cultivated on Shodoshima in Kagawa Prefecture. Yukinosita is a evergreen perennial plant originating in China and Japan and is used as a folk medicine. In Japan, it is cultivated in a wide area from Hokkaido to Kyushu. The rose family Potentilla genus Tormentilla is a perennial plant distributed in Europe and has an effect of attracting skin and antibacterial action. The rose family Potentilla spp. Is a perennial alpine plant that grows in China's native gravel and grassland. In Japan, the rose family Potentilla spp. Is a perennial that grows on sunny rivers and sands in Honshu, Shikoku, and Kyushu. The whole plant is called whitening herb and the root is red saiko. The leguminous aspartus rooibos is a plant with coniferous leaves that grows only in the Sedelberg Mountains in the north of the Western Cape Province in South Africa. Rosaceae is a perennial small shrub native to Japan and China, and is native to Honshu, Shikoku, and Kyushu west of Kanto. Asteraceae Artemisia is a cold-tolerant perennial plant native to Europe and North Africa, and has long been used in Japan, such as grassy mochi and rice cake mushrooms. In Japan, it grows in a wide range from Honshu to Kyushu and Okinawa. The leguminous genus Astragalus is a biennial plant native to China and is known to have diuretic and antipyretic effects. It is cultivated throughout Japan.

  In order to produce an extract of such a plant, the plant itself can be cut, crushed, ground, etc. and extracted with a solvent. Preferably, all or a part of the plant body or a processed product thereof is used as a solvent. It is preferable to extract by. In addition, in order to obtain the above-mentioned plant extract, it can be used without particular limitation as long as it is all or a part of the plant body, for example, fruit, pericarp, bark, trunk, branch, leaf, flower, root, seed, etc. Is mentioned. These may use single site | parts and may use 2 or more site | parts.

As the extraction solvent used for producing the plant extract, preferably a polar solvent, water, ethanol, isopropyl alcohol, alcohol such as butanol, 1,3-butanediol Lumpur polyhydric alcohol such as polypropylene glycol, ketones such as acetone and methyl ethyl ketone, diethyl chromatography ether, one to be selected from the error over ethers, such as tetrahydrofuran 2 or more kinds suitably be exemplified.

  The AGEs decomposing agent of the present invention is 0.0001% by mass to 10% by mass, more preferably 0.001% by mass to 5% by mass, and still more preferably 0.05% by mass to 3%, based on the total amount of the external preparation for skin. It is preferable to contain by mass. This indicates that if the content of the AGEs decomposing agent is too small, a tendency to reduce the excellent preventive or ameliorating effect on the skin symptoms of the external preparation for skin of the present invention is observed. This is because the degree of freedom of this system may be lost. Furthermore, even when the skin external preparation of the present invention is formulated for the purpose of preventing or improving other skin symptoms such as moisturizing, rough skin prevention or improvement, the skin external preparation of the present invention is In the case of exhibiting a preventive or ameliorating action for skin symptoms, the configuration and effects of the present invention are satisfied, and therefore belong to the technical scope of the present invention.

Ingredients having AGEs-degrading action obtained from the above-mentioned plant extract in the present invention may be prepared by using plants grown in Japan or grown in Japan, as well as Japanese herbal medicine raw materials. It is also possible to purchase and use commercially available extracts sold by companies that handle plant extracts such as Maruzen Pharmaceutical Co., Ltd. In the extraction, it is preferable to process the plant body, the above-ground part or the tree trunk part in advance so as to improve the extraction efficiency by crushing or chopping. For the extract, 1 to 30 parts by mass of a solvent is added to 1 part by mass of the plant body, the above-ground part or its dried product, and immersed for several days at room temperature and for several hours at a temperature near the boiling point. After the immersion, the solution can be cooled to room temperature, insoluble matter can be removed if desired, and then the solvent can be removed by concentration under reduced pressure. Thereafter, fractionated purified such by column chromatography packed with silica gel or ion exchange resin, it is possible to obtain the desired extract.

<Production Example 7: production method of Oleaceae olive genus cage over Buyori resulting extract of the present invention>
Olive leaf 3 (kg) to 50% ethanol aqueous solution 5L added, heated under reflux for 2 hours, filtered through concentrated in vacuo remove insolubles, the plant extract obtained cage over Buyori of the present invention 44 (G) Obtained.

<Manufacture example 8: The manufacturing method of the plant extract obtained from the saxifrage family Yukinosita genus Yukinosita>
Leaves of Saxifraga 3.5 (kg) to 50% ethanol aqueous solution 6L added, heated under reflux for 2 hours, and concentrated under vacuum to give remove insoluble by filtration, the plant extract obtained from saxifrage of the present invention 41 (g )Obtained.

