Melanin decomposition promoter and melanin production inhibitor

Abstract

A melanin decomposition promoter containing a compound represented by formula (1). (In the formula, R1 is OH, B(OH)2, B(OCH3)2, B(OCH2CH3)2, or B(OCH2CH2CH3)2, R2 and R3 are each independently H, OH, a methyl group, a C3-10 cycloalkyl group, a halogen, or a phenyl group which may have a substituent, the substituent being at least one substituent selected from the group consisting of OH, a halogen, a C1-5 alkyl group, and a C1-5 alkoxy group, and R4 is H, OH, or a halogen, with exceptions where R1is B(OH)2, B(OCH3)2, B(OCH2CH3)2, or B(OCH2CH2CH3)2, one of R2 and R3 is OH and the other is a phenyl group which may have a substituent, and R2, R3, and R4 are all H.)　According to the present invention, it is possible to provide a novel melanin decomposition promoter and / or a novel melanin production inhibitor, and a cosmetic composition, a pharmaceutical composition, and a topical skin preparation which contain the melanin decomposition promoter and / or the melanin production inhibitor.

Description

Melanin decomposition promoter and melanin production inhibitor

[0001] The present invention relates to a novel melanin decomposition promoter and / or a novel melanin production inhibitor, and to a cosmetic composition, a pharmaceutical composition, and an external skin preparation containing the same.

[0002] Melanin, a black pigment, is produced and stored in melanosomes within melanocytes, the pigment cells, in the basal layer of the epidermis. Melanosomes containing accumulated melanin migrate to epidermal keratinocytes and are distributed above the cell nuclei within the epidermal keratinocytes.

[0003] While melanin plays a role in protecting the skin from UV damage, it can also cause cosmetic problems such as age spots and freckles, which are caused by excessive accumulation of melanin, with excessive melanin production due to UV rays and external stimuli being a major contributing factor.

[0004] Tyrosinase is known as a melanin-producing enzyme. Tyrosinase acts in two processes: a reaction to produce dopa from tyrosine, an amino acid, and a reaction to produce dopaquinone from the produced dopa (Non-Patent Document 1), (Non-Patent Document 2). Melanin is ultimately produced from the dopaquinone produced by these reactions, but since the reactions after dopaquinone proceed spontaneously, tyrosinase, which acts during the production of dopa and dopaquinone, can be said to be the rate-limiting enzyme in melanin production. Because tyrosinase is activated by ultraviolet rays and external stimuli, it is important to suppress excessive tyrosinase activity in order to suppress excessive melanin production.

[0005] Many cosmetics focused on age spots and freckles are primarily designed to inhibit tyrosinase. For example, kojic acid and 4-butylresorcinol are known as tyrosinase inhibitors. Kojic acid is a compound discovered in koji and is widely known as a skin-lightening agent with tyrosinase inhibitory activity (Non-Patent Document 3), (Non-Patent Document 4). 4-Butylresorcinol is a chemically synthesized tyrosinase inhibitor known to have significantly greater inhibition than kojic acid (Non-Patent Document 5), (Non-Patent Document 6).

[0006] Melanin is produced in small vesicles called melanosomes within melanocytes. The melanosomes that store melanin are transported to surrounding keratinocytes via melanocyte dendrites. The transported melanosomes cover the supranuclear surface of keratinocytes (called the melanin cap), which protects against DNA damage caused by harmful ultraviolet rays and promotes skin darkening (Non-Patent Document 7).

[0007] Melanosomes are normally decomposed and excreted as keratinocyte turnover occurs. However, if turnover does not occur normally and melanosomes accumulate in keratinocytes, melanin pigments are deposited, resulting in age spots. Furthermore, it has been reported that excessive accumulation of melanosomes may reduce keratinocyte cell division and slow turnover, and this vicious cycle is thought to escalate pigmentation (Non-Patent Document 8).

[0008] Therefore, promoting the breakdown of melanosomes not only improves pigmentation such as age spots and freckles that have already formed, but also helps prevent the occurrence of further age spots, making it a very important factor in terms of whitening.

[0009] Melanosomes are degraded by autophagy in keratinocytes. Cathepsin V, present in lysosomes, is believed to be involved in this degradation (Non-Patent Document 9). Light skin has higher autophagy activity and a faster rate of melanin loss than dark skin (Non-Patent Document 10), (Non-Patent Document 11). Furthermore, light skin has a higher expression level of cathepsin V than dark skin, a characteristic that is unique to cathepsin V among the several types of cathepsins present, and therefore cathepsin V is believed to be involved in the degradation of melanosomes and melanin (Non-Patent Document 12).

[0010] Arch Pharm Res. 32(3), 367-373, 2009Int J Mol Sci. 10(6), 2440-2475, 2009Eur J Med Chem. 201, 2020Biomed Pharmacother. 110, 582-593, 2019J Eur Acad Dermatol Venereol. 27(Suppl 1), 19-23, 2013Journal of the Japanese Society of Cosmetic Chemists 35(1), 42-49, 2001Microscope 48(1), 26-32, 2013Arch Dermatol Res. 306, 59-66, 2014Cell Cycle. 17(7), 844-857, 2018J Invest Dermatol. 133(10), 2416-2424, 2013J Invest Dermatol. 131(6), 1226-1233, 2011J Invest Dermatol. 126(10), 2345-2347. 2006

[0011] The present invention relates to providing a novel melanin decomposition promoter and / or a novel melanin production inhibitor, and a cosmetic composition, pharmaceutical composition, and topical skin preparation containing the same.

