TW201023909A - Melanin formation inhibitor and preparation for external application - Google Patents

Abstract

Disclosed is a melanin formation inhibitor which is safe and has a high activity. More specifically, the melanin formation inhibitor contains a compound having a germacrone-like skeleton represented by chemical formula (1) as an active ingredient. The compound can be produced by the purification from a plant such as a zedoary plant (Curcuma zedoaria Roscoe (Zingiberaceae)) or a turmeric plant (Curcuma longa [syn. C. domestica]), and has a melanin formation inhibitory activity 400 times higher than that of arbutin. The melanin formation inhibitor can be added, together with an additive such as a surfactant, a pH-adjusting agent, a water-soluble polymer, an antioxidant agent and a moisturizing agent, to a base material for a cosmetic or a pharmaceutical external preparation (wherein the base material comprises various types of oily raw materials, water, an alcohol, a polyhydric alcohol or the like) in such an amount that the content of the melanin formation inhibitor in the cosmetic or preparation becomes 0.000001 to 1.0%.

Description

201023909 VI. Description of the Invention: [Technical Field] The present invention relates to a melanin production inhibitor and a skin external preparation using the same. [Prior Art] Various external preparations for whitening which have improved skin tone, black or chloasma, freckles and the like have been provided. Arbutin or kojic acid, ascorbic acid and derivatives thereof, glutathione, colloidal sulphur Colloidal sulfur) has been used as a well-known substance. In recent years, 4-MSK (4-methoxy salicylic acid) or Rucinol (registered trademark), Magn〇lignan (registered trademark) ), ellagic acid or linoleic acid is used as an active ingredient of a commercially available external preparation for whitening. In addition to the above compounds, various extracts of animal and plant extracts such as uva ursi extract or zedoary extract, chamomilla recutita extract, mulberry extract, placenta extract, and seaweed extract are also used. Whitening is used with the active ingredient of the external preparation. However, there are few records indicating which components of the extracts such as these animals and plants exert a whitening effect. So far, it has only been known that arbutin in bear grape leaf extract has a whitening effect. In recent years, only the condensation-type tannin-type substance of a specific structure in the extract of hymenaea courbaril known by the whitening effect has been revealed. It has a whitening effect (refer to Patent Document 145235.doc 201023909 1). On the other hand, various plant whitening components have also been found in plant extracts which are not known from the whitening effect (see, for example, Patent Document 2). Since the existence of zedetone represented by the following sputum has been confirmed in the request (Curcuma zedoaria Roseoe (Zingiberaceae, Gingeraceae): the name is purple turmeric) (Non-Patent Document 1), It has been reported that the flavonoids are not only present in the genus, but also in the genus Curcuma of its neighbors. For example, c phae〇_HsM is called turmeric (Curcuma longa [syn·] Cd〇mestica]: alias for autumn tomb yellow), spring turmeric (Curcuma belongs to the genus (Chloranthus refers to non-patent literature 2 to 4). [Chemical 1] aromatica Sa〗 isb), Golden Chestnut serratus (Chloranthaceae) ) etc. (for example

There are many reports that (4) extracts and turmeric extracts exhibit anti-allergic effects in addition to whitening effects (see Patent Documents 3 to 6) or have a squatting effect (refer to the patent literature for strength and hair growth promoting effects). Refer to Patent Document 8), have a blood circulation promoting action (refer to Patent Document 9), and have various pharmacological effects such as anti-aging or wrinkling (refer to Patent Document 1). However, in this case, the person who has been confirmed as turmeric The autumn turmeric of the plant is not 145235.doc 201023909, t whitening effect (refer to the patent document 1U, and even if it also contains the edulis; the plant extract of the enamel, not all play a whitening effect, therefore can not be considered a box ring Oxy ketone is the essence of whitening ingredients. Further, various studies have been conducted on the mechanism of whitening action in the industry, and various types of action have been found. For example, it has been found that the production of e-kit gene in melanin is disclosed in Patent Document 11 above. The 50% (v/v, volume ratio) ethanol extract of the planting technique plays a role in whitening by suppressing the gene expression of ^^疋 Even though the expression inhibition of the c_kit gene was found as the action pattern of the extract of zedoary sinensis as described above, it is still unclear what kind of substance contained in the extract is involved in inhibiting the expression of the e_kit gene. It is known that the epoxy ketone is known to have an antibacterial activity (see Non-Patent Document 5), and the prevention of liver disease induced by (g actosamine/ilpop〇lysaccharide, d-galactosamine/lipopolysaccharide) (see Non-Patent Document 6). Further, in the above Patent Document 3, it is disclosed that the extract containing the epoxy resin is required to extract the extract, and the above-mentioned patent document can be promoted. The essential oil component of the scorpion scorpion exhibits the promotion of liver detoxification function and the diuretic action, cardiotonic action, antibacterial action, and inhibition of blood cholesterol. ^ 〒 (4) class shows resistance to living habits; East; ^ ^ ^ ^, 乍 use 'but not all patent documents have not clearly pointed out that the epoxies and ketones directly express these effects. As a substance active in the disease, it is known that it contains a furanodienone (see Non-Patent Document 7), and the component which is separated from the sputum has a pressure ulcer (4) such as *-〇η 145235.doc 201023909 "As a substance having anti-ulcer activity, it is known that it is a cyclodextrene (see Non-Patent Document 8). It is widely used as an antibacterial, antibacterial, and antiviral effect. Knowing that there are two kinds of stagnation in the lotus and the box to find the bite 嗣 ((4) verbose. For example, refer to Patent Document 13). As mentioned above, 'the report on the whitening effect of substances such as ketones and ketones has not been seen so far. The actual situation is almost unknown to the whitening ingredients in the extract of Curcuma. In the technical context of this, the inventors of the present invention sought a different whitening component. That is, ascorbic acid is easily oxidized and unstable, and therefore various derivatives thereof are currently used, but it is a component which is a cosmetic material which is in contact with human skin, and is preferably a component derived from a natural product. Glutosin or colloidal sulfur has the disadvantage of producing a characteristic odor or precipitate. Animal and plant extracts and seaweed extracts have insufficient effects or unstable quality. Kojic acid, arbutin with phenolic group, and citric acid have the effect of causing coloration in the presence of alkali or metal ions, and therefore have problems in preparations that have to be considered for maintaining their stability. Further, the sesquiterpene Lactones disclosed in the above Patent Document 2 have a characteristic odor, and it is known that the stability of the oily compound is not good, so that it is difficult to stably mix into a product. As mentioned above, the whitening ingredients so far have some disadvantages. [PRIOR ART DOCUMENT] [Patent Document 1] Japanese Patent Laid-Open No. Hei. No. Hei. No. Hei. No. Hei. [Patent Document 5] Japanese Patent Laid-Open Publication No. SHO 61-108524. [Patent Document 5] Japanese Patent Laid-Open Publication No. SHO-62-108822 [Patent Document 6] Japanese Patent Laid-Open No. 09-208480 [Patent Document 7] Japanese Laid-Open Patent Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. 2002-242435. [Patent Document 11] Japanese Patent Laid-Open Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. -1191 No. 88 [Non-Patent Document] [Non-Patent Document 1] Hiroshi Hikino et al., Chemical Pharmaceutical Bulletin (1968), 16(6), 1081-1087. ❹ [Non-Patent Document 2] Yu-Chi Hou et al., Chinese Pharmaceutical

Journal (Taipei) (1997), 49(2), 119-125. [Non-Patent Document 3] Jun Kawabata et. al., Agricultural and Biological Chemistry (1985), 49(5), 1479-1485 o [Non-Patent Document 4] Minh Giang Phan et al., Tap Chi Hoa Hoc (2000) , 38(4), 96-99 ° [Non-Patent Document 5] Minh Giang Phan et al., Tap Chi Hoa Hoc (2000), 38(1), 91-94 ° [Non-Patent Document 6] Hisashi Matsuda, Chemical Pharmaceutical 145235.doc 201023909

Bulletin (2001), 49(12), 1558-1566. [Non-Patent Document 7] H. Makabe et al., Natural Product Research, Part B: Bioactive Natural Products (2006), 20(7), 680-685. [Non-Patent Document 8] Kazuo Watanabe et al., Yakugaku Zasshi (1986), 106(12), 1137-1142. SUMMARY OF THE INVENTION [Problems to be Solved by the Invention] The present invention has been developed in view of the above background art, and an object of the present invention is to provide a melanin production inhibitor which is easily formulated into a formulation and which is highly effective. [Means for Solving the Problems] The inventors of the present invention have diligently studied under the above-mentioned background art, and as a result, have found that a group of compounds having a medicinal extract as an initial substance has an excellent whitening effect, thereby completing the present invention. In other words, the present invention provides: [1] A melanin production inhibitor which comprises one or more compounds represented by the following formula as an active ingredient: Formula: [Chemical 2]