<Manufacture example 9: The manufacturing method of the plant extract obtained from the Rosaceae Potentilla genus Tormentilla of this invention>
After chopping 100 g of dried whole plant of the family Rosaceae, Tormentilla, 500
3 hours by addition of 50% ethanol aqueous solution (mL), heated to reflux, after removing insoluble matter by cooling after filtration, concentrated in vacuo, then lyophilized to give a plant extract 1. Thereafter, 200 (mL) water and 200 (mL) ethyl acetate are added to the plant extract 1, liquid-liquid extraction is performed, and the ethyl acetate phase is taken and concentrated under reduced pressure. The resulting plant extract was obtained.

<Manufacture example 10: The manufacturing method of the plant extract obtained from the Rosaceae Potentilla genus Kawara psycho of this invention>
After chopping 100 g of dried whole plant of the rose family Potentilla spp.
(ML) of 50% ethanol aqueous solution was added and heated to reflux for 3 hours. After cooling, insoluble materials were removed by filtration, followed by concentration under reduced pressure, followed by lyophilization to obtain plant extract 2. Thereafter, ethyl acetate was added water and 200 (mL) of 200 (mL) to the plant extract 2 performs liquid-liquid extraction, takes ethyl acetate phase was concentrated under reduced pressure, from the Rosaceae Potenchira genus Kawarasaiko of the present invention The resulting plant extract was obtained.

<Manufacture example 11: The manufacturing method of the plant extract obtained from the Rosaceae Potentilla spp.
After chopping 100 g of dried whole plant of Rosaceae Potassilla sp.
0 (mL) 3 hours by addition of 50% ethanol aqueous solution, heated to reflux, after removing insoluble matter by cooling after filtration, concentrated in vacuo, then lyophilized to give a plant extract 3. Thereafter, 200 (mL) water and 200 (mL) ethyl acetate are added to the plant extract 3, liquid-liquid extraction is performed, the ethyl acetate phase is taken, and the solution is concentrated under reduced pressure. The resulting plant extract was obtained.

<Manufacture example 12: The manufacturing method of the plant extract obtained from the leguminous aspartus genus rooibos of this invention>
Drying of the leaves of leguminous asparagus toe scan genus Rooibos 100 (g), after minced, 500 3 hours by the addition of 50% ethanol aqueous solution (mL), heated to reflux, insoluble materials in the cooling after filtration Then, the mixture was concentrated under reduced pressure, and then freeze-dried to obtain an extract 4. Thereafter, 200 (mL) of water and 200 (mL) of ethyl acetate are added to the extract 4, liquid-liquid extraction is performed, and the ethyl acetate phase is taken and concentrated under reduced pressure. From the leguminous aspartus rooibos of the present invention, The resulting plant extract was obtained.

<Manufacture example 13: The manufacturing method of the plant extract obtained from the Rosaceae genus Shimoke of the present invention>
After chopping 100 (g) of a dried whole plant of the rose family Potentilla spp.
3 hours by addition of 50% ethanol aqueous solution (mL), heated to reflux, after removing insoluble matter by cooling after filtration, concentrated in vacuo, then lyophilized to give an extract 5. Thereafter, 200 (mL) of water and 200 (mL) of ethyl acetate are added to the extract 5, liquid-liquid extraction is performed, and the ethyl acetate phase is taken and concentrated under reduced pressure, which is obtained from the genus Rhododendron spp. Obtained plant extract.

<Manufacture example 14: The manufacturing method of the plant extract obtained from the Asteraceae Artemisia mugwort of this invention>
After chopping 100 (g) of dry matter of the whole plant of Asteraceae Artemisia, 500 (mL) of 5
3 hours by the addition of 0% ethanol aqueous solution, heated to reflux, after removing insoluble matter by cooling after filtration, concentrated in vacuo, then lyophilized to give an extract 6. Thereafter, 200 (mL) of water and 200 (mL) of ethyl acetate are added to the extract 6, liquid-liquid extraction is performed, and the ethyl acetate phase is taken and concentrated under reduced pressure. Obtained plant extract.

<Manufacture example 15: The manufacturing method of the plant extract obtained from the leguminous genus Astragalus of this invention>
Dry matter leguminous Astragalus whole plant and seeds Rengesou 1 (kg) was chopped, the error <br/> Tano Lumpur solution of 10 (L), and the mixture was immersed overnight at 50 ° C. below the temperature after, by removing the insolubles by filtration to obtain an extract is ethanol solution extract.

  According to the following method, the AGEs decomposing action of the AGEs decomposing agent of the present invention was evaluated.