[0012] The present invention relates to the following items [1] to

[17] : [1] A melanin decomposition promoter comprising a compound represented by the following formula (1):

[0013]

[0014] (In the formula, R １ OH, B(OH) ２ , B(OCH ３ ) ２ , B(OCH ２ CH ３ ) ２ , or B(OCH ２ CH ２ CH ３ ) ２ , R ２ and R ３are each independently H, OH, a methyl group, a cycloalkyl group having 3 to 10 carbon atoms, a halogen, or a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, a halogen, an alkyl group having 1 to 5 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms; R ４ is H, OH, or halogen. １ But B(OH) ２ , B(OCH ３ ) ２ , B(OCH ２ CH ３ ) ２ , or B(OCH ２ CH ２ CH ３ ) ２ , and R ２ and R ３ and one of R is OH and the other is an optionally substituted phenyl group, and ２ , R ３ , and R ４ Except for those where all are H.) [2] R １ is B(OH) ２ or B(OCH ３ ) ２ and R ２ and R ３ [3] The melanin decomposition accelerator according to [1], wherein one of R is a halogen and the other is H, OH, a methyl group, or an optionally substituted phenyl group, or one is OH and the other is H or a methyl group, or one is an optionally substituted phenyl group and the other is H or a methyl group. ４ The melanin decomposition accelerator according to [1] or [2], wherein R is H. [4] １ and R ２ is OH and R ３ [5] The melanin decomposition accelerator according to [1], wherein R is a cycloalkyl group having 3 to 10 carbon atoms, a halogen atom, or a phenyl group which may have a substituent. ４is H. [6] A cosmetic composition comprising the melanin decomposition promoter according to any one of [1] to [5]. [7] A pharmaceutical composition comprising the melanin decomposition promoter according to any one of [1] to [5]. [8] A skin external preparation comprising the melanin decomposition promoter according to any one of [1] to [5]. [9] A method for producing a melanin decomposition promoter, comprising a step of blending a compound represented by the following formula (1):

[0015]

[0016] (In the formula, R １ OH, B(OH) ２ , B(OCH ３ ) ２ , B(OCH ２ CH ３ ) ２ , or B(OCH ２ CH ２ CH ３ ) ２ , R ２ and R ３ are each independently H, OH, a methyl group, a cycloalkyl group having 3 to 10 carbon atoms, a halogen, or a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, a halogen, an alkyl group having 1 to 5 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms; R ４ is H, OH, or halogen. １ But B(OH) ２ , B(OCH ３ ) ２ , B(OCH ２ CH ３ ) ２ , or B(OCH ２ CH ２ CH ３ ) ２ , and R ２ and R ３ and one of R is OH and the other is an optionally substituted phenyl group, and ２ , R ３ , and R ４

[10] A method for promoting the decomposition of melanin using a compound represented by the following formula (1):

[0017]

[0018] (In the formula, R １ OH, B(OH) ２ , B(OCH ３ ) ２ , B(OCH ２ CH ３ ) ２ , or B(OCH ２ CH ２ CH ３ ) ２ , R ２ and R ３ are each independently H, OH, a methyl group, a cycloalkyl group having 3 to 10 carbon atoms, a halogen, or a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, a halogen, an alkyl group having 1 to 5 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms; R ４ is H, OH, or halogen. １ But B(OH) ２ , B(OCH ３ ) ２ , B(OCH ２ CH ３ ) ２ , or B(OCH ２ CH ２ CH ３ ) ２ , and R ２ and R ３ and one of R is OH and the other is an optionally substituted phenyl group, and ２ , R ３ , and R ４

[11] A melanin production inhibitor comprising a compound represented by the following formula (2) and / or (3):

[0019]

[0020] (In the formula, R ５ is a cycloalkyl group having 3 to 10 carbon atoms, a halogen, or -X-R ６ , where -X- is a single bond, -CH ２ - or -CH(CH ３ )-, and —X- is a single bond or —CH ２R when - ６ is a phenyl group substituted with halogen, -X- is -CH(CH ３ )- when R ６ is a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, halogen, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms.

[0021]

[0022] (In the formula, R ７ is halogen, R ８ is a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, halogen, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms.)

[12] R ５ is a cycloalkyl group having 3 to 10 carbon atoms, a halogen atom, a phenyl group substituted with a halogen atom, a benzyl group substituted with a halogen atom, or a methylbenzyl group optionally substituted with a halogen atom.

[13] A cosmetic composition comprising the melanin production inhibitor according to

[11] or

[12] .

[14] A pharmaceutical composition comprising the melanin production inhibitor according to

[11] or

[12] .

[15] A skin external preparation comprising the melanin production inhibitor according to

[11] or

[12] .

[16] A method for producing a melanin production inhibitor, comprising a step of blending a compound represented by the following formula (2) and / or (3):

[0023]

[0024] (In the formula, R ５ is a cycloalkyl group having 3 to 10 carbon atoms, a halogen, or -X-R ６ , where -X- is a single bond, -CH ２ - or -CH(CH ３ )-, and —X- is a single bond or —CH ２ R when - ６ is a phenyl group substituted with halogen, -X- is -CH(CH ３ )- when R ６is a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, halogen, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms.

[0025]

[0026] (In the formula, R ７ is halogen, R ８ is a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, halogen, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms.)

[17] A method for suppressing melanin production using a compound represented by the following formula (2) and / or (3):

[0027]

[0028] (In the formula, R ５ is a cycloalkyl group having 3 to 10 carbon atoms, a halogen, or -X-R ６ , where -X- is a single bond, -CH ２ - or -CH(CH ３ )-, and —X- is a single bond or —CH ２ R when - ６ is a phenyl group substituted with halogen, -X- is -CH(CH ３ )- when R ６ is a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, halogen, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms.

[0029]

[0030] (In the formula, R ７ is halogen, R ８ is a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, halogen, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms.

[0031] According to the present invention, it is possible to provide a novel melanin decomposition promoter and / or a novel melanin production inhibitor, as well as a cosmetic composition, a pharmaceutical composition, and an external skin preparation containing the same.

[0032] 10 is a fluorescent microscope image in Test Example 2. 11 is a fluorescent microscope image in Test Example 2. 12 is a fluorescent microscope image in Test Example 4.

[0033] The present inventors believed that melanin production inhibitors or melanin degradation promoters could regulate the amount of intracellular melanin and thereby reduce the amount of melanin present between cells in the stratum corneum, thereby preventing and improving age spots and freckles caused by melanin pigmentation and maintaining cell turnover function. Therefore, the inventors comprehensively investigated the inhibitory activity against melanin production and / or the promoting effect against melanin degradation of a wide variety of substances, and found that certain compounds have specific inhibitory activity against melanin production and / or excellent promoting effect against melanin degradation. Furthermore, the inventors confirmed that these specific compounds have the activity of reducing the amount of melanin in cells, and based on this, the present invention was completed. Furthermore, the inventors confirmed that certain compounds have both of these effects.

