JP7102658B2 - Whitening composition - Google Patents

Description

The present invention relates to a whitening composition having an excellent whitening effect.

In addition to sunburn caused by exposure to ultraviolet rays, skin symptoms caused by pigmentation such as spots, freckles, chloasma, and skin blackening caused by drugs are caused by the melanin pigment produced after the melanin production of pigment cells (melanocytes) is enhanced. It is known that it is caused by depositing on the skin due to abnormal turnover or the like.
Such skin symptoms associated with pigmentation are easily observed from the appearance and therefore greatly affect the impression of the face. Therefore, interest in the prevention and improvement of skin pigmentation is very high, especially for those who have a desire to make the skin look beautiful, and the demand for whitening agents and whitening cosmetics has been increasing in recent years.

Ascorbic acid, hydroquinone, and the like have long been known as whitening agents for the purpose of preventing or improving skin pigmentation, and external skin preparations containing these have been widely used for preventing or improving skin pigmentation. Has been used. In recent years, by elucidating the mechanism of action that causes pigmentation, melanin production inhibitor, tyrosinase inhibitor, tyrosinase gene expression inhibitor, α-MSH inhibitor, antioxidant, melanocyte dendride elongation inhibitor. , A whitening agent having a mechanism of action different from that of conventional whitening agents such as an inhibitor of melanocyte delivery to keratinocytes of melanocytes is being actively developed.
Cetraxate or a salt thereof is also one of the active ingredients of a whitening agent developed in recent years, and is a compound that is decomposed into tranexamic acid by metabolism (Patent Document 1). Tranexamic acid has an action of suppressing the production of prostaglandin E2 that activates melanocytes and an action of inhibiting tyrosinase, and is known to exert a whitening effect. It has been reported that cetraxate has a whitening effect due to the activity of the compound itself in addition to the whitening effect due to its metabolite tranexamic acid.

By the way, the aminocarboxylic acid derivative described in Patent Document 2 has been confirmed to have an anti-ulcer effect, and its use as a pharmaceutical product has been proposed. The structure of the compound is partially consistent with tranexamic acid.

Japanese Unexamined Patent Publication No. 2008-110967 Tokukousho 64-4508 Gazette

An object of the present invention is to provide a whitening composition having an excellent whitening effect.

As a result of intensive studies for a compound having a whitening effect, the present inventors have found that an aminocarboxylic acid derivative having a specific structure and an acid addition salt thereof exhibit an excellent whitening effect. Furthermore, he came up with the idea that a more excellent whitening effect can be obtained by using the compound in combination with another component having a whitening action, and has completed the present invention.

That is, the present invention is a whitening composition containing a compound represented by the following general formula (1) or an acid addition salt thereof, and other components having a whitening action.

（１）
（式（１）中、Ｘ_１は水素原子がメチル基で置換されていてもよい炭素数１～２のアルキレン基を表し、Ｙ_１はＣＯＯＲ_１又はＣＨ_２ＯＲ_２を表し、Ｒ_１は水素原子又は分岐を有してもよい炭素数１～６のアルキル基を表し、Ｒ_２は水素原子又は分岐を有してもよい炭素数１～６のアシル基を表す。）

(1)
(In the formula (1), X ₁ represents an alkylene group having 1 to 2 carbon atoms in which a hydrogen atom may be substituted with a methyl group, Y ₁ represents COOR ₁ or CH ₂ OR ₂ , and R ₁ represents hydrogen. It represents an alkyl group having 1 to 6 carbon atoms which may have an atom or a branch, and R ₂ represents an acyl group having 1 to 6 carbon atoms which may have a hydrogen atom or a branch.)

In a preferred embodiment of the present invention, the other component having a whitening effect is one or more selected from the following (a) to (l).
(A) Compound represented by the following general formula (2) or a salt thereof (b) Compound represented by the following general formula (3) or a salt thereof (c) Compound represented by the following general formula (4) or a salt thereof Salt (d) Compound represented by the following general formula (8) or a salt thereof (e) Alkyl resorcinol (f) D-pantothenyl alcohol (g) Retinol and its derivative (f) Nicotinic acid derivative (h) Sugar alcohol derivative (I) Cyclic carboxamide derivative (j) Tranexamic acid and its derivative (k) Ursoleic acid phosphate ester (l) Plant extract having melanin production inhibitory action

（２）
［式（２）中、Ｒ_３は、－ＳＨ、－ＳＯ_３Ｈ、－Ｓ－Ｓ－Ｘ_２、－Ｓ－Ｘ_３、－ＳＯ－Ｘ_４、又は－ＳＯ_２－Ｘ_５を表し、前記Ｘ_２～Ｘ_５は、独立して、水素原子又は炭素数１～８の脂肪族炭化水素基である。Ｒ_４は無置換若しくは置換基を有していてもよい、炭素数５～１２の芳香族基を表す。ｎは、１又は２の整数を表す。］

(2)
[In formula (2), R ₃ represents -SH, -SO ₃ H, -S-S-X ₂ , -S-X ₃ , -SO-X ₄ , or -SO ₂ -X ₅ , as described above. X2 to _{X5 are} independently hydrogen atoms or aliphatic hydrocarbon groups having 1 to 8 carbon atoms. R ₄ represents an aromatic group having 5 to 12 carbon atoms, which may have an unsubstituted or substituent. n represents an integer of 1 or 2. ]