Wherein R1 is HSCw alkyl, 145235.doc 201023909 R2 and R3 are independently Η, 011 or €1_3 alkyl, or "form with 妒", R is Η or Ci_3 alkyl, X and Y form A divalent group represented by [Chemical Formula 3] or a divalent group represented by [Chemical Formula 5]: Μ [Chemical 3]

R10 [wherein, the symbol: [Chemical 4] represents a single bond or a double bond, R5 is a hydrazine or a Cw alkyl group, R6 is a fluorene, (^ or a heart) alkyl group, and R7 and R8 are independently a HiCu alkyl group, or a bond In the case where the knot (1) is a double bond, R5 and R7 or R8 are not present, or ^ is formed to form '0 _ ' R9 is Η or Cw alkyl, R10 is ^1 or (^ · 3 alkyl, or in the case where the bond (2) is a double bond, r1 〇 145235.doc 201023909 does not exist] [Chemical 5]

Wherein R11 is a linear or branched iC!·5 alkyl or a linear or branched fluorenyl group, and R12 is a straight or branched chain (^.5 alkyl or straight or branched) R13 is hydrazine or Cw alkyl]}. [2] A melanin production inhibitor which is represented by the following formula or two or more compounds as an active ingredient, which is [Chemical 6]

As indicated, {where R1 is methyl, 145235.doc •10- 201023909 R2 and R3 are independently Η or oh, R4 is Η, or R2 and R3 together form ^^ not a valence group or by [ X and Y represented by chemistry 9] form a divalent group represented by [Chemical 7]: [Chemical 7]

[wherein, the symbol: [Chemical 8] represents a single bond or a double bond, R5 is Η or absent, R6 is Η or ΟΗ, R and R are independently Η or methyl, or the bond (1) is a double bond In the case where R or R or R8 does not exist, or R6 and R7 together form 'R9 is a methyl group, R is H, or when the bond (2) is a double bond, Rio does not exist. ] [Chem. 9] 145235.doc •11- 201023909

R11

R12 [wherein R11 is an isopropenyl group, R12 is a vinyl group, and R13 is a fluorenyl group]}. [3] The melanin production inhibitor according to the above [1], wherein the compound is one or more selected from the group consisting of the following compounds: From [Chemical 10]:

The indicated phoenix ketone, ❹ by [化11]: η

The indicated dipyridamole, by [Chem. 12]: 145235.doc •12· 201023909

The indicated 莪 咬 咬 s s, with [化13]:

The hydrogenated porphyrin epoxy copper is represented, as well as by [Chem. 14]:

The hydrogenated porphyrin cyclodienone is represented. [4] A method for producing a melanin production inhibitor, comprising the steps of: (1) impregnating a dried rhizome of Curcuma zedoaria with a solution selected from the group consisting of methanol, ethanol, an aqueous solution of decyl alcohol, an aqueous solution of ethanol, hexane, and acetic acid. An extract of zedoary turmeric is prepared from one or more solvents of the group consisting of ethyl esters; 145235.doc -13· 201023909 (2) filtering the extract of zedoary turmeric; (3) distributing the liquid-liquid of the filtrate Between the hexane-water layers; then (4) The hexane layer was evaporated to dryness to obtain a melanin production inhibitor. [5] The method for producing a melanin production inhibitor according to the above [4], which further comprises the step of: 'dispensing the aqueous layer liquid-liquid between the ethyl acetate-water layer in the step (3), in the step ( In 4), the ethyl acetate layer was evaporated to dryness to obtain a melanin production inhibitor. [6] A method for producing a melanin production inhibitor, comprising the steps of: (1) impregnating a dried rhizome of Curcuma zedoaria in hexane to prepare a zedoary extract; & (2) placing a zedoary extract The liquid is crystallized; (3) the crystals are washed with a small amount of hexane; and then (4) the washed crystals are recrystallized to obtain a melanin production inhibitor. [7] A skin external preparation for whitening, which comprises a melanin production inhibitor of any one of the above-mentioned Π] to [3], which is about 0.000001 to 丨〇% by mass. [8] A skin external preparation comprising an anthraquinone or a combination of two or more selected from the group consisting of epoxicone, porphyrin, and fluorenone, and excluding the active ingredient selected from the group consisting of An extract of the group consisting of epoxies, ketones, ketones and ketones, or more than two kinds of natural extracts. [Effects of the Invention] M5235.doc -14- 201023909 According to the present invention, there is provided a melanin production inhibitor having a high effect, which is produced by or by a specific compound which is one or two or more kinds of compounds which are separated from each other. The compound for whitening can be used for the purpose of producing a whitening external preparation which is excellent in stability and has an extremely high whitening effect which has not appeared in the cosmetics. Further, in addition to the above-mentioned substances which have confirmed the whitening effect in the present invention, hydroquinone furanone or the following compounds are also known, and according to the present invention, whitening effects can be expected for these compounds. [化15]

7α-hydroxy neodymidine dione: R=a-OH 7β-hydroxy guanidine diketone: R=jg -〇H

Jima

-嗣:R=Of-H L Two vehicles: R=;g-H

(+)-Gimerone (+)-Gimerone -4,5-epoxide -4,5-epoxide

13-hydroxy geminone

Gimarone-1 (10), 4-diepoxide

Eurasian blood-dandanone furan geranone

Isoformin

Puffing epoxy ketone epoxide

Pleurotus Cyclodiene-6-ketone [Embodiment] In a first aspect of the present invention, a melanin production inhibitor is provided. The melanin production inhibitor of the present invention has a group σ235.doc -15-201023909 grouped σ substance having a gemasketone-like skeleton as an active ingredient. As described above, the compounds used in the present invention are known as components contained in plants which are representative of the family of Zingiberaceae, which are represented by the pleadings. Further, the compound used in the present invention also includes a gasifier which is formed by gasification of a natural component which is isolated from a plant belonging to the family Zingiberaceae. As shown in the following examples, the group compound of the melanin production inhibitor of the present invention exhibits an effect of about 400 times that of the effect of the melanin production, which is considered to be a melanin production inhibitor, that is, bearnut. An amount of about 1/400 of the amount of glycoside used can exhibit an equivalent melanin production inhibitory effect. One of the compounds contained in the melanogenesis inhibitor of the present invention can be obtained by the root, stem, leaf, etc. of the Curcuma zed〇aria (Zhimaceae). Preferably, it is a rhizome thereof, which is extracted by using various organic solvents, and uses activated carbon, a styrene-divinylbenzene-based synthetic adsorbent (for example, manufactured by Mitsubishi Chemical Corporation: HP-20), octadecyldecyl phthalocyanine or The tannin extract is purified. In this case, as the extraction solvent, those selected from the group consisting of two or more of the following may be used. Water, methanol, or ethanol, such as a lower alcohol having a carbon number of about 44 or a water/valley thereof Liquid, ketones such as propyl hydrazine or methyl ethyl ketone; methyl acetate or ethyl acetate, ethyl acetate, s S··# esters, Zhengwu or Zhengjiyuan, Huanjiyuan, benzene, 曱本4 Various saturated or unsaturated hydrocarbons of chains or branches. Further, it is possible to appropriately distinguish between the use of such solvents, for example, when extracting from a plant, using a polar solvent over a non-polar solvent, and then separating by reducing the polarity. Further, the hydride contained in the melanogenesis inhibitor of the present invention can be obtained by subjecting the obtained compound to hydrogenation by 145235.doc •16-201023909 according to a well-known method. · However, the melanin production inhibitor of the present invention does not have to be purified into a single pure compound, as described in the following examples, and can also be extracted, adsorbed, liquid-liquid partitioned, crystallized, chromatographically separated, etc. by using various solvents. The operation comprises obtaining a relatively high concentration, for example, a purity of 60% (w/w) or more, 65% or more, 70% or more, 75% or more, preferably 80% or more, more preferably 85% or more, and still more preferably 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, and most preferably 99.5% or more of the crude purified product. A group of compounds contained in the melanogenesis inhibitor of the present invention as an active ingredient includes:

The eponymous epoxy ketone represented by [Chemical 17] η

The porphyrin ring diene ketone represented by 145235.doc -17· 201023909 [Chem. 18]

The indicated cockroach ketone, by [Chem. 19]

Represented by hydrogenated porphyrin epoxy ketone, as well as by [Chem. 20]

