JP2011178761A - Composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a melanine production inhibitor having a new mother nucleus and suitable for cosmetics (including quasi-drugs), foods, and the like, and to provide a composition containing the ingredient. <P>SOLUTION: The melanine production inhibitor comprises a compound represented by formula (1) (wherein, R<SB>1</SB>, R<SB>2</SB>and R<SB>3</SB>are each independently H or 1C to 4C straight chain or branched alkyl; R<SB>4</SB>is 1C to 12C straight chain or branched alkyl), an isomer thereof and/or pharmacologically acceptable salts thereof; and the composition includes the ingredient. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

（１）
[式中、Ｒ１、Ｒ２及びＲ３は、それぞれ独立に、水素原子又は炭素数１〜４の直鎖又は分岐のアルキル基を表し、Ｒ４は、炭素数１〜１２の直鎖又は分岐のアルキル基を表す。]
The present invention relates to a composition suitable for cosmetics (including quasi-drugs), foods, and the like. Specifically, the compound represented by the following general formula (1), its isomers and / or their drugs: The present invention relates to a melanin production inhibitor comprising a physically acceptable salt and a composition containing the component.

(1)
[Wherein R1, R2 and R3 each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R4 represents a linear or branched alkyl group having 1 to 12 carbon atoms. Represents. ]

Pigmentation, blemishes, liver spots, senile pigment spots, etc. after sunburn in the skin are skin symptoms caused by markedly increased melanin production by activation of pigment cells (melanocytes) present in the skin. As a component having an action to prevent or improve such skin pigmentation-related trouble occurrence and deterioration, compounds having a whitening action such as ascorbic acids, hydrogen peroxide, colloidal sulfur, glutathione, hydroquinone, and catechol ( Whitening agents) are well known (for example, see Non-Patent Document 1 and Non-Patent Document 2), and external preparations for skin containing these active ingredients are widely used. Currently, existing whitening agents have a mechanism of inhibiting tyrosinase enzyme (see, for example, Patent Document 1), tyrosinase-related proteolysis, and suppression of dendrite elongation in melanocytes (for example, see Patent Document 2). Various mechanisms of action such as inhibition of melanin transport by) have been reported. However, the above-mentioned whitening agent includes compounds having problems in safety or stability, and it is difficult to say that the situation is sufficiently satisfactory. Therefore, a new whitening agent was sought, a compound having a new core having high effectiveness and selectivity with respect to an existing target molecule, a compound that simultaneously acts on multiple whitening mechanisms, and a new action Research on compounds having a mechanism has been actively conducted.

A proton pump inhibitor acts on a proton pump that transports protons against the proton concentration gradient inside and outside the cell or organelle, and exerts the desired biological activity by adjusting the proton concentration inside and outside the cell or organelle To do. In addition to membrane ATPase (F-type ATPase group, V-type ATPase group, P-type ATPase group) that actively and dynamically transports, the proton pump works in conjunction with Na ⁺ / K ⁺ -ATPase and transports protons. There are Na ⁺ / H ⁺ exchange transporters. At present, proton pump inhibitors such as lansoprazole have membrane ATPase (H ⁺ / K ⁺ -ATPase) inhibitory action and are used as therapeutic agents for gastric ulcer, duodenal ulcer and the like. However, nothing is known about the pharmacological action of proton pump inhibitors in the skin, especially the action on Na ⁺ / H ⁺ exchange transporters. In such a situation, the applicant has determined that a proton pump inhibitor, particularly a proton inhibitor that acts on the Na ⁺ / H ⁺ exchange transporter, has an acidifying effect in pigment cells or organelles. It was found that melanin production-inhibiting action and whitening action are exerted through the action. That is, the proton pump inhibitor reduces the tyrosinase enzyme activity by acidifying the inside of a cell or organelle, and exerts pigmentation prevention or improvement effects such as melanin production inhibitory action and whitening action. For this reason, proton pump inhibitors are completely different from conventional whitening agents having various mechanisms such as tyrosinase enzyme inhibitory action, tyrosinase-related proteolytic action, and melanin transport inhibition action by suppressing dendriide elongation in melanocytes. It is useful as a new whitening agent having a different mechanism of action.

Further, plants belonging to the family Ginger include various physiologically active compounds such as gingerol derivatives, gingerol derivatives, gingerdiol derivatives, and aliphatic ketones (for example, Non-patent Document 3). Have been reported). Furthermore, plants belonging to the family Ginger are known to contain ginger-dione and dehydroginger-dione derivatives in addition to the aforementioned derivatives. These compounds include organisms such as a nitric oxide production inhibitory effect and a phagocytosis promoting action. It is known that there exists activity (for example, refer nonpatent literature 4). However, it is not known at all that the dehydrogin jar-dione derivative has a melanin production inhibitory action and a proton pump inhibitory action, and that the composition containing the compound has a pigmentation preventing or improving action. It was. For this reason, the compound represented by the general formula (1) is useful as a melanin production inhibitor having a new mechanism of action, and the composition containing the compound has an excellent effect of preventing or improving pigmentation. Can be expected.

JP 2009-196895 A Japanese Patent Laid-Open No. 2003-113027

Supervised by Katsuyuki Takeda et al., “Usefulness of cosmetics, evaluation technology and future prospects”, published by Yakuji Nippo (2001). Noriyuki Omori, FRAGRANCE JOURNAL Special Issue, No. 14, 1995, 118-126. Zhang K. et al. Se Pu. 26 (6), 692-696 (2008) Koh EM. et al. Planta Med. , 75 (2), 148-151 (2009)

  The present invention has been made under such circumstances, and inhibits melanin production comprising the compound represented by the general formula (1), its isomer and / or pharmacologically acceptable salt thereof. It is an object to provide an agent and a composition containing the compound.

In view of such a situation, the present inventors have intensively searched for a suitable melanin production inhibitor for cosmetics (however, including quasi-drugs), foods, etc. It has been found that the compounds represented by 1), isomers thereof and / or pharmacologically acceptable salts thereof have a melanin production inhibitory action by a proton pump inhibitory action, thereby completing the present invention. The present invention is as follows.
<1> A melanin production inhibitor comprising a compound represented by the following general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof.

（１）
[式中、Ｒ１、Ｒ２及びＲ３は、それぞれ独立に、水素原子又は炭素数１〜４の直鎖又は分岐のアルキル基を表し、Ｒ４は、炭素数１〜１２の直鎖又は分岐のアルキル基を表す。]

(1)
[Wherein R1, R2 and R3 each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R4 represents a linear or branched alkyl group having 1 to 12 carbon atoms. Represents. ]

<2> The compound represented by the general formula (1) is a compound represented by the following general formula (2), an isomer thereof and / or a pharmacologically acceptable salt thereof. The melanin production inhibitor according to <1>.

（２）
[式中、Ｒ５、Ｒ６及びＲ７は、それぞれ独立に、水素原子又は炭素数１〜４の直鎖又は分岐のアルキル基を表し、Ｒ８は、炭素数１〜１２の直鎖又は分岐のアルキル基を表す。]

(2)
[Wherein R5, R6 and R7 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R8 represents a linear or branched alkyl group having 1 to 12 carbon atoms. Represents. ]

<3> The compound represented by the general formula (2) is a compound represented by the following general formula (3), an isomer thereof and / or a pharmacologically acceptable salt thereof. The melanin production inhibitor according to <1> or <2>.

（３）
[式中、Ｒ９は、水素原子又は炭素数１〜４の直鎖又は分岐のアルキル基を表し、Ｒ１０は、炭素数１〜１２の直鎖又は分岐のアルキル基を表す。]

(3)
[Wherein, R9 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R10 represents a linear or branched alkyl group having 1 to 12 carbon atoms. ]

<4> The compound represented by the general formula (3) is a compound represented by the following general formula (4), an isomer thereof and / or a pharmacologically acceptable salt thereof. The melanin production inhibitor according to <1> or <2>.