<Test Example 1: AGEs degradation action evaluation 1 (measurement of CC bond cleavage action of α-diketone)>
22 mM 1-phenyl-1,2-propanedione / methanol + 0.1 M phosphate buffer (pH 7.4) 1 (mL) A plant extract obtained from Yukinoshita, a plant extract obtained from the rose family Potentilla genus Tormentilla, a plant extract obtained from the rose family Potentilla spp., A plant extract obtained from the Rosa family Potentilla spp. Plant extract obtained from Aspartus rooibos, plant extract obtained from Rosaceae genus Shimotake, plant extract obtained from Artemisia genus Artemisia, plant extract obtained from Legume genus Astragalus 1 (mL ) And reacted at 37 ° C. for 10 hours, and the amount of benzoic acid was determined by HPLC. It was.
(HPLC conditions)
Analysis conditions Detector: Ultraviolet absorptiometer (measurement wavelength: 260 nm)
Column: Tosoh TSK-ODS80TsQA
Column temperature: Room temperature Moving bed: Glacial acetic acid 2 (g) / acetonitrile 500 (mL) + edetate disodium solution (
1 → 250) 500 (mL)
Flow rate: 1 (mL) / min.

With the AGEs decomposing agent of the present invention described above, AGEs decomposing action evaluation (measurement of CC bond cleaving action of α-diketone) was performed according to the method described in Test Example 1. The cutting action of the plant extract having the AGEs-decomposing action of the present invention is as follows: plant extract obtained from olive genus olives (29%), plant extract obtained from Yukinoshita genus Yukinoshita (35%), rose family Plant extract obtained from Potentilla genus Tormentilla (32%), plant extract obtained from Rosaceae Potassilla spp. (29%), plant extract obtained from Rosaceae Potentilla spp. A plant extract obtained from the genus Rooibos (25%), a plant extract obtained from the genus Rosaceae (37%), a plant extract (33%) obtained from the Artemisia genus Artemisia, a leguminous genus Astragalus More plant extract obtained (43%). The AGEs decomposing agent of the present invention was found to have an excellent AGEs decomposing action.

<Test Example 2: AGEs decomposition action Evaluation 2 (glucose - measurement of bovine serum albumin AGEs decomposition)>
AGEs decomposition action evaluation was implemented using the following test materials.
AGE-BSA: gluco - Graphics and bovine serum albumin (BSA) and incubate <br/> preparative least 12 weeks at 37 ℃, PD-10 columns ( Amersham Biosciences 17-0851-01) at extra grayed <br /> that except for Turkey over the scan, the primary antibody: Anti-Albumin, Bovine Serum, Rabbit-Poly ROCKLAND 201-41331 / 20000,2 primary antibody: Goat anti-rabbit IgG horseradish peroxidase conjugate BioRAD 170-6515 1/10000 , Substrate: TMB solution
Wako 546-01911
(procedure)
Type I Kola over Genko and reports open 96-well microplate over preparative (Bio Coat 35 4407
) 100 μL of 10 (μg / mL) AGE-BSA and 1.0 μg (AGE-BSA / well) at 37 ° C.
After standing for 4 hours at, 0.05% Tween20 / PBS - 3 times washed with (room temperature on a micro mixer, 3 minutes shaken), PBS () (-) was dissolved in concentration (1 × ^10-4 %) sample is added (100 L) and reacted at 37 ° C for 10 hours or more. Thereafter, the plate is washed 3 times with 0.05% Tween 20 / PBS (−), 100 μL / well of the primary antibody is added to each well, and left at room temperature for 30 minutes. Wash 3 times with 0.05% Tween20 / PBS (-) and add 100 μL of secondary antibody.
/ Well) and leave at room temperature for 30 minutes. Wash three times with 0.05% Tween20 / PBS (−), add 100 (μL / well) of TMB, and react at room temperature for 15 minutes. 100% 1N hydrochloric acid
(ΜL / well) is added, the reaction is stopped, and the absorbance at 450 nm is measured. Change the amount of AGEs,
A calibration curve was drawn, and the amount of residual AGEs was quantified from this calibration curve. The AGEs decomposition rate was calculated by subtracting the remaining AGEs from the added AGEs, dividing by the added AGEs, and multiplying by 100.

With the AGEs decomposing agent of the present invention described above, AGEs decomposing action evaluation (measurement of glucose-bovine serum albumin AGEs degrading action) was performed according to the method described in Test Example 2. Glucose-bovine serum albumin AGEs-degrading action of the plant extract having AGEs-degrading action of the present invention is obtained from plant extracts obtained from olive genus olives (25%), 28%), a plant extract obtained from the rose family Potentilla Tormentilla (24%), a plant extract obtained from the rose family Potentilla spp.
), A plant extract obtained from the rose family Potentilla spp. (31%), a plant extract obtained from the leguminous aspartus rooibos (24%), a plant extract obtained from the rose family Pseudoaceae (32%) They were a plant extract (33%) obtained from Asteraceae Artemisia and a plant extract (37%) obtained from Leguminosae. The AGEs decomposing agent of the present invention was found to have an excellent AGEs decomposing action.