[0034] (Melanin Decomposition Promoter) The melanin decomposition promoter of the present invention contains a compound represented by the following formula (1).

[0035]

[0036] (In the formula, R １ OH, B(OH) ２ , B(OCH ３ ) ２ , B(OCH ２ CH ３ ) ２ , or B(OCH ２ CH ２ CH ３ ) ２ , R ２ and R ３are each independently H, OH, a methyl group, a cycloalkyl group having 3 to 10 carbon atoms, preferably 4 to 8 carbon atoms, and more preferably 6 carbon atoms, a halogen, or a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, a halogen, an alkyl group having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms, and more preferably 1 to 2 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms, and more preferably 1 to 2 carbon atoms; R ４ is H, OH, or halogen. １ But B(OH) ２ , B(OCH ３ ) ２ , B(OCH ２ CH ３ ) ２ , or B(OCH ２ CH ２ CH ３ ) ２ , and R ２ and R ３ and one of R is OH and the other is an optionally substituted phenyl group, and ２ , R ３ , and R ４ Except for those where all are H.)

[0037] From the viewpoint of promoting melanin decomposition, in the above formula (1), R ４ is preferably H, and when it is OH or halogen, it is preferably at the 6-position. An example of a compound in which OH or halogen is at the 6-position is 4,6-dichlororesorcinol.

[0038] In this specification, examples of halogen include fluorine, chlorine, bromine, and iodine, and from the viewpoint of promoting melanin decomposition, fluorine, chlorine, and bromine are preferred in the above formula (1).

[0039] As used herein, alkyl refers to a straight or branched chain saturated hydrocarbon group having the specified number of carbon atoms. For example, an alkyl group having 1 to 5 carbon atoms is intended to include straight or branched chain hydrocarbon groups having 1 to 5 carbon atoms.

[0040] By alkoxy herein is meant an -O-alkyl group having the specified number of carbon atoms.

[0041] From the viewpoint of promoting melanin decomposition, in the above formula (1), R １ is B(OH) ２ or B(OCH ３ ) ２ and R ２ and R ３ is preferably one in which one is a halogen and the other is H, OH, a methyl group, or an optionally substituted phenyl group, one in which OH is and the other is H or a methyl group, or one in which one is an optionally substituted phenyl group and the other is H or a methyl group. Examples of such compounds include 2-fluoro-4-biphenylboronic acid, 3-hydroxyphenylboronic acid, 3-fluoro-4-biphenylboronic acid, 3-fluorophenylboronic acid, 3-chlorophenylboronic acid, 3-bromophenylboronic acid, 3-fluoro-4-methylphenylboronic acid, 3-fluoro-4-hydroxyphenylboronic acid, and 4-biphenylboronic acid. Of these, 2-fluoro-4-biphenylboronic acid is preferred from the viewpoint of both promoting the degradation of and inhibiting the production of melanin.

[0042] In addition, from the viewpoint of both promoting the decomposition of melanin and inhibiting its production, R １ and R ２ is OH and R ３is a cycloalkyl group having 3 to 10 carbon atoms, a halogen atom, or a phenyl group which may have a substituent. Examples of such compounds include 4-chlororesorcinol, 4,6-dichlororesorcinol, 4-phenylresorcinol, 2,4,4'-trihydroxybiphenyl, [1,1'-biphenyl]-2,2',4-triol, 4'-methyl-[1,1'-biphenyl]-2,4-diol, 3'-ethyl-[1,1'-biphenyl]-2,4-diol, 4'-fluoro-[1,1'-biphenyl]-2,4-diol, 4'-chloro ... ]-2,4-diol, 3'-fluoro-[1,1'-biphenyl]-2,4-diol, 2'-fluoro-[1,1'-biphenyl]-2,4-diol, 4'-chloro-[1,1'-biphenyl]-2,4-diol, 3'-chloro-[1,1'-biphenyl]-2,4-diol, 2'-chloro-[1,1'-biphenyl]-2,4-diol, 4-cyclohexylresorcinol, and the like.

[0043] The content of the compound of formula (1) in the melanin decomposition accelerator of the present invention is usually about 0.1 to 100% by mass, in terms of dry weight, and can be 10% by mass or more, 20% by mass or more, 30% by mass or more, 40% by mass or more, 50% by mass or more, 60% by mass or more, 70% by mass or more, 80% by mass or more, 90% by mass or more, or 90% by mass or less, 80% by mass or less, etc. When two or more compounds of formula (1) are used, the content refers to the total amount thereof.