The hydrogenated porphyrin cyclododel ketone and the like are preferably selected from the group consisting of ketones, ketones, ketones, and ketones. These melanin production inhibitors may be synthesized by a well-known method, in addition to those synthesized by the methods disclosed in the present specification, or 145235.doc -18·201023909 or a commercially available person. A method for producing a melanin production inhibitor in the second aspect of the present invention is provided. Obtained by the melanin production inhibitor method of the present invention: it can be impregnated into a solvent by a dried product comprising the following steps of producing zedoaria)

(1) Curcuma (Curcuma preparation of zedoary extract; (7) to remove the solvent of the zedoary extract from the steam reduction hall; (3) cleaning the crystal component formed with a small amount of solvent; and then (4) crystallization obtained The component is recrystallized from a solvent. Further, the melanin production inhibitor of the present invention can be obtained by a production method comprising the following steps: (1) immersing the dried product in a solvent in a solvent to prepare a zedoary turmeric extract; (2) Distilling the solvent of the extract of Rhizoma Curcumae under reduced pressure; (3) Dissolving the obtained dry solid in a solvent, and separating (4) (4) as a filler column chromatography; then (4) removing the solvent from the separation The product is crystallized from a solvent. Further, the melanin production inhibitor of the present invention can be obtained by a production method comprising the following steps: (1) impregnating a dried product of zedoary turmeric in a solvent to prepare an extract, (2) Adding activated carbon to the zedoary turmeric extract and stirring; (3) filtering the mixture, washing the residue with a solvent; and then (4) extracting the melanin production inhibitor from the washed residue by the solvent. Further, the melanin production inhibition of the present invention The agent can be obtained by the method of 145235.doc •19-201023909 comprising the following steps: :: the dried product is immersed in a solvent to prepare an extract of the essence; and the liquid-liquid distribution is carried out between the aqueous solvent and the hydrophilic solvent; 3) ^ The solvent of the knife is evaporated from the knife; then (4) recrystallized from the non-aqueous solvent. In a preferred embodiment, the U extract is prepared in such a manner that the dry matter is obtained in a ratio of about 1:5 Torr to about 1:3 (volume ratio), preferably about 1 to about 1: pour ratio. Bath ratio, about 丨〇.仏, υ C to the boiling point of the extraction solvent, preferably from room temperature to soluble (four) point. Stirring, Soxhlet extraction or standing is carried out at a temperature of from about 2 hours to about 14 days, preferably about 7 days. In a preferred embodiment, the solvent used for the extraction, adsorption, liquid-liquid distribution, crystallization, and movement of the chromatograph is water, methanol, ethanol, 3^)~(v/v) Ethyl alcohol solution, hexane or ethyl acetate may be used, and these solvents may be used alone or in combination of two or more. In a preferred form, the conditions of the chromatograph are as follows. Column: Chemc〇b〇nd 5-ODS-W (6.0x150 (6A)) (ChemC〇) Mobile phase: 75% (v/v) aqueous methanol column temperature: 5 5 °C Flow rate: 1 〇mL/min Injection amount: 10 μΐ^ Monitor: UV (ultraviolet) monitor 280 nm absorbance in the preferred form 145235.doc -20- 201023909 included in the melanin production inhibitor of the present invention The oxime epoxy ketone can be obtained by a method comprising the steps of: immersing the dried stem of the stalk of the stalk of the stalk in ethyl acetate and extracting it by placing it; and (2) filtering and extracting by using a filter (ADVANTEC No. 131) The liquid is distilled under reduced pressure to remove the solvent of the filtrate; (3) the dry solid is supplied to a mixture of hexane and ethyl acetate as a mobile phase, and the mobile phase is used as a mobile phase. The column chromatography of tannin as a filler (same conditions as over-cracking) 'is separated by UV absorption at a wavelength of 2 1 〇nm as the standard; q (4) The separation of the absorption is confirmed by subtraction The solvent is removed by distillation, and then, (5) the distillation is recrystallized using hexane. Thus, a fluffy epoxy ketone is obtained. In a preferred embodiment, the cyclamate cyclodienone contained in the melanogenesis inhibitor of the present invention can be obtained by a process comprising the following steps: (1) drying the rhizome of the scorpion The product is concentrated under reflux of hexane; (2) the collected extract is distilled under reduced pressure, and the obtained dry solid is dissolved in a small amount of hexane; (3) supplied to the ruthenium dioxide column, Alkane, hexane: ethyl acetate (9:1 by volume), hexane: ethyl acetate (8:2 by volume) were sequentially dissolved; (4) Hexane: ethyl acetate (8:2 by volume) Separating and separating the fraction; then (5) dissolving in a small amount of 75% (v/v) aqueous methanol solution, and then supplying it to the ODS column, and dispensing a specific fraction to obtain a cyclamate ring _ 145235. Doc • 21-201023909 In a preferred embodiment, the furfuryl ketone contained in the melanin production inhibitor of the present invention can be obtained by a process comprising the following steps: (1) drying the rhizome of Rhizoma Curcumae under hexane reflux Concentrated; (7) Distilling the collected extract under reduced pressure to dissolve the dried solid obtained a small amount of hexane; ridge (3) is supplied to the ruthenium dioxide column, with hexane, hexane: ethyl acetate (9:1 by volume), hexane: ethyl acetate (8:2 by volume) (4) Separate the separated fractions by collecting hexane:ethyl acetate (8:2 by volume); then (5) dissolve in a small amount of 75% (v/v) aqueous methanol solution, and then supply to 〇DS. The column 'packages a specific separation point to obtain a sulphuric acid _. In a preferred embodiment, the hydrogenated porphyrin epoxy ketone contained in the melanogenesis inhibitor of the present invention can be obtained by a process comprising the following steps: (1) A pimple epoxy obtained by the above-mentioned preparation method or the like The ketone is dissolved in 99.5% (v/v) ethanol; (2) 5% Pd (Palladium, palladium) alumina is added, hydrogenation is carried out using hydrogen background; then (3) filtration is completed after the reaction The solvent of the filtrate was distilled off under reduced pressure to obtain hydrogenated ketone epoxy ketone. In a preferred embodiment, the hydrogenated porphyrin cyclodienone contained in the melanogenesis inhibitor of the present invention can be obtained by a process comprising the following steps: (1) A scallop ring obtained by the method described by Ji et al. The dilute bismuth is dissolved in 99.5% (v/v) ethanol; (2) 5% Pd_alumina is added, hydrogenation is carried out using hydrogen background; then 145235.doc •22-201023909, (3) after the reaction is over The solvent was removed by steaming under reduced pressure to obtain a hydrogenated porphyrin cyclic dienone. In a preferred embodiment, the hydroformylation inhibitor of the present invention may be obtained by a process comprising the following steps: (1) The furfurylfuran obtained by the above-mentioned preparation method or the like is dissolved at 99.5% ( v/v) in ethanol; listen to (7) add 5% of Pd·alumina, use hydrogen background to react; then & () reaction. After the beam was over-treated, the solvent was removed under reduced pressure to obtain a hydrogenated hydrazine furan. In a third aspect of the invention, there is provided a skin external preparation for whitening comprising a melanin production inhibitor. The melanin production inhibitor of the present invention is usually used by being formulated in various cosmetic bases or external pharmaceutical bases, and is, for example, provided as an external preparation for skin including: creams, lotions, lotions, dressings, Various facial makeups such as facial cleansers, foundation makeup, blush, honey powder, shampoo, hair restorer, shampoo, moisturizer, and other hair cosmetics and soap nails / by, cologne Other cosmetics such as water, and quasi-drugs for medical use and external preparations for medical use. The base for the cosmetic or the base for external use, for example, in the form of a liquid or a solid, various oily materials such as oils and fats, waxes, hydrocarbon oils, higher fatty acids, ester oils, and polyoxygenated oils, water, and alcohol can be exemplified. ,Polyol. Further, in the above cosmetic or medical external preparation, in addition to the above-mentioned base, the following additions can be added! : anionic surfactant, cationic interface activity 145235.doc -23- 201023909 agent, amphoteric surfactant, nonionic surfactant, pH adjuster, various water-soluble polymers, thickeners, UV absorbers, metal ions Blocking agent (seque fine ng agent) (chelating agent), sugar, amino acid, organic amine, polymer emulsion, vitamins, antioxidants, antioxidant additives, Bao (four), anti-inflammatory agent 'antibacterial agent, cell activator Coloring agents such as perfumes, pigments or pigments, preservatives, etc. The external preparation for skin of the present invention is formulated from the above-mentioned base agent by a group compound or a synthetic group compound which is isolated from the natural substance, and does not contain a natural one containing a group of compounds which are isolated from the natural substance. Extract. Also, the skin external preparation for obtaining a single group of compounds or by synthesizing a group of compounds can be preferably used without 'using a natural extract containing a group of compounds such as Poncho Epoxy _. For whitening agents. The actual present month is characterized in that a single or a group of compounds is used as a melanin production inhibitor, and the present invention is characterized in that a skin external preparation for artificially adding only a group of compounds or artificially adding a group of compounds is used. The natural extract is used as a skin external preparation which is further separated from a group of compounds to exert a whitening effect.剂 There is no particular limitation on the dosage form of the cosmetic or the external preparation for medical use, and examples thereof include a liquid or emulsion, an ointment, a solution, a gel, a powder, a spray, and the like. By making such a cosmetic or a medical external preparation, it is possible to exert a whitening effect. In the case of a cosmetic or the like, the present invention is used in an amount effective to impart a whitening effect to each of the dosage forms, but specifically, the compounding amount is one or two kinds with respect to the total amount of the external preparation for skin. The total amount of the above 145235.doc -24-201023909 is about 0.000001 to about 1.0% by mass, preferably about 〇〇〇〇〇ι to about 〇% by mass, and is about 0.0001% to about 0_005% by mass. The effect can be obtained again, based on the best extraction efficiency of the xanthene epoxy ketone 7 〇〇 / 0 . (ν / ν) aqueous ethanol extract for HpLC (high perf 〇 (10) chromatography, high performance liquid chromatography) The results of the analysis (not shown) can be considered to include about 1% of the deciduous epoxy ketone relative to the dried product. The extract of the medicinal herb which can be used in the cosmetic raw material is water extract 10, an ethanol extract, and an extract obtained by using a water-ethanol mixture. In the extracts, at least about 25 g of extract dried material (dry extract of Curcuma sinensis) can be obtained from i kg of the dried plant material. Thus, the zedoary turmeric extract (converted into a dry product) blended in the cosmetic contains only about 1 〇 mass.乂 之 之 之 环氧 环氧 环氧 环氧 环氧 环氧. In consideration of odor or coloring, it is converted into a dry matter, and the blending amount of the extract of zedoary turmeric is approximately 〇〇丨% by mass in the cosmetic, and is at most about 0.05% by mass or less. Therefore, even if the content of the epoxy ketone in the cosmetic materials known to date is relatively high, the Φ is about 005.005 mass 0/〇. Therefore, in the whitening cosmetic of the present invention, it is preferred to blend about 0 to 5% by mass of the ketone epoxicontone, and more preferably to arsenic ketone of about 0.01% by mass or more. In this way, the whitening effect that the previous whitening cosmetics do not have can be exerted. Next, the present invention will be described in more detail based on the following examples, but the present invention is not limited by the contents of the examples. [Example 1] [Extraction from Separation and Purification] When extracting and purifying the melanin production inhibitor of the present invention from the sputum, the first 145235.doc -25-201023909 first 'differentiation operation by the method shown in Fig. 1, And check the whitening effect on each distinction. The whitening effect was examined by examining the inhibition of melanin production as described below. In addition, the Department of Surgery is a recipient of the company. After 300 g of Curcuma zedoaria R〇scoe (add 50% (v/v) of aqueous ethanol solution to dryness 8 〇〇mL, let stand for 5 days at room temperature. Thereafter, filter to obtain 1600 mL The extract is concentrated under reduced pressure to obtain a dry solid of 75 g (box extract powder (4)). The dry solid of 1 § φ is dissolved in a small amount of 5 % (v/v) aqueous ethanol solution, and is put into Into the separatory funnel, add water and hexane (1:1 by volume) and = shake the sentence 'and then let stand. Take out the lower layer of water, and put the upper layer of the burned layer: in another flask The taken water layer is sent back to the separatory funnel and the operation is performed in the same manner as the water layer. Then, the water layer is again:, and then the same layer is roughly repeated twice to achieve the same phase ηι*# In the knives liquid funnel, the same volume of ethyl acetate was added to the water to carry out the liquid separation operation. The ethyl acetate layer of the upper layer was collected, and the extracted m “the upper layer of 叹 ^ ^ was sent back to the separatory funnel again. In addition, add the same volume of ethyl acetate vinegar as the water layer, and operate in the same way. - The water layer of the remaining part of the human body is subjected to a concentration of the ethyl acetate layer and the remaining (samples (4) to (10). The sample obtained by the melanin production inhibition test (melanin production inhibition test) is tested as a melanin production inhibition test. At this time, a three-dimensional culture skin model was used to test the melanin amount and protein amount as indicators. 145235.doc • 26 · 201023909 The melanin production inhibition test system uses a commercially available three-dimensional culture skin model (MEL-300 kit) Asian donor: Kurabo). According to the method of use of the kit, the MEL-300 skin model cup is placed in each well of the 6-well culture tray, and the kit heated by the 37 °C incubator is maintained. The medium (EPI-100: SCF (Stem Cell Factor) was added at a final concentration of 10 ng/mL when the medium was added) to be aseptically added to each skin model cup at 5 ml, respectively. Inside the model cup, 100 gL of each sample solution was directly added, and a 6-well culture plate containing a skin model cup was placed in an incubator (37 ° C, 5% CO 2 , humidified state) for 14 days. The new medium was replaced every two days, and each time the replacement was carried out, 100 KL of each sample solution was added to the skin model cup. Further, the solution for each sample was used for PBS for cell culture (Phosphate). Buffered saline, (-) buffer. After incubation, the MEL-300 skin model cup was washed 3 times with PBS(-), then the cells were partially stripped and placed in a 1.5 mL microcentrifuge tube (eppendorf tube). Inside, add 2 mol/L-NaOH with a σ 0.5 mL and leave it at room temperature overnight. After boiling for 15 minutes, 250 pL of each sample was transferred to a 96-well culture dish, and melanin was quantified at 405 nm. Further, the boiled melanin quantification sample was transferred to a 96-well culture dish by using 40 pL of the sample, and the protein was quantified using BCA (bicinchoninic acid) reagent (trade name: Takara Bio Co., Ltd.) 200. pL was placed in each well, and after incubation at 37 ° C for 30 minutes, the absorbance at 540 nm was measured. Further, using PBS(-) as a control, the same test was carried out using arbutin-PBS(-) solution 145235.doc -27-201023909 (2.0% (w/v)) as a positive control, and the reference substance was calculated. When the amount of melanin (relative ratio) and the amount of protein (relative ratio) were set to 100, the degree of inhibition of melanin production was examined. The results are shown in Table 1. Further, a photograph showing the results of the three-dimensional culture skin model at this time is shown in Fig. 2 . [Table 1] Concentration (%) Melanin amount (%) Protein amount (%) PBS(-) 100.0 100.0 Bearberry bud 2.00 54.4 58.3 莪 萃取 extraction powder (A) 0.05 60.5 80.5 莪 萃取 extraction powder hexane separation (B) 0.015 51.4 96.4 Ethyl acetate extract powder ethyl acetate separation (C) 0.025 85.4 93.9 莪 萃取 extraction powder water separation (D) 0.05 103.1 97.0 (using TLC (Thin-Layer Chromatography, thin layer chromatography) separation and purification) according to Table 1 and As a result of 2, it was found that the burned extraction fraction shown in (B) of Fig. 1 exhibited the strongest inhibition of melanin production (Fig. 2 (d)). Therefore, the fraction was further purified by preparative TLC (Preparative Thin-Layer Chromatography). After distilling off the solvent from the hexane extract layer, the concentrate was dissolved in a small amount of hexane, and a thin layer chromatography plate (silicone 60 · F254, Merck, thickness 2 mm) was prepared for use in hexane and acetic acid. The mixture of vinegar (volume ratio 7:3) was separated by developing solvent. Detection was carried out by visual inspection and UV light with a wavelength of 254/366 nm. The result is shown in Fig. 3. As shown in Fig. 3, three bands (S1 to S3) which are clear, two bands (S5, S7) which are faintly visible, and one band which is gradually narrowed from the origin (S8) are observed. Therefore, as shown in Fig. 145235.doc -28-201023909, it is separated into 8 bands (with S1 to S8). Each of the separated belt portions was taken out, extracted with ethyl acetate, and then distilled to remove ethyl acetate, thereby obtaining each separated component.

