JP2008308428A - External preparation for skin, having skin-lightening effect - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an external preparation for skin, which contains a skin-lightening effect-having compound and is excellent in thermal stability. <P>SOLUTION: This external preparation for the skin comprises (1) a skin-lightening effect-having compound represented by general formula (1) and/or its salt, (2) one or more compounds selected from at least three conjugated double bonds-having compounds which are liquid at 25°C at 1 atm (especially, tocopherol compounds), and (3) a reducing substance (especially, ascorbic acid derivative, hydroquinone derivative). Therein, in the general formula (1), R1, R2 are each independently a 3-6C alkyl; R3 is H, a 1-4C acyl, or a 1-4C alkyl; and R4 is a group having aromatic property. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a skin external preparation, and more particularly to a skin external preparation suitable for a cosmetic having a whitening effect.

  Spots, buckwheat, and pigmentation after sunburn in the skin are a state in which melanin production is remarkably enhanced by activation of pigment cells (melanocytes) existing in the skin. For the purpose of preventing or improving these skin pigment troubles, external preparations for skin (especially whitening agents) containing ascorbic acids, hydrogen peroxide, colloidal sulfur, glutathione, hydroquinone or catechol are known (for example, non-patented) Reference 1 and Non-Patent Document 2). However, these whitening agents may have problems in terms of whitening effect, stability and safety, or may be effective only for symptoms with limited effects. Therefore, it can be said that these effects are not sufficient. In addition, there are various whitening features such as tyrosinase inhibitory effect, degradation of tyrosinase-related proteins, and inhibition of melanin transport by suppressing the extension of melanocyte dendrites. However, there are cases where a single inhibition does not have a sufficient effect, and in addition, it is considered that there is a chemical structure suitable for each. From such a viewpoint, the present inventors have found a compound group represented by the general formula (1) as a compound having a new mother nucleus structure having a whitening effect. The compound represented by the general formula (1) includes a known compound. For example, if it is 2,6-di-tert-butyl-4- (2′-thenoyl) phenol, in addition to the whitening effect, It is known that it has an anti-inflammatory action, an anti-allergic action and an anti-rheumatic action based on the anti-oxidant action and suppression of prostaglandin (for example, Patent Document 1, Patent Document 2, Patent Document 3, Patent (Refer to Literature 4, Non-Patent Literature 3, and Non-Patent Literature 4).

  Although it is a compound represented by General formula (1) which has such an effect | action, there exists a subject about the formulation. That is, the compound represented by the general formula (1) is derived from an aromatic ketone structure in which two aromatic groups are connected by a ketone group, and therefore, because of its good crystallinity and strong aromaticity, This is because the compatibility with other oil component is poor and there is a problem of reprecipitation of crystals, or the surfactant is consumed for the compatibility, and the emulsification characteristics over time may be impaired. In addition, in order to form the compatible system, the type of surfactant tends to be specified and limited. Furthermore, it is already known that the emulsified state affects the percutaneous absorption of the active ingredient (see, for example, Non-Patent Document 5). It can be said that development of means for alleviating the limitation of such formulation is desired for the external preparation for skin containing the compound represented by the general formula (1). About this subject, the present inventors formulate combining 1 type, or 2 or more types selected from the compound which is a liquid at 1 atmosphere and 25 degreeC, and has at least 3 conjugated double bonds. However, by adopting such a configuration, a high temperature of 50 ° C. or higher, which is thought to be due to a compound having at least three conjugated double bonds that is liquid at 1 atm and 25 ° C. In some cases, coloration occurred during storage. That is, one or more selected from the compound represented by the following general formula (1) and / or a salt thereof and a compound having at least three conjugated double bonds that is liquid at 1 atm and 25 ° C. It can be said that the development of a technique for improving the stability to heat in a skin external preparation containing two or more kinds has been desired.

  On the other hand, it is selected from 1) a compound represented by the following general formula (1) and / or a salt thereof, and 2) a compound having at least three conjugated double bonds that is liquid at 1 atm and 25 ° C. There is no known external preparation for skin containing one or more kinds and 3) a reducing substance.

JP-A-53-141265 JP 63-008380 A JP 63-502281 A Japanese Translation of National Publication No. 06-501919 George N, Ziakas et al, Bioorganic & Medicinal Chemistry, 14, 5616-5624 (2006) Shaukath Ara. Khanum et al, Bioorganic & Medicinal Chemistry Letters, 14, 5351-5355 (2004) Agents and Action, Vol.12, No.5, 674-683, (1982) Bioorganic & Medicinal Chemistry, Vol.11, 4207-4216, (2003) Luppi B., et al, Drug Deli. 2002; 9 (3): 147-52

  The present invention has been made under such circumstances, and the compound represented by the general formula (1) and / or a salt thereof and at least three conjugated dimers which are liquid at 1 atm and 25 ° C. An object of the present invention is to provide a technique for improving the stability to heat in a skin external preparation containing one or more selected from compounds having a heavy bond.

In view of such a situation, the present inventors have at least three conjugated double bonds which are liquid at 1 atm and 25 ° C. with the compound represented by the general formula (1) and / or a salt thereof. In the topical skin preparation containing one or more selected from the compounds having an odor, we have sought to develop a technique to improve the stability to heat, and as a result of earnest research efforts, coexisting reducing substances As a result, it has been found that such an improvement in stability can be obtained, and the present invention has been completed. That is, the present invention is as follows.
<1> 1) selected from the compound represented by the general formula (1) and / or a salt thereof, and 2) a compound having at least three conjugated double bonds that is liquid at 1 atm and 25 ° C. A skin external preparation characterized by containing one or more kinds and 3) a reducing substance.
<2> The compound represented by the general formula (1) is a compound represented by the following general formula (2) or general formula (3), according to <1> Skin external preparation.

一般式（２）
（但し、式中Ｒ１及びＲ２は一般式（１）と同じ基を表し、Ｒ５は水素原子、水酸基、炭素数１〜４のアルキル基、炭素数１〜４のアシルオキシ基又は炭素数１〜４のアルキルオキシ基を表し、Ｘは水素原子と結合した窒素原子、酸素原子又は硫黄原子を表す。）

General formula (2)
(In the formula, R1 and R2 represent the same group as in general formula (1), and R5 represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, an acyloxy group having 1 to 4 carbon atoms, or 1 to 4 carbon atoms. X represents a nitrogen atom, an oxygen atom or a sulfur atom bonded to a hydrogen atom.)