（３）
［式（３）中、Ｒ_５は、無置換の又は置換基を有する芳香族基を表し、該置換基は炭素数１～４の直鎖若しくは分岐のアルキル基、炭素数１～４の直鎖若しくは分岐のアルコキシ基、ハロゲン原子、又は炭素数１～４のハロゲン化アルキル基であり、該芳香族基はフェニル基、ナフチル基、又はビフェニル基である。
Ｒ_６は、水素原子、炭素数１～４の直鎖若しくは分岐のアルキル基、又は炭素数１～３の直鎖若しくは分岐のアルキルアシル基を表す。
Ｒ_７は、水素原子又は炭素数１～４の直鎖若しくは分岐のアルキル基を表す。］

(3)
[In the formula (3), R ₅ represents an aromatic group having an unsubstituted or substituent, and the substituent is a linear or branched alkyl group having 1 to 4 carbon atoms and a direct group having 1 to 4 carbon atoms. It is a chain or branched alkoxy group, a halogen atom, or an alkyl halide group having 1 to 4 carbon atoms, and the aromatic group is a phenyl group, a naphthyl group, or a biphenyl group.
R ₆ represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkyl acyl group having 1 to 3 carbon atoms.
R ₇ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. ]

（４）
［式（４）中、Ａ_１、Ａ_２、Ａ_３は独立して、置換基を有していてもよいフェニルを表す。前記置換基はヒドロキシル、炭素数１～４のアルキル、及び炭素数１～４のアルキルオキシから選択される。Ｘ_６は窒素原子又は酸素原子である。－Ｘ_６－Ｒ_８は、下記一般式（５）、（６）又は（７）で表される。］

(4)
[In formula (4), A ₁ , A ₂ , and A ₃ independently represent phenyl, which may have a substituent. The substituent is selected from hydroxyl, alkyl having 1 to 4 carbon atoms, and alkyloxy having 1 to 4 carbon atoms. X ₆ is a nitrogen atom or an oxygen atom. -X ₆ -R ₈ is represented by the following general formulas (5), (6) or (7). ]

（５）
［式（５）中、Ｘ_７は、窒素原子である。Ｒ_９及びＲ_１０は互いに結合して、Ｘ_７とともに、置換基を有していてもよい、炭素数２～８の複素環又は炭化水素環を形成する。前記置換基は、炭素数１～４のアルキル、炭素数１～４のアルキルオキシ、ヒドロキシル、アミノ、及びオキソから選ばれる。前記複素環の炭素数は３～５である。］

(5)
[In formula (5), X ₇ is a nitrogen atom. R ₉ and R ₁₀ bond with each other to form a heterocycle or hydrocarbon ring having 2 to 8 carbon atoms, which may have a substituent, together with X ₇ . The substituent is selected from alkyl having 1 to 4 carbon atoms, alkyloxy having 1 to 4 carbon atoms, hydroxyl, amino, and oxo. The heterocycle has 3 to 5 carbon atoms. ]

（６）
［式（６）中、Ｘ_８は、窒素原子又は酸素原子である。ｍは、１～５の整数である。Ｙ_２は、ヒドロキシル基又はアミノ基である。Ｒ_１１は、Ｘ_８が窒素原子のとき存在し、水素原子を表す。Ｒ_１１は、Ｘ_８が酸素原子のときは存在しない。］

(6)
[In formula (6), X ₈ is a nitrogen atom or an oxygen atom. m is an integer from 1 to 5. Y ₂ is a hydroxyl group or an amino group. R ₁₁ exists when X ₈ is a nitrogen atom and represents a hydrogen atom. R ₁₁ does not exist when X ₈ is an oxygen atom. ]

（７）
［式（７）中、Ｘ_９は、酸素原子又は窒素原子である。一般式（７）中、ｌは、Ｘ_９に応じて存在する整数である。］

(7)
[In formula (7), X ₉ is an oxygen atom or a nitrogen atom. In the general formula (7), l is an integer existing according to X ₉ . ]

（８）
[式（８）中、Ｒ_１２は、カルボキシル基により置換された炭素数１～４の直鎖若しくは
分岐のアルキル基、又は炭素数１～４のアルキル鎖を有するカルボン酸エステル基により置換された炭素数１～４の直鎖若しくは分岐のアルキル基を表し、Ｒ_１３及びＲ_１４は、それぞれ独立に、炭素数１～４の直鎖又は分岐のアルキル基を表す。]

(8)
[In formula (8), R ₁₂ was substituted with a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, or a carboxylic acid ester group having an alkyl chain having 1 to 4 carbon atoms. Represents a linear or branched alkyl group having 1 to 4 carbon atoms, and R ₁₃ and R ₁₄ independently represent a linear or branched alkyl group having 1 to 4 carbon atoms. ]

In a preferred embodiment, the composition of the present invention is a composition for external use on the skin, more preferably a cosmetic.

INDUSTRIAL APPLICABILITY The present invention provides a whitening composition having an excellent whitening effect.

The whitening composition of the present invention contains a compound represented by the following general formula (1) or an acid addition salt thereof.

（１）

(1)

In the general formula (1), X ₁ represents an alkylene group having 1 to 2 carbon atoms in which a hydrogen atom may be substituted with a methyl group. Examples of the alkylene group having 1 to 2 carbon atoms are a methylene group and an ethylene group. X ₁ is preferably -CH (CH ₃ )-or -CH ₂ -CH _2- .

In the general formula (1), Y ₁ represents COOR ₁ or CH ₂ OR ₂ , R ₁ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may have a branch, and R ₂ represents a hydrogen atom. Alternatively, it represents an acyl group having 1 to 6 carbon atoms which may have a branch.