Next, the separation of the above separated components was confirmed by TLC. After a small amount of each of the separated concentrates was redissolved in a small amount of hexane, a thin layer chromatography plate (the thickness of Shiqijiao 60. F254' was 〇.2 mm (Merck)) was used, and the developing solvent was used for development. The result is shown in Fig. 4. Fig. 4 shows a zone in which the hexane solution of the belts S1, S2, S3, ..., S8 is sequentially indicated by dots from the left side. As a result, a single point is detected in the belt S2 (using iodine) (Detection) (Melanin production inhibition test) Next, the isolated sample was subjected to a melanin production inhibition test. At the time of the test, based on the result of the TLC, each of the bands 81 and S2 was used as a sample (test Sample B-1, sample B-2), with respect to the belt S3 to belt S5 and the belt S6 to S8', the above-mentioned belts were used as a sample (sample, sample B-4), respectively. The results of the inhibition of melanin production by the amount of protein are shown in Table 2. Further, as a reference, the extract powder (a) and the burned layer; the agricultural shrinkage (B) were also tested. The sample of the point-knife-off knife showed the strongest inhibition of melanin production. In addition, a photograph showing the result of the three-dimensional culture skin model at this time is shown in Fig. 5. 145235.doc -29- 201023909 [Table 2] Concentration (% by mass) melanin amount (%) protein amount (%) PBS(-) 100.0 100.0 arbutin 2 54.4 58.3 莪Take powder (A) 0.05 60.5 80.5 Purchasing powder hexane separation (B) 0.015 51.4 96.4 Preparation of zedoary extract powder TLC-S1 (B-1) 0.005 101.8 112.8 Preparation of zedoary extract powder TLC-S2 (B-2) 0.005 47.3 102.2 Preparation of zedoary extract powder TLC-S3-5 (B-3) 0.003 75.8 101.3 Preparation of zedoary turmeric extract powder TLC-S6~8 (B-4) 0.0045 82.3 103.4 [Structural determination of melanin production inhibitory substance] The separation fraction with S2 exhibits the strongest inhibition of melanin production, and in the detection by ultraviolet light absorption, the detection of iodine can also confirm a single point, thereby determining the inhibition of melanin production existing in the separation. The structure of the substance. The structure is determined based on the analysis of ultraviolet absorption spectrum (solvent: burned), infrared absorption analysis (IR), mass spectrometry, 1H-NMR (solvent: CDCI3) and 13C-NMR (solvent: CDC13). The results are as follows, and the graphs of the respective analyses are shown in Fig. 6 to Fig. 10. Further, the assignment of NMR is shown in Table 3. Based on these results, the melanin production inhibitory substance produced was identified. Peng Epoxy ketone. As understood from Table 2, the melanin production inhibition of the substance is compared with arbutin which has hitherto been considered to have a whitening effect, and the substance has a concentration of about 1/400 of arbutin concentration. It can exhibit approximately the same effect, so it can be considered that the intensity of its action is about 400 times that of arbutin. 145235.doc -30- 201023909 traits: white crystalline solid ultraviolet absorption · maximal absorption wavelength 〇max) is 281 nm mass spectrometry analysis: 246 (m/e) . infrared absorption spectrum (cm·1): 1662, 1523, 1427, 1400, 1232, 1066, 1020, 929, 881, 863. [Table 3] NMR spectrum