（４）
[式中、Ｒ１１は、炭素数１〜１２の直鎖又は分岐のアルキル基を表す。]

(4)
[Wherein, R 11 represents a linear or branched alkyl group having 1 to 12 carbon atoms. ]

<5> The compound represented by the general formulas (1) to (4) is 1- (4-hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-decadien-5-one (1- ( 4-hydroxy-3-methoxyphenyl) -1-decene-3,5-dione, 1-dehydro-6-gingerdione, compound 1), 1- (4-hydroxy-3-methoxyphenyl) -3-hydroxy -1,3-dodecadien-5-one (1- (4-hydroxy-3-methoxyphenyl) -1-dodecene-3,5-dione, 1-dehydro-8-gingerdione, compound 2), 4- (4-hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-tetradecadien-5-one (1- (4-hydroxy-3-methoxyphenyl) -1-tetradecene-3,5-dione, 1- <1> to <4>, characterized in that it is hydro-10-gingerdione, compound 3), an isomer thereof and / or a pharmacologically acceptable salt thereof. Melanin production inhibitor.

１−（４−ヒドロキシ−３−メトキシフェニル）−３−ヒドロキシ−１，３−デカジエン−５−オン（化合物１）

1- (4-Hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-decadien-5-one (Compound 1)

１−（４−ヒドロキシ−３−メトキシフェニル）−３−ヒドロキシ−１，３−ドデカジエン−５−オン（化合物２）

1- (4-Hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-dodecadien-5-one (compound 2)

４−（４−ヒドロキシ−３−メトキシフェニル）−３−ヒドロキシ−１，３−テトラデカジエン−５−オン（化合物３）

4- (4-Hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-tetradecadien-5-one (compound 3)

<6> The melanin production according to any one of <1> to <5>, wherein the origin of the melanin production inhibitor is a plant extract obtained from a plant belonging to the genus Ginger. Inhibitor.
<7> The melanin production inhibitor according to <6>, wherein the plant belonging to the genus Ginger is a ginger genus.
<8> The melanin production inhibitor according to any one of <1> to <7>, wherein the melanin production inhibitory action is based on a proton pump inhibitory action.
<9> The melanin production inhibitor according to any one of <1> to <8>, wherein the proton pump inhibitory action is an action on a Na ⁺ / H ⁺ exchange transport system.
<10> A composition comprising the melanin production inhibitor according to <1> to <9>.
<11> The composition according to <10>, comprising 0.000001% by mass to 20% by mass of the melanin production inhibitor according to <1> to <9> with respect to the total amount of the composition.
<12> The composition according to <10> or <11>, which is for preventing or improving pigmentation.
<13> The composition according to any one of <10> to <12>, wherein the composition is food, medicine, or cosmetic (including quasi-drugs).
<14> The composition according to any one of <10> to <13>, which is a skin external preparation.

It is a figure which shows a result for the acidification detection (proton pump inhibitory action) in the melanocyte of the compound 1 of this invention. Detection of acidification (proton pump inhibitory action) in melanocytes of plant extracts obtained from the ginger family ginger of the present invention

<Compound represented by the general formula (1) which is an essential component of the composition of the present invention>
The composition of the present invention is characterized by containing a melanin production inhibitor comprising the compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof. The compounds represented by the general formulas (1) to (4) include tautomers in addition to geometric isomers. Such isomers are also represented by the general formulas (1) to (1) of the present invention. It is included in the melanin production inhibitor which consists of a compound represented by (4). The melanin production inhibitor comprising the compound represented by the general formula (1) of the present invention, its isomer and / or a pharmacologically acceptable salt thereof is a compound represented by the general formula (1). Among them, any compound having a melanin production inhibitory action can be applied without any particular limitation, and more preferably, in the “Evaluation of melanin production inhibitory action” described in the examples below, it exhibits a melanin production inhibitory action. Substances can be preferably exemplified. In the “melanin production inhibition evaluation” of the present invention, a component that exhibits a melanin production inhibitory activity is a component that inhibits melanin production to a level of 50% or less compared to the control group at a test substance addition concentration that does not exhibit cytotoxicity. Means. Moreover, as an action mechanism which the melanin production inhibitor which consists of the compound represented by the said General formula (1) of this invention, its isomer, and / or those pharmacologically acceptable salts has, it is a pigment cell ( Any action mechanism that suppresses melanin production in melanocytes can be applied without any particular limitation, and more preferably a melanin production inhibitory action by proton pump inhibition action. In the present invention, the component having a proton pump inhibitory action regulates the proton concentration inside and outside the cell or organelle by acting on a biofunctional molecule having a function of regulating the proton concentration inside or outside the cell or organelle. Any component having an action can be applied without particular limitation. Among the components having a proton pump inhibitory action, preferable ones include protons that function in combination with not only membrane H ⁺ -ATPase responsible for active proton transport but also ion pumps such as Na ⁺ / K ⁺ -ATPase. A component that regulates the proton concentration inside and outside the cell or organelle by acting on the Na ⁺ / H ⁺ exchange transporter that passively transports can be preferably exemplified, and more preferably, the acidification action in the cell or organelle The component which has (proton pump inhibitory action) can illustrate suitably. In addition, specific examples of preferable components among the components having a proton pump inhibitory action in the present invention include an action of acidifying the inside of melanocytes (proton in “examination of melanocyte acidification detection (proton pump inhibitory action) examination” described later). A proton pump inhibitor exhibiting a pump inhibitory action) can be preferably exemplified. Incidentally, the proton pump inhibitor having an acidifying action in the melanocyte of the present invention refers to a color development of a pH sensitive fluorescent dye by visual observation with a fluorescence microscope in the “examination of melanocyte acidification detection (proton pump inhibiting action)” described later. It means a component in which an increase in strength is observed.

Here, the compound represented by the general formula (1) will be described. In the formula, R1, R2 and R3 each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. R4 represents a linear or branched alkyl group having 1 to 12 carbon atoms. R1, R2 and R3 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. Specific examples include a hydrogen atom, a methyl group, an ethyl group, a propyl group, and butyl. The group can be preferably exemplified, and more preferably, a hydrogen atom and a methyl group can be suitably exemplified. The substitution positions on the phenyl groups of R1 and R2 are not particularly limited, but more preferably, the meta and para positions are substituted on the substituent having R3 and R4. R4 represents a linear or branched alkyl group having 1 to 12 carbon atoms, more preferably 5 to 9 carbon atoms, and specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, and a pentyl group. Hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group and the like can be preferably exemplified, and more preferably, pentyl group, hexyl group, heptyl group, octyl group and nonyl group are suitably exemplified. I can do it. Among the compounds represented by the general formula (1), preferred are the compounds represented by the general formula (2), isomers thereof and / or pharmacologically acceptable salts thereof. As a more preferable example, a compound represented by the general formula (3), an isomer thereof and / or a pharmacologically acceptable salt thereof can be preferably exemplified. Preferred examples include compounds represented by the general formula (4), isomers thereof and / or pharmacologically acceptable salts thereof. Specific examples of preferred compounds among the compounds represented by the general formula (1) include 1- (4-hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-decadien-5-one. (1- (4-hydroxy-3-methoxyphenyl) -1-decene-3,5-dione, 1-dehydro-6-gingerdione, compound 1), 1- (4-hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-dodecadien-5-one (1- (4-hydroxy-3-methoxyphenyl) -1-dodecene-3,5-dione, 1-dehydro-8-gingerdione, compound 2 ), 4- (4-hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-tetradecadien-5-one (1- (4-hydroxy-3-methoxyphenyl) -1-tetradecene- , 5-dione, 1-dehydro-10-ginger - dione, Compound 3), its isomers and / or their pharmacologically acceptable salts are suitably be exemplified. The compound represented by the general formula (1), its isomer and / or pharmacologically acceptable salt thereof has an excellent melanin production inhibitory action based on a proton pump inhibitory action. The suppression of melanin production possessed by such compounds is due to the proton pump inhibitory action, especially the Na ⁺ / H ⁺ exchange transporter inhibitory action. In addition, such compounds have excellent solubility in polar or non-polar solvents used for formulation and the like, stability in the formulation, easy formulation, and excellent skin retention, preventing or improving pigmentation. Demonstrate whitening effect. In addition, such a compound is a compound contained in a natural product and is excellent in safety.