That is, when Y ₁ is COOR ₁ , Y ₁ is a carboxyl group when R ₁ is a hydrogen atom, and Y ₁ is an ester group when R ₁ is an alkyl group having 1 to 6 carbon atoms which may have a branch. Is. Examples of the alkyl group having 1 to 6 carbon atoms which may have a branch include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group and a tert-butyl group. , N-pentyl group, n-hexyl group and the like. From the viewpoint of whitening action, it is particularly preferable that R ₁ is a hydrogen atom, and when R ₁ is an alkyl group, it is more preferable that the number of carbon atoms is small.

Further, when Y ₁ is CH ₂ OR ₂ , Y ₁ is a hydroxymethyl group when R ₂ is a hydrogen atom, and Y ₁ is an acyl group having ₁ to 6 carbon atoms which may have a branch. Is an ester group. Examples of the acyl group having 1 to 6 carbon atoms which may have a branch include a formyl group, an acetyl group, an acryloyl group, a propionyl group, a propioloyl group, a butyryl group, an isobutyryl group, a methacryloyl group, a valeryl group and a caproyl group. Can be mentioned. From the viewpoint of whitening action, it is particularly preferable that R ₂ is a hydrogen atom, and when R ₂ is an acyl group, it is more preferable that the number of carbon atoms is small.

In the general formula (1), the 1,4-cyclohexylene group may be in either a chair type or a boat type. Also, the two bonds may be in a cis or trans relationship. Preferably, it is in the form of a chair and has a transformer relationship.

Examples of the acid addition salt of the compound represented by the following general formula (1) include a salt with an inorganic acid, an organic carboxylate, or an organic sulfonic acid. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and examples of the organic carboxylate include acetic acid, propionic acid, maleic acid, fumaric acid, oxalic acid, citric acid, butyric acid and lactic acid. , Tartrate acid and the like, and examples of the organic sulfonic acid include methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid and the like. Of these, inorganic acid salts are preferable, and hydrochlorides are more preferable.
As the active ingredient of the whitening composition of the present invention, either the compound represented by the general formula (1) or an acid addition salt thereof may be used, but the acid addition salt is more preferable.

Specific examples of the compound represented by the general formula (1) are given below, but it goes without saying that the compound is not limited to these.
2- [p- (4-Aminomethylcyclohexylcarbonyl) phenyl] acetic acid, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] methyl acetate, 2- [p-(
4-Aminomethylcyclohexylcarbonyl) phenyl] ethyl acetate, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] propyl acetate, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] butyl acetate, 2- [P- (4-Aminomethylcyclohexylcarbonyl) phenyl] pentyl acetate, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] hexyl acetate;
2- [p- (4-Aminomethylcyclohexylcarbonyl) phenyl] ethanol, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] ethylformate, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl ] Ethyl acetate, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] ethyl propionate, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] ethylbutyrate, 2- [p- (4) -Aminomethylcyclohexylcarbonyl) phenyl] ethylpentanoate, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] ethylhexanoate;
2- [p- (4-Aminomethylcyclohexylcarbonyl) phenyl] propionic acid, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] methyl propionate, 2- [p- (4-aminomethylcyclohexylcarbonyl) Phenyl] ethyl propionate, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] propyl propionate, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] butyl propionate, 2- [p-( 4-Aminomethylcyclohexylcarbonyl) phenyl] pentyl propionate, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] hexyl propionate;
2- [p- (4-Aminomethylcyclohexylcarbonyl) phenyl] propanol, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] propylformate, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl ] Propyl acetate, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] propylpropionate, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] propylbutyrate, 2- [p- (4) -Aminomethylcyclohexylcarbonyl) phenyl] propylpentanoate, 2- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] propylhexanoate;
3- [p- (4-Aminomethylcyclohexylcarbonyl) phenyl] propionic acid (Compound 1), 3- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] methyl propionate, 3- [p- (4-amino) Methylcyclohexylcarbonyl) phenyl] ethyl propionate, 3- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] propyl propionate, 3- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] butyl propionate, 3- [P- (4-Aminomethylcyclohexylcarbonyl) phenyl] pentyl propionate, 3- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] hexyl propionate (Compound 2);
3- [p- (4-Aminomethylcyclohexylcarbonyl) phenyl] propanol (Compound 3), 3- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] propylformate, 3- [p- (4-aminomethyl) Cyclohexylcarbonyl) phenyl] propyl acetate, 3- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] propylpropionate, 3- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] propylbutyrate, 3-[ p- (4-Aminomethylcyclohexylcarbonyl) phenyl] propylpentanoate, 3- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] propylhexanoate (Compound 4);
2-Methyl-3- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] propanol, 2-methyl-3- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] propylformate, 2-methyl-3- [P- (4-Aminomethylcyclohexylcarbonyl) phenyl] propylacetate, 2-methyl-3- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] propylpropionate, 2-methyl-3-
[P- (4-Aminomethylcyclohexylcarbonyl) phenyl] propylbutyrate, 2-methyl-3- [p- (4-aminomethylcyclohexylcarbonyl) phenyl] propylpentanoate, 2-methyl-3- [p- (4-Aminomethylcyclohexylcarbonyl) phenyl] propylhexanoate (Compound 5).

The compound represented by the general formula (1) can be obtained by synthesizing and purifying by a conventional method. For example, it can be synthesized by an acylation reaction of an acid addition salt of an aminocarboxylic acid halide in the presence of Lewis acid described in Patent Document 2, and can be produced by an appropriate isolation / purification method.