Position!h-nmr 13c-nmr C-1 7.08 s, 1H 138.05 CH C-2 122.23 C C-3 2.15 s, 3H 10.25 ch3 C-4 123.25 C C-5 192.19 C C-6 3.81 s, 1H 66.53 CH C-7 63.95 C C-8 1.34 s, 3H 15.15 ch3 C-9 1.65, 1.28 m, 2H 37.99 ch2 C-10 2.50, 2.21 m, 2H 24.63 ch2 C-11 5.47 d, 1H 131.21 CH C-12 131.05 C C-13 1.6 s, 3H 15.72 ch3 C-14 3.71 d, 2H 41.88 ch2 C-15 157.08 C

[Chem. 21]

145235.doc •31· 201023909 [Confirmation of Stability] The liquid obtained by dissolving 100 mg of Pulmonary Epoxy Ketone obtained by the above method in 200 mL of 50% (v/v) ethanol aqueous solution at a high temperature (60°) Under C), add 0.5 mol/L-NaOH to the liquid to make a final concentration of 0.125 mol/L-NaOH, and add 0.5 mol/L-HCl to a final concentration of 0.125 mol/L. The liquid obtained by HCl was stored at room temperature to confirm stability. Further, as a control, a solution in which the same ethanol solution as above was stored at 4 ° C was used. High-performance liquid chromatography was carried out under the following conditions, and the residual ratio was calculated based on the percentage of the peak area, thereby measuring the stability. Further, the sample solution which was preserved by alkali and acid-storage was neutralized and then measured. (Analysis conditions) Column: Chemcobond 5-ODS-W (6.0x150 (6 A)) (Chemco Co., Ltd.) Mobile phase: sterol