Here, the compound represented by the general formula (2) will be described. In the formula, R5, R6 and R7 each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. R8 represents a linear or branched alkyl group having 1 to 12 carbon atoms. R5, R6 and R7 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. Specific examples include a hydrogen atom, a methyl group, an ethyl group, a propyl group, and butyl. The group can be preferably exemplified, and more preferably, a hydrogen atom and a methyl group can be suitably exemplified. R8 represents a linear or branched alkyl group having 1 to 12 carbon atoms, more preferably 5 to 9 carbon atoms. Specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, and a pentyl group. Hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group and the like can be preferably exemplified, and more preferably, pentyl group, hexyl group, heptyl group, octyl group, nonyl group and the like are suitable. A pentyl group, a heptyl group, and a nonyl group can be preferably exemplified. Specific examples of the compound represented by the general formula (2) that do not belong to the general formula (3) and the general formula (4) include 1- (3-hydroxy-4-methoxyphenyl). -1,3-hexadien-5-one, 1- (3-hydroxy-4-methoxyphenyl) -1,3-heptadiene-5-one, 1- (3-hydroxy-4-methoxyphenyl) -1,3 -Octadiene-5-one, 1- (3-hydroxy-4-methoxyphenyl) -1,3-nonadiene-5-one, 1- (3-hydroxy-4-methoxyphenyl) -1-decadien-5-one 1- (3-hydroxy-4-methoxyphenyl) -1,3-undecadien-3-one, 1- (3-hydroxy-4-methoxyphenyl) -1,3-dodecadien-5-one, 1- ( 3-hi Loxy-4-methoxyphenyl) -1,3-tridecadien-5-one, 1- (3-hydroxy-4-methoxyphenyl) -1,3-tetradecadien-5-one, 1- (3-hydroxy- 4-methoxyphenyl) -1,3-pentadecadien-5-one, 1- (3-hydroxy-4-methoxyphenyl) -1,3-hexadecadien-5-one, 1- (4-ethoxy-) 3-hydroxyphenyl) -1,3-hexadien-5-one, 1- (4-ethoxy-3-hydroxyphenyl) -1-heptadien-5-one, 1- (4-ethoxy-3-hydroxyphenyl)- 1,3-octadien-5-one, 1- (4-ethoxy-3-hydroxyphenyl) -1,3-nonadien-5-one, 1- (4-ethoxy-3-hydroxyphenyl)- , 3-Decadien-5-one, 1- (4-Ethoxy-3-hydroxyphenyl) -1,3-undecadien-5-one, 1- (4-Ethoxy-3-hydroxyphenyl) -1,3-dodecadiene -5-one, 1- (4-ethoxy-3-hydroxyphenyl) -1,3-tridecadien-5-one, 1- (4-ethoxy-3-hydroxyphenyl) -1,3-tetradecadiene-5 -One, 1- (4-ethoxy-3-hydroxyphenyl) -1,3-pentadecadien-5-one, 1- (4-ethoxy-3-hydroxyphenyl) -1,3-hexadecadien-5 -One, 1- (3-hydroxy-4-propyloxyphenyl) -1,3-hexadien-5-one, 1- (3-hydroxy-4-propyloxyphenyl) -1,3-heptadie 5-one, 1- (3-hydroxy-4-propyloxyphenyl) -1,3-octadien-5-one, 1- (3-hydroxy-4-propyloxyphenyl) -1,3-nonadiene- 5-one, 1- (3-hydroxy-4-propyloxyphenyl) -1,3-decadien-5-one, 1- (3-hydroxy-4-propyloxyphenyl) -1,3-undecadiene-5 ON, 1- (3-hydroxy-4-propyloxyphenyl) -1,3-dodecadien-5-one, 1- (3-hydroxy-4-propyloxyphenyl) -1,3-tridecadien-5-one, 1- (3-hydroxy-4-propyloxyphenyl) -1,3-tetradecadien-5-one, 1- (3-hydroxy-4-propyloxyphenyl) -1,3- Ntadecadien-5-one, 1- (3-hydroxy-4-propyloxyphenyl) -1,3-hexadecadien-5-one, 1- (4-butyloxy-3-hydroxyphenyl) -1,3-hexadiene -5-one, 1- (4-butyloxy-3-hydroxyphenyl) -1,3-heptadiene-5-one, 1- (4-butyloxy-3-hydroxyphenyl) -1,3-octadien-5-one 1- (4-butyloxy-3-hydroxyphenyl) -1,3-nonadien-5-one, 1- (4-butyloxy-3-hydroxyphenyl) -1,3-decadien-5-one, 1- ( 4-butyloxy-3-hydroxyphenyl) -1,3-undecadien-5-one, 1- (4-butyloxy-3-hydroxyphenyl) -1,3-do Cadien-5-one, 1- (4-butyloxy-3-hydroxyphenyl) -1,3-tridecadiene-5-dione, 1- (4-butyloxy-3-hydroxyphenyl) -1,3-tetradecadiene- 5-one, 1- (4-butyloxy-3-hydroxyphenyl) -1,3-pentadecadien-5-one, 1- (4-butyloxy-3-hydroxyphenyl) -1,3-hexadecadien- 5-one, its isomer and / or a salt thereof can be preferably exemplified. Among the compounds represented by the general formula (2), isomers thereof and / or pharmacologically acceptable salts thereof, 1- (4-hydroxy-3-methoxyphenyl) -3 is preferable. -Hydroxy-1,3-decadien-5-one (1- (4-hydroxy-3-methoxyphenyl) -1-decene-3,5-dione, 1-dehydro-6-gingerdione, compound 1), 1- (4-hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-dodecadien-5-one (1- (4-hydroxy-3-methoxyphenyl) -1-dodecene-3,5-dione, 1-dehydro-8-gingerdione, compound 2), 4- (4-hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-tetradecadien-5-one (1- (4-hydroxy- 3 Methoxyphenyl) -1-tetradecene-3,5-dione, 1-dehydro-10-ginger - dione, Compound 3), its isomers and / or their pharmacologically acceptable salts are suitably be exemplified. Among the compounds represented by the general formula (2), more preferred are the compounds represented by the general formula (3), isomers thereof and / or pharmacologically acceptable salts thereof. More preferable examples include compounds represented by the general formula (4), isomers thereof and / or pharmacologically acceptable salts thereof. Such a compound has an excellent melanin production inhibitory action based on a proton pump inhibitory action. The suppression of melanin production possessed by such compounds is due to the proton pump inhibitory action, especially the Na ⁺ / H ⁺ exchange transporter inhibitory action. In addition, such compounds have excellent solubility in polar or non-polar solvents used for formulation and the like, stability in the formulation, easy formulation, and excellent skin retention, preventing or improving pigmentation. Demonstrate whitening effect. In addition, such a compound is a compound contained in a natural product and is excellent in safety.