Since the compound represented by the general formula (1) and its acid adduct have an excellent whitening effect, they are active ingredients of the whitening composition.
In the present specification, whitening refers to prevention and / or improvement of pigmentation, and more specifically, enhancement of melanin production such as spots, dullness, freckles, sunburn, darkening due to skin inflammation and irritation, and excessive accumulation. , And pigmentation symptoms caused by abnormal deposition, etc., and pigmentation symptoms caused by diseases that cause pigmentation such as skin blackening caused by drugs such as steroids, etc., are prevented and / or improved.
The mechanism of the whitening action of the compound represented by the general formula (1) and its acid adduct is unknown, but it has a tyrosinase inhibitory action, a tyrosinase gene expression inhibitory action, and a tyrosinase protein expression. Prevents and / or improves pigmentation by inhibitory action, tyrosinase activity inhibitory action such as tyrosinase-related proteolytic action, proton pump inhibitory action, melanocyte transfer inhibitory action of melanocytes to keratinocytes, or a new mechanism of action. It is speculated that it will be done.

It is known that the structure of the compound represented by the general formula (1) is partially consistent with tranexamic acid, but is not metabolized to tranexamic acid in vivo. That is, the whitening action of the compound represented by the general formula (1) is considered to be due to a mechanism different from that of tranexamic acid, and at least the structure of the (4-aminomethylcyclohexylcarbonyl) phenyl group is involved in exerting the action. It is presumed to be.
The cetraxate described in Patent Document 1 is an ester derivative of tranexamic acid, and exerts a whitening effect by its own structure and by breaking the ester bond by metabolism to become tranexamic acid.

In the whitening composition of the present invention, the content of the compound represented by the general formula (1) or an acid addition salt thereof is the total amount, preferably 0.01% to 20% by mass, based on the total amount of the composition. It is preferably 0.1 to 10% by mass, more preferably 1 to 5% by mass. Within such a range, the desired effect can be easily obtained, and the degree of freedom in formulation design can be ensured.

The whitening composition of the present invention contains a compound represented by the general formula (1) or an acid addition salt thereof, as well as other components having a whitening effect. The other component having a whitening effect is preferably one or more selected from the following (a) to (l).
(A) Compound represented by general formula (2) or salt thereof (b) Compound represented by general formula (3) or salt thereof (c) Compound represented by general formula (4) or salt thereof (d) ) Compound represented by the general formula (8) or a salt thereof (e) Alkyl resorcinol (f) D-pantothenyl alcohol (g) Retinol and its derivative (f) Nicotinic acid derivative (h) Sugar alcohol derivative (i) Cyclic Carboxamide derivative (j) Tranexamic acid and its derivative (k) Ursoleic acid phosphate (l) Plant extract having melanin production inhibitory effect

Unless otherwise specified, the present invention includes any of L-form, D-form, and racemic-form (DL-form) for compounds in which optical isomers are present.
Further, the salt referred to here can be used without particular limitation as long as it is used as an external preparation for skin. For example, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, organic amine salts such as ammonium salt, triethylamine and triethanolamine, and basic amino acid salts such as lysine and arginine are preferably exemplified. To. Of these salts, particularly preferable ones are alkali metals, and among them, sodium salts are particularly preferable.

(A) In the general formula (2), R ₃ is -SH, -SO ₃ H, -S-S-X ₂ , -S-X ₃ , -SO-X ₄ , or -SO ₂ -X ₅ . Represented, X2 to _{X5 are} independently hydrogen atoms or aliphatic hydrocarbon groups having 1 to 8 carbon atoms. R ₄ represents an aromatic group having 5 to 12 carbon atoms, which may be unsubstituted or may have a substituent, and the aromatic group is preferably a phenyl group. n represents an integer of 1 or 2. The substituent is preferably an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a phenyl group.
For more details on the compound represented by the general formula (2), refer to International Publication No. 2010/058730.
Preferred specific examples of the compound represented by the general formula (2) are the following compounds 6 to 13.

（２）

(2)

(B) In the following general formula (3), R ₅ represents an unsubstituted or aromatic group having a substituent, and the substituent is a linear or branched alkyl group having 1 to 4 carbon atoms and 1 carbon number. It is a linear or branched alkoxy group of ~ 4, a halogen atom, or an alkyl halide group having 1 to 4 carbon atoms, and the aromatic group is a phenyl group, a naphthyl group, or a biphenyl group. R ₆ represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkyl acyl group having 1 to 3 carbon atoms. R ₇ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms.
For more details on the compound represented by the general formula (3), refer to International Publication No. 2011/0746443.
Preferred specific examples of the compound represented by the general formula (3) are the following compounds 14 to 28.

（３）

(3)

(C) In the general formula (4), A ₁ , A ₂ and A ₃ independently represent phenyl which may have a substituent. The substituent is selected from hydroxyl, alkyl having 1 to 4 carbon atoms, and alkyloxy having 1 to 4 carbon atoms. X ₆ is a nitrogen atom or an oxygen atom. -X ₆ -R
₈ is represented by the following general formula (5), (6) or (7).

（４）

(4)

In the general formula (5), X ₇ is a nitrogen atom. R ₉ and R ₁₀ bond with each other to form a heterocycle or hydrocarbon ring having 2 to 8 carbon atoms, which may have a substituent, together with X ₇ . The substituent is selected from alkyl having 1 to 4 carbon atoms, alkyloxy having 1 to 4 carbon atoms, hydroxyl, amino, and oxo. The heterocycle has 3 to 5 carbon atoms.
Preferred specific examples of the compounds in which -X ₆ -R ₈ in the general formula (4) are represented by the general formula (5) are the following compounds 29 to 40.