一般式（３）
（但し、式中Ｒ６は、水素原子、アルキル基、アルケニル基、フェニル基、アルキルオキシ基、水酸基、メルカプト基、トリフルオロメチル基、アミノ基、アルキルアミノ基、ニトロ基、シアノ基、ホルミル基、カルボキシル基、アルキルアミド基、スルフェニル基、スルホニル基又はハロゲン原子を表す。）

General formula (3)
(In the formula, R6 is a hydrogen atom, an alkyl group, an alkenyl group, a phenyl group, an alkyloxy group, a hydroxyl group, a mercapto group, a trifluoromethyl group, an amino group, an alkylamino group, a nitro group, a cyano group, a formyl group, Represents a carboxyl group, an alkylamide group, a sulfenyl group, a sulfonyl group or a halogen atom.)

<3> The compound represented by the general formula (1) is 2,6-di-tert-butyl-4- (2′-thenoyl) phenol, 3,5-di-tert-butyl-4-hydroxybenzophenone. 3,5-di-tert-butyl-4-hydroxy-4′-fluorobenzophenone, 3,5-di-tert-butyl-4-hydroxy-4′-chlorobenzophenone, 3,5-di-tert-butyl -4-hydroxy-4'-methylbenzophenone, 3,5-di-tert-butyl-4-hydroxy-4'-methoxybenzophenone, 3,5-di-tert-butyl-4-hydroxy-2 ', 4' , 6′-trimethylbenzophenone, 3,5-di-tert-butyl-4,4′-dihydroxybenzophenone, 3,3 ′, 5,5′-tetra-tert-butyl-4,4′-di <1> or <2> characterized by being selected from hydroxybenzophenone and (3,5-di-tert-butyl-4-hydroxyphenyl) -2-naphthalenylmethanone Skin external preparation.
<4> The compound having at least three conjugated double bonds that is liquid at 1 atm and 25 ° C. is α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, vitamin E nicotinate, acetic acid Tocopherol, vitamin D2, vitamin D3, retinol, retinal, retinoic acid, 4-methoxycinnamic acid or its derivative, aminobenzoic acid or its derivative, phenoxyethanol, phenethyl alcohol, methyl cinnamate, lilyal, anisole, cyclamenaldehyde, acetic acid Characterized in that it is selected from dimethylbenzyl carvinyl, isopentyl salicylate, benzyl salicylate, phenylacetic acid, styryl acetate, 2-isobutyl-3-methoxypyrazine, vanillin and jasminal, <> ~ <3> skin external preparation according to any one.
<5> The sum of the contents of the compound represented by the general formula (1) and the sum of the contents of the compound having at least three conjugated double bonds that are liquid at 1 atm and 25 ° C. The skin external preparation according to any one of <1> to <4>, wherein the ratio is 1: 1 to 1:10 by mass ratio.
<6> Sum of the sum of the contents of the compound represented by the general formula (1) and the sum of the contents of the compounds having at least three conjugated double bonds that are liquid at 1 atm and 25 ° C. And a component (oil agent component) other than the compound represented by the general formula (1) in the oil phase and the compound having at least three conjugated double bonds, which is liquid at 1 atm and 25 ° C. The skin external preparation according to any one of <1> to <5>, wherein the ratio of the total to the total is 1: 2 to 1:50 in terms of mass ratio.
<7> The oil agent component is composed only of components that are liquid at 1 atm and 25 ° C. except for the compound represented by the general formula (1) and a salt thereof, <1> to <6> The external preparation for skin according to any one of items 1.
<8> The reducing substance is one or more selected from ascorbic acid, ascorbic acid derivatives, hydroquinone, hydroquinone derivatives and salts thereof, <1> to <7> The external preparation for skin according to any one of the above.
<9> The skin external preparation according to any one of <1> to <8>, which is a cosmetic for whitening.

  According to the present invention, 1 selected from the compound represented by the general formula (1) and / or a salt thereof and a compound having at least three conjugated double bonds that is liquid at 1 atm and 25 ° C. In the external preparation for skin containing seeds or two or more kinds, it is possible to provide a technique for improving the stability to heat.

(1) Compound represented by general formula (1) which is an essential constituent of the external preparation for skin of the present invention The external preparation for skin of the present invention contains the compound represented by general formula (1) and / or a salt thereof. It is characterized by that. In the general formula (1), R1 and R2 are each independently an alkyl group having 3 to 6 carbon atoms, more preferably a branched structure, such as 1-methylethyl group, 1-methylpropyl group, 2-methyl. An alkyl group such as a propyl group, a tert-butyl group or an amyl group, particularly preferably a tert-butyl group, and R3 is an acyl having 1 to 4 carbon atoms such as a hydrogen atom, a formyl group, an acetyl group, a propanoyl group or a butanoyl group. Represents a group or an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, or a butyl group, and R4 represents an aromatic group, more preferably a group having 5 to 15 carbon atoms. . In R4, it may be composed only of an aromatic group or an aliphatic group may be interposed. The aromatic group may be a hydrocarbon or a heteroaromatic group having a hetero atom such as an oxygen atom, a sulfur atom, or a nitrogen atom. Depending on the type of the aromatic group, the compound represented by the general formula (1), which is an essential component of the external preparation for skin of the present invention, is represented by the compound represented by the general formula (2) and the general formula (3). It is divided roughly into the compound to be made.

  In the general formula (2), R1 and R2 represent the same group as in the general formula (1), and R5 represents a hydrogen atom, a hydroxyl group, a methyl group, an ethyl group, a propyl group, an iso-propyl group, an n-butyl group, sec. An alkyl group having 1 to 4 carbon atoms such as a butyl group or a tert-butyl group, more preferably an acyl group having 1 to 4 carbon atoms such as a methyl group, a formyl group, an acetyl group, a propanoyl group or a butanoyl group, more preferably An acetyl group, or an alkyloxy group such as a methoxy group, an ethoxy group, a propyloxy group, or a butyloxy group, more preferably a hydrogen atom, and X is a nitrogen atom, oxygen atom, or sulfur atom bonded to a hydrogen atom, more preferably Represents a sulfur atom. Among these compounds represented by the general formula (2), 2,6-di-tert-butyl-4- (2′-thenoyl) phenol (compound 1) is particularly preferable. The compound represented by the general formula (2) can be used in the free form of the skin external preparation of the present invention, but can also be used as a salt using an alkali or the like. For example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, organic amine salts such as ammonium salt, triethanolamine salt and triethylamine salt, basic such as lysine salt and arginine salt Preferred examples include amino acid salts.