Here, the compound represented by the general formula (3) will be described. In the formula, R9 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R10 represents 1 carbon atom. -12 linear or branched alkyl groups are represented. R9 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. Specific examples include a hydrogen atom, a methyl group, an ethyl group, a propyl group, and a butyl group. Preferably, a hydrogen atom and a methyl group can be illustrated suitably. R10 represents a linear or branched alkyl group having 1 to 12 carbon atoms, more preferably 5 to 9 carbon atoms, and specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, and a pentyl group. Hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group and the like can be preferably exemplified, and more preferably, pentyl group, hexyl group, heptyl group, octyl group and nonyl group are suitably exemplified. More preferably, a pentyl group, a heptyl group, and a nonyl group can be illustrated suitably. Specific examples of the compound represented by the general formula (3) include 1- (4-hydroxy-3-methoxyphenyl) -1,3-hexadien-5-one and 1- (4-hydroxy-3- Methoxyphenyl) -1,3-heptadien-5-one, 1- (4-hydroxy-3-methoxyphenyl) -1,3-octadien-5-one, 1- (4-hydroxy-3-methoxyphenyl)- 1,3-nonadien-5-one, 1- (4-hydroxy-3-methoxyphenyl) -1,3-decadien-5-one (1-dehydro-6-gingerdione, compound 1), 1- ( 4-hydroxy-3-methoxyphenyl) -1,3-undecadien-5-one, 1- (4-hydroxy-3-methoxyphenyl) -1,3-dodecadien-5-one (1-dehydro-8- Nja-dione compound 2), 1- (4-hydroxy-3-methoxyphenyl) -1,3-tridecadien-5-one, 1- (4-hydroxy-3-methoxyphenyl) -1,3-tetradecadiene -5-one (1-dehydro-10-gingerdione, compound 3), 1- (4-hydroxy-3-methoxyphenyl) -1,3-pentadecadien-5-one, 1- (4-hydroxy -3-methoxyphenyl) -1,3-hexadecadien-5-one, 1- (3-ethoxy-4-hydroxyphenyl) -1,3-hexadien-5-one, 1- (3-ethoxy-4) -Hydroxyphenyl) -1,3-heptadien-5-one, 1- (3-ethoxy-4-hydroxyphenyl) -1,3-octadien-5-one, 1- (3-ethoxy-4-hydride) Xylphenyl) -1,3-nonadien-5-one, 1- (3-ethoxy-4-hydroxyphenyl) -1,3-decadien-5-one, 1- (3-ethoxy-4-hydroxyphenyl) -1, 3-undecadiene-5-one, 1- (3-ethoxy-4-hydroxyphenyl) -1,3-dodecadien-5-one, 1- (3-ethoxy-4-hydroxyphenyl) -1,3-tridecadiene- 5-one, 1- (3-ethoxy-4-hydroxyphenyl) -1,3-tetradecadiene-5-one, 1- (3-ethoxy-4-hydroxyphenyl) -1,3-pentadecadien-5 -One, 1- (3-ethoxy-4-hydroxyphenyl) -1,3-hexadecadien-5-one, 1- (4-hydroxy-3-propyloxyphenyl) -1,3- Hexadien-5-one, 1- (4-hydroxy-3-propyloxyphenyl) -1,3-heptadiene-5-one, 1- (4-hydroxy-3-propyloxyphenyl) -1,3-octadiene- 5-one, 1- (4-hydroxy-3-propyloxyphenyl) -1,3-nonadien-5-one, 1- (4-hydroxy-3-propyloxyphenyl) -1,3-decadiene-5 ON, 1- (4-hydroxy-3-propyloxyphenyl) -1,3-undecadien-5-one, 1- (4-hydroxy-3-propyloxyphenyl) -1,3-dodecadien-5-one, 1- (4-hydroxy-3-propyloxyphenyl) -1,3-tridecadien-5-one, 1- (4-hydroxy-3-propyloxyphenyl) -1 3-tetradecadien-5-one, 1- (4-hydroxy-3-propyloxyphenyl) -1,3-pentadecadien-5-one, 1- (4-hydroxy-3-propyloxyphenyl)- 1,3-hexadecadien-5-one, 1- (3-butyloxy-4-hydroxyphenyl) -1,3-hexadien-5-one, 1- (3-butyloxy-4-hydroxyphenyl) -1, 3-heptadiene-5-one, 1- (3-butyloxy-4-hydroxyphenyl) -1,3-octadien-5-one, 1- (3-butyloxy-4-hydroxyphenyl) -1,3-nonadiene- 5-one, 1- (3-butyloxy-4-hydroxyphenyl) -1,3-decadien-5-one, 1- (3-butyloxy-4-hydroxyphenyl)- , 3-Undecadiene-5-one, 1- (3-butyloxy-4-hydroxyphenyl) -1,3-dodecadien-5-one, 1- (3-butyloxy-4-hydroxyphenyl) -1,3-tridecadiene -5-one, 1- (3-butyloxy-4-hydroxyphenyl) -1,3-tetradecadiene-5-one, 1- (3-butyloxy-4-hydroxyphenyl) -1,3-pentadecadien -5-one, 1- (3-butyloxy-4-hydroxyphenyl) -1,3-hexadecadien-5-one, its isomers and / or salts thereof can be preferably exemplified, and among these, Preferred is 1- (4-hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-decadien-5-one (1- (4-hydroxy-3-methoxy). Ciphenyl) -1-decene-3,5-dione, 1-dehydro-6-gingerdione, compound 1), 1- (4-hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-dodecadiene- 5-one (1- (4-hydroxy-3-methoxyphenyl) -1-dodecene-3,5-dione, 1-dehydro-8-gingerdione, compound 2), 4- (4-hydroxy-3- Methoxyphenyl) -3-hydroxy-1,3-tetradecadien-5-one (1- (4-hydroxy-3-methoxyphenyl) -1-tetradecene-3,5-dione, 1-dehydro-10-ginger Preferred examples include -dione, compound 3), isomers thereof and / or pharmacologically acceptable salts thereof. The compound represented by the general formula (1), its isomer and / or pharmacologically acceptable salt thereof has an excellent melanin production inhibitory action based on a proton pump inhibitory action. The suppression of melanin production possessed by such compounds is due to the proton pump inhibitory action, especially the Na ⁺ / H ⁺ exchange transporter inhibitory action. In addition, such compounds have excellent solubility in polar or non-polar solvents used for formulation and the like, stability in the formulation, easy formulation, and excellent skin retention, preventing or improving pigmentation. Demonstrate whitening effect. In addition, such a compound is a compound contained in a natural product and is excellent in safety.

