JP2013129615A5 - - 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. ]

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 compounds represented by the general formulas (1) to (4) are N- (p-toluyl) cysteic acid (compound 1), N- (m-toluyl) cysteic acid (compound 2), N- (O-toluyl) cysteic acid (compound 3), N- (p-methoxybenzoyl) cysteic acid (compound 4), N
The external preparation for skin according to any one of <1> to <4>, which is-(4-phenylbenzoyl) cysteic acid (compound 5 ) .
<6> The compounds represented by the general formulas (1) to (3) are N- (p-toluyl) homocysteic acid (compound 6), wherein <1> to <3> The external preparation for skin according to any one of the above.

<7> The compound represented by the general formula (1), its optical isomers and one or more selected from those pharmaceutically acceptable salts, to the total amount of the skin treatment composition, 0.0001 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 external preparation for skin according to any one of <1> to < 7 >, wherein the AGE decomposition agent is one or more selected from plant extracts obtained from the following plants.
(Plant) legume Astragalus belonging to the plant, plant belonging to the Oleaceae olive species, plants belonging to the Saxifragaceae Saxifraga, plant belonging to the Rosaceae Potenchira genus, plant belonging to the Rosaceae Potentilla, leguminous asparagus-to-scan the genus belonging to the plant, plant belonging to the Rosaceae filipendula, plants belonging to the Asteraceae Artemisia <9> said AGEs decomposition agent, legume Astragalus Rengesou, Oleaceae olive species olive, Saxifragaceae Saxifraga saxifrage, One or more species selected from plant extracts obtained from Rosaceae Potentilla genus Tormentilla, Rosaceae Physalis spp., Rosaceae Potentilla spp., Lotus, Aspartus rooibos, Rosaceae genus Pseudomonas, Artemisia genus Artemisia and characterized in that, according to any one of <1> to <8> External preparation for skin.
< 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> characterized in that it is a cosmetic, <1> to the skin external preparation according to any one of <11>.
< 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 skin symptoms, characterized in that it is a pigmentation due to ultraviolet rays exposure, skin external preparation as described in <13>.
<15> the pigmentation, characterized in that the cell inactivation of keratinocytes caused by melanin excess transport is due to pigmentation abnormalities involving the skin external preparation as described in <14>. <16> The skin condition, characterized in that a wrinkle formation, skin external preparation as described in <13>.

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 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.

<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.

<Production Example 2: Synthesis of L isomer of Compound 2>
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) in 100 (mL) eggplant type flask 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 and evaporated in vacuo 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.

<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 and evaporated in vacuo 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.

<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 and evaporated in vacuo 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.

<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 and evaporated in vacuo 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.

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 and evaporated in vacuo 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.

<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. As the AGEs decomposing agent of the present invention, for example, measurement of the CC bond cleavage action of AGEs decomposition evaluation (alpha-diketones as described in JP-A-2007-161662, glucose - bovine serum albumin AGEs decomposition The component which shows AGEs decomposition | disassembly effect | action etc. can be illustrated 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. theoretical amount of acid relative to that, the actual amount of product benzoic acid in is 20% or more substances, or glucose - in the measurement evaluation of bovine serum albumin AGEs decomposition, AGEs 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 olive genus, Saxifragaceae Saxifraga, Rosaceae Potenchira genus Leguminosae asparagus toe scan genus Rosaceae filipendula, Rosaceae Potentilla, Asteraceae Artemisia plant extract obtained from leguminous Astragalus belongs plants can preferably exemplified, more preferably, Oleaceae olive genus olive, Saxifragaceae Saxifraga saxifrage, Rosaceae Potenchira genus Torumenchira Preferable examples include plant extracts obtained from rosaceae genus Kawara psycho, rosaceae potentia genus miyamakinbai, legume aspartus rooibos, rosaceae spruce genus shimokeso, chrysanthemum genus mugwort, leguminous genus genus genus. 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. As the component with AGEs decomposition present in such human stratum corneum in, in AGEs decomposition evaluation in human stratum corneum in, the stratum corneum samples taken from panelists over, is reacted with anti-AGEs antibody, the reaction When the site is detected and there are clearly fewer reactive sites in the coexistence with the AGEs decomposing agent than in the non-coexistence, it can be said to be a component having the action of decomposing AGEs present in the stratum corneum. As the component having the effect of inhibiting the formation of AGEs in such human stratum corneum in, in AGEs formation inhibitory evaluation in human stratum corneum in, allowed to horny layer specimen at 37 ° C. is immersed in glucose solution When AGEs are generated, a component having an action of suppressing the generation of AGEs in the stratum corneum when there are clearly fewer reaction sites in the coexistence with the AGEs decomposing agent than in the non-coexistence is preferable. I can do it. 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. Examples of such AGEs decomposing agent, according to the study by the inventors of the present invention, the legume Astragalus, Oleaceae olive genus, Saxifragaceae Saxifraga, Rosaceae Potenchira genus, Rosaceae Potentilla, leguminous asparagus-to-scan the genus, Rosaceae filipendula, can plant extract preferably exemplified obtained from plants belonging to the Asteraceae Artemisia, more preferably, Leguminosae Astragalus Rengesou, Oleaceae olive genus olive, Saxifragaceae Saxifraga saxifrage, A plant extract obtained from a rose family Potentilla genus Tormentilla, a Rosaceae mosquito sp. A plant extract obtained from the genus Astragalus can suitably be exemplified. The plant extract obtained from the leguminous genus Astragalus is superior in AGEs degrading action, in particular, epidermal AGEs degrading action.