２，６−ジ−ｔｅｒｔ−ブチル−４−（２‘−テノイル）フェノール（化合物（１））

2,6-di-tert-butyl-4- (2′-thenoyl) phenol (compound (1))

  Moreover, these compounds can be manufactured by arbitrary methods, for example, can be manufactured by the method outlined in the following scheme 1 or 2, but are not limited to these methods. Of course, depending on the type of substituent and the like, the production method can be appropriately changed to a form suitable for the purpose.

スキーム１

Scheme 1

The reaction in Scheme 1 will be briefly described.
By treating 3,5-di-alkyl-4-hydroxybenzoic acid with thionyl chloride by a conventional method, acid chloride of 3,5-di-alkyl-4-hydroxybenzoic acid (A) And This acid chloride (A) is treated with a Lewis acid such as aluminum chloride or titanium tetrachloride in a suitable solvent such as carbon disulfide. Subsequently, the compound of General formula (2) can be obtained by adding thiophene (B) and making it Friedel-Craft reaction.

  As 3,5-di-alkyl-4-hydroxybenzoic acid, for example, 3,5-di-tert-butyl-4-hydroxybenzoic acid commercially available from Sigma-Aldrich can be used. . As the compound (B), an unsubstituted product in which R5 is a hydrogen atom, or a substituted product such as methylthiophene or methoxythiophene can be used. Here, when thiophene is used as the compound (B) (X = S), the compound represented by the general formula (2) is obtained, and 3,5-di-tert- When an acid chloride of butyl-4-hydroxybenzoic acid is used, 2,6-di-tert-butyl-4- (2′-thenoyl) phenol (compound (1)) is obtained.

スキーム２

Scheme 2

The reaction in Scheme 2 will be briefly described.
The thiophenecarboxylic acid is treated with thionyl chloride by a conventional method to obtain an acid chloride form (C) of thiophenecarboxylic acid. This acid chloride (C) is treated with a Lewis acid such as aluminum chloride or titanium tetrachloride in a suitable solvent such as carbon disulfide. Subsequently, the compound of General formula (2) can be obtained by adding 2, 6- dialkylphenol (D) and carrying out Friedel-Craft reaction. In order to obtain the compound (C), 2-thiophenecarboxylic acid, 3-methyl-2-thiophenecarboxylic acid, or 5-methyl-2-thiophenecarboxylic acid, in which R5, which is commercially available from Sigma-Aldrich, is a hydrogen atom. Etc. can be used. Here, when an acid chloride of 2-thiophenecarboxylic acid is used as the compound (C) (X = S), a compound represented by the general formula (2) is obtained. As 2,6-dialkylphenol (D), 2,6-di-tert-butyl-phenol, 2,6-di-isopropylphenol and the like commercially available from Sigma-Aldrich can be used. When acid chloride of 2-thiophenecarboxylic acid is used as compound (C) and 2,6-di-tert-butyl-phenol is used as compound (D), 2,6-di-tert-butyl-4- ( 2'-thenoyl) phenol (compound (1)) is obtained.

  By replacing the thiophene or thiophenecarboxylic acid with furan, furancarboxylic acid, pyrrole or pyrrolecarboxylic acid, a compound represented by the general formula (2) in which X is a nitrogen atom bonded with an oxygen atom or a hydrogen atom is produced. can do.

  In the general formula (3), R6 is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an iso-propyl group, an n-butyl group, a sec-butyl group, a tert-butyl group or the like, more preferably a methyl group. , Alkenyl groups such as vinyl group, propenyl group and n-butenyl group, more preferably alkyloxy groups such as propenyl group, methoxy group, ethoxy group, propyloxy group and butyloxy group, more preferably methoxy group, hydroxyl group and mercapto group Alkylamino groups such as trifluoromethyl group, amino group, methylamino group, ethylamino group, propylamino group, iso-propylamino group, n-butylamino group, sec-butylamino group, tert-butylamino group, More preferably tert-butylamino group, nitro group, cyano group, carbonyl group , A carboxyl group, a methylamide group, a sulfenyl group, a sulfonyl group or a halogen atom, more preferably a chlorine atom. Specific examples of the compound represented by the general formula (3) include 3,5-di-tert-butyl-4-hydroxybenzophenone and 3,5-di-tert-butyl-4- Hydroxy-4′-fluorobenzophenone, 3,5-di-tert-butyl-4-hydroxy-4′-chlorobenzophenone, 3,5-di-tert-butyl-4-hydroxy-4′-methylbenzophenone, 3, 5-di-tert-butyl-4-hydroxy-4′-methoxybenzophenone, 3,5-di-tert-butyl-4-hydroxy-2 ′, 4 ′, 6′-trimethylbenzophenone, 3,5-di- tert-butyl-4,4′-dihydroxybenzophenone, 3,3 ′, 5,5′-tetra-tert-butyl-4,4′-dihydroxybenzophenone 3,5-di-tert-butyl-4-hydroxy-4′-phenylbenzophenone, (3,5-di-tert-butyl-4-hydroxyphenyl)-(4′-methoxybiphenyl-4-yl) methanone And (3,5-di-tert-butyl-4-hydroxyphenyl) -2-naphthalenylmethanone can be preferably exemplified. Of these, more preferred are 3,5-di-tert-butyl-4-hydroxybenzophenone, 3,5-di-tert-butyl-4-hydroxy-4′-fluorobenzophenone, 3,5-di- tert-butyl-4-hydroxy-4'-chlorobenzophenone, 3,5-di-tert-butyl-4-hydroxy-4'-methylbenzophenone, 3,5-di-tert-butyl-4-hydroxy-4 ' -Methoxybenzophenone, 3,5-di-tert-butyl-4-hydroxy-2 ', 4', 6'-trimethylbenzophenone, 3,5-di-tert-butyl-4,4'-dihydroxybenzophenone, 3, 3 ′, 5,5′-tetra-tert-butyl-4,4′-dihydroxybenzophenone and (3,5-di-tert-butyl -4-hydroxyphenyl) -2-naphthalenylmethanone.