Here, the compound represented by the general formula (4) will be described. In the formula, R11 represents a linear or branched alkyl group having 1 to 12 carbon atoms. R11 represents a linear or branched alkyl group having 1 to 12 carbon atoms, more preferably 5 to 9 carbon atoms, and specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, and a pentyl group. Hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group and the like can be suitably exemplified, and among these, pentyl group, hexyl group, heptyl group, octyl group, nonyl group are more preferable. Can be preferably exemplified, and more preferably, a pentyl group, a heptyl group, and a nonyl group can be suitably exemplified. Specific examples of the compound represented by the general formula (5) include 1- (4-hydroxy-3-methoxyphenyl) -1,3-hexadien-5-one, 1- (4-hydroxy-3- Methoxyphenyl) -1,3-heptadien-5-one, 1- (4-hydroxy-3-methoxyphenyl) -1,3-octadien-5-one, 1- (4-hydroxy-3-methoxyphenyl)- 1,3-nonadien-5-one, 1- (4-hydroxy-3-methoxyphenyl) -1,3-decadien-5-one (1-dehydro-6-gingerdione, compound 1), 1- ( 4-hydroxy-3-methoxyphenyl) -1,3-undecadien-5-one, 1- (4-hydroxy-3-methoxyphenyl) -1,3-dodecadien-5-one (1-dehydro-8- Nja-dione compound 2), 1- (4-hydroxy-3-methoxyphenyl) -1,3-tridecadien-5-one, 1- (4-hydroxy-3-methoxyphenyl) -1,3-tetradecadiene -5-one (1-dehydro-10-gingerdione, compound 3), 1- (4-hydroxy-3-methoxyphenyl) -1,3-pentadecadien-5-one, 1- (4-hydroxy -3-Methoxyphenyl) -1,3-hexadecadien-5-one, its isomers and / or their salts can be suitably exemplified, and among these, more preferred is 1- (4-hydroxy -3-methoxyphenyl) -3-hydroxy-1,3-decadien-5-one (1- (4-hydroxy-3-methoxyphenyl) -1-decene-3,5-dione, 1-dehydride -6-gingerdione, compound 1), 1- (4-hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-dodecadien-5-one (1- (4-hydroxy-3-methoxyphenyl) -1-dodecene-3,5-dione, 1-dehydro-8-gingerdione, compound 2), 4- (4-hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-tetradecadiene- 5-one (1- (4-hydroxy-3-methoxyphenyl) -1-tetradecene-3,5-dione, 1-dehydro-10-ginger-dione, compound 3), its isomers and / or their drugs Physiologically acceptable salts can be preferably exemplified. The compound represented by the general formula (1), its isomer and / or pharmacologically acceptable salt thereof has an excellent melanin production inhibitory action based on a proton pump inhibitory action. The suppression of melanin production possessed by such compounds is due to the proton pump inhibitory action, especially the Na ⁺ / H ⁺ exchange transporter inhibitory action. In addition, such compounds have excellent solubility in polar or non-polar solvents used for formulation and the like, stability in the formulation, easy formulation, and excellent skin retention, preventing or improving pigmentation. Demonstrate whitening effect. In addition, such a compound is a compound contained in a natural product and is excellent in safety.

  The thus obtained compounds represented by the above general formulas (1) to (4) and their isomers can be used as they are, or can be used in the form of a salt by treating with an alkali. You can also. The compounds represented by the general formulas (1) to (4) and isomer salts thereof are not particularly limited as long as they are pharmacologically acceptable salts. Examples of pharmacologically acceptable salts include alkali metals such as sodium salt and potassium salt, alkaline earth metals such as calcium salt and magnesium salt, triethylamine salt, triethanolamine salt, ammonium salt, monoethanolamine salt, piperidine. Preferred examples include organic amine salts such as salts, basic amino acid salts such as lysine salts and alginates.

The compound represented by the general formula (1), isomers thereof and / or pharmacologically acceptable salts thereof are novel compounds. Moreover, as a melanin production inhibitor consisting of the compound represented by the general formula (1) of the present invention, an isomer thereof and / or a pharmacologically acceptable salt thereof, a simple chemical substance, A form represented by a plant-derived extract containing the compound represented by the general formula (1), isomers thereof and / or pharmacologically acceptable salts thereof can be suitably exemplified, and such compound or plant extract Can contain only 1 type, and can also contain 2 or more types in combination. Here, the plant-derived extract means a generic name of the plant extract itself, a fraction obtained by fractionating and purifying the plant extract, a plant extract or fraction, and a solvent-removed product of the purified product. Among such plant extracts, preferred examples include plant extracts obtained from plants belonging to the genus Ginger, and more preferred examples include plant extracts obtained from Ginger ginger. I can do it. Ginger Ginger is a perennial plant native to tropical Asia that is cultivated all over the world. In Japan, it is produced as food or herbal medicine in Shizuoka, Aichi, Okayama, etc., in the form of herbal medicine or extract etc. It is commercially available. The rhizome is called “shower” and is used for herbal medicine. The plant extract obtained from Ginger ginger genus ginger containing the compound represented by the general formula (1), its isomer and / or pharmacologically acceptable salt thereof is described in Example 1. It can also be produced according to the method, and an extract marketed by Maruzen Co., Ltd., Ichimaru Falcos Co., Ltd., Uchida Wakayaku Co., Ltd., etc. can be purchased and used. In addition, ginger rhizomes grown and sold in Japan can be obtained by solvent extraction.

The extract obtained from a plant belonging to the family Ginger in the present invention can be produced in Japan by using a native or grown plant, a Japanese product sold as a herbal medicine raw material, etc. Commercial extracts sold by companies that handle commercial plant extracts can be purchased and used. The plant part used for preparing the plant extract obtained from the plant is not particularly limited, and whole plants can be used. Of course, the plant body, the above-ground part, the rhizome part, the trunk part, the leaf part, the stem It is also possible to use only parts such as parts, flower spikes and flower buds, and more preferably, rhizomes can be suitably exemplified. At the time of extraction, it is preferable that a part used for extraction of a plant body or the like is processed in advance so as to improve extraction efficiency by crushing or chopping. In the production of extracts, 1 to 30 parts by mass of a solvent is added to 1 part by mass of a part used for extraction of a plant or the like, or a dry product thereof. Immerse. After the immersion, the solution can be cooled to room temperature, insoluble matter can be removed if desired, and then the solvent can be removed by concentration under reduced pressure. Thereafter, fractionation and purification can be performed by column chromatography packed with silica gel or an ion exchange resin to obtain a desired extract. Here, the extract obtained from the plant of the present invention means the generic name of the extract itself, the fraction of the extract, the purified fraction, the extract or the fraction, and the solvent-free product of the purified product.

As the extraction solvent, any solvent that can dissolve fat-soluble components contained in plants belonging to the family Gingeraceae can be applied without particular limitation, and particularly preferably a lipid-soluble solvent, methanol. Alcohols such as alcohol, ethanol, isopropyl alcohol and butanol, polyhydric alcohols such as 1,3-butanediol and polypropylene glycol, and ketones such as acetone and methyl ethyl ketone One or more selected from ethers such as diethyl ether and tetrahydrofuran, hydrocarbons such as hexane and pentane, and the like can be preferably exemplified.

The melanin production inhibitor comprising the compound represented by the general formula (1) of the present invention, its isomer and / or a pharmacologically acceptable salt thereof is a membrane component present in a cell or an organelle Cell or organelle by inhibiting the proton pump (membrane H ⁺ -ATPase) or Na ⁺ / H ⁺ exchange transport system that works in conjunction with the ion pump Na ⁺ / K ⁺ -ATPase It excels in acidifying action (proton pump inhibitory action) that inhibits proton transport inside and outside and regulates the proton concentration inside and outside the cell or organelle, and increases the proton concentration inside the cell or organelle. Acidification in a cell or organelle changes the biological activity or function of a pH-dependent functional molecule (eg, enzyme, ion channel, etc.) present in the cell or organelle. In particular, acidifying cells or organelles reduces enzyme activity such as tyrosinase, which is one of pH-dependent functional molecules, and suppresses melanin production, including whitening. Expected to have preventive or therapeutic effects on diseases associated with pigment abnormalities.

The melanin production inhibitor of the present invention is 0.000001% by mass to 20% by mass, more preferably 0.000005% by mass to 10% by mass, and further preferably 0.00001% by mass to 5% by mass with respect to the total amount of the composition. More preferably. This is because, if the content of the melanin production inhibitor of the present invention is too small, the tyrosinase enzyme activity lowering action by the acidification action (proton pump inhibition action) in the cells or organelles, and the melanin production inhibition action This is because there is a case where the effect is not achieved, and even if it is too much, the effect reaches a peak and the degree of freedom of this system may be impaired. In addition, such a component has high selectivity for a target molecule in a cell or organelle, and further has excellent accumulation and selectivity at a target site, and high safety and stability. Use in medicine, food, cosmetics and the like is preferable.