Among plant extracts with AGEs decomposition of the, Oleaceae olive genus olive is evergreen tree of North Africa native, fruits are used as a cage over Buoiru and 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. Rosaceae Potenchira genus Torumenchira is a perennial that is distributed to the yaw Europe, there is an effect and antibacterial action to tighten the skin. The rose family Potentilla spp. Is a perennial alpine plant that grows in China's native gravel and grassland. In Japan, it grows in the north of Honshu, Hokkaido, the Kuril Islands, etc. In Japan, the Rosaceae 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, and it is used as an antipyretic medicine. Legume asparagus-to-scan genus rooibos is a plant with a conifer-like leaves that grows naturally only in Sedaruba Hague Mountains zone that extends to the north of Nishike-loop State of the Republic of South Africa, the leaves are dried used in the health tea. 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.

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.

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 Yukinoshita of this invention>
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 of the genus Rosaceae of the present invention>
After chopping 100 (g) of a dried whole plant of the genus Roseaceae,
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 2. Thereafter, 200 (mL) water and 200 (mL) ethyl acetate are added to the plant extract 2, 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 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.

<Test Example 1: AGEs degradation action evaluation 1 (measurement of CC bond cleavage action of α-diketone)>
22 mM 1-phenyl-1,2-propane dione / methanol + 0.1 M phosphate buffer solution and (pH7.4) 1 (mL), plant extracts of the present invention (Oleaceae olive genus cage over Buyori Obtained plant extract, plant extract obtained from Yukinoshita genus Yukinoshita, plant extract obtained from Rosaceae Potentilla genus Tormentilla, plant extract obtained from Rosaceae genus Kawarasaicho, obtained from Rosaceae Potentilla spp. Plant extract, plant extract obtained from leguminous aspartus rooibos, plant extract obtained from rosaceae genus genus shimoke, plant extract obtained from asteraceae wormwood, plant obtained from legume genus genus Extract) 1 (mL) was mixed 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 over 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. Cutting action of plant extracts with AGEs decomposition of the present invention, Oleaceae olive genus cage over Buyori plant extract obtained (29%), plant extracts obtained from Saxifragaceae Saxifraga saxifrage (35% ), A plant extract (32%) obtained from the rose family Potentilla genus Tormentilla, a plant extract (29%) obtained from the Rosaceae genus Kawara Psycho, a plant extract (34%) obtained from the Rosaceae Potentilla spp. Plant extract obtained from leguminous aspartus rooibos (25%), plant extract obtained from rosaceae spruce spruce (37%), plant extract obtained from asteraceae mugwort mugwort, legumes It was a plant extract (43%) obtained from the genus Astragalus. 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 the mixture is allowed to stand 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 decomposer of the present invention described above, AGEs decomposition evaluation according to the method described in Test Example 2 - it was carried out (glucose measurements of bovine serum albumin AGEs decomposition). Glucose plant extracts with AGEs decomposition of the present invention - bovine serum albumin AGEs decomposition is Oleaceae olive genus cage over Buyori plant extract obtained (25%), from the Saxifragaceae Saxifraga saxifrage Obtained from a plant extract (28%), a plant extract (24%) obtained from a rose family Potentilla genus Tormentilla, a plant extract (28%) obtained from a rose family Potato genus Kawara Psycho, obtained from a Rosaceae Potentilla spp. Plant extract (31%), plant extract obtained from leguminous aspartus rooibos (24%), plant extract obtained from rose family genus Aspertus (32%), plant obtained from Artemisia genus mugwort It was an extract (33%) and a plant extract (37%) obtained from leguminous genus Astragalus. 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.