  The compound represented by the general formula (3) can be used in the free form of the skin external preparation of the present invention, but can also be used as a salt using an alkali or the like. For example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, organic amine salts such as ammonium salt, triethanolamine salt and triethylamine salt, basic such as lysine salt and arginine salt Preferred examples include amino acid salts.

  In addition, the compound represented by the general formula (3) can be produced by an arbitrary method, for example, by appropriately applying the method outlined in Scheme 1 or 2, It is not limited to these methods.

  For example, in Scheme 1 above, various aromatic hydrocarbons are used instead of (substituted) thiophene, and this is reacted with an acid chloride of 3,5-di-tert-butyl-4-benzoic acid. It is possible to manufacture by. Moreover, in the said scheme 2, instead of thiophenecarboxylic acid, using (substituted) benzoic acid, this is made into an acid chloride body, This is manufactured by making it react with 3, 5- di-tert- butylphenol. Is possible.

  The preferable content of the compound represented by the general formula (1) in the external preparation for skin of the present invention is 0.001% by mass or more, preferably 0.01% by mass or more, more preferably 0.1% by mass or more in total. It is. On the other hand, the upper limit is 3% by mass or less, preferably 1% by mass or less, and more preferably 0.8% by mass or less. This is because the melanin production-suppressing action is stably expressed in such an amount range.

(2) The compound having at least three conjugated double bonds, which is liquid at 1 atm and 25 ° C., which is an essential component of the external preparation for skin of the present invention, has the general formula (1) And a compound having at least three conjugated double bonds, which is liquid at 1 atm and 25 ° C. As such a compound, any compound having at least three conjugated double bonds that is liquid at 1 atm and 25 ° C. can be used. The type of conjugated bond may be aromatic or aliphatic. Preferred examples include the following compounds. α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, vitamin E nicotinic acid ester, acetate tocopherol, vitamin D2, vitamin D3, retinol, retinal, retinoic acid, p-methoxycinnamic acid, p-methoxycinnamic acid ethyl Esters, p-methoxycinnamic acid or its derivatives such as p-methoxycinnamic acid-2 ethylhexyl ester, p-aminobenzoic acid-2 ethylhexyl ester, N, N-dimethyl-p-aminobenzoic acid-2 ethylhexyl ester P-aminobenzoic acid or derivatives thereof, phenoxyethanol, phenethyl alcohol, methyl cinnamate, lilyal, anisole, cyclamenaldehyde, dimethylbenzylcarbyl acetate, isopentyl salicylate, benzyl salicylate, 4 Methoxy salicylic acid alkyl ester, phenyl acetate, styrallyl, 2-isobutyl-3-methoxy pyrazine, vanillin and Jasumi knurls are preferred. Among these, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, vitamin E nicotinic acid ester, tocopherol acetate, 4-methoxycinnamic acid-2-ethylhexyl ester, phenoxyethanol are more preferable, δ-tocopherol, 4-methoxycinnamic acid-2 ethylhexyl ester is particularly preferred.

  Regarding the content of the compound having at least three conjugated double bonds that is liquid at 1 atm and 25 ° C. in the external preparation for skin of the present invention, the content of the compound represented by the general formula (1) And the sum of the contents of compounds having at least three conjugated double bonds that are liquid at 1 atm and 25 ° C. in a mass ratio of 1: 1 to 1:10. It is preferable to set. By adopting such a configuration, the compatibility of the compound represented by the general formula (1) in the oil phase of the preparation is remarkably improved. In addition to this, an oil component that is liquid at 1 atm and 25 ° C. in the oil phase is contained at least 90% by mass of the oil phase components other than the above components, more preferably substantially such components. Preferably only. Examples of such oil components include macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, coconut oil, palm oil and other vegetable oils, liquid paraffin, Liquid oils such as squalane, unsaturated or branched fatty acids such as oleic acid, palmitoleic acid, isostearic acid, isopalmitic acid, unsaturated or branched alcohols such as oleyl alcohol, isostearyl alcohol, octyldodecanol, jojoba alcohol, cetyl isooctanoate , Isopropyl myristate, hexyldecyl isostearate, diisopropyl adipate, di-2-ethylhexyl sebacate, cetyl lactate, diisostearyl malate, ethylene glycol di-2-ethylhexanoate, 2-ethyl Ester oils such as sanmityl palmitate, glycerin tri-2-ethylhexanoate, chain polysiloxanes such as dimethylpolysiloxane, methylphenylpolysiloxane, diphenylpolysiloxane, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, Preferred examples include silicone oils such as cyclic polysiloxanes such as dodecamethylcyclohexanesiloxane, amino-modified polysiloxanes, polyether-modified polysiloxanes, alkyl-modified polysiloxanes, and modified polysiloxanes such as fluorine-modified polysiloxanes. Among these, tri-2-ethylhexanoic acid glycerin, methylphenylpolysiloxane, diphenylpolysiloxane, and isostearic acid are preferable, and tri-2-ethylhexanoic acid glycerin ester is particularly preferable. The sum of the contents of the compounds represented by the general formula (1), the sum of the contents of the compounds having at least three conjugated double bonds that are liquid at 1 atm and 25 ° C., and oil. The sum of the contents of the compound (oil agent component) other than the compound represented by the general formula (1) in the phase and the compound having at least three conjugated double bonds that is liquid at 1 atm and 25 ° C. The mass ratio is preferably 1: 2 to 1:50, more preferably 1: 2 to 1:10, and still more preferably 1: 2 to 1: 5.