Column temperature: 55 ° C Flow rate · 1.0 ml/min Injection volume: 10 μΐ ^ Monitor: UV monitor 280 nm absorbance The results are shown in Table 4. It is well known that phenolic compounds such as arbutin or citric acid are browned in the alkaline region, but there is no change in the epoxidized ketone. In addition, although the degree of inhibition of melanin production was slightly decreased in the acidic region, it was found to be stable under alkaline conditions and high temperature conditions, so that it was found that the combination of various physical conditions can be formulated with epoxifene. -32- 201023909, and can be used under various conditions. [Table 4] After 5 days, after 5 days, acidity 88% 82% testability 97% 105% 60 ° C 102% 100% [Example 2] Next, the melanin production inhibitor of the present invention was prepared according to the following production method. Contains a group of compounds. [Production Example 1] Clostridium Epoxy Ketone 1 kg of dried rhizome of Curcuma zedoaria was immersed in 6 L of hexane and placed at room temperature for 7 days for extraction. The extract was filtered through a filter (ADVANTEC No. 13 1), and the filtrate solvent was distilled off under reduced pressure, and then placed in a cool dark place. The crystal components produced by the separation were divided and washed with a small amount of calcined. Further, the obtained crystalline component was recrystallized from hexane to obtain 300 mg of pepoxidone (purity: about 95%). The purity was calculated by operating under the conditions of the above liquid chromatography. The ketone epoxy ketone obtained in Example 1 was used as a standard, and the ketone epoxy ketone was quantified according to the peak height ratio of the detection wavelength of 220 nm (the same was true in Production Example 2). [Production Example 2] Pampering Epoxy Ketone 1 kg of dried rhizome of Rhizoma Curcumae was immersed in 6 L of ethyl acetate, and allowed to stand at room temperature for 4 days for extraction. The extract was filtered through a filter (ADVANTEC No. 131), and the solvent of the filtrate was distilled off under reduced pressure, and then a mixture of hexane and ethyl acetate (volume ratio: 7:3) was used as a mobile phase. The column chromatograph (same as the above analysis conditions) in which the silicone is a filler is subjected to pure 145235.doc -33 - 201023909. The separation was carried out by a fraction collector, and the ultraviolet light absorption at a wavelength of 280 nm measured for each separation was used as an index for separation. The solvent distillation residue of the fraction which was observed to be absorbed was recrystallized using hexane to obtain white crystals of 2200 mg (the content of the oxime oxime was 2000 mg). [Production Example 3] Rhododendron Cyclodienone 350 g of dried rhizome of Rhizoma Curcumae was refluxed for 3 hours using hexane 1750 mL. The solvent was removed by transfer and concentrated. Add 175 mL of hexane to the residue for reflux, and repeat the same operation. The collected extract was distilled under reduced pressure to give 3.12 g of dry solid. Dissolve it in a small amount of hexane (about 20 mL), filter the insoluble components, and supply it to a ruthenium dioxide column (BW300 (Fuji Silysia), φ = 20 mm, h = 200 mm), using hexane, The hexane:ethyl acetate (volume ratio: 9:1) and hexane:ethyl acetate (volume ratio: 8:2) were each eluted in 100 mL portions. The hexane:ethyl acetate (volume ratio: 8:2) was collected to dissolve the fraction, and the solvent was evaporated to give a yield of 0.484 g. Then, it was dissolved in a small amount of a 75% (v/v) aqueous methanol solution and supplied to a column under the following conditions. The fractionation was carried out by means of a liquid separator, and each fraction was analyzed using a liquid chromatograph under the following conditions, and a fraction having only a peak corresponding to *1 in the graph of Fig. 11 was collected and distilled off. After the solvent, 0.10 g (yield 0.028%) of a white crystalline solid was obtained. The structure of the melanin production inhibitory substance present in the fraction is determined. The structure was determined based on analysis by ultraviolet light absorption spectrum (solvent: hexane), infrared absorption analysis (IR), and i-NMR (solvent: CDC13), and the following physical property values were obtained. A diagram of ultraviolet absorption and infrared absorption analysis 145235.doc • 34- 201023909 is shown in Figures 12 and 13. Based on the physical property values, it was found that the obtained melanin production inhibitory substance was a cyclodextrin. Column: Chemcobond 5-ODS-W (6.0x150(6 A)) (Chemco) Mobile phase: Methanol: Water = 75:25 (v:v) Column temperature: 55 °C Flow rate: 1.0 mL / Min Injection volume: 1 〇pL Detection wavelength: 280 nm Ultraviolet absorption: Maximum absorption wavelength “max”: No infrared absorption spectrum (cm·1): 1644, 1523, 1375, 1270, 1240, 1105, 1020, 931 H- NMR spectrum: 1.30 (3H, s), 1.99 (3H, s), 2.13 (3H, s), 1.85-2.49 (4H, m), 3.70 (2H, m), 5.17 (1H, m), 5.81 (1H , s), 7.07 (1H, s). [Production Example 4] Purification of furanone In addition, a fraction having only a peak corresponding to *2 in the graph of Fig. 11 was collected, and the solvent was distilled off to obtain hydrazine. 〇7 g (yield 0 〇 2%) of a transparent oily liquid. Determine the structure of the melanin production inhibitory substance present in the separation. The structure is determined based on the analysis of ultraviolet absorption spectrum (solvent. hexane) Infrared absorption analysis (IR) and W-NMR (solvent: CDC13) were carried out to obtain the following physical property values. The ultraviolet absorption and infrared absorption analysis are shown in Fig. 14 and Fig. 15. 145235.doc • 35· 201023909 According to the things The value of 'the value of the melanin production inhibitor was obtained as the sputum ketone. Rabbit external light absorption · Maximum absorption wavelength (Xmax): 272 nm Infrared absorption spectrum (cm·1): 1675, 1562, 1427, 1257, 1070, 997 W-NMR spectrum: 1.222 (3H), 1.658 (3H), 2.97 (1H, q), 2.262 (3H), 3.166 (1H, d), 3.249 (1H, d), 3.104 (1H), 5.028 (1H , d), 5.029 (1H, d) 5 5.039 (1H, d), 5.126 (1H, d), 5.729 (1H, d), 7.068 (1H) [Production Example 5] Hydrogenated Puffin Epoxy Ketone will be manufactured 5 〇〇mg of the epoxigenone obtained in Example 2 was dissolved in 100 mL of 99 5 〇 / 〇 (v / v) ethanol, and 5% of Pd-alumina was added, and hydrogenation was carried out using a hydrogen background. The reaction was carried out for 5 hours at room temperature. After the completion of the reaction, filtration was carried out, and the solvent of the filtrate was distilled off under reduced pressure to obtain 500 mg of a white crystalline solid. The melanin production inhibition in the separation was determined. The structure of matter. The structure was determined based on the analysis of the ultraviolet absorption spectrum (solvent: Hyun:) and 1H-NMR (solvent: CDC13), and the following physical properties were obtained. A diagram showing the ultraviolet absorption analysis is shown in Fig. 16. Based on these physical property values, it was found that the obtained melanin production inhibitory substance was hydrogenated pulverized epoxy ketone. Ultraviolet absorption: Maximum absorption wavelength 287 nm H_NMR spectrum: 2.180 (3H, m), 1.008 (3H, d), 1.059 (3H, d), 7.093 (1H), 1.434 (1H, d), 1.604 (1H, d ), 1.434 (1H, d), 1.653 (1H, d), 1.343 (iH, d), 1.474 (1H, d), 2.995 (1H, d), 2-454 (1H, d), 1.743 (1H, d), 1.657 (1H, d), 2.113 (1H, d), 145235.doc • 36- 201023909 1.776 (1H, d), 4.199 (1H, d). [Manufacturing Example 6] Hydrogenated Pomfon cyclodextrene 〇〇 5 〇〇mg of the cyclodextrin obtained in Production Example 3 was dissolved in 100 mL of 99.5 〇/〇• of the yeast, and 5% iPd_alumina was added. 100 mg, hydrogenation using a hydrogen background. The reaction was carried out at room temperature for 15 hours. After the completion of the reaction, filtration was carried out, and the solvent of the filtrate was distilled off under reduced pressure to obtain 500 mg of a white crystalline solid. The structure of the melanin production inhibitory substance present in the fraction is determined. The structure was determined based on analysis by ultraviolet light absorption spectrum (solvent: hexane) and 1H-NMR (solvent: CDC13) to obtain the following physical properties. A graphical representation of the UV absorption analysis is shown in Figure 7. Based on these physical property values, it was found that the obtained melanin production inhibitory substance was hydrogenated lotus root cyclobutadienone. UV absorption: Maximum absorption wavelength (Imax): No H-NMR spectrum: 2.167 (3H, m), 0.467 (3H, d), 0.909 (3H, d), 6.594 (1H), 1.440 (1H, d), 1.579 (1H, d), 1.400 (1H, d), φ 1.779 (1H, d), 1.601 (1H, d), 1.366 (1H, d), 2.808 (1H, d), 2.676 (1H,d), 2.212 (1H,d), 1.884 (1H,d), 4.774 (1H, d), 3.665 (1H,d). [Melanin production inhibition test using human melanocytes] (culture of human melanocytes) Implanted with Medium254 medium (containing growth factor HMGS-2 (Human Melanocyte Growth Supplement-2)) Human melanocytes were seeded on a 12-well culture plate of 〇μΐ at 2 5 χ 〇 4 per well (NHEM (Normal Human Epidermal 145235.doc -37- 201023909)

Melanocytes, human normal epidermal melanocytes) (M〇derateiy, moderate) 'Kurabo), the next day, add stem cell proliferation factor (SCF 'final concentration 1 ng / mL) to the medium, then add after 4 hours Test sample. Put it at 37. (: culture was carried out, the medium was changed after 3 days, SCF was added again (final concentration was 10 ng/mL), and then the test sample was added after 4 hours, and cultured at 37 C for 7 days. Thereafter, based on The amount of melanin and the amount of protein were measured by the following method (Quantification of melanin) The medium in the well was removed, and the cells were washed 3 times with PBS〇5〇〇吣, and then the PBS(-) was completely removed. Addition to the washed cells 4 〇() of 2 mol/L-NaOH was used to dissolve the cells, and the cell lysate was prepared by shaking with a shaker for 3 minutes. Transfer each cell lysate to a 15 mL microcentrifuge tube and heat it with /Feng Teng hot water 1 〇 Minutes were dispensed vigorously using a Voltex mixer. 350 pL of cell lysate was transferred to a 96-well culture dish and the absorbance was measured at 4 〇 5 nm. (Quantification of protein) The cell lysate obtained above was used as a solution. (2) After culturing for 30 minutes at 37 C, the absorbance was measured at 540 nm. The ketone epoxy ketone obtained in [Production Example 1] and [Production Example 3] to [Production Example 6] Rhododendron, cyclohexanone, hydrogenated ketone, epoxy ketone, and hydrogen The carbosin production inhibition test using the quantitative determination of melanin and protein as the index was carried out. The amount of melanin and the amount of protein of each component are shown in Table 5. [Production Example] and [Production Example 3] 〜[Production Example 6] obtained from the epoxies, ketones, cyclodextrin, hydrazine furanone, hydrogen 145235.doc -38-201023909 The melanin production inhibitory effect is approximately the same as or higher than that of the xanthones which are separated by the thin layer chromatography. [Table 5] Concentration | Melanin amount (%) Protein amount (%) PBS(-) 100.0 100.0 Arbutin 0.02% 168.8 76.5 0.01% 84.4 80.1 Puffin Epoxy Ketone 0.001% 87.5 135.0 0.0001% 85.2 141.5 0.00001% 69.0 127.9 Pleurotus ring dilute ketone 0.10% 43.6 110.7 0.01% 45.3 110.1 0.001% 47.6 108.3 莪 吱Ketone 0.10% |71.3 118.7 b.oi% 60. i 123.4 6.001% 163.6 123.1 Hydrogenated pompon epoxy ketone 0.10% 54.0 111.0 0.01% 67.5 113.9 0.001% 63.1 111.0 Hydrogenated pompon cyclodextrin 0.10% 73.4 130.9 0.01% 76.3 109.2 0.001% |71.9 132.0 〇Improve all of the well-known whitening effect of Epoxy Ketone, Pleurotus Cyclodienone, Curcumin, Hydrogenone, Hydrogenone, and Hydrogenone Compared with bitterness, the toxicity to cells is weak and the whitening effect can be exhibited at a very low concentration. Further, in the same manner as in the above (melanin production inhibition test), the melanin production inhibition test was carried out on the xanthones ketone obtained in [Production Example 1] using a three-dimensional skin culture model. The results are shown in Table 6 and Figure 18. It can be confirmed that the epoxigenone epoxy ketone obtained in [Production Example 1] has a melanin production inhibitory effect similar to that of the phi further 145235.doc-39-201023909 by the thin layer chromatography. 6]