[0044] The melanin decomposition accelerator of the present invention may contain, in addition to the compound of formula (1), a whitening ingredient known in the art, such as placenta extract, magnesium L-ascorbyl phosphate, sodium L-ascorbyl phosphate, kojic acid, arbutin, L-ascorbic acid 2-glucoside, ellagic acid, 4-n-butylresorcinol, linoleic acid S, tranexamic acid, potassium 4-methoxysalicylate, 3-O-ethyl ascorbic acid, adenosine monophosphate disodium (energy signal AMP), 5,5'-dipropyl-biphenyl-2,2'-diol (magnolignan), tetra-2-hexyldecanoate ascorbyl EX (VC-IP), methylparaben, ... EX), Nicotinamide (D-Melano), Cetyl Tranexamate Hydrochloride (TXC), Dexpanthenol W (PCE-DP), Retinol, Caprylyl 2-Glyceryl Ascorbate, Disodium Isostearyl Ascorbyl Phosphate, Sodium Ascorbyl Phosphate, Ascorbyl Glucoside, Adenosine Monophosphate Disodium OT, Adenosine Phosphate Disodium, Hydroquinone, Trisodium Ascorbyl Palmitate Phosphate, Magnesium Ascorbyl Phosphate, Ascorbyl Tetra-2-hexyldecanoate, Ascorbyl Tetrahexyldecanoate, Cynara Scolymus Extract, Rehmannia Root Extract, Asparagus Stem Extract, Acerola Fruit Extract, Aloe Barbadensis Leaf Juice, Polygonum Cuspidatum Extract, Polygonum Cuspidatum Root Extract, Turmeric Extract, Turmeric Rhizome Extract, Scutellaria Baicalensis Root Extract, Hypericum Wort Extract, Hypericum Perforatum Flower / Leaf / stem extract, Pueraria lobata extract, Rosa canina fruit extract, Chamomilla ET, Artemisia capillaris extract, Artemisia capillaris flower extract, Licorice extract, Licorice root extract, Licorice extract powder, Licorice flavonoids, Rubus idaeus extract, Kiwi extract, Pueraria lobata root extract, Sasa veitchii extract, Sasa veitchii leaf extract, Sophora flavonoids (1), Sophora flavonoids root extract, Alpinia speciosa leaf extract, Gentian extract, Gentianian rhizome / root extract, Coffee extract, Coffee seed extract, Burdock extract, Burdock root extract, Averrhoa carambola leaf extract, Hawthorn extract, Rehmannia root extract, Peony extract, Peony root extract, Ginger rhizome extract, Ginger extract, Ginger tincture, Calamus root extract, Calamus rhizome extract, Horsetail extract, Star fruit leaf extract, Hypericum perforatum flower / leaf / stem extract, Horse chestnut seed extract,Yarrow extract, Swertia japonica extract, Soybean isoflavones, Soybean extract, Soybean seed extract, Placenta extract (1), Placenta extract (2), Thyme extract (1), Thyme extract (2), Thymus vulgaris flower / leaf / stem extract, Angelica acutiloba extract (1), Angelica acutiloba root extract, Calendula officinalis extract, Calendula officinalis flower extract, Wild rose extract, Pineapple fruit extract, Pineapple ceramide, Papaya fruit extract, Loquat leaf extract, Grape seed extract, Fullerene, Placenta extract (1), placenta extract (2), placenta extract (3), prune enzymatic hydrolysate, prune hydrolysate, peony extract, horse chestnut extract, evening primrose seed extract, evening primrose extract, melissa extract, melissa leaf extract, peach leaf extract, saxifrage extract, oil-soluble licorice extract (2), mugwort extract, mugwort leaf extract, wild thyme extract, burnet extract, etc., and can be optionally contained, and can be used in combination with the melanin production inhibitor of the present invention described below.

[0045] The melanin decomposition promoter of the present invention can be prepared by any production method known in the art, except for the step of blending the compound of formula (1). The present invention also provides a method for promoting the decomposition of melanin using the compound of formula (1).

[0046] (Melanin Production Inhibitor) The melanin production inhibitor of the present invention contains a compound represented by the following formula (2) and / or (3).

[0047]

[0048] (In the formula, R ５ is a cycloalkyl group having 3 to 10 carbon atoms, preferably 4 to 8 carbon atoms, and more preferably 6 carbon atoms, a halogen, or -X-R ６ , where -X- is a single bond, -CH ２ - or -CH(CH ３ )-, and —X- is a single bond or —CH ２ R when - ６ is a phenyl group substituted with halogen, -X- is -CH(CH ３ )- when R ６is a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, halogen, an alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, and more preferably 1 to 2 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, and more preferably 1 to 2 carbon atoms.

[0049]

[0050] (In the formula, R ７ is halogen, R ８ is a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, halogen, an alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, and more preferably 1 to 2 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, and more preferably 1 to 2 carbon atoms.

[0051] From the viewpoint of inhibiting melanin production, in the above formula (2), R ５ is preferably a cycloalkyl group having 3 to 10 carbon atoms, a halogen, a phenyl group substituted with a halogen, a benzyl group substituted with a halogen, or a methylbenzyl group which may be substituted with a halogen. Examples of such compounds include 4-chlororesorcinol, 4-bromoresorcinol, 4'-bromo-[1,1'-biphenyl]-2,4-diol, 4-(α-methylbenzyl)resorcinol, 4'-fluoro-[1,1'-biphenyl]-2,4-diol, 3'-fluoro-[1,1'-biphenyl]-2,4-diol, 2'-fluoro-[1,1'-biphenyl]-2,4-diol, 4'-chloro-[1,1'-biphenyl]-2,4-diol, 3'-chloro-[1,1'-biphenyl]-2,4-diol, 2'-chloro-[1,1'-biphenyl]-2,4-diol, 4-cyclohexylresorcinol, etc. Also, examples of the compounds of formula (3) include 4-cyclohexylresorcinol, etc.

[0052] The content of the compound of formula (2) and / or (3) in the melanin production inhibitor of the present invention is usually about 0.1 to 100% by mass, in terms of dry weight, and can be 10% by mass or more, 20% by mass or more, 30% by mass or more, 40% by mass or more, 50% by mass or more, 60% by mass or more, 70% by mass or more, 80% by mass or more, 90% by mass or more, or 90% by mass or less, 80% by mass or less, etc. When two or more types of compounds of formula (2) and / or (3) are used, the amount refers to the total amount thereof.