（５）

(5)

In the general formula (6), X ₈ is a nitrogen atom or an oxygen atom. m is an integer from 1 to 5. m is preferably an integer of 1 to 3. Y ₂ is a hydroxyl group or an amino group. R ₁₁ exists when X ₈ is a nitrogen atom and represents a hydrogen atom. R ₁₁ does not exist when X ₈ is an oxygen atom.
Preferred specific examples of the compounds in which -X ₆ -R ₈ in the general formula (4) are represented by the general formula (6) are the following compounds 41 to 49.

（６）

(6)

In the general formula (7), X ₉ is an oxygen atom or a nitrogen atom. In the general formula (7), l is an integer existing according to X ₉ .
Preferred specific examples of the compounds in which -X ₆ -R ₈ in the general formula (4) are represented by the general formula (6) are the following compounds 50 to 56.

（７）

(7)

For more details on the compound represented by the general formula (4), refer to International Publication No. 2010/074052.

（８） (D) In the general formula (8), R ₁₂ is composed of a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, or a carboxylic acid ester group having an alkyl chain having 1 to 4 carbon atoms. Substituted linear or branched alkyl groups having 1 to 4 carbon atoms, and R ₁₃ and R ₁₄ independently represent linear or branched alkyl groups having 1 to 4 carbon atoms, respectively.

(8)

The compound represented by the general formula (8) is preferably a compound represented by the general formula (9).
In the general formula (9), R ₁₅ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, and R ₁₆ and R ₁₇ independently have 1 to 4 carbon atoms, respectively. Represents a linear or branched alkyl group.

（９）

(9)

More preferable compounds represented by the general formula (9) are 3-[[4- (carboxymethylaminocarbonyl) phenylcarbonyl] -valyl-prolyl] amino-1,1,1-trifluoro-4-methyl. -2-oxopentane, more preferably 3 (RS)-[[4- (carboxymethylaminocarbonyl) phenylcarbonyl] -L-valyl-L-prolyl] amino-1,1,1-trifluoro-4. -Methyl-2-oxopentane (Compound 57) or a sodium salt thereof.
For more details on the compound represented by the general formula (8), refer to Japanese Patent Publication No. 06-99378 and International Publication No. 2017/221973.

(E) For more details on alkylresorcinol, see WO 2007/148472.
The alkyl group in 4-alkylresorcinol is preferably an alkyl group having 3 to 10 carbon atoms, and more preferably an alkyl group having 3 to 6 carbon atoms. Specific examples thereof include n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, amyl group, n-hexyl group, cyclohexyl group, octyl group and isooctyl group. can. In the present invention, 4-n-butyl resorcinol is particularly preferable.

(F) D-pantothenic alcohol is an alcohol-type derivative of pantothenic acid and has the structure shown below.

(G) As the retinol and its derivative, retinol, retinol palmitate, retinol acetate, retinal and the like are preferably mentioned.

(F) As the nicotinic acid derivative, nicotinic acid amide, nicotinic acid ester and the like are preferably mentioned, and as the nicotinic acid ester, tocopherol nicotinate, benzyl nicotinate, methyl nicotinate, ethyl nicotinate and the like are preferable.

As the sugar alcohol derivative, isosorbide, diisopropyridene-D-mannitol and the like are preferably mentioned. For more details on sugar alcohol derivatives, refer to Japanese Patent Application Laid-Open No. 2008-081474.

As the cyclic carboxamide derivative (i), 1- (2-hydroxyethyl) -2-imidazolidinone, 1- (2-hydroxyethyl) -2-pyrrolidone and the like are preferably mentioned. For more details on cyclic carboxamide derivatives, see International Publication 2011-0404996.

(J) Tranexamic acid and its derivatives include tranexamic acid, dimer of tranexamic acid (trans-4- (trans-4-aminomethylcyclohexanecarbonyl) aminomethylcyclohexanecarboxylic acid), ester of tranexamic acid and hydroquinone. (Trans-4-aminomethylcyclohexanecarboxylic acid 4'-hydroxyphenyl ester), ester of tranexamic acid and gentisic acid (2- (trans-4-aminomethylcyclohexylcarbonyloxy) -5-hydroxybenzoic acid and its salt) , Tranexamic acid amide (trans-4-aminomethylcyclohexanecarboxylic acid methylamide and its salt, trans-4-acetylaminomethylcyclohexanecarboxylic acid and its salt, trans-4- (p-methoxybenzoyl) aminomethylcyclohexanecarboxylic acid And salts thereof, trans-4-guanidinomethylcyclohexanecarboxylic acid and salts thereof, etc.) and the like are preferably mentioned. For more details on tranexamic acid and its derivatives, refer to Japanese Patent Application Laid-Open No. 10-265321.

(K) Ursolic acid phosphate has the structure shown below.
For more information on ursolic acid phosphates, see WO 2006/132033.

(L) Examples of plant extracts having a melanin production inhibitory effect include Asenyaku extract, Hikiokoshi extract, Echinashi leaf extract, Shikon extract, Benibana extract, Avocado extract, Okla extract, Kiwi extract, Getto leaf extract, Sabonsou extract, and Suikazura extract. , Cha extract, pepper extract, garlic extract, lime juice extract, natto extract, orange extract, kanokosou extract, cucumber extract, kyonin extract, cuttlefish extract, grapefruit extract, gobo extract, tea extract, sugina extract, zegnaoi extract, taiso extract, tomato extract , Carrot extract, Bukuryo extract, Yuri extract, Reishi extract, Lettuce extract, Lemon extract, Royal jelly extract and the like are preferably mentioned. As these plant extracts, only one kind may be used, or two or more kinds may be used in combination.