(3) Reducing substance which is an essential component of the external preparation for skin of the present invention The external preparation for skin of the present invention is characterized by containing a reducing substance as an essential component. Preferred examples of the reducing substance include ascorbic acid, ascorbic acid derivatives, hydroquinone, hydroquinone derivatives, kojic acid, and salts thereof. Examples of the derivatives include alkyl esters having 1 to 30 carbon atoms, more preferably 12 to 22 carbon atoms, esters such as phosphate esters and sulfate esters, glycosides such as rutinosides, rhamnosides, glucosides, and the like. Preferred examples include acylated products. Ascorbic acid, ascorbic acid glucoside, ascorbic acid phosphate ester, ascorbic acid sulfate ester, hydroquinone, and hydroquinone glucoside are all raw materials for cosmetics and are readily available. Derivatives not belonging to this can also be easily produced according to conventional methods. For example, glycosides can be produced by decondensing a sugar protected with an acetyl group and the like with ascorbic acid or hydroquinone in the presence of Lewis acid. An acylated product can be produced by reacting an acyl chloride in the presence of an alkali. Such a component may contain only one species or may contain two or more species in combination. Such a component is a compound having at least three conjugated double bonds, which is liquid at 1 atm and 25 ° C., in a period of 1 to 3 under high temperature storage, for example, storage at 50 to 70 ° C. It has the effect of preventing coloration during storage for weeks. In order to express such an effect, the total amount of one or more selected from the reducing substances is 0.1 to 10% by mass with respect to the total amount of the external preparation for skin. Preferably, it is 0.5-5 mass% more preferably. This is because if the amount is too small, the above-mentioned effect may not be obtained. If the amount is too large, the effect reaches a peak, and the degree of freedom of prescription may be obstructed.

(4) External preparation for skin of the present invention The external preparation for skin of the present invention is 1) a compound represented by the general formula (1) and / or a salt thereof, and 2) a liquid at 1 atm and 25 ° C. 1 type or 2 types or more selected from the compound which has at least 3 conjugated double bond, and 3) The said reducing substance is contained, It is characterized by the above-mentioned. By adopting such a configuration, the external preparation for skin of the present invention has a characteristic excellent in stability. In particular, even under extremely harsh conditions, and the possibility of such conditions being undeniable, even under short-term storage conditions at high temperatures of 50 to 70 ° C., phenomena such as coloring Expression is suppressed. For this reason, the effect of the component represented by the general formula (1), which is the original effective substance, is exhibited regretfully. As said effect, the melanin production inhibitory effect and the whitening effect | action based on it can be illustrated suitably. Of course, since the anti-inflammatory effect etc. are expressed and the skin care effect which the base has is also exhibited, the use of the skin external preparation of the present invention is not limited to melanin production suppression. The external preparation for skin of the present invention can be applied without particular limitation as long as it is a dosage form administered externally to the skin, for example, cosmetics including quasi-drugs, external preparations for skin, sundries for skin use, etc. However, it is particularly preferable to apply to a cosmetic that can fully utilize the function of the external preparation for skin of the present invention.

  In the external preparation for skin of the present invention, in addition to the above-mentioned components, optional components usually used in external preparations for skin such as cosmetics can be contained. Such optional ingredients include, for example, macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, coconut oil, palm oil, liquid lanolin, hydrogenated coconut oil Oil, wax, oils such as beeswax, owl, hardened castor oil, beeswax, candelilla wax, carnauba wax, botarou, lanolin, reduced lanolin, hard lanolin, jojoba wax , Hydrocarbons such as microcrystalline wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid; cetyl alcohol, stearyl alcohol, isostearyl Higher alcohols such as alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol, cetostearyl alcohol; cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, diisopropyl adipate, di-2-ethylhexyl sebacate, cetyl lactate, malic acid Diisostearyl, di-2-ethylhexanoic acid ethylene glycol, dicaprate neopentyl glycol, di-2-heptylundecanoic acid glycerin, tri-2-ethylhexanoic acid glycerin, tri-2-ethylhexanoic acid trimethylolpropane, tri Synthetic ester oils such as trimethylolpropane isostearate and pentane erythritol tetra-2-ethylhexanoate; dimethylpolysiloxane, methylphenylpoly Linear polysiloxanes such as oxane and diphenylpolysiloxane; cyclic polysiloxanes such as octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, and dodecamethylcyclohexanesiloxane; amino-modified polysiloxane, polyether-modified polysiloxane, alkyl-modified polysiloxane, Oil agents such as silicone oils such as modified polysiloxanes such as fluorine-modified polysiloxanes; Anionic surfactants such as fatty acid soap (sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, triethanolamine ether of alkyl sulfates; Cationic surfactants such as stearyltrimethylammonium, benzalkonium chloride, laurylamine oxide; imidazoline-based amphoteric surfactants (2-cocoyl-2-imida Zolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), betaine surfactants (alkyl betaine, amide betaine, sulfobetaine, etc.), and amphoteric surfactants such as acylmethyltaurine; sorbitan fatty acid esters (sorbitan) Monostearate, sorbitan sesquioleate, etc.), glycerin fatty acids (eg, glyceryl monostearate), propylene glycol fatty acid esters (eg, propylene glycol monostearate), hardened castor oil derivatives, glycerin alkyl ethers, POE sorbitan fatty acid esters (POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbite fatty acid esters (POE-sorbitol monolaurate, etc.), POE glycerin fatty acid ester Tells (POE-glycerol monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE alkylphenyl ethers (POE nonylphenyl) Ethers, etc.), Pluronic types, POE / POP alkyl ethers (POE / POP2-decyltetradecyl ether, etc.), Tetronics, POE castor oil / hardened castor oil derivatives (POE castor oil, POE hardened castor oil, etc.), Nonionic surfactants such as sucrose fatty acid ester and alkyl glucoside; polyethylene glycol, glycerin, 1,3-butylene glycol, erythritol, sorbitol, xylitol, maltitol, propylene Polyhydric alcohols such as recall, dipropylene glycol, diglycerin, isoprene glycol, 1,2-pentanediol, 2,4-hexanediol, 1,2-hexanediol, 1,2-octanediol; sodium pyrrolidonecarboxylate Moisturizing ingredients such as lactic acid and sodium lactate; powders such as mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, anhydrous silicic acid (silica), aluminum oxide, barium sulfate, etc. whose surface may be treated Body, the surface may be treated, inorganic pigments such as bengara, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, bitumen, titanium oxide, zinc oxide; surface may be treated, mica Pearl agents such as titanium, fish phosphorus foil, bismuth oxychloride; red 202 which may be raked, red Color 228, Red 226, Yellow 4, Blue 404, Yellow 5, Red 505, Red 230, Red 223, Orange 201, Red 213, Yellow 204, Yellow 203, Blue 1 No., green 201, purple 201, red 204, etc .; organic powders such as polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane elastomer; lower alcohols such as ethanol and isopropanol; Preferred examples include antibacterial agents such as methylparaben. The skin external preparation of this invention can be manufactured by processing this component according to a conventional method. The external preparation for skin of the present invention can be applied without particular limitation as long as it is administered externally to the skin, and examples thereof include cosmetics including quasi-drugs, external preparations for skin, and external items for skin. It is particularly preferable to apply to cosmetics.