<Test Example 3: Evaluation of AGEs production inhibitory action in human stratum corneum>
AGEs in the stratum corneum can be detected as follows. Performed corneum collected by tape over TOPS stripping using commercially available adhesive tape or the like from the skin, was treated half a day with a solvent to remove the adhesive tape portion. The obtained stratum corneum is subjected to immunohistochemical staining, and the stained stratum corneum specimen is observed under a microscope. The results are shown in FIG. Preferred examples of the solvent include organic solvents, particularly xylene. As conditions for immunohistochemical staining, primary antibody (anti AGE monocronal antibody (mouse) TransGenic KH001), biotinylated secondary antibody (Biotin-Rabbit Anti Mouse IGg conjugate ZYMED 81-6740), ABC reagent (RTU VECTASTAIN Elite ABC REAGENT BECTOR PK -7100) and AEC substrates (ENVISION kit / HRP (AEC) Dako K3464). As a control, it was prepared immersed corneum sample 70% ethanol solution. The stratum corneum samples are immersed in 70% ethanol solution of 100mM glucose. Further, AGEs were detected after standing for 8 days at 37 ° C. in the presence or absence of 0.1% plant extract obtained from the leguminous genus Astragalus, which is the AGEs decomposing agent of the present invention. In the non-presence of a plant extract obtained from Leguminosae Astragalus Rengesou clearly reaction site compared to the control lot, AGEs by glucose was found to have produced. Plant extract obtained from leguminous genus Astragalus: In the presence of 0.1%, there are clearly fewer reaction sites than in the absence of coexistence. It was found to have a production inhibitory effect. This degree can be quantified by the ratio of the existing area of the label, and the existing ratio of the label can be easily quantified by a score or the like as will be described later. The results are shown in FIG.

<Skin external preparation of the present invention>
The external preparation for skin of the present invention contains 1) a compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) an AGE decomposition agent. It is characterized by. The compound represented by the general formula (1) of the present invention, an optical isomer thereof and / or a pharmacologically acceptable salt thereof, together with an AGEs decomposing agent, is contained in an external skin preparation, thereby preventing skin symptoms. It exhibits an excellent preventive or ameliorating action, in particular, a preventive or ameliorating action against pigmentation due to UV exposure, and a preventive or improving action against wrinkle formation.

Further, 1) a compound represented by the above general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, which is an essential component of the external preparation for skin of the present invention, and 2) AGE decomposition When formulating an external preparation for skin containing an agent, it can contain optional components used in formulating ordinary pharmaceuticals, quasi drugs, cosmetics and the like. As the skin external preparation of the present invention, pharmaceuticals, quasi-drugs, cosmetics and the like can be suitably exemplified, and since they can be taken on a daily basis, it is preferable to apply to cosmetics, quasi-drugs and the like. The administration route is preferably such that these components are administered continuously, or transdermally in consideration of safety. The external skin preparation of the present invention can be used without particular limitation as long as it is applied externally to the skin, for example, cosmetics, skin external medicine, skin external goods and the like can be suitably exemplified, It is particularly preferable to apply to cosmetics. This is because the external preparation for skin of the present invention has an unparalleled feeling of use and is particularly suitable for cosmetics where the feeling of use is important. As the external preparation for skin of the present invention, for example, B Activation of such cosmetics, milky lotion, essence, creams, face pack, face wash cosmetic, cleansing cosmetics can be preferably exemplified. Still the dosage form, as long as it is known in the cosmetic area particular limitation is no B Activation formulations, oil-in-water emulsion formulations, water-in-oil emulsion formulation, preferably exemplified composite emulsion emulsifying formulations, etc. it can.