In addition, the inventors of the present invention described the compound represented by the general formula (1), isomers thereof and / or pharmacologically acceptable salts thereof, in particular, the compounds 1 to 3 are contained in natural products. Found it to exist. Such a compound can be isolated and purified by a plant belonging to the genus Ginger. Furthermore, various spectra were measured for the isolated and purified compound, and its chemical structure was determined. Detailed purification methods and structural analysis results will be described later in Example 1.

<Composition of the present invention>
The composition of the present invention is characterized by containing a melanin production inhibitor comprising the compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof. In the composition of the present invention, the compound represented by the general formula (1), its isomer and / or pharmacologically acceptable salt thereof may be used alone or in combination of two or more thereof. The substance may be used in the composition as it is, and such a compound is obtained from a plant belonging to the genus Ginger family, more preferably as a plant extract obtained from the ginger family ginger. It can also be blended. The plant extract of the present invention is a generic name for the extract itself, a fraction obtained by fractionating and purifying the extract, the extract or fraction, and the solvent-removed product of the purified product. Inclusion of a crude product of the compound represented by the general formula (1), isomers thereof and / or pharmacologically acceptable salts thereof in the composition of the present invention increases the degree of freedom of formulation. This is more preferable.

Further, a compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and a plant extract obtained from a ginger ginger genus ginger containing the compound. In formulating, it can contain arbitrary components used in formulating normal foods, pharmaceuticals, cosmetics and the like. Examples of such optional components include oral excipients such as excipients such as lactose and white sugar, binders such as starch, cellulose, gum arabic, and hydroxypropyl cellulose, carboxymethyl cellulose, Disintegrants such as sodium and carboxymethylcellulose calcium, surfactants such as soy lecithin and sucrose fatty acid ester, sweeteners such as malt and sorbitol, sour agents such as citric acid, phosphates, etc. Buffering agents, film forming agents such as shellac and zein, lubricants such as talc and wax, glidants such as light anhydrous silicic acid and dry aluminum hydroxide gel, diluents such as physiological saline and aqueous glucose solution, Suitable examples include flavoring agents, coloring agents, bactericides, preservatives, and fragrances. If it is a composition for transdermal administration, hydrocarbons such as squalane, petrolatum and microcrystalline wax, esters such as jojoba oil, carnauba wax, octyldodecyl oleate, triglycerides such as olive oil, beef tallow and coconut oil , Fatty acids such as stearic acid, oleic acid, retinoic acid, higher alcohols such as oleyl alcohol, stearyl alcohol, octyl decanol, anionic interfaces such as sulfosuccinic acid ester and sodium polyoxyethylene alkyl sulfate Activators, amphoteric surfactants such as alkylbetaine salts, cationic surfactants such as dialkylammonium salts, sorbitan fatty acid esters, fatty acid monoglycerides, their polyoxyethylene adducts, polyoxyethylene alkyl ethers, poly Oxyethylene Nonionic surfactants such as fatty acid esters, polyhydric alcohols such as polyethylene glycol, glycerin, 1,3-butanediol, thickening / gelling agents, antioxidants, UV absorbers, colors Agents, preservatives, powders and the like. Manufacture can be done without difficulty by treating these components according to conventional methods.

As the composition of the present invention, pharmaceuticals, cosmetics, foods, beverages and the like can be suitably exemplified, and since they can be taken on a daily basis, it is preferable to adapt to foods, cosmetics and the like. The administration route can be either oral administration or transdermal administration. The administration route can be either oral administration or transdermal administration. For the purpose of detoxification (detox), It is preferable to adopt oral administration with good reach efficiency and adopt the form of oral administration composition such as food. Moreover, when such a component is continuously administered, and further considering safety, it is preferably administered transdermally. As long as it can be applied to the skin for external use, it can be applied without particular limitation. For example, cosmetics including quasi-drugs, external preparations for skin, miscellaneous items for external use, etc. can be preferably exemplified. The external skin preparation of the present invention can be used without particular limitation as long as it is applied externally to the skin, for example, cosmetics, skin external medicine, skin external goods and the like can be suitably exemplified, It is particularly preferable to apply to cosmetics. This is because the external preparation for skin of the present invention has an unparalleled feeling of use and is particularly suitable for cosmetics where the feeling of use is important. The cosmetic is not particularly limited as long as the water-in-oil emulsifier form can be applied. For example, basic cosmetics such as essence, milky lotion, cream, under-makeup, foundation, -Makeup cosmetics such as kukara, mascara and eyeliner, hair cosmetics such as hair cream, etc. can be preferably exemplified.

  The composition of the present invention is for suppressing melanin production. Applications for “suppression of melanin production” include uses mainly for the purpose of achieving melanin production suppression, such as “for pigmentation improvement”, “for whitening”, “for spot improvement”, etc. It is.

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.

<Manufacture example 1: The manufacturing method of the plant extract obtained from the ginger department ginger genus ginger of this invention, isolation and purification of the compound represented by the said General formula (1)>
The manufacturing method of the plant extract obtained from the ginger department ginger genus ginger (ginger) of this invention is shown. This extract was produced by immersing the rhizome of ginger Zingiber officinale Roscoe (Zingiberaceae) in ethanol. Specifically, about 600 mL of diluted ethanol (37-50%) is added to 200 g of ginger ginger (ginger), and left to stand until the soluble components are sufficiently dissolved. Wash the cloth, wash the residue with a small amount of diluted ethanol (37-50%), squeeze, combine the leachate and washings, leave for 2 days, filter, and further dilute ethanol (37 ˜50%) was added, and a total of 1000 mL of plant extract obtained from the ginger family ginger of the present invention was produced. In addition, the plant extract obtained from the ginger department ginger genus ginger of this invention can also be manufactured according to said manufacturing method, and purchases the extract marketed by Maruzen Co., Ltd., Ichimaru Falcos Co., Ltd., etc. Can also be used.
The compounds (compound 1, compound 2 and compound 3) represented by the general formula (1) of the present invention were isolated and purified. That is, 1.8 g (kg) of commercially available ginger (dried product, chopped, Uchida Wakayaku Co., Ltd.) was heated and refluxed twice in 9 (L) methanol for 2 hours, and after filtration twice The combined filtrate was concentrated and dried under reduced pressure to obtain 159 g of show methanol extract. Showa methanol extract 159 (g) was dissolved in a methanol solution containing 10% water, liquid-liquid partition extraction was performed with n-hexane, and the resulting n-hexane fraction was concentrated and dried under reduced pressure. N-hexane extract 61.8 (g) was obtained. Shown n-hexane extract 61.8 (g) with silica gel column chromatography (silica gel: Fuji Silysia PSQ100B, 600 g), eluting while changing the ratio of mixed solution of n-hexane and ethyl acetate, 28 fractions It was fractionated. Of these, the 20th fraction 4 (g) was further fractionated and purified by preparative HPLC equipped with a TSK-gel ODS-80Ts (manufactured by Tosoh Corporation) column, and compound 1 (72 mg), compound 2 (36 mg), compound 3 (99 mg) was obtained. The chemical structure of 1- (4-hydroxy-3-methoxyphenyl) -1-decene-3 was determined by measuring ¹ H- and ¹³ C-NMR and then analyzing the obtained NMR spectral data. 5-dione (1-dehydro-6-gingerdione, compound 1), 1- (4-hydroxy-3-methoxyphenyl) -1-dodecene-3,5-dione (1-dehydro-8-gingerdione) And 2) and 1- (4-hydroxy-3-methoxyphenyl) -1-tetradecene-3,5-dione (1-dehydro-10-gingerdione, compound 3). In addition, in the “evaluation of melanin production inhibitory effect” and “investigation of melanocyte acidification detection (proton pump inhibitory effect) of the present invention” described later in the present invention, Compound 1, Compound 2, and Compound 3 and also a plant extract obtained from Ginger ginger genus were used. The physical constants of each compound are described below.