  The skin external preparation of this invention can be manufactured by processing the said essential component and arbitrary components in accordance with a conventional method, and processing into a lotion, emulsion, cream, essence, etc.

  Hereinafter, the present invention will be described in more detail with reference to examples, but it goes without saying that the present invention is not limited to such examples.

<Reference Example 1>
Production of 2,6-di-tert-butyl-4- (2′-thenoyl) phenol (compound (1)) 3,5-di-tert-butyl-4-hydroxybenzoic acid 23.2 g and thionyl chloride 60 g After stirring for 1 hour at room temperature, excess thionyl chloride was distilled off under reduced pressure. This was dissolved by adding 300 ml of carbon disulfide, and 13.5 g of aluminum chloride was further added. After stirring for 30 minutes at 40 ° C., 88.2 g of thiophene was added. Next, the reaction solution was poured into 10% hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and fractionated and purified with a silica gel column to obtain compound (1).

<Reference Example 2>
Preparation of 3,5-di-tert-butyl-4-hydroxybenzophenone (compound (2)) 1.45 g of benzoyl chloride and 2.06 g of 2,6-di-tert-butylphenol were dissolved in 12 ml of methylene chloride, and aluminum chloride was used. 1.40 g was added and stirred at room temperature for 40 minutes. The reaction solution was poured into ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, fractionated and purified with a silica gel column to obtain compound (2).

<Reference Example 3>
Production of 3,5-di-tert-butyl-4-hydroxy-4′-fluorobenzophenone (Compound (3)) Similar to Production Example 2 using 4-fluorobenzoyl chloride and 2,6-di-tert-butylphenol. To give compound (3).

<Reference Example 4>
Production of 3,5-di-tert-butyl-4-hydroxy-4′-chlorobenzophenone (compound (4)) Similar to Production Example 2 using 4-chlorobenzoyl chloride and 2,6-di-tert-butylphenol. To give compound (4).

<Reference Example 5>
Production of 3,5-di-tert-butyl-4-hydroxy-4′-methylbenzophenone (compound (5)) Similar to Production Example 2 using 4-methylbenzoyl chloride and 2,6-di-tert-butylphenol To give compound (5).

<Reference Example 6>
Production of 3,5-di-tert-butyl-4-hydroxy-4'-methoxybenzophenone (Compound (6)) Using 4-methoxybenzoyl chloride and 2,6-di-tert-butylphenol, the same as in Production Example 2 To give compound (6).

<Reference Example 7>
Preparation of 3,5-di-tert-butyl-4-hydroxy-2 ', 4', 6'-trimethylbenzophenone (compound (7)) 2,4,6-trimethylbenzoyl chloride and 2,6-di-tert The compound (7) was obtained in the same manner as in Production Example 2 using butylphenol.

<Reference Example 8>
Production of 3,5-di-tert-butyl-4,4′-dihydroxybenzophenone (Compound (8)) To 3 ml of dimethylformamide was added 0.34 g of sodium ethanethiolate under ice cooling. To this, 0.53 g of 3,5-di-tert-butyl-4-hydroxy-4′-methoxybenzophenone produced in Production Example 6 was added, heated under reflux for 4 hours, and further stirred overnight at room temperature. The reaction solution was poured into dilute hydrochloric acid and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, concentrated, and fractionated and purified on a silica gel column to obtain compound (8).

<Reference Example 9>
Preparation of 3,3 ′, 5,5′-tetra-tert-butyl-4,4′-dihydroxybenzophenone (compound (9)) 2,6-di-tert-butylbenzoyl chloride and 2,6-di-tert The compound (9) was obtained by operating in the same manner as in Production Example 2 using butylphenol.

<Reference Example 10>
Production of (3,5-di-tert-butyl-4-hydroxyphenyl) -2-naphthalenylmethanone (compound (10)) Production using 2-naphthyl chloride and 2,6-di-tert-butylphenol In the same manner as in Example 2, compound (10) was obtained.

<Reference Example 11>
Production of 3,5-di-tert-butyl-4-hydroxy-4'-phenylbenzophenone (compound (11)) Using 4-biphenylcarbonyl chloride and 2,6-di-tert-butylphenol, the same as in Production Example 2 To give compound (11).

  According to the formulation shown below, a cosmetic (oil-in-water emulsifier type cream), which is an external preparation for skin of the present invention, was produced. That is, each component of (A) was mixed and heated to 80 ° C. On the other hand, the components (B) and (C) were mixed and heated to 80 ° C. To the mixture of (A), the mixture of (B) is gradually added and emulsified with stirring. Subsequently, (C) is added in the same manner as (B), and then cooled to 35 ° C. to obtain Cream 1. It was. In the same manner, Comparative Example 1 in which δ-tocopherol and N, N-dimethyl-p-aminobenzoic acid-2-ethylhexyl were replaced with water, Comparative Example 2 in which ascorbic acid-2-glucoside was replaced with water, Comparative Example 3 in which δ-tocopherol, N, N-dimethyl-p-aminobenzoic acid-2-ethylhexyl, and ascorbic acid-2-glucoside were replaced with water was similarly prepared.