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 components, e.g., macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower over oil, cottonseed oil, jojoba oil, coconut oil, palm oil, liquid Lanolin, hydrogenated palm oil, hydrogenated oil, molasses, hydrogenated castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba oil, waxes; liquid paraffin, squalane, pristane, ozokerite, paraffin, ceresin, vaseline, 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; Sechiruaruko Lumpur, stearyl alcohol Lumpur, Isosuteari Alcohol, behenyl alcohol, octyl dodecanoate Lumpur, myristyl alcohol, higher alcohols such as cetostearyl alcohol; isooctane cetyl, isopropyl myristate, isostearate hexyl decyl, diisopropyl adipate, sebacic acid di-2-ethylhexyl, cetyl lactate, diisostearyl malate, di-2-ethyl hexanoate of ethylene glycol, neopentyl glycol dicaprate, glyceryl di-2-heptylundecanoate, tri-2-ethylhexanoate glycerin , tri-2-ethylhexanoate trimethylol over trimethylolpropane triisostearate trimethylol over trimethylolpropane, synthetic ester oils such as tetra-2-ethylhexanoate pentane pentaerythritol; dimethyl polysiloxane, methylphenyl Rokisan, linear polysiloxanes such as diphenyl polysiloxane; octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, cyclic polysiloxanes such as dodeca methylcyclohexane siloxane; amino-modified polysiloxane, polyether chromatography ether-modified polysiloxane, alkyl-modified polysiloxane , oils such silicone over emissions oils of modified polysiloxanes and fluorine-modified polysiloxane; fatty acid soap (sodium laurate, sodium palmitate), potassium lauryl sulfate, alkyl sulfate triethanol over Ruamin'e chromatography ether such anionic surfactants Agents; cationic surfactants such as stearyltrimethylammonium chloride, benzalkonium chloride, laurylamine oxide; imidazoline-based amphoteric surfactants (2-cocoyl-2-imida) Zolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), betaine surfactants (alkyl betaine, amide betaine, sulfobetaine, etc.), and amphoteric surfactants such as acylmethyltaurine; sorbitan fatty acid esters (sorbitan) Monosuteare over DOO, sorbitan sesquioleate etc.), glycerol fatty acids (glycerol monostearate, etc.), propylene glycol fatty acid esters (monostearate propylene glycol, etc.), hardened castor oil derivatives, glycerin alkyl error over ether , POE sorbitan fatty acid esters (POE sorbitan monooleate over preparative, polio monostearate key sorbitan, etc.), POE sorbitol fatty acid esters (POE- sorbit monolaurate over preparative etc.), POE glycerin fatty et Ethers (POE- glyceryl monoisostearyl array over preparative etc.), POE fatty acid esters (polyethylene glycol Rumonoore over preparative, POE Jisuteare over preparative etc.), POE alkyl ether over ethers (POE2- octyldodecyl error over ether, etc.), POE alkylphenyl et chromatography ethers (POE nonylphenyl error over ether, etc.), Pluronic type compound, POE-POP alkyl ether over ethers (POE-POP2- decyltetradecyl et chromatography ether, etc.), Tetronic compounds, POE castor oil, Hardened castor oil derivatives (POE castor oil, POE hardened castor oil, etc.), nonionic surfactants such as sucrose fatty acid ester, alkyl glucoside; moisturizing ingredients such as sodium pyrrolidone carboxylate, lactic acid, sodium lactate; surface treatment may be, mica, talc, kaolin, synthetic mica, Calcium, magnesium carbonate, silicic anhydride (silica), aluminum oxide powder such as barium sulfate; may be surface treated, red iron oxide, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, iron blue, be processed surface; titanium oxide, inorganic pigments zinc oxide
There, mica titanium, Sakanarinhaku, Pas Lumpur agent such as bismuth oxychloride; les over key of which may Red No. 202 even if the red No. 228, Red No. 226, Yellow No. 4, Blue No. 404, Yellow Organic dyes such as No. 5, Red No. 505, Red No. 230, Red No. 223, Orange No. 201, Red No. 213, Yellow No. 204, Yellow No. 203, Blue No. 1, Green No. 201, Purple No. 201, Red No. 204 s, polyethylene powder, polymethyl methacrylate, nylon powder, organic powders such as organopolysiloxane elastomers; para-aminobenzoic acid UV absorbers; anthranilic acid UV absorbers; salicylic acid type ultraviolet absorbers; cinnamic acid UV absorbents; benzophenone ultraviolet absorbers; sugar-based ultraviolet absorbent; 2- (2'-hydroxy-5'-t-octylphenyl) benzotriazole, 4-methoxy 4'-t-butyl-dibenzo yl ultraviolet absorbers such as methane; ethanol, lower alcohols such as isopropanol Lumpur; vitamin A or a derivative thereof, vitamin B ₆ hydrochloride, vitamin B ₆ Toriparumite over preparative, vitamin B ₆ Jiokutanoe over preparative, vitamin _{B 2} or derivatives thereof, vitamin _{B 12,} vitamin B such as vitamin _{B 15} or a derivative thereof; alpha-tocopherol Lumpur, beta-tocopherol Lumpur, .gamma. tocopherol Lumpur, vitamin E Asete over organomodified such hectorite, dimethyl distearyl ammonium modified hectorite; vitamin E such as bets, vitamin D, vitamin H, pantothenic acid, pantethine, vitamins such as pyrroloquinoline quinone and the like; antibacterial agents such as phenoxyethanol Lumpur Preferred examples include clay minerals.

The external preparation for skin of the present invention contains the above-mentioned essential components. The external preparation for skin of the present invention, as long as it is known in the cosmetic area particular limitation is no emulsifier b Activation formulations, oil-in-water emulsion formulations, water-in-oil emulsion formulation, to a composite emulsion emulsifying formulations, etc. The form may be either a water-in-oil emulsifier form or an oil-in-water emulsifier form, but the water-in-oil emulsifier form is particularly preferred. Here, the water-in-oil emulsifier type is a word called comprehensively the emulsifier shape with the oil phase to the Foreign Minister, may also contain an aqueous phase to the internal phase, have the emulsion, such as oil-in-water emulsions You may do it.