The extraction method of these plant extracts is not particularly limited, but an extraction method using a solvent is preferable. When extracting, the raw material plant can be used as it is, but it is better to crush and shred it into powder and use it for extraction under mild conditions in a short time with high extraction efficiency. It can be carried out.
The extraction temperature is not particularly limited, and may be appropriately set according to the size of the pulverized raw material, the type of solvent, and the like. Usually, it is set in the range from room temperature to the boiling point of the solvent. Further, the extraction time is not particularly limited, and may be appropriately set according to the size of the pulverized raw material, the type of solvent, the extraction temperature, and the like. Further, at the time of extraction, stirring may be performed, the mixture may be allowed to stand without stirring, or ultrasonic waves may be applied.

For example, the above plant extract can be extracted at room temperature or 80 ° C. to 100 ° C. by immersing the raw material in a solvent. The extract obtained by the extraction treatment is filtered and then concentrated or dried as it is, or if necessary, it can be used as an active ingredient. In this extraction process, the raw material may be shredded or crushed. In addition, raw raw materials or dried raw materials may be used, or roasted raw materials may be used. The roasting method is not particularly limited, and examples thereof include a method of roasting at 80 to 120 ° C. for 0.5 to 2 hours.

The type of solvent used for extraction is not particularly limited, but water (including hot water, etc.), alcohol (for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol). , Glycol (eg 1,3-butylene glycol, propylene glycol), glycerin, ketones (eg acetone, methyl ethyl ketone), ethers (eg diethyl ether, dioxane, tetrahydrofuran, propyl ether), acetonitrile, esters (eg ethyl acetate, butyl acetate) , An aliphatic hydrocarbon (for example, hexane, heptane, liquid paraffin), an aromatic hydrocarbon (for example, toluene, xylene), a halogenated hydrocarbon (for example, chloroform), or a mixed solvent of two or more of these is preferable.

By such an extraction operation, the active ingredient is extracted from the raw material and dissolved in the solvent. The solvent containing the extract may be used as it is, or it may be allowed to stand for several days for aging before use. Further, it may be used after being subjected to conventional purification treatments such as sterilization, washing, filtration, decolorization and deodorization. Further, it may be used after being concentrated or diluted if necessary. Further, the solvent may be completely volatilized to form a solid (dried product) before use, or the dried product may be redissolved in an arbitrary solvent before use.

In the whitening composition of the present invention, the content of the component having a whitening action selected from (a) to (l) is the total amount, preferably 0.01% to 20% by mass, based on the total amount of the composition. It is more preferably 0.1 to 10% by mass, still more preferably 1 to 5% by mass. Within such a range, the desired effect can be easily obtained, and the degree of freedom in formulation design can be ensured. In the case of (l) plant extract, the amount is converted to dry weight.

The whitening composition of the present invention is preferably a composition for external use on the skin, which is expected to have an effect of percutaneous absorption. The mode of the composition for external use on the skin is not particularly limited as long as it is applied to the skin for external use, but cosmetics (including quasi-drugs), pharmaceuticals and the like are preferably mentioned. The compound represented by the general formula (1) has been confirmed to have high safety, and can be continuously applied in the form of cosmetics used on a daily basis.
The dosage form of the external composition for skin is not particularly limited, and examples thereof include a lotion formulation, an emulsifier form such as a milky lotion or cream, an oil formulation, a gel formulation, a pack, and a cleansing agent.

In addition to the above, the whitening composition of the present invention may optionally contain components other than those described above that are blended in ordinary external composition for skin, as long as the effects of the present invention are not impaired.
Such 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, palm oil, palm oil, liquid lanolin, hardened palm oil, hardened oil. , Mokuro, hardened castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojobaro and other oils and waxes; Hydrocarbons such as wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, bechenic acid, undesylene acid; cetyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol, octyldodeca Higher alcohols such as ol, myristyl alcohol, cetostearyl alcohol, etc .; cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, diisopropyl adipate, di-2-ethylhexyl sebatate, cetyl lactate, diisostearyl malate, di- Ethylene glycol 2-ethylhexanoate, neopentylglycol dicaprate, glycerin di-2-heptylundecanoate, glycerin tri-2-ethylhexanoate, trimethylolpropane tri-2-ethylhexanoate, trimethylolpropane triisostearate, Synthetic ester oils such as penta-2-ethylhexanoic acid pentanelitrit; chain polysiloxanes such as dimethylpolysiloxane, methylphenylpolysiloxane, diphenylpolysiloxane; octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, dodecamethyl Cyclic polysiloxanes such as cyclohexanesiloxane; oils such as silicone oils such as amino-modified polysiloxanes, polyether-modified polysiloxanes, alkyl-modified polysiloxanes, and modified polysiloxanes such as fluorine-modified polysiloxanes;