１−（４−ヒドロキシ−３−メトキシフェニル）−１−デセン−３，５−ジオン（１−デヒドロ−６−ジンジャ−ジオン、化合物１）（８）

1- (4-Hydroxy-3-methoxyphenyl) -1-decene-3,5-dione (1-dehydro-6-gingerdione, compound 1) (8)

< ¹ H- and ¹³ C-NMR spectral data of Compound 1>
¹ H-NMR (400 MHz, CDCL ₃ ) δ: 0.9 (3H, t, J = 7.0 Hz), 1.31-1.36 (4H, m), 1.61-1.69 (2H M), 2.36 (2H, t, J = 7.0 Hz), 3.92 (3H, s), 5.62 (1H, s), 5.90 (1H, brs), 6.93 ( 1H, d, J = 16.0 Hz), 6.91 (1H, d, J = 8.0 Hz), 7.01 (1H, d, J = 1.5 Hz), 7.07 (1H, dd, J = 8.0 Hz, J = 1.5 Hz), 7.52 (1H, d, J = 16.0 Hz)
¹³ C-NMR (100 MHz, CDCL ₃ ) δ: 13.9, 22.4, 25.3, 31.5, 40.0, 56.0, 100.0, 109.6, 114.8, 120 .7, 122.6, 127.8, 139.8, 146.8, 147.7, 178.2, 200.0

１−（４−ヒドロキシ−３−メトキシフェニル）−１−ドデセン−３，５−ジオン（１−デヒドロ−８−ジンジャ−ジオン、化合物２）（９）

1- (4-Hydroxy-3-methoxyphenyl) -1-dodecene-3,5-dione (1-dehydro-8-ginger-dione, compound 2) (9)

< ¹ H- and ¹³ C-NMR spectral data of Compound 2>
¹ H-NMR (400 MHz, CDCL ₃ ) δ: 0.89 (3H, t, J = 7.0 Hz), 1.23-1.36 (8H, m), 1.61-1.36 (8H) M), 1.61-1.68 (2H, m), 2.36 (2H, t, J = 7.0 Hz), 3.92 (3H, s), 5.62 (1H, s), 5.96 (1H, brs), 6.33 (1H, d, J = 16.0 Hz), 6.91 (1H, d, J = 8.0 Hz), 7.01 (1H, d, J = 1) .5 Hz), 7.07 (1 H, d, J = 1.5 Hz), 7.52 (1 H, d, J = 16.0 Hz)
¹³ C-NMR (100 MHz, CDCL ₃ ) δ: 14.0, 22.6, 25.6, 29.0, 29.2, 31.6, 40.1, 55.9, 100.0, 109 .6, 114.8, 120.6, 122.6, 127.7, 139.8, 146.8, 147.4, 178.2, 200.0

１−（４−ヒドロキシ−３−メトキシフェニル）−１−テトラデセン−３，５−ジオン（１−デヒドロ−１０−ジンジャ−ジオン、化合物３）（１０）

1- (4-Hydroxy-3-methoxyphenyl) -1-tetradecene-3,5-dione (1-dehydro-10-ginger-dione, compound 3) (10)

< ¹ H- and ¹³ C-NMR spectral data of Compound 3>
¹ H-NMR (400 MHz, CDCL ₃ ) δ: 0.88 (3H, t, J = 7.0 Hz), 1.22-1.34 (12H, m), 1.55-1.63 (2H M), 1.55-1.63 (2H, m), 2.47-2.53 (4H, m), 2.71 (2H, t, J = 7.0 Hz), 3.87 (3H) , S), 5.53 (1H, brs), 6.10 (1H, dt, J = 16.0 Hz, J = 1.5 Hz), 6.66 (1H, d, J = 1.5 Hz), 6 .67 (1H, dd, J = 8.0 Hz, J = 1.5 Hz), 6.82 (1H, dt, J = 16.0 Hz, J = 7.0 Hz), 6.83 (1H, d, J = 8.0Hz)
¹³ C-NMR (100 MHz, CDCL ₃ ) δ: 14.0, 22.6, 24.3, 29.2, 29.3, 29.4, 29.4, 31.8, 34.2, 34 .4, 40.2, 55.9, 111.0, 114.4, 120.9, 130.7, 132.7, 144.1, 145.8, 146.5, 200.8

<Test Example 1: Evaluation of melanin production inhibitory action of plant extracts obtained from the compounds 1 to 3 and the ginger genus Ginger of the present invention>
Regarding the compounds 1 to 3 of the present invention and the plant extract obtained from the ginger genus Ginger of the present invention, the melanin production inhibitory action was evaluated according to the method described below. At the same time, hydroquinone was used as a positive target, and the melanin production inhibitory action was evaluated. 22500 (cells / cm ² ) of normal human melanocytes (Kurabo Co., Ltd.) are seeded in a 24-well plate. The next day, the medium was replaced with a medium 0.5 containing evaluated substances (mL / well), was continued by adding cultured ^{0.25 (μCi) 2- [2- 14} C] thiouracil (GE Healthcare Bio-Sciences) . Four days after seeding, the medium was removed, and the plate was washed once with PBS. Then, in order to evaluate cell viability, the medium was replaced with a medium to which a viable cell count reagent SF (Nacalai Tesque) was added, The color reaction was carried out for 3 hours. After the reaction, the absorbance at 450 (nm) was measured using a microplate reader Benchmark Plus (Bio-Rad Laboratories). A sample containing no evaluation substance as a control was prepared in the same manner as described above, and the percentage of absorbance of the sample containing the evaluation substance relative to the control was determined to obtain the cell viability.
After measuring the absorbance to measure the amount of melanin, the plate was washed once with PBS, TCA was added, the cells were lysed, distilled water was added, and the solution was transferred to a vial. After leaving it on ice, it was centrifuged at 15000 rpm for 5 minutes, and then the supernatant was removed. Again, 10% TCA 500 (μL) was added to each vial and left on ice for 15 minutes. After centrifugation at 15000 rpm for 5 minutes, the supernatant was removed. Aquazol-2 (Perkin Elmer) 1 (mL) was added to the residue, and the radiation dose was measured with a liquid scintillation counter LSC-6100 (Aloka). A sample containing no evaluation substance as a control was prepared in the same manner as described above, and the percentage of the radiation dose of the sample containing the evaluation substance relative to the control was determined and used as the melanin amount (%). The 50% inhibitory concentration (IC ₅₀ value) of melanin production was calculated using SAS software version 9.1.3 (SAS Institute Inc.) within the range where cytotoxicity was not observed. The results are shown in Table 1 and FIG.

The plant extracts obtained from the compounds 1 to 3 of the present invention and the ginger ginger genus showed significant melanin production inhibitory action at a concentration not showing cytotoxicity. Moreover, the melanin production inhibitory effect was higher than the positive control hydroquinone.