The skin external preparation of the present invention can contain a non-surfactant used in skin external preparations such as ordinary cosmetics. Furthermore, it is also preferred to incorporate an alkyl-modified carboxyvinyl polymer over and / or salt thereof in the sense to maintain the emulsified state stably. The preferable content of such components is 0.01 to 0.5 mass%, more preferably 0.05 to 0.3 mass%, based on the total amount of the external preparation for skin. Such a component is preferably contained also in that sense because it forms a composite film with the essential ingredient amodimethicone after administration to the skin and enhances the effect of amodimethicone. For such alkyl-modified carboxyvinyl polymer over commercial products resides, it can be used to purchase such commercially. Preferred commercially available from Nippon support over Fakutanto Industrial Co., alkyl denaturated with an alkyl group having 10 to 30 carbon atoms "Pemulen (PEMUREN; R) TR-1", "Pemulen (PEMUREN; Registration R) TR-2 ", BF Goodrich (USA)" mosquito turbo port Lumpur available from (CARBOPOL; registered trademark) 1382 "include, as the carboxyvinyl polymers over that are not alkyl-modified, BF Goodrich is commercially available from (US) "mosquito turbo port Lumpur (CARBOPOL; registered trademark) Ultrez10", "Carbopol (CARBOPOL; registered trademark) 940", and the like. Such hydrophilic polymers may be used alone or in combination of two or more. The oil-in-water emulsified skin external preparation of the present invention preferably contains 0.05 to 1% by mass of such hydrophilic polymer, more preferably 0.08 to 0.5% by mass. When less than this, an emulsification system will become unstable, and when more than this, the viscosity of a system will become high too much and applicability | paintability will worsen.

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

The skin external preparation of the present invention contains 1) a compound represented by the above general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) an AGE decomposition agent. "For prevention or improvement of skin symptoms", "For prevention or improvement of pigmentation due to UV exposure", "For prevention or improvement of wrinkle formation", "For improvement of skin transparency", "For dullness improvement" It is effective for preventing or improving skin symptoms related to beautifying skin. In addition, in the case of expecting an effect of preventing or ameliorating other skin symptoms and including the above ingredients in an external preparation for skin, the effect of the present invention is exhibited when the effect of preventing or ameliorating the skin symptoms is exerted. Since it uses, it belongs to the technical scope of this invention. The action other than the skin softening, moisturizing effect, skin roughness preventing or ameliorating action, and the like - aging improving effect.

  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.

<Manufacture example 16: Manufacturing method 1 of the skin external preparation of this invention>
According to the formulations shown in Table 1 and Table 2 below, the cosmetic is a skin external preparation of the present invention (B Activation 1 to 11) were prepared. That is, the formulation ingredients were heated to 80 ° C., and stirred, lysed, after stirring cooled to obtain cosmetics (b Activation 1 to 11). Similarly, “Compound represented by the above general formula (1) of the present invention” in the formulation components of Table 1 was replaced with “Water”, and Comparative Example 1 “AGEs decomposing agent of the present invention” was changed to “Water”. A substituted comparative example 2, a comparative example 3 in which “the compound represented by the general formula (1) of the present invention” and “AGEs decomposing agent of the present invention” were both replaced with “water” was prepared.

<Test Example 4: Evaluation 1 of pigmentation inhibitory action of the external preparation for skin of the present invention>
Used cosmetics (b Activation 1 to 11) and Comparative Examples 1 to 3 prepared according to the method described in Example 1, was examined pigmentation inhibitory effect. The panelists over the back who participated voluntarily, providing a test site of 1.5cm × 1.5cm to test the first day (day 1), skin brightness (L * value) of the color difference meter of the test site (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.
UV irradiation end tid immediately after, 14 consecutive days, each sample (B Activation 1 to 11 and Comparative Examples 1 to 3) was 50μL applied to each test site. Skin lightness (L * value) of each test site 24 hours after application (15th day) with a color difference meter (CR-300, Konica Minolta, Inc.)
And ΔL * value obtained by subtracting the L * value on the 15th day from the L * value on the first day of the test was calculated. A larger L * value indicates higher skin brightness. Therefore, the smaller the ΔL * value, the smaller the difference between the L * value on the first day of the test and the L * value on the 15th day, and it can be determined that pigmentation has been suppressed. The results are shown in Table 3. B Activation 1 to 11 which is the external preparation for skin of the present invention has a small [Delta] L * value in comparison with Comparative Example 3, it is found to have excellent pigmentation inhibitory effect. Further, Comparative Example 1 and Comparative Example 2 also, [Delta] L * value smaller than that of Comparative Example 3, although pigmentation inhibitory effect was observed, the effect was weaker as compared to the B Activation 1-11. Thus, the cosmetic is a skin external preparation of the present invention (B Activation 1 to 11) is found to exhibit a preventing or alleviating effect on good pigmentation.