[0053] The melanin production inhibitor of the present invention may contain, in addition to the compounds of formula (2) and / or (3), skin-whitening ingredients known in the art, such as placenta extract, magnesium L-ascorbyl phosphate, sodium L-ascorbyl phosphate, kojic acid, arbutin, L-ascorbic acid 2-glucoside, ellagic acid, 4-n-butylresorcinol, linoleic acid S, tranexamic acid, potassium 4-methoxysalicylate, 3-O-ethyl ascorbic acid, adenosine monophosphate disodium (energy signal AMP), 5,5'-dipropyl-biphenyl-2,2'-diol (magnolignan), tetra-2-hexyldecanoate ascorbyl EX (VC-IP), and the like. EX), Nicotinamide (D-Melano), Cetyl Tranexamate Hydrochloride (TXC), Dexpanthenol W (PCE-DP), Retinol, Caprylyl 2-Glyceryl Ascorbate, Disodium Isostearyl Ascorbyl Phosphate, Sodium Ascorbyl Phosphate, Ascorbyl Glucoside, Adenosine Monophosphate Disodium OT, Adenosine Phosphate Disodium, Hydroquinone, Trisodium Ascorbyl Palmitate Phosphate, Magnesium Ascorbyl Phosphate, Ascorbyl Tetra-2-hexyldecanoate, Ascorbyl Tetrahexyldecanoate, Cynara Scolymus Extract, Rehmannia Root Extract, Asparagus Stem Extract, Acerola Fruit Extract, Aloe Barbadensis Leaf Juice, Polygonum Cuspidatum Extract, Polygonum Cuspidatum Root Extract, Turmeric Extract, Turmeric Rhizome Extract, Scutellaria Baicalensis Root Extract, Hypericum Wort Extract, Hypericum Perforatum Flower / Leaf / stem extract, Pueraria lobata extract, Rosa canina fruit extract, Chamomilla ET, Artemisia capillaris extract, Artemisia capillaris flower extract, Licorice extract, Licorice root extract, Licorice extract powder, Licorice flavonoids, Rubus idaeus extract, Kiwi extract, Pueraria lobata root extract, Sasa veitchii extract, Sasa veitchii leaf extract, Sophora flavonoids (1), Sophora flavonoids root extract, Alpinia speciosa leaf extract, Gentian extract, Gentianian rhizome / root extract, Coffee extract, Coffee seed extract, Burdock extract, Burdock root extract, Averrhoa carambola leaf extract, Hawthorn extract, Rehmannia root extract, Peony extract, Peony root extract, Ginger rhizome extract, Ginger extract, Ginger tincture, Calamus root extract, Calamus rhizome extract, Horsetail extract, Star fruit leaf extract, Hypericum perforatum flower / leaf / stem extract, Horse chestnut seed extract,Yarrow extract, Swertia japonica extract, Soybean isoflavones, Soybean extract, Soybean seed extract, Placenta extract (1), Placenta extract (2), Thyme extract (1), Thyme extract (2), Thymus vulgaris flower / leaf / stem extract, Angelica acutiloba extract (1), Angelica acutiloba root extract, Calendula officinalis extract, Calendula officinalis flower extract, Wild rose extract, Pineapple fruit extract, Pineapple ceramide, Papaya fruit extract, Loquat leaf extract, Grape seed extract, Fullerene, Placenta The melanin decomposition promoter of the present invention may optionally contain, for example, placenta extract (1), placenta extract (2), placenta extract (3), prune enzymatic hydrolysate, prune hydrolysate, peony extract, horse chestnut extract, evening primrose seed extract, evening primrose extract, melissa extract, melissa leaf extract, peach leaf extract, saxifrage extract, oil-soluble licorice extract (2), mugwort extract, mugwort leaf extract, wild thyme extract, burnet extract, etc., and may be used in combination with the melanin decomposition promoter of the present invention.

[0054] The melanin production inhibitor of the present invention can be prepared by any production method known in the art, except for the step of blending the compound of formula (2) and / or (3). The present invention also provides a method for inhibiting melanin production using the compound of formula (2) and / or (3).

[0055] (Uses, etc.) The form of the melanin decomposition promoter of the present invention and / or the melanin production inhibitor of the present invention is not particularly limited as long as it can be applied to the skin surface or ingested into the body, and they may be formulated as they are, or may be prepared into a form that can be used as a raw material for pharmaceuticals, quasi-drugs, cosmetics, etc.

[0056] The present invention also provides a composition containing the melanin degradation promoter of the present invention and / or the melanin production inhibitor of the present invention. The form of the composition is not particularly limited as long as it is capable of incorporating the melanin degradation promoter of the present invention and / or the melanin production inhibitor of the present invention into cells, and examples of the composition include a composition for external use from the perspective of exerting its effects, and a composition for internal use from the perspective of easy ingestion.

[0057] The topical or oral composition can be provided as a pharmaceutical composition, a quasi-drug composition, a cosmetic composition, etc. (hereinafter, these are also referred to as "compositions of the present invention"), and is preferably used as a topical skin composition.

[0058] Examples of topical preparation compositions include solid, semisolid, or liquid preparations for transdermal or transmucosal (oral or nasal) administration. Examples of topical preparation compositions include emulsions such as emulsions and lotions, liquid preparations such as topical tinctures and transmucosal liquid preparations, ointments such as oily ointments and hydrophilic ointments, patches for transdermal or transmucosal administration such as films, tapes, and poultices, sprays such as aerosols and sprays, and bath additives. Furthermore, cosmetic compositions may be used in any form, including basic cosmetics such as lotions, emulsions, creams, oils, packs, and gels, makeup cosmetics such as foundations, blushes, lipsticks, waxes, and hair tonics, cleansers such as soaps, shampoos, facial cleansers, cleansers, and body washes, skin perfumes such as colognes, deodorants, and perfumes, and bath additives.

[0059] Examples of the form of the oral composition include forms that can be easily formulated (e.g., powder, granules), and from the viewpoint of easy ingestion, forms such as tablets and liquids. Specifically, the composition can be used in any form such as liquids, extracts, elixirs, capsules (hard capsules, soft capsules, etc.), granules, pills, suspensions, emulsions, suppositories, powders, spirits, tablets, syrups, infusions, decoctions, tinctures, lozenges, aromatic perfumes, lemonades, and liquid extracts.

[0060] The composition of the present invention, so long as it contains the melanin decomposition promoter of the present invention and / or the melanin production inhibitor of the present invention, can be prepared in accordance with conventional methods by appropriately blending carriers, bases, and / or additives that are commonly used in the fields of pharmaceuticals, cosmetics, etc., within the scope that achieves the object of the present invention.

[0061] Examples of carriers, bases, and / or additives used in the field of formulations include excipients (glucose, lactose, sucrose, sodium chloride, starch, calcium carbonate, kaolin, crystalline cellulose, cocoa butter, hardened vegetable oil, talc, etc.), binders (distilled water, physiological saline, ethanol water, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrants (sodium alginate, agar, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearate monoglyceride, starch, lactose, powdered gum arabic, gelatin, ethanol, etc.), disintegration inhibitors (sucrose, stearin, cocoa butter, hydrogenated oil, etc.), absorption enhancers (quaternary ammonium base, sodium lauryl sulfate, etc.), adsorbents (glycerin, starch, lactose, kaolin, bentonite, silicic acid, etc.), and lubricants (purified talc, stearates, polyethylene glycol, etc.). The content of these is not particularly limited, and can be used according to known techniques.