(Table 1)
Ingredient Mass%
(A)
POE (30) hexyl decyl ether 2.0
2-Ethylhexanoic acid triglyceride 7.0
Methylphenylpolysiloxane 1.0
Methylparaben 0.3
δ-tocopherol 0.5
N, N-dimethyl-p-aminobenzoic acid-2-ethylhexyl 0.5
Compound (1) 0.5
(B)
C10-30 alkyl modified carboxyvinyl polymer 0.2
("PEMULEN TR-2"; manufactured by BFGoodrich)
Carboxyvinyl polymer 0.1
1,3-butanediol 15.0
Sodium hydroxide 0.1
Purified water 42.8
(C)
Ascorbic acid-2-glucoside 2.0
Water 28.0
Total 100.0

<Test Example 1>
Low-temperature storage test Each sample of Example 1 and Comparative Examples 1 to 3 was put in a glass storage container, sealed, and stored in a thermostatic chamber at 20 ° C, 5 ° C, and -10 ° C for 6 months. After 6 months, for each stored sample, 20 mg of its contents are placed on a glass slide, covered with a glass slide, pressurized until the sample is clear, and deposited in 10 fields under a microscope at a magnification of 150 times. This number was counted and the average was calculated. The results are shown in Table 2. From this, it can be seen that the combination of δ-tocopherol and N, N-dimethyl-p-aminobenzoic acid-2-ethylhexyl suppresses the precipitation of precipitates. Moreover, it turns out that the mixing | blending of ascorbic acid-2-glucoside has no influence on precipitation of a precipitate.

(Table 2)
Sample average number of precipitates
20 ° C 5 ° C -10 ° C
Cream 1 0 0 0
Comparative Example 1 0 0.5 ± 0.3 21.7 ± 6.8
Comparative Example 2 0 0 0
Comparative Example 3 0 0.7 ± 0.4 23.2 ± 8.2

<Test Example 2>
High-temperature storage test Each sample of Example 1 and Comparative Examples 1 to 3 was put in a glass storage container, sealed, and stored at 20 ° C and 50 ° C for 1 week. After completion of storage, each sample was measured using a Konica Minolta color difference meter CR400, and the color difference (ΔE) between the 20 ° C. storage product and the 50 ° C. storage product was calculated. The results are shown in Table 3. From this, it can be understood that the coloring under this condition is caused by the combination of δ-tocopherol and N, N-dimethyl-p-aminobenzoic acid-2-ethylhexyl, and this coloring can be suppressed by the addition of ascorbic acid.

(Table 3)
Sample color difference (ΔE)
Cream 1 0.23
Comparative Example 1 0.31
Comparative Example 2 1.57
Comparative Example 3 0.46

  As in Example 1, creams 2 to 5 which are external preparations for skin (cosmetics) of the present invention were prepared by changing the type of reducing component. The degree of precipitates was measured with the procedure of Test Example 1 at −10 ° C. under storage conditions for 6 months, and the procedure of Test Example 2 was used to measure the degree of coloration when stored at 50 ° C. for 1 week. These results are shown in Table 5. The same effect as in Example 1 was confirmed.

(Table 4)
Ingredient Mass%
(A)
POE (30) hexyl decyl ether 2.0
2-Ethylhexanoic acid triglyceride 7.0
Methylphenylpolysiloxane 1.0
Methylparaben 0.3
δ-tocopherol 0.5
N, N-dimethyl-p-aminobenzoic acid-2-ethylhexyl 0.5
Compound (1) 0.5
(B)
C10-30 alkyl modified carboxyvinyl polymer 0.2
("PEMULEN TR-2"; manufactured by BFGoodrich)
Carboxyvinyl polymer 0.1
1,3-butanediol 15.0
Sodium hydroxide 0.1
Purified water 42.8
(C)
Ingredients listed in Table 5 2.0
Water 28.0
Total 100.0

(Table 5)
Specimen Component -10 ° C Number of precipitates 50 ° C Color difference (ΔE)
Cream 2 Ascorbic acid phosphate 0 0.32
Potassium salt cream 3 Arbutin 0 0.46
Cream 4 Kojic acid 0 0.49
Cream 5 Hydroquinone 0 0.52

  A cream 6 of the present invention was prepared in the same manner as in Example 1 according to the following formulation. Comparative Example 4 in which δ-tocopherol and N, N-dimethyl-p-aminobenzoic acid-2-ethylhexyl in this cream were replaced with water was also prepared in the same manner. When the product stored at −10 ° C. for 6 months was evaluated by the procedure of Test Example 1, no deposits of cream 6 were observed in any field of view, and 0 in Comparative Example 4 and 18.9 ± 5.5. there were. Moreover, in the evaluation by the procedure of Test Example 2, the color difference of the cream 6 was 0.39, and the same effect was confirmed.

(Table 6)
Ingredient Mass%
(A)
POE (30) hexyl decyl ether 2.0
2-Ethylhexanoic acid triglyceride 7.0
Methylphenylpolysiloxane 1.0
Methylparaben 0.3
δ-tocopherol 0.5
N, N-dimethyl-p-aminobenzoic acid-2-ethylhexyl 0.5
Compound (2) 0.5
(B)
C10-30 alkyl modified carboxyvinyl polymer 0.2
("PEMULEN TR-2"; manufactured by BFGoodrich)
Carboxyvinyl polymer 0.1
1,3-butanediol 15.0
Sodium hydroxide 0.1
Purified water 42.8
(C)
Ascorbic acid-2-glucoside 2.0
Water 28.0
Total 100.0

  A cream 7 of the present invention was prepared in the same manner as in Example 1 according to the following formulation. Comparative Example 5 was also prepared in the same manner except that δ-tocopherol and N, N-dimethyl-p-aminobenzoate-2-ethylhexyl in this cream were replaced with water. When the product stored at −10 ° C. for 6 months was evaluated by the procedure of Test Example 1, 0 precipitates were not observed in any field of view, and 24.1 ± 4.8 in Comparative Example 5. there were. Moreover, in the evaluation by the procedure of Test Example 2, the color difference of the cream 7 was 0.41, and the same effect was confirmed. Moreover, it can also be confirmed that the precipitation that is the subject of Test Example 1 is a problem that generally occurs with respect to the compound of the general formula (1). To suppress this, δ-tocopherol, N, N-dimethyl-p- It has also been confirmed that a component having three or more conjugate bonds such as aminobenzoic acid-2-ethylhexyl is useful. Furthermore. It was also confirmed that by containing a component having three or more such conjugated bonds, coloring under high temperature storage is likely to occur.