<Production Example 17: Method 2 for producing skin external preparation of the present invention>
Table 4 and cosmetics of the water-in-oil emulsifier type according to the formulation described in Table 5 (creams 1 to 3) were prepared. That is, each of the components (a), (b), and (c) is heated to 80 ° C., and (d) is added and dissolved in a. emulsified by adding leaves, stirred cooled, to prepare cosmetic is a skin external preparation of the present invention (creams 1 to 3). By the same operation, comparison was substituted cosmetics "the compound represented by the general formula (1) of the present invention" contained in (creams 1) and "AGEs degradation agent of the present invention" together "water" Example 4 was made.

<Test Example 5: Evaluation 2 of pigmentation inhibitory action of the external preparation for skin of the present invention>
Cosmetics prepared according to the method described in Example 3 relates to (creams 1 to 3) and Comparative Example 4 were evaluated for pigmentation inhibitory effect according to the method of testing described in Example 2. The results are shown in Table 6. Cosmetic is a skin external preparation of the present invention (creams 1 to 3) has a smaller [Delta] L * value in comparison with Comparative Example 4, it is found to have a preventing or alleviating effect on good pigmentation.

<Production Example 18: Method 3 for producing skin external preparation of the present invention>
Attempts were made to prepare Cream 4 in which “Benton 38V” was replaced with POE (25) stearic acid in the formulation components of the external preparation for skin (Cream 1) described in Table 4 and Table 5. It was separated and an emulsion was not obtained.

<Test Example 6: Evaluation 1 on the wrinkle improvement effect of the external preparation for skin of the present invention>
Regarding the skin external preparations (cosmetics 1 to 7) produced according to the method described in Example 1 and Comparative Examples 1 to 3, the wrinkle improvement effect was examined according to the following test method. In other words, the panelists over the crow's feet is a concern (female, age 40 to 60 years of age) in the group consisting of each group of five, the external preparation for skin (cosmetics 1 to 7), pass the Comparative Examples 1 to 3, 1 Used twice a day in the morning and every day for 8 weeks, score 0: no improvement, score 1: slight improvement felt, score 2: felt improved, score 3: clearly improved, score 4 : Score evaluation was performed according to the criteria of marked improvement. The results are shown in Table 7 as the number of appearances. From this, it can be seen that 1) the compound represented by the general formula (1) of the present invention and 2) the external preparation for skin (cosmetics 1 to 7) containing the AGEs decomposing agent are excellent in the wrinkle improving effect. Moreover, the higher skin wrinkle improvement effect was recognized by the plant extract obtained from the said general formula (1) leguminous genus Astragalus having the decomposition | disassembly effect | action of stratum corneum AGEs, and the anti-wrinkle improving agent.

From the results of Table 7, the cosmetic of the present invention (B Activation 1 and B Activation 5) is found to have excellent wrinkle improving effect.

<Test Example 7 : Evaluation 2 on wrinkle improvement effect of external preparation for skin of the present invention>
Relates cosmetics (creams 1 to 3) and Comparative Example 4 prepared according to the method described in Example 3, according to the method described in Example 6, antiwrinkle using photoaging model of skin external preparation of the present invention The effect was evaluated. The results are shown in Table 8.

From the results of Table 8, cosmetics (creams 1 to 3) is found to have excellent wrinkle improving effect.

<Test Example 8 : Evaluation 3 of pigmentation inhibitory action of the external preparation for skin of the present invention>
It relates Example cosmetics prepared according to the method described in 1 (b Activation 1, lotions 5 and lotions 7) and Comparative Example 3 were subjected to pigmentation inhibitory effect evaluation according to the following procedure. In selecting the amount of melanin is more panelists over the average, the specimens corneocytes collected by the adhesive tape over TOPS tripping from the skin was visualized by performing the melanin staining with silver nitrate solution, which is observed under a microscope It was judged by. In the determination, the average existence situation was scored and determined. Free of subjects who participated at will, the incidence is higher than the average of the nucleated cells with the stratum corneum sample, to the degree of overlay peeling was selected panelists over by observing the human more than the average. Panelists provided 4 places the test site of 1.5 cm × 1.5 cm in the upper inner arm portion of the chromatography, minimal erythemal dose (1 MED) UV irradiation once a day, were irradiated 3 consecutive days 3 times. From 1 day after the completion of irradiation, 50 μL of sample was applied once a day for 28 consecutive days. 24 hours after the application (day 29), the skin lightness (L * value) of each test site was measured with a color difference meter (CR-300, Konica Minolta Co., Ltd.), and 29 days from the L * value on the first day of the test. The ΔL * value was calculated by subtracting the L * value of the eye. A larger L * value indicates higher skin brightness. Therefore, the smaller the ΔL * value, the smaller the difference between the L * value on the first day of the test and the L * value on the 29th day, and it can be determined that pigmentation was suppressed. The results are shown in Table 9. Thus, the cosmetic is a skin external preparation of the present invention (B Activation 1, lotions 5 and lotions 7) is found to exhibit excellent pigmentation inhibitory effect.