[0062] Carriers, bases, and / or additives used in the field of cosmetics include oils (butyl myristate, isobutyl myristate, butyl palmitate, isobutyl palmitate, butyl stearate, isobutyl stearate, butyl isostearate, cetyl myristate, isostearyl laurate, isostearyl myristate, propylene glycol dicaprate, isostearyl adipate, squalane, liquid paraffin, isoparaffin, beef tallow, lard, mink oil, fish oil, corn oil, cocoa butter, almond oil, beeswax, lanolin), , reduced lanolin, liquid lanolin, etc.), higher alcohols (lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, behenyl alcohol, hexadecyl alcohol, etc.), fatty acids (caprylic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, behenic acid, etc.), UV absorbers (para-aminobenzoic acid, ethyl dihydroxypropyl para-aminobenzoate, amyl para-aminobenzoate, urocanic acid, hydrochloric acid, hydroxypropyl methylparaben ... sodium hydroxymethoxybenzophenone disulfonate, octyl salicylate, phenyl salicylate, triethanolamine salicylate, etc.), powders and pigments (Red No. 104, Red No. 201, Yellow No. 4, Blue No. 1, Black No. 401, nylon powder, silk powder, chromium oxide, carbon black, aluminum silicate, magnesium myristate, bentonite, zinc palmitate, sericite, calcium carbonate, barium sulfate, etc.), surfactants (fatty acid soap, alkyl sulfonates, alkyl aryl sulfonates, alkyl amide sulfates, alkyl methacrylates, etc.), alkyl phosphates, alkyltrimethylammonium chloride, stearyltrimethylammonium chloride, stearyltrimethylammonium bromide, benzalkonium chloride, carboxybetaine type amphoteric surfactants, phosphobetaine type amphoteric surfactants, lecithin, saponin, glycerin fatty acid esters, sorbitan fatty acid esters, etc.), polyhydric alcohols and sugars (ethylene glycol, diethylene glycol, propylene glycol, mannitol, erythritol, glucose, sucrose, fructose, trehalose, maltitol, sulfated trehalose, etc.),Examples of such additives include polymer compounds (acrylic acid ester / methacrylic acid ester copolymers, vinyl acetate / crotonic acid copolymers, etc.), antioxidants (sodium sulfite, erythorbic acid, sodium erythorbate, butylhydroxyanisole, lignans, tannins, flavonoids, carotenoids, ascorbyl stearate, parahydroxyanisole, etc.), and solvents (ethanol, purified water, lower alcohols, ethers, N-methylpyrrolidone, fluoroalcohols, etc.). The content of these additives is not particularly limited, and they can be used in accordance with known techniques.

[0063] These compositions can be prepared according to known manufacturing methods for pharmaceuticals, quasi-drugs, or cosmetics.

[0064] Specifically, for example, a cosmetic liquid and / or a cosmetic cream can be prepared by mixing the melanin degradation promoter and / or the melanin production inhibitor of the present invention with a highly water-soluble solvent or compound such as purified water, ethanol, or glycerin, and slowly mixing the resulting solution with a pre-mixed highly fat-soluble substance such as squalane, jojoba oil, or glycerin monostearate. Alternatively, the melanin degradation promoter and / or the melanin production inhibitor of the present invention can be dried, made into various solutions, or pastes, and then formulated with various additives, carriers, base materials, and the like to form solid preparations such as tablets, granules, powders, powders, and capsules, or liquid preparations such as ordinary liquids, suspensions, and emulsions, according to conventional methods in the art.

[0065] The composition of the present invention may also contain, for example, placenta extract, magnesium L-ascorbyl phosphate, sodium L-ascorbyl phosphate, kojic acid, arbutin, L-ascorbic acid 2-glucoside, ellagic acid, 4-n-butylresorcinol, linoleic acid S, tranexamic acid, potassium 4-methoxysalicylate, 3-O-ethyl ascorbic acid, adenosine monophosphate disodium (energy signal AMP), 5,5'-dipropyl-biphenyl-2,2'-diol (magnolignan), ascorbyl tetra-2-hexyldecanoate EX (VC-IP), and / or PEG-10 ... EX), Nicotinamide (D-Melano), Cetyl Tranexamate Hydrochloride (TXC), Dexpanthenol W (PCE-DP), Retinol, Caprylyl 2-Glyceryl Ascorbate, Disodium Isostearyl Ascorbyl Phosphate, Sodium Ascorbyl Phosphate, Ascorbyl Glucoside, Adenosine Monophosphate Disodium OT, Adenosine Phosphate Disodium, Hydroquinone, Trisodium Ascorbyl Palmitate Phosphate, Magnesium Ascorbyl Phosphate, Ascorbyl Tetra-2-hexyldecanoate, Ascorbyl Tetrahexyldecanoate, Cynara Scolymus Extract, Rehmannia Root Extract, Asparagus Stem Extract, Acerola Fruit Extract, Aloe Barbadensis Leaf Juice, Polygonum Cuspidatum Extract, Polygonum Cuspidatum Root Extract, Turmeric Extract, Turmeric Rhizome Extract, Scutellaria Baicalensis Root Extract, Scutellaria Baicalensis Root Extract, Hypericum Wort Extract, Hypericum Wort Flower / Leaf / Stem Extract, Pueraria Root Extract, Rosa Canina Fruit Fruit extract, chamomilla ET, Artemisia capillaris extract, Artemisia capillaris flower extract, Licorice extract, Licorice root extract, Licorice extract powder, Licorice flavonoids, Rubus extract, Kiwi extract, Pueraria lobata root extract, Sasa veitchii extract, Sasa veitchii leaf extract, Sophora flavonoids (1), Sophora flavonoids root extract, Alpinia speciosa leaf extract, Gentian extract, Gentianian rhizome / root extract, Coffee extract, Coffee seed extract, Burdock extract, Burdock root extract, Averrhoa carambola leaf extract, Hawthorn extract, Rehmannia root extract, Peony extract, Peony root extract, Ginger rhizome extract, Ginger extract, Ginger tincture, Calamus root extract, Calamus rhizome extract, Horsetail extract, Star fruit leaf extract, Hypericum perforatum flower / leaf / stem extract, Horse chestnut seed extract, Yarrow extract, Swertia japonica extract, Soy isoflavones, Soybean extract,It may further contain known whitening ingredients such as soybean seed extract, placenta extract (1), placenta extract (2), thyme extract (1), thyme extract (2), thyme flower / leaf / stem extract, Angelica acutiloba extract (1), Angelica acutiloba root extract, calendula officinalis extract, calendula officinalis flower extract, wild rose extract, pineapple fruit extract, pineapple ceramide, papaya fruit extract, loquat leaf extract, grape seed extract, fullerene, placenta extract (1), placenta extract (2), placenta extract (3), prune enzymatic hydrolysate, prune hydrolysate, peony extract, horse chestnut extract, evening primrose seed extract, evening primrose extract, melissa extract, melissa leaf extract, peach leaf extract, saxifrage extract, oil-soluble licorice extract (2), mugwort extract, mugwort leaf extract, wild thyme extract, and burnet extract.