<Test Example 2: Investigation of acidification in melanocytes (proton pump inhibitory action)>
Regarding the plant extract obtained from Compound 1 of the present invention and Ginger ginger genus, live intracellular acidification (proton pump inhibitory action) was detected according to the following procedure. Normal human melanocytes (Kurabo Co., Ltd.) were seeded at 10,000 cells / cm ² in a 4-well Lab-Tek chamber slide (Thormo Fisher Scientific), and the following day, the medium containing the evaluation substance was replaced with 0.55 mL / well for 1 hour 30 Separate culture was performed. A sample containing no evaluation substance as a control was prepared in the same manner as described above. Thereafter, Lysosensor 189 (Molecular Probes: final concentration 1 μM) was added and incubated for 15 minutes. After completion of the culture, the cells were washed with PBS and fixed with 4% paraformaldehyde for 15 minutes at room temperature. Thereafter, the sample was sealed with a slide glass and observed with a fluorescence microscope (Karlzeitz). The final concentration of Compound 1 was 5 × 10 ⁻⁵ (%), and the plant extract obtained from Ginger ginger genus was adjusted to a final concentration of 0.001 (w / v%). In the present invention, a substance having a proton pump inhibitory action means that the color intensity of a pH-sensitive fluorescent dye is detected by visual observation with a fluorescence microscope in melanocyte acidification (proton pump inhibitory action) detection using the normal human melanocytes. In this case, it means that the emission intensity is enhanced. The results are shown in FIGS. If the fluorescence intensity (green) of Lysosensor 189 is enhanced by the evaluation substance treatment as compared with the control without the evaluation substance treatment, it is considered that the acidification in human normal melanocytes is enhanced.

In FIG. 1 and FIG. 2, the control has a weak fluorescence coloring intensity indicating the acidification degree. On the other hand, when the compound 1 of the present invention or a plant extract obtained from the ginger family ginger is added, The fluorescence intensity is enhanced. Therefore, it was found that the plant extract obtained from Compound 1 of the present invention and Ginger ginger genus shows a remarkable acidifying action (proton pump inhibitory action) in melanocytes.

<Manufacture example 2: Manufacture of the external preparation for skin containing the melanin production inhibitor of this invention>
According to the formulations shown in Tables 3 and 4 below, essence cosmetics, which are external preparations for skin of the present invention, were prepared. That is, the ingredients of a, b and c are heated to 75 ° C., and b is gradually added to emulsify. Further, c is added to neutralize and thicken, and the mixture is cooled with stirring to make an essence emulsion cosmetic (cosmetics). 1-4) were obtained. In addition, Comparative Example 1 in which the “melanin production inhibitor of the present invention” was replaced with “arbutin” in the prescription components of Table 3, and further, Comparative Example 2 in which “the melanin production inhibitor of the present invention” was replaced with water. Was made.

<Production Example 3: Production Example 2 of the skin external preparation of the present invention>
According to the formulations shown in Tables 5 and 6, cosmetics (lotions) which are external preparations for skin of the present invention were prepared. That is, the prescription ingredients were heated to 80 ° C., stirred, dissolved, stirred and cooled to obtain a cosmetic (lotion 1).

<Test Example 3: Effect of inhibiting pigmentation by ultraviolet rays in humans>
Using the cosmetics 1 to 4 and the cosmetics of Comparative Examples 1 and 2 produced according to the above examples, the pigmentation inhibitory effect was examined. Participants who participated voluntarily The inner part of the upper arm of the paneler was divided into two upper and lower parts of 1.5cm x 1.5cm. A total of seven places were provided, and UV irradiation with a minimum amount of erythema (1 MED) was given once a day for 3 days. Irradiated 3 times in succession. From 1 day after the completion of irradiation, 50 μL of sample was applied once a day for 28 consecutive days. One site was an untreated site. 24 hours after the completion of application, the skin lightness (L * value) of each test site was measured with a color difference meter (CR-300, Konica Minolta Co., Ltd.), and the ΔL * value relative to the L value of the untreated site was calculated. The L * value decreases as the degree of pigmentation increases. Therefore, it can be determined that the greater the ΔL * value, the more pigmentation is suppressed. The results are shown in Table 7. Thereby, it turns out that the cosmetics 1-4 which are the skin external preparations of this invention, and the comparative example 1 show the pigmentation inhibitory effect. Moreover, the pigmentation inhibitory effect of the cosmetics 1-4 was excellent compared with the comparative example 1 which mix | blended arbutin. This is considered to be due to the melanin production inhibitory action of the compound represented by the general formula (1) contained in cosmetics 1 to 4, its isomer and / or pharmacologically acceptable salt thereof.

<Production Example 4: Production of health food containing the melanin production inhibitor of the present invention>
According to the formulation shown in Table 8, health food 1 was prepared. That is, the prescription ingredients were tumbled phase granulated with 10 parts by weight of water (“New Malmerizer” manufactured by Fuji Powder Co., Ltd.) and tableted to obtain a tablet-like health food. In addition, the unit of the numerical value in a table | surface represents a weight part. This health food had an excellent inhibitory effect on obesity.

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

Claims (14)

A melanin production inhibitor comprising a compound represented by the following general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof.

(1)
[Wherein R1, R2 and R3 each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R4 represents a linear or branched alkyl group having 1 to 12 carbon atoms. Represents. ] The compound represented by the general formula (1) is a compound represented by the following general formula (2), an isomer thereof and / or a pharmacologically acceptable salt thereof, Item 4. The melanin production inhibitor according to Item 1.

(2)
[Wherein R5, R6 and R7 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R8 represents a linear or branched alkyl group having 1 to 12 carbon atoms. Represents. ] The compound represented by the general formula (2) is a compound represented by the following general formula (3), an isomer thereof and / or a pharmacologically acceptable salt thereof, Item 3. The melanin production inhibitor according to item 1 or 2.

(3)
[Wherein, R9 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R10 represents a linear or branched alkyl group having 1 to 12 carbon atoms. ] The compound represented by the general formula (3) is a compound represented by the following general formula (4), an isomer thereof and / or a pharmacologically acceptable salt thereof, Item 3. The melanin production inhibitor according to item 1 or 2.

(4)
[Wherein, R 11 represents a linear or branched alkyl group having 1 to 12 carbon atoms. ] The compound represented by the general formulas (1) to (4) is 1- (4-hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-decadien-5-one (1- (4-hydroxy -3-methoxyphenyl) -1-decene-3,5-dione, 1-dehydro-6-gingerdione, compound 1), 1- (4-hydroxy-3-methoxyphenyl) -3-hydroxy-1, 3-dodecadien-5-one (1- (4-hydroxy-3-methoxyphenyl) -1-dodecene-3,5-dione, 1-dehydro-8-gingerdione, compound 2), 4- (4- Hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-tetradecadien-5-one (1- (4-hydroxy-3-methoxyphenyl) -1-tetradecene-3,5-dione, 1-dehydro The inhibition of melanin production according to any one of claims 1 to 4, which is 10-gingerdione, compound 3), an isomer thereof and / or a pharmacologically acceptable salt thereof. Agent.

1- (4-Hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-decadien-5-one (Compound 1)

1- (4-Hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-dodecadien-5-one (compound 2)

4- (4-Hydroxy-3-methoxyphenyl) -3-hydroxy-1,3-tetradecadien-5-one (compound 3) The melanin production inhibitor according to any one of claims 1 to 5, wherein the origin of the melanin production inhibitor is a plant extract obtained from a plant belonging to the genus Ginger. The melanin production inhibitor according to claim 6, wherein the plant belonging to the genus Ginger is a ginger genus. The melanin production inhibitor according to any one of claims 1 to 7, wherein the melanin production inhibitory action is based on a proton pump inhibitory action. The melanin production inhibitor according to any one of claims 1 to 8, wherein the proton pump inhibitory action is an action on a Na ⁺ / H ⁺ exchange transport system. A composition comprising the melanin production inhibitor according to claim 1. The melanin production inhibitor of Claims 1-9 is contained 0.000001 mass%-20 mass% with respect to the composition whole quantity, The composition of Claim 10 characterized by the above-mentioned. The composition according to claim 10 or 11, which is used for preventing or improving pigmentation. The composition according to any one of claims 10 to 12, wherein the composition is food, medicine or cosmetic (including quasi-drugs). It is a skin external preparation, The composition as described in any one of Claims 10-13 characterized by the above-mentioned.

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