Rhizoma Extract Powder (A) Puffin Epoxy Ketone (Manufacturing 彳^1丁0.005 [Functional Evaluation Test] (Selected by Subject) Six males with healthy normal skin (2〇~years old) (sample preparation) (0 arbutin solution (positive control; 7 mass%) (11) Epoxy ketone (2 concentrations; 0.01% by mass, 0.0025% by mass) (in) 莪 萃取 extraction powder (A) (extract dry matter 〇 〇5 mass 〇 / 〇 (iv) does not contain the active ingredient using the above five total samples, and 8% by mass of bismuth, 3 - butanediol, 5 mass / glycerol G. 3 mass% of polyoxyethylene The sorbitan coconut oil fatty acid B 曰 (20E.O.), 2.2% by mass of the benzoic acid vinegar and the remaining amount of purified water were used to prepare a lotion as a sample preparation by a method known per se. (Ultraviolet radiation to the human body 7) Ultraviolet irradiation is set on the skin of the abdomen of 6 subjects (ΐ5χΐ5' is 15 times the minimum amount of erythema, and the wavelength is ultraviolet y M_DMR 8〇, Toshiba medical supplies). Self-illumination At the beginning of the day, the sample preparation was applied for 4 weeks in the morning and evening. The ultraviolet irradiation was 145235. .doc •40· 201023909 After the first 4 weeks, each part was determined by the naked eye, and the coating portion of the preparation (control) containing no active ingredient and the pigmentation of the coating portion of each sample preparation were determined according to the following evaluation criteria. Degree of recovery. (Determination method) After 4 weeks from the irradiation date, photographs were taken and the photos were judged according to the evaluation criteria. (Evaluation criteria) [Table 7] Significant effect 3 and contrast compared with the control The effect is very large 2 The effect is very small compared with the control 1 Compared with the control, there is no effect 0 (measurement method) (1) First, take a picture with the same positional relationship (status) as the previous time. The previous data was taken while the first shot was taken. (2) The effect was judged by 10 professional judges. (Results) [Table 8] Average Pulmonary Epoxy Ketone 0.01% 1.13 Puffin Epoxy Ketone 0.0025% 0.67 莪 萃取 extraction powder (A) 0.60 arbutin 7% 0.53 As shown in Table 8, the following can be confirmed: Compared with the arbutin which is known to have a whitening effect, the epoxigenone is very low concentration. Can be confirmed to 1452 35.doc •41 - 201023909 The restoration of pigmentation, even for the skin in the tanning state of the human body, also showed excellent whitening effect. 'No erythema or wetness was found in the sample application site of the subject. A skin irritation reaction such as a rash can confirm that the epoxy ketone is highly safe even in the form of the preparation. [Example 3] Hereinafter, a formulation example in which the melanin production inhibitor of the present invention is applied will be listed. Example 1> Lotion Pamper Epoxy Ketone Polyoxyethylene Desorbed Sorbitan Monolaurin (20E.O.) (Quality. 0.005 1.5

1,3-butanediol glycerin preservative•antioxidant fragrance purified hydration<formulation example 2> cosmetic cream, fluster, epoxy ketone, beeswax, stearyl stearate, self-emulsifying monostearic acid Glyceryl ester polyoxyethylene hexadecanyl ether (20E.O.) 5.0 3.0 Appropriate amount of the remaining part 100.0 (% by mass) 0.052.0 5.08.0 10.0 3.01.0 ❹ 145235.doc -42·

201023909 Propylene glycol potassium hydroxide preservative•Antioxidant fragrance purification water meter <Formulation Example 3> Emulsion Puffing Epoxy ketone squalane Vaseline beeswax sorbitan sesquiolee polyoxyethylene ether ether (20E.O. Carboxy Ethylene Polymer Propylene Glycol Potassium Hydroxide Ethanol Preservative • Antioxidant Perfume Purification Water Total &lt;Formulation Example 4&gt; Beauty Liquid Puffing Epoxy Ketone Sorbitol 5.0 0.3 Appropriate amount of the remaining part 100.0 (% by mass) 0.01 8.0 2.0 0.5 0.8 1.2 0.2 0.5 0.1 7.0 Appropriate amount of the remaining part 100.0 (% by mass) 0.001 4.0 145235.doc -43· 201023909 1,3-butanediol 5.0 magnesium ascorbate 0.5 POE (polyoxyethylene, polyoxyethylene) dehydrated water 0.4 sorbitol Monolaurate agar 1.0 Natural gellan gum 0.5 Trimethylglycine 1.0 Preservative appropriate pH adjuster (pH adjusted to 8.0) Total remaining part of purified water 100.0 <Formulation 5> Lotion (% by mass) Pulmonary Epoxy Ketone 0.001 Pampercene Cyclodienone 0.010 Glycerin 5.0 Polyoxyethylene Desorbate Monolaurate 1.5 (20E.O.) Ethanol 8.0 Triethyl citrate • 2.0 Preservative suitable amount Antioxidant Purified water balance Total 100.0 part <Formulation Example 6 &gt; Lotion (mass%) 145235.doc • 44-

201023909 Curcumin furosemide Cyclodextrin glycerol 1,3-butanediol polyoxyethylene sorbitan monolaurate (20E.O.) Preservatives•Antioxidant Purified Hydrate&lt;Formulation Example 7&gt; Emulsion Puffin Epoxy Ketone Hydrogenated Puffing Epoxy Ketone Squalane Vaseline Beeswax Water Sorbitol Sesquid Polyoxyethylene Ether Ether (20E.O.) Carboxy Ethylene Polymer Glycerin Potassium Hydroxide Ethanol Perfume Preservative • Antioxidant purified water 0.020 0.010 2.0 7.0 1.5 Appropriate amount of the remaining part 100.0 (% by mass) 0.010 0.010 8.0 2.0 0.5 0.8 1.2 0.2 1.5 0.1 7.0 Appropriate amount of the remaining part 145235.doc •45· 201023909 Total 100.0 <Formulation Example 8> Emulsion (% by mass Hydrogenated Pompon Epoxy Ketone 0.005 Hydrogenated Pompon Rhodidene 0.010 Squalane 8.0 Vaseline 2.0 Beeswax 0.5 Sorbitan Sesamelate 0.8 Polyoxyethylene Ether (20E.O.) 1.2 Carboxylic Ethylene Polymer 0.2 1,3-butanediol 5.0 Potassium hydroxide 0.1 Perfume amount of preservatives • Antioxidant amount of purified water remaining in total 100.0 &lt;Formulation Example 9&gt; Beauty liquid · (% by mass) Ketone 〇.〇1 POB (polyoxybutylene) 5.0 (3) POE (8) POP (polyoxypropylene 5 polyoxypropylene) (5) glyceryl ether squalane 8.0 Vaseline 2.0 beeswax 0.5 145235.doc -46- 201023909 Dehydrated sorbitan succinic acid S 0.8 0.8 carboxyethylene polymer 0.2 glycerol 1.5 ethanol 7.0 preservative appropriate amount of potassium hydroxide appropriate amount of purified water remaining 100.0 total

&lt;Formulation Example 10&gt; Beauty liquid (mass °/〇) Pampering epoxy ketone 0.01 Ponchocycline cyclodienone 0.02 glyceryl monostearate 0.7 sorbitan trioleate 1.7 stearic acid 0.3 ceramide 0.05 squalane 3.5 glycyrrhizinate 0.05 cholesterol hydroxystearate 1.0 white mango seed oil 6.0 jojoba oil 3.5 lauric acid glutamate bis (octyl dodecyl ester / plant 1.0 stearyl ester / Dodecyl ester) agar 0.25 sucrose fatty acid ester 0.20 145235.doc •47- 201023909 1,3-butanediol 6.0 glycerol 4.5 tridecylglycine 1.5 oxime resin 0.05 hyaluronic acid (0.5% aqueous solution) 0.5 antibiotic Oxidizer Appropriate Preservatives Appropriate amount of purified water Total 100.0 &lt;Formulation Example 11&gt; Dressing Agent (% by mass) Hydrogenated Puffin Epoxy Ketone 0.005 Rhizoma Oxanone 0.005 Vinyl Acetate Resin Emulsion 15.0 Polyvinyl Alcohol 10.0 Joss S Oil 3.0 Glycerin 5.0 Titanium oxide 8.0 Kaolin 7.0 Ethanol 5.0 Perfume amount of preservatives • Antioxidant amount of purified water remaining in total 100.0 <Formulation 12> Ointment (% by mass) 145235.doc •48-

201023909 Puffulon, Epoxy Ketone, Rumex, Rhoddione, Rhenyl ketone, Furanone, Octyl dimethyl benzoate, Butyl methoxy methoxy decane, Stearyl lacquer, Sodium glyceryl monostearate, Vaseline, Preservatives, Antioxidants Purified water total &lt;Formulation Example 13&gt; Cream Foundation