[0066] The composition of the present invention may also contain an antioxidant in addition to the above. Examples of antioxidants include, but are not limited to, tocopherol, tocopherol acetate, propyl gallate, butylhydroxyanisole, dibutylhydroxytoluene, coenzyme Q10, α-lipoic acid, fullerene, astaxanthin, organic germanium, dimethylaminoethanol, hydroxytyrosol, and platinum nanocolloid.

[0067] The content of the melanin degradation promoter and / or melanin production inhibitor of the present invention in the composition of the present invention is not particularly limited, as long as it is an amount that can achieve the desired effects of the present invention, taking into consideration the mode of use, method of use, etc. For example, when used as an external preparation composition, the content of the melanin degradation promoter and / or melanin production inhibitor of the present invention is, in terms of dry weight, preferably 0.0001% by mass or more, more preferably 0.001% by mass or more, even more preferably 0.01% by mass or more, and even more preferably 0.1% by mass or more, from the viewpoint of exerting the effects, and the upper limit can be, for example, 50% by mass or less, 20% by mass or less, 10% by mass or less, 5% by mass or less, etc. Note that when two or more types of the melanin degradation promoter and / or melanin production inhibitor of the present invention are used, the content refers to the total amount thereof.

[0068] The composition of the present invention can be used in an appropriate manner depending on the embodiment, specifically, for example, it can be used internally, externally, or by injection.

[0069] The amount of the composition of the present invention to be used is not fixed and is determined appropriately depending on the form, method of use, purpose of use, and the age, weight, and symptoms of the patient to whom the composition is to be used. For example, in the case of a topical composition, the amount is typically preferably about 1 μg to 1000 mg / day in dry weight per adult weighing about 50 kg, and may be used once or in several divided doses within the desired range of use within a day. The duration of use is also optional. In this specification, "use" includes not only "use" but also "administration" and "ingestion."

[0070] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. Unless otherwise specified, "%" means "% by mass."

[0071] Test Example 1: Measurement of tyrosinase activity To a 96-well plate, 60 μL of 0.05 M phosphate buffer (pH 6.8), 20 μL of sample solution (solvent: DMSO) or DMSO, and 70 μL of 1.25 mM L-tyrosine solution or 0.05 M phosphate buffer were added, and the mixture was preincubated at 25° C. for 10 minutes. 50 μL of 170 U / mL tyrosinase solution was added, and the mixture was incubated at 25° C. for 30 minutes. The absorbance of the reaction product at 505 nm was measured.

[0072] The reaction was carried out using the following four combinations of inhibitor, substrate, and enzyme: (A) DMSO, L-tyrosine solution, and tyrosinase solution (B) DMSO, phosphate buffer, and tyrosinase solution (C) Sample solution, L-tyrosine solution, and tyrosinase solution (D) Sample solution, phosphate buffer, and tyrosinase solution. The absorbances of reaction systems A, B, C, and D were measured as A and B, respectively. ａｂｓ , B ａｂｓ , C ａｂｓ , D ａｂｓ The inhibition rate (%) was calculated using the following formula: Inhibition rate (%) = {[(A ａｂｓ-B ａｂｓ )-(C ａｂｓ -D ａｂｓ )] / (A ａｂｓ -B ａｂｓ )}×100 Next, a graph was created with the sample concentration on the horizontal axis and the inhibition rate on the vertical axis, and the concentration at which each evaluation sample inhibited 50% of tyrosinase activity (IC ５０ The results are shown in Table 1. ５０ is preferably 5.0 or less, more preferably 3.0 or less, even more preferably 1.0 or less, and even more preferably 0.5 or less, the effect of inhibiting melanin production can be expected.

[0073]

[0074] As shown in Table 1, it has been newly discovered that 4-chlororesorcinol, 4-bromoresorcinol, 2,4,4'-trihydroxybiphenyl, 4'-bromo-[1,1'-biphenyl]-2,4-diol, and 4-(α-methylbenzyl)resorcinol have tyrosinase activity inhibitory effects, and it has been found that these compounds are expected to have the effect of suppressing melanin production.

[0075] Test Example 2: Melanin Production Inhibition Test B16F10 mouse melanoma cells (RCB2630) were obtained from RIKEN BRCCELL BANK and incubated at 37°C and 5% CO ２The cells were cultured under the following conditions. RPMI-1640 medium containing 10% BS was used. Penicillin-streptomycin was added as an antibiotic. Each test sample ((a) control, (b) kojic acid, (c) 4-butylresorcinol, (d) 4-bromoresorcinol, (e) 4-phenylresorcinol) was dissolved in DMSO. The solution was diluted with medium to prepare a final sample concentration of 100 μM (or a specified concentration below) and a final DMSO concentration of 0.1%. Medium containing DMSO (final concentration 0.1%) was used as a control. A 100 μM α-MSH solution was diluted with medium to prepare a final concentration of 0.1 μM. D-MEM medium containing 2 mM L-glutamine, 10% BS, and 1 mM sodium pyruvate was used. Penicillin-streptomycin was added as an antibiotic. 2.0 x 10 cells in a 24-well plate ４ cells / cm ２ The cells were seeded at 37°C and 5% CO ２ The cells were pre-cultured for 24 hours at 37°C in 5% CO. The medium used was D-MEM containing 2 mM L-glutamine, 10% BS, and 1 mM sodium pyruvate. Penicillin-streptomycin was added as an antibiotic. Then, the α-MSH solution and the sample solution or control were added, and the cells were incubated at 37°C in 5% CO. ２ After culturing, the cells were photographed using an inverted fluorescent microscope (Figure 1). After culturing for an additional 48 hours, the state of the medium was photographed (Figure 2).