<Test Example 9: Evaluation 4 of pigmentation inhibitory action of the external preparation for skin of the present invention>
Cosmetics prepared according to the method described in Example 3 relates to (creams 1 to 3) and Comparative Example 4, according to the method described in Example 8 was evaluated pigmentation inhibitory effect. The results are shown in Table 10. From the results of Table 10, the skin external preparation of the present invention (creams 1 to 3), it is found to exhibit excellent pigmentation inhibitory effect.

  The present invention can be applied to cosmetics for whitening, preventing or improving wrinkle formation.

Claims (13)

1) one or more selected from the compounds represented by the following general formula (1), optical isomers and pharmacologically acceptable salts thereof, and 2) advanced glycation end products (AGEs: in Advanced glycation end-products) characterized by containing a decomposing agent or AGEs production inhibitor, one or more of the AGEs decomposing agent or AGEs production inhibitor is selected from plant extracts obtained from the following plants Oh Ru, external preparation for skin.
(Plants) Plants belonging to the genus Leguminous genus, plants belonging to the genus Oligoceae, plants belonging to the genus Yukinoshita, plants belonging to the family Rosaceae Potentira, plants belonging to the legume Asparatus genus, belonging to the genus Rosaceae Plant, plant belonging to the genus Artemisia

[In the formula, R ₁ represents a hydrogen atom, R ₂ represents a hydrogen atom, R ₃ is a phenyl group, methylphenyl group, ethylphenyl group, propylphenyl group, methoxyphenyl group, ethoxyphenyl group , A propyloxyphenyl group, or a biphenyl group , m represents 0, and n represents an integer of 1 or 2. ] The skin external preparation according to claim 1 , wherein the compound represented by the general formula ( 1 ) is a compound represented by the following general formula (4).

Wherein, R ₈ represents a hydrogen atom, R ₉ is a phenyl group, methylphenyl group, Echirufeni
Represents a ruthenium group, a propylphenyl group, a methoxyphenyl group, an ethoxyphenyl group, a propyloxyphenyl group, or a biphenyl group . ] Formula (1) or a compound represented by (4) is, N-(p-torr OIL) cysteic acid (Compound 1), N-(m-torr OIL) cysteic acid (Compound 2), N - (o-torr OIL) cysteic acid (compound 3), characterized in that the N-(p-methoxybenzoyl) cysteic acid (compound 4), or N-(4-phenylbenzoyl) cysteic acid (compound 5) And
The external preparation for skin according to claim 1 or 2 .

N-(p-torr OIL) cysteic acid (Compound 1)

N-(m-torr OIL) cysteic acid (Compound 2)

N-(o-torr OIL) cysteic acid (Compound 3)

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

N- (4-Phenylbenzoyl) cysteic acid (Compound 5) The compound represented the general formula (1) is, N- and wherein the (p- torr OIL) homocysteine acid (compound 6), the skin external preparation according to claim 1.

N-(p-torr OIL) homocysteic acid (Compound 6) One or more selected from the compound represented by the general formula (1), optical isomers thereof, and pharmacologically acceptable salts thereof is 0.0001% by mass to 20% with respect to the total amount of the external preparation for skin. The skin external preparation according to any one of claims 1 to 4 , which is contained by mass%. The AGEs decomposing agent or AGEs production inhibitor, legume Astragalus Rengesou, Oleaceae olea Olive, Saxifragaceae Saxifraga saxifrage, Rosaceae Potenchira genus Torumenchira, Rosaceae Potenchira genus Kawarasaiko, Rosaceae Potenchira genus Miyamakinba Lee, leguminous It is 1 or more types selected from the plant extract obtained from Asparatus genus Rooibos, the Rosaceae genus Shimoketsu genus Shimoke, Asteraceae Artemisia genus Artemisia, The any one of Claims 1-5 characterized by the above-mentioned. Skin external preparation. The external preparation for skin according to any one of claims 1 to 6 , wherein the AGEs decomposing agent or the AGEs production inhibitor has a degrading action of AGEs present in the horny layer of the skin. The skin external preparation according to any one of claims 1 to 7 , wherein the AGEs decomposing agent or the AGEs production inhibitor is contained in an amount of 0.0001% by mass to 10% by mass based on the total amount of the external preparation for skin. . The external preparation for skin according to any one of claims 1 to 8 , which is a cosmetic. The external preparation for skin according to any one of claims 1 to 9 , wherein the preparation is for prevention or improvement of skin symptoms. The skin external preparation according to claim 10 , wherein the skin symptom is pigmentation by exposure to ultraviolet rays. The skin external preparation according to claim 11 , wherein the pigmentation is caused by abnormal pigmentation involving cell inactivation of keratinocytes caused by melanin overtransport. The skin external preparation according to claim 10 , wherein the skin symptom is wrinkle formation.

Images