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 coconut oil, hydrogenated oil, molasses, hydrogenated castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba wax, oils, waxes; liquid paraffin, squalane, pristane, ozokerite, 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.

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 is used, it belongs to the technical scope of the present invention. The action other than the skin softening, moisturizing effect, skin roughness preventing or ameliorating action, and the like - aging improving effect.

<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 (b), kneaded to form a gel, and then added to (b) and diluted. 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.

<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: feels a little improved, score 2: feels 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.

Claims (16)

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 Products (AGEs : Advanced glycation end-products)
Skin external preparation.

(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. ] The compound represented by the general formula (1), characterized in that a compound represented by the following general formula (2), the skin external preparation according to claim 1.

(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. ] The compound represented by the general formula (2), characterized in that a compound represented by the following general formula (3), the skin external preparation according to claim 2.

(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. ] The compound represented by the general formula (3), characterized in that a compound represented by the following general formula (4), the skin external preparation of claim 3.

(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. ] The compounds represented by the general formulas (1) to (4) are N- (p-toluyl) cysteic acid (compound 1), N- (m-toluyl) cysteic acid (compound 2), N- (o- Toluyl) cysteic acid (compound 3), N- (p-methoxybenzoyl) cysteic acid (compound 4), N- (4-
The external preparation for skin according to any one of claims 1 to 4, which is phenylbenzoyl) cysteic acid (compound 5 ) .

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

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

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

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

N- (4-Phenylbenzoyl) cysteic acid (Compound 5) The compound represented by the general formulas (1) to (3) is N- (p-toluyl) homocysteic acid (compound 6), according to any one of claims 1 to 3. The skin external preparation as described.

N- (p-Toluyl) 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 6 , wherein the skin external preparation is contained by mass%. The skin external preparation according to any one of claims 1 to 7 , wherein the AGEs decomposing agent is at least one selected from plant extracts obtained from the following plants.
(Plant) legume Astragalus belonging to the plant, plant belonging to the Oleaceae olive species, plants belonging to the Saxifragaceae Saxifraga, plant belonging to the Rosaceae Potenchira genus, plant belonging to the Rosaceae Potentilla, leguminous asparagus-to-scan the genus Plants belonging to the family, plants belonging to the genus Rosaceae, plants belonging to the genus Artemisia The AGEs decomposition agent, legume Astragalus Rengesou, Oleaceae olive species olive, Saxifragaceae Saxifraga saxifrage, Rosaceae Potenchira genus Torumenchira, Rosaceae Potentilla Kawarasaiko, Rosaceae Potenchira genus Miyama Kinbae, leguminous asparagus The skin according to any one of claims 1 to 8 , wherein the skin is one or more selected from plant extracts obtained from the genus Tuus rooibos, the rosaceae genus Shimotsukiso, and the asteraceae Artemisia. Topical agent. The external preparation for skin according to any one of claims 1 to 9 , wherein the AGEs decomposing agent has an action of decomposing AGEs present in the horny layer of the skin. The skin external preparation according to any one of claims 1 to 10 , wherein the AGEs decomposing agent is contained in an amount of 0.0001 mass% to 10 mass% with respect to the total amount of the external preparation for skin. The external preparation for skin according to any one of claims 1 to 11 , which is a cosmetic. The external preparation for skin according to any one of claims 1 to 12 , which is used for prevention or improvement of skin symptoms. It said skin symptoms, characterized in that it is a pigmentation due to ultraviolet rays exposure, skin external agent of claim 13. The external preparation for skin according to claim 14 , wherein the pigmentation is due to abnormal pigmentation involving cell inactivation of keratinocytes caused by melanin overtransport. The skin condition, characterized in that a wrinkle formation, skin external agent of claim 13.