Anionic surfactants such as fatty acid soap (sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, triethanolamine ether alkylsulfate; cationic surfactants such as stearyltrimethylammonium chloride, benzalconium chloride, laurylamine oxide, etc. Kind: Imidazoline-based amphoteric surfactant (2-cocoyl-2-imidazolinium hydroxide-1-carboxyethyroxy disodium salt, etc.), betaine-based surfactant (alkylbetaine, amidobetaine, sulfobetaine, etc.), acyl Amphoteric surfactants such as methyltaurin; sorbitan fatty acid esters (sorbitan monostearate, sorbitan sesquioleate, etc.), glycerin fatty acids (glycerin monostearate, etc.), propylene glycol fatty acid esters (propylene glycol monostearate, etc.) ), Hardened castor oil derivative, glycerin alkyl ether, POE sorbitan fatty acid esters (POE sorbitan monooleate, polyochiethylene sorbitan monostearate, etc.), POE sorbit fatty acid esters (POE-sorbit monolaurate, etc.), POE glycerin Fatty acid esters (POE-glycerin monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE alkylphenyl ethers (POE nonyl, etc.) Phenyl ether, etc.), Pluronic type, P
OE / POP alkyl ethers (POE / POP2-decyltetradecyl ethers, etc.), tetronics, POE castor oil / cured castor oil derivatives (POE castor oil, POE cured castor oil, etc.), sucrose fatty acid esters, alkyl glucosides, etc. Nonionic surfactants; polyethylene glycol, glycerin, 1,3-butylene glycol, erythritol, sorbitol, xylitol, martitol, propylene glycol, dipropylene glycol, diglycerin, isoprene glycol, 1,2-pentanediol, 2, , 4-Hexanediol, 1,2-hexanediol, 1,2-octanediol and other polyhydric alcohols;

Moisturizing ingredients such as sodium pyrrolidone carboxylate, lactic acid, sodium lactate; surface treated, mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, silicic anhydride (silica), aluminum oxide, sulfuric acid Powders such as barium; surface-treated inorganic pigments such as red iron oxide, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, dark blue, titanium oxide, zinc oxide; even if the surface is treated Good, pearl agents such as mica titanium, fish phosphorus foil, bismuth oxychloride; may be raked Red No. 202, Red No. 228, Red No. 226, Yellow No. 4, Blue No. 404, Yellow Organic pigments such as No. 5, Red No. 505, Red No. 230, Red No. 223, Orange No. 201, Red No. 213, Yellow No. 204, Yellow No. 203, Blue No. 1, Green No. 201, Purple No. 201, Red No. 204, etc. Kind; Organic powders such as polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane elastomer; paraaminobenzoic acid-based UV absorber; anthranilic acid-based UV absorber; salicylic acid-based UV absorber; cinnamic acid-based UV absorber Agent; Benzophenone-based UV absorber; Sugar-based UV absorber; 2- (2'-Hydroxy-5'-t-octylphenyl) benzotriazole, 4-methoxy-4'-t-butyldibenzoylmethane, etc. Agents;

Lower alcohols such as ethanol and isopropanol; Vitamin A or its derivatives, Vitamin B ₆ hydrochloride, Vitamin B ₆ trypalmitate, Vitamin B ₆ dioctanoate, Vitamin B ₂ or its derivatives, Vitamin B ₁₂ , Vitamin B ₁₅ or its derivatives Vitamin Bs such as α-tocopherol, β-tocopherol, γ-tocopherol, vitamin E acetate and other vitamin Es, vitamin Ds, vitamin H, pantothenic acid, pantetin, pyroquinolinquinone and other vitamins; methylparaben, Antibacterial agents (preservatives) such as ethylparaben, butylparaben, phenoxyethanol; anti-inflammatory agents such as glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokithiol, zinc oxide, allantin; retinol, ascorbic acid, tocopherol, farnesyl acetate, etc. Wrinkle improver; various extracts (eg, Oubaku, Ouren, Shikon, Shakuyaku, Senburi, Birch, Sage, Biwa, Carrot, Aloe, Zeniaoi, Iris, Grape, Yokuinin, Hechima, Yuri, Saffron, Senkyu, Shokyu, Otogirisou, Ononis, Carrot, Togarashi, Chimpi, Touki, Seaweed, etc.); Activators such as royal jelly, photosensitizers, cholesterol derivatives; Fat leaking agents; anti-inflammatory agents such as tranexamic acid, thiotaurine and hypotaurin; water-soluble polymers such as collagen and hyaluronic acid; and the like.

Hereinafter, the present invention will be described in more detail with reference to specific experimental examples, but the present invention is not limited to the following aspects.

The cosmetics shown in Table 1 (Examples 1 to 16, Comparative Examples, and Reference Examples) were prepared by a conventional method.
The whitening effect (improvement effect of pigmentation) was evaluated for each of the prepared cosmetics by the following method. That is, 0.5 cm x 0.5 c on the medial side of the left and right upper arms of eight panelists who participated voluntarily.
A total of 8 test sites of m were provided. The provided site was irradiated with ultraviolet rays having a minimum amount of erythema (1 MED) once a day, three times in a row for three days. From the end of the ultraviolet irradiation on the first day of the test (after the end of the first irradiation), the formulation of the comparative example was applied to one test site twice a day for 25 consecutive days, and Examples 1 to 9 and each of the remaining 7 sites. 50 μL of each of the cosmetics of any one of the reference examples was applied (comparative example: n = 8, each example and reference example: n = 3). Twenty-four hours after the end of application for 25 days, the skin brightness (L * value) of each test site was measured with a color difference meter (CR-300, Konica Minolta Co., Ltd.), and the application site of the cosmetic of the example or reference example was measured. The difference in skin lightness (ΔL * value) was calculated by subtracting the L * value of the application site of the cosmetic in the comparative example from the L * value. Since the L * value becomes lower as the degree of pigmentation is stronger, it can be judged that the pigmentation is improved as the ΔL * value is larger.