Hydrogenated Pompon Epoxy Brewing I Hydrogenated Pompon Cyclic Diene Ketone Talc Mica Titanium Dioxide Color Pigment Monoisostearic Acid Polyglycerol Polyoxyethylene Hydrogenated Castor Oil Isodecanoic Acid Tridecyl Acetate Alcohol 0.005 0.005 0.005 4.0 4.0 18.0 20.0 0.3 33.0 Appropriate amount of the remaining part 100.0 (% by mass) 0.001 0.001 5.0 8.0 5.0 Appropriate amount 3.0 1.5 10.0 5.0 145235.doc -49- 201023909 Antioxidant preservative purified water meter &lt;Formulation Example 14&gt; Cosmetics hydrogenated pompon epoxy ketone hydrogenated porphyrin cyclic dienone ketone titanium oxide. zinc oxide PEG (polyethylene glycol-polyethylene glycol)-9 polydimethyl decyloxyethyl polydimethyl fluorene lauryl PEG-9 polydidecyl decyloxyethyl polydimethyl oxocyclopentaoxane polydimethyl methoxy oxane (polydimethyl methoxy oxane / vinyl poly dimethyl decane) Co-polymer cetyl polydidecyl oxalate glycyrrhizinate methyl glucose 20 ethylene oxide 1,3-butanediol sodium oxide antioxidant preservative appropriate amount of the remaining amount 100.0 (% by mass) 0.005 0.010 10.0 10.0 1.5 1.5 20.0 10.0 0.5 0.25 0.05 1.0 10.0 Appropriate amount Appropriate amount 145235.doc •50- 201023909 Remaining part 100.0 The present invention relates to a field of a melanin production inhibitor having excellent stability and an extremely high whitening effect and a skin external preparation containing the same. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a flow chart showing separation of a powder extracted from a sputum by liquid-liquid distribution; Fig. 2 is a graph showing a melanin production-inhibiting effect of a liquid-liquid distribution of a powder (Α) The photo '(4) is the result of the control, (b) is the result of Xiongguopu, (4) is the result of the end of the extract (4), and (4) is the separation of the hospital (B): the result '(4) is the result of the separation of ethyl acetate (6) (f) is the result of the water separation component (D); Figure 3 is the chromatogram of the preparation of the thin layer chromatography; ❿ Purification of the hydration meter L to produce a certain profitable figure 4 by preparing a thin layer chromatography The chromatogram of each of the obtained fractions is shown in Fig. 5. Fig. 5 shows the melanin obtained by the preparation of the thin layer chromatograph: the photograph of the dried fruit '(4) is the result of the control' (9) is arbutin (9) Fruit = the result of extracting the powder (8), (4) the result of the fruit strip S1) of the subclass S2) '(f) is the result of the test strip 2 (band: two" = sample - S5) &amp; purple == Figure 173235.doc -51· 201023909 of melanin production inhibitor (Fig. 7) is a purified melanin production inhibitor (Peng Qiandong IR diagram) Figure 8 is a purified melanin production inhibitory substance (Peng 莪, ten mass spectrum; 壤 鲷), Figure 9 is a purified melanin production inhibitor (Peng 嚭 +, 哉 环氧 epoxy _) 1H-NMR spectrum; Figure 10 shows the purified melanin production inhibitor (Pengyi 13C-NMR spectrum; Figure 11 is the hexane-acetate wall of the extraction powder (A) (8, .J / gluten fraction) HPLC diagram; Figure 12 is a purified melanin production inhibitory substance (ultraviolet absorption spectrum of the circumcision; a dilute ketone) 紫) of the purple map 13 is a purified melanin production inhibitory substance (the IR of the lotus box) Figure 14 is a purified melanin production inhibitory substance (supplied π-furan external light absorption spectrum; Figure 15 is a diagram of the purified melanin production inhibitor (莪 呋 furan _) ir Figure; Ultraviolet light absorption spectrum of the melanin production inhibitor (hydrogenated fluorene ring _); &lt; Figure 17 is an ultraviolet absorption spectrum of the melanin production inhibitor (hydrogenated fluorene ring); and Fig. 18 shows Manufacturing the melanin of the manufactured product To suppress the effect of photo '⑷ as a result of reference' (b) as a result of arbutin, ⑷ the result Curcuma extract powder (A) of, (d) Production Example of! The results. 145235.doc -52-

Claims (1)

201023909 VII. Patent application scope: 1 · A melanin production inhibitor which is composed of more than one compound as an active ingredient: Formula: [Chemical Formula 22] One or two of the following formulas Wherein R1 is 11 or (:1.3 alkyl, R2 and R3 are independently Η, OH or Ci.3 alkyl ==◦, or R2 is formed together with R3 R4 is a HiCw alkyl group, and X and Y form a divalent group represented by [Chem. 23] or a divalent group represented by the formula: [Chemical 2S] [Chem. 23] R [wherein, symbol: 145235.doc 201023909 [Chem. 24] represents a single bond or a double bond, R5 is Η or Cu alkyl, R6 is Η, OHSCw alkyl, and R7 and R8 are independently Η or 匸! .3 calcination, or in the case where the bond (!) is a double bond, R5 and R7 or R8 are not present, or ... together with ^^ form -〇- ^ R9 is Η or Cu alkyl , R10 is 11 or (^_3 alkyl, or when the bond (2) is a double bond, R1G does not exist] [Chem. 25] R12 [wherein R&quot; is a linear or branched C]-5 alkyl group or a linear or branched Cb5 refinery group, and R12 is a linear or branched C丨_5 alkyl group or a straight chain or a branch. The chain is 烯基(alkenyl), and R13 is hydrazine or CN3 alkyl]}. 145235.doc -2- 201023909 One or two of the compounds represented by the following formula are two kinds of melanin production inhibitors, which are compounds having more than one kind of compound as an active ingredient: [Chem. 26] R4 As indicated, in the formula, R1 is a fluorenyl group, R2 and R3 are independently Η or OH, or R2 and R3 together form =〇, R4 is Η, and X and Υ are formed by [化.27] The valence group or the divalent group represented by [Chem. 29]: [Chem. 27] [In the formula, the symbol: [Chem. 28] 145235.doc 201023909 represents a single bond or a double bond; R5 is Η or absent, R6 is Η or ΟΗ, and the case of double bond is independent of R7-starting R and R8 or Methyl group, or when bond (1) is present, R5 and R7 or R8 are not present, or Μ-〇-, R9 is methyl, Rl° is absent, R10 is Η, or bond When the knot (2) is a double bond, [29] R11 R12 [wherein R 1 is an isopropyl group, R12 is a vinyl group, and Rl3 is a methyl group]. 3. In the melanin production inhibitor of the requester, the compound is selected from the group consisting of the following compounds or two or more species: [Chemical 3〇]: 145235.doc 201023909 η The indicated sputum epoxide ι, by [Chem. 31]: η The indicated diuretic ring dilute ketone, by [Chem. 32]: The indicated 莪 吱 南 南 酮, by [化33]: 145235.doc 201023909 represents hydrogenated porphyrin epoxy oxime, and by [Chem. 34]: The hydrogenated porphyrin cyclodienone is represented. A method for producing a melanin production inhibitor, comprising the steps of: (1) immersing a dried stem of a curcuma (Curcuma zedoaria) in a solvent selected from the group consisting of methanol 'ethanol, an aqueous solution of decyl alcohol, an aqueous solution of ethanol, hexane, and acetic acid. The solvent extract is prepared from one or more solvents of the group consisting of ethyl vinegar; (2) the zedoary turmeric extract is filtered; (3) the transition liquid-liquid is distributed between the hexahydrate-water layer Then (4) The hexane layer was evaporated to dryness to obtain a melanin production inhibitor. 5. The method for producing a melanin production inhibitor according to claim 4, which further comprises the following steps: in the step (3), the aqueous layer liquid-liquid is partitioned between the ethyl acetate-water layer, in the step (4) The ethyl acetate layer was evaporated to dryness to give a melanin production inhibitor. A method for producing a melanin production inhibitor, comprising the following steps: 145235.doc 201023909 (1) immersing a dried stem of Curcuma zedoaria in hexane to prepare a zedoary extract; (2) placing an extract of zedoary The liquid is crystallized; (3) the crystals are washed with a small amount of hexane; and then (4) the washed crystals are recrystallized to obtain a melanin production inhibitor. 7. A whitening external preparation for skin whitening comprising a melanin production inhibitor according to any one of claims 1 to 3, which is about 〇 11% by mass. 8. An external preparation for skin comprising one or more active ingredients selected from the group consisting of ketones, ketones, and ketones, and excluding the active ingredient selected from the group consisting of A extract of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus. also 145235.doc