(Table 7)
Ingredient Mass%
(A)
POE (30) hexyl decyl ether 2.0
2-Ethylhexanoic acid triglyceride 7.0
Methylphenylpolysiloxane 1.0
Methylparaben 0.3
δ-tocopherol 0.5
N, N-dimethyl-p-aminobenzoic acid-2-ethylhexyl 0.5
Compound (11) 0.5
(B)
C10-30 alkyl modified carboxyvinyl polymer 0.2
("PEMULEN TR-2"; manufactured by BFGoodrich)
Carboxyvinyl polymer 0.1
1,3-butanediol 15.0
Sodium hydroxide 0.1
Purified water 42.8
(C)
Ascorbic acid-2-glucoside 2.0
Water 28.0
Total 100.0

  According to the following formulation, creams 8 to 15 of the present invention were prepared in the same manner as in Example 1. The evaluation results of Test Example 2 are shown in Table 9. It can be seen that the same effect can be obtained with the compound of the general formula (1).

(Table 8)
Ingredient Mass%
(A)
POE (30) hexyl decyl ether 2.0
2-Ethylhexanoic acid triglyceride 7.0
Methylphenylpolysiloxane 1.0
Methylparaben 0.3
δ-tocopherol 0.5
N, N-dimethyl-p-aminobenzoic acid-2-ethylhexyl 0.5
Ingredients listed in Table 9 0.5
(B)
C10-30 alkyl modified carboxyvinyl polymer 0.2
("PEMULEN TR-2"; manufactured by BFGoodrich)
Carboxyvinyl polymer 0.1
1,3-butanediol 15.0
Sodium hydroxide 0.1
Purified water 42.8
(C)
Ascorbic acid-2-glucoside 2.0
Water 28.0
Total 100.0

(Table 9)
Specimen Component Color difference (ΔE)
Cream 8 Compound 3 0.38
Cream 9 Compound 4 0.44
Cream 10 Compound 5 0.47
Cream 11 Compound 6 0.51
Cream 12 Compound 7 0.37
Cream 13 Compound 8 0.42
Cream 14 Compound 9 0.54
Cream 15 Compound 10 0.36

  The present invention can be applied to external preparations for skin such as cosmetics.

Claims (9)

1) One type selected from the compound represented by the following general formula (1) and / or a salt thereof, and 2) a compound having at least three conjugated double bonds that is liquid at 1 atm and 25 ° C. The skin external preparation characterized by containing 2 or more types and 3) a reducing substance.

General formula (1)
(In the formula, R1 and R2 each independently represents an alkyl group having 3 to 6 carbon atoms, R3 represents a hydrogen atom, an acyl group having 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms, and R4 represents Represents a group having aromaticity.) The skin external preparation according to claim 1, wherein the compound represented by the general formula (1) is a compound represented by the following general formula (2) or general formula (3): .

General formula (2)
(In the formula, R1 and R2 represent the same group as in general formula (1), and R5 represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, an acyloxy group having 1 to 4 carbon atoms, or 1 to 4 carbon atoms. X represents a nitrogen atom, an oxygen atom or a sulfur atom bonded to a hydrogen atom.)

General formula (3)
(In the formula, R6 is a hydrogen atom, an alkyl group, an alkenyl group, a phenyl group, an alkyloxy group, a hydroxyl group, a mercapto group, a trifluoromethyl group, an amino group, an alkylamino group, a nitro group, a cyano group, a formyl group, Represents a carboxyl group, an alkylamide group, a sulfenyl group, a sulfonyl group or a halogen atom.) The compound represented by the general formula (1) is 2,6-di-tert-butyl-4- (2′-thenoyl) phenol, 3,5-di-tert-butyl-4-hydroxybenzophenone, 3, 5-di-tert-butyl-4-hydroxy-4′-fluorobenzophenone, 3,5-di-tert-butyl-4-hydroxy-4′-chlorobenzophenone, 3,5-di-tert-butyl-4- Hydroxy-4'-methylbenzophenone, 3,5-di-tert-butyl-4-hydroxy-4'-methoxybenzophenone, 3,5-di-tert-butyl-4-hydroxy-2 ', 4', 6 ' -Trimethylbenzophenone, 3,5-di-tert-butyl-4,4'-dihydroxybenzophenone, 3,3 ', 5,5'-tetra-tert-butyl-4 , 4'-dihydroxybenzophenone and (3,5-di-tert-butyl-4-hydroxyphenyl) -2-naphthalenylmethanone, characterized in that The skin external preparation as described. The compound having at least three conjugated double bonds which is liquid at 1 atm and 25 ° C. is α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, vitamin E nicotinic acid ester, tocopherol acetate, vitamin D2, vitamin D3, retinol, retinal, retinoic acid, 4-methoxycinnamic acid or its derivative, aminobenzoic acid or its derivative, phenoxyethanol, phenethyl alcohol, methyl cinnamate, lilyal, anisole, cyclamenaldehyde, dimethylbenzyl carbamate 2. It is selected from vinyl, isopentyl salicylate, benzyl salicylate, phenylacetic acid, styrylyl acetate, 2-isobutyl-3-methoxypyrazine, vanillin and jasminal. 3 external skin preparation according to any one. The ratio of the sum of the contents of the compound represented by the general formula (1) and the sum of the contents of the compound having at least three conjugated double bonds, which is liquid at 1 atm and 25 ° C., The skin external preparation according to any one of claims 1 to 4, wherein the mass ratio is 1: 1 to 1:10. The sum of the contents of the compounds represented by the general formula (1), the sum of the contents of the compounds having at least three conjugated double bonds that are liquid at 1 atm and 25 ° C., and oil. The sum of the contents of the compound (oil agent component) other than the compound represented by the general formula (1) in the phase and the compound having at least three conjugated double bonds that is liquid at 1 atm and 25 ° C. The skin external preparation according to any one of Claims 1 to 5, wherein the ratio of is a mass ratio of 1: 2 to 1:50. The oil agent component is composed only of a component that is liquid at 1 atm and 25 ° C except for the compound represented by the general formula (1) and a salt thereof. The external preparation for skin according to Item. 8. The method according to claim 1, wherein the reducing substance is one or more selected from ascorbic acid, ascorbic acid derivatives, hydroquinone, hydroquinone derivatives, and salts thereof. The skin external preparation as described. The skin external preparation according to any one of claims 1 to 8, which is a cosmetic for whitening.