Since the whitening composition of the present invention exerts an excellent whitening effect, it is suitable as an external composition for skin such as whitening cosmetics, and is very useful industrially.

Claims (4)

It contains a compound represented by the following general formula (1) or an acid addition salt thereof, and other components having a whitening effect.
A whitening composition in which the other component having a whitening action is one or more selected from the following (a) to (k) .
(A) A compound represented by the following general formula (2) or a salt thereof.
(B) A compound represented by the following general formula (3) or a salt thereof.
(C) A compound represented by the following general formula (4) or a salt thereof.
(D) A compound represented by the following general formula (8) or a salt thereof.
(E) Alkylresorcinol
(F) D-pantothenyl alcohol
(G) Retinol, retinol palmitate, retinyl acetate, or retinal
(H) Nicotinamide, tocopherol nicotinate, benzyl nicotinate, methyl nicotinate, or ethyl nicotinate
(I) Isosorbide or diisopropylidene-D-mannitol
(J) 1- (2-Hydroxyethyl) -2-imidazolidinone, or 1- (2-hydroxyethyl) -2-pyrrolidone
(K) Tranexamic acid, dimer of tranexamic acid, ester of tranexamic acid and hydroquinone, ester of tranexamic acid and gentisic acid, or amide of tranexamic acid

[In formula (1), X ₁ represents an alkylene group having 1 to 2 carbon atoms in which a hydrogen atom may be substituted with a methyl group, Y ₁ represents COOR ₁ or CH ₂ OR ₂ , and R ₁ represents hydrogen. It represents an alkyl group having 1 to 6 carbon atoms which may have an atom or a branch, and R ₂ represents an acyl group having 1 to 6 carbon atoms which may have a hydrogen atom or a branch. ]

[In formula (2), R ₃ represents -SH, -SO ₃ H, -S-S-X ₂ , -S-X ₃ , -SO-X ₄ , or -SO ₂ - X ₅ , as described above. X2 to X5 _{are independently} hydrogen atoms or aliphatic hydrocarbon groups having 1 to 8 carbon atoms. R ₄ represents an aromatic group having 5 to 12 carbon atoms, which may have an unsubstituted or substituent. n represents an integer of 1 or 2. ]

[In the formula (3), R ₅ represents an aromatic group having an unsubstituted or substituent, and the substituent is a linear or branched alkyl group having 1 to 4 carbon atoms and a direct group having 1 to 4 carbon atoms. It is a chain or branched alkoxy group, a halogen atom, or an alkyl halide group having 1 to 4 carbon atoms, and the aromatic group is a phenyl group, a naphthyl group, or a biphenyl group.
R ₆ represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkyl acyl group having 1 to 3 carbon atoms.
R ₇ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. ]

[In formula (4), A ₁ , A ₂ , and A ₃ independently represent phenyl, which may have a substituent. The substituent is selected from hydroxyl, alkyl having 1 to 4 carbon atoms, and alkyloxy having 1 to 4 carbon atoms. X ₆ is a nitrogen atom or an oxygen atom. -X ₆ - R ₈ is represented by the following general formulas (5), (6) or (7). ]

[In formula (5), X ₇ is a nitrogen atom. R ₉ and R ₁₀ bond with each other to form a heterocycle or hydrocarbon ring having 2 to 8 carbon atoms, which may have a substituent, together with X ₇ . The substituent is selected from alkyl having 1 to 4 carbon atoms, alkyloxy having 1 to 4 carbon atoms, hydroxyl, amino, and oxo. The heterocycle has 3 to 5 carbon atoms. ]

[In formula (6), X ₈ is a nitrogen atom or an oxygen atom. m is an integer from 1 to 5. Y ₂ is a hydroxyl group or an amino group. R ₁₁ exists when X ₈ is a nitrogen atom and represents a hydrogen atom. R ₁₁ does not exist when X ₈ is an oxygen atom. ]

[In formula (7), X ₉ is an oxygen atom or a nitrogen atom. In the general formula (7), l is an integer existing according to X ₉ . ]

[In the formula (8), R ₁₂ is a straight chain having 1 to 4 carbon atoms substituted with a carboxyl group or
Represents a branched alkyl group or a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxylic acid ester group having an alkyl chain having 1 to 4 carbon atoms, and R ₁₃ and R ₁₄ are independent of each other. , Represents a linear or branched alkyl group having 1 to 4 carbon atoms. ] The dimer of tranexamic acid is trans-4- (trans-4-aminomethylcyclohexanecarbonyl) aminomethylcyclohexanecarboxylic acid, which is a hydrochloric acid trans-4- (trans-4-aminomethylcyclohexanecarbonyl) aminomethylcyclohexanecarboxylic acid.
The ester of tranexamic acid and hydroquinone is a trans-4-aminomethylcyclohexanecarboxylic acid 4'-hydroxyphenyl ester.
The ester of tranexamic acid and gentisic acid is 2- (trans-4-aminomethylcyclohexylcarbonyloxy) -5-hydroxybenzoic acid and a salt thereof.
The amide form of tranexamic acid is trans-4-aminomethylcyclohexanecarboxylic acid methylamide and its salt, trans-4-acetylaminomethylcyclohexanecarboxylic acid and its salt, trans-4- (p-methoxybenzoyl) aminomethylcyclohexanecarboxylic. The composition according to claim 1, which is selected from an acid and a salt thereof, and a trans-4-guanidinomethylcyclohexanecarboxylic acid and a salt thereof. The composition according to claim 1 or 2, which is a composition for external use on the skin. The composition according to claim 3, which is a cosmetic.