[0076] As shown in Figures 1 and 2, (b) kojic acid had no effect, whereas (c) 4-butylresorcinol, (d) 4-bromoresorcinol, and (e) 4-phenylresorcinol showed a high inhibitory effect on melanin production.

[0077] Test Example 3: Melanin Degradation Promotion Test As mentioned above, cathepsin V is believed to be involved in the degradation of melanosomes and melanin. Therefore, cathepsin V was stained and the level of color development for each compound shown in Table 2 was observed. HMV-II human melanoma cells (RCB0777) were obtained from Riken Briccell Bank. 5.0 x 10 cells were placed in a T-25 cell culture flask.４ cells / cm ２ The cells were seeded at 37°C and 5% CO ２ The cells were cultured for 7 days under the conditions of 30°C, 37°C, 5% CO. The medium used was D-MEM / Ham's F-12 containing 10% BS. Penicillin-streptomycin was added as an antibiotic. The melanoma cells cultured for 7 days were collected, and melanosome pellets were obtained according to standard methods. PHK16-0b human keratinocytes (JCRB0141) were obtained from the JCRB Cell Bank and incubated at 37°C, 5% CO. ２ The medium was KGM-Gold. ＴＭ BulletKit ＴＭ Each test sample was dissolved in DMSO. This was diluted with medium to prepare a final sample concentration of 100 μM and a final DMSO concentration of 0.1%. Medium containing DMSO (final concentration 0.1%) was used as a control. Immunostaining was performed according to the following procedure. PLL-Coated culture cover glasses were placed in a 24-well plate, and 2.0 × 10 ４ cells / cm ２ The keratinocytes were seeded so that the total volume of the medium was 100 ml, and the medium was incubated at 37°C and 5% CO ２The cells were cultured at 4°C for 7 days. The extracted melanosome pellet was then suspended in 100 μL of medium and added to the keratinocyte cells. Sample solution or control solution was added and cultured for 24 hours. After culture, the medium in the wells was removed and washed with PBS. Cells were fixed by treatment with 4% phosphate-paraformaldehyde buffer for 20 minutes. After washing with PBS, the cells were permeabilized with 0.2% Triton X-100 / PBS for 20 minutes. After washing with PBS, the cells were blocked with 0.2% BSA / PBS for 20 minutes. After washing with PBS, primary antibodies diluted with 0.2% BSA / PBS were added and the cells were left to stand at room temperature for 1 hour. The primary antibodies used were anti-pan-cytokeratin antibody (1:150), anti-melanoma gp100 antibody (1:100), and anti-cathepsin V antibody (1:100). After the primary antibody reaction, the plate was washed with PBS, and a secondary antibody diluted with 0.2% BSA / PBS was added. The plate was then left to stand at room temperature for 30 minutes in the dark. The secondary antibodies used were goat anti-mouse IgG H&L (Alexa Fluor® 594), goat anti-rabbit IgG H&L (Alexa Fluor® 488), and donkey anti-rabbit IgG H&L (Alexa Fluor® 405), all at a dilution of 1:150. After the secondary antibody reaction, the plate was washed with PBS, and the PLL-Coated culture cover glass was mounted on a FINE FROST® microslide using PBS. The specimen was then observed and photographed using an upright fluorescent microscope, and the images were analyzed. Intracellular cathepsin V was quantified using a cathepsin V ELISA kit according to the protocol.

[0078] The promotion of melanin degradation was evaluated as the "increase (%)" relative to the control intracellular cathepsin V, which was set at 100%. The results are shown in Table 2. If the increase is preferably more than 100%, more preferably 150% or more, even more preferably 200% or more, and even more preferably 250% or more, the effect of promoting melanin degradation can be expected.

[0079]

[0080] As shown in Table 2, 2-fluoro-4-biphenylboronic acid, 3-hydroxyphenylboronic acid, 3-fluorophenylboronic acid, 3-chlorophenylboronic acid, 3-bromophenylboronic acid, 3-fluoro-4-methylphenylboronic acid, 3-fluoro-4-hydroxyphenylboronic acid, 4-biphenylboronic acid, 4-chlororesorcinol, 4-phenylresorcinol, and 2,4,4'-trihydroxybiphenyl showed a high rate of increase in cathepsin V, indicating that they can be expected to have an effect of promoting melanin degradation. Furthermore, 4-chlororesorcinol, 4-phenylresorcinol, and 2,4,4'-trihydroxybiphenyl also exhibited the melanin production inhibitory effect shown in Table 1, indicating that they can exhibit both effects of promoting melanin degradation and inhibiting melanin production.

[0081] Test Example 4: Verification of the effect of promoting melanin degradation Melanosome gp100, a melanosome structural protein that forms the skeleton of melanosomes, was stained by immunostaining. The extent to which the color of melanosome gp100 was reduced by the addition of each sample solution ((a) control, (b) 4-phenylresorcinol, (c) kojic acid, (d) 4-butylresorcinol) was observed to evaluate the effect of promoting melanosome degradation. After adding each of the sample solutions and culturing for 24 hours, melanosome gp100 was immunostained and observed under a fluorescence microscope (Figure 3).

[0082] As shown in Figure 3, the increase in cathepsin V was higher than in the control (b) and the addition of 4-phenylresorcinol reduced melanosome gp100, demonstrating the melanin degradation promoting effect of (b). On the other hand, the addition of (c) kojic acid or (d) 4-butylresorcinol, which increased cathepsin V less than in the control, did not reduce melanosome gp100 and did not demonstrate a melanin degradation promoting effect.

[0083] Furthermore, the tyrosinase inhibitory activity of the compounds shown in Table 2-1 was confirmed and the cathepsin V increase rate was measured in the same manner as in Test Example 1. The cathepsin V increase rate here was measured according to the method in Test Example 5 below.

[0084]

[0085] As shown in Table 2-1, these compounds were found to be highly useful compounds having both tyrosinase inhibitory activity and cathepsin V increasing activity.

[0086] Test Example 5: Measurement of Cathepsin V Increase Rate by Western Blot 1. Preparation of Sample Solution Each test sample was dissolved in DMSO. This was diluted with medium to prepare a final sample concentration of 100 μM and a final DMSO concentration of 0.1%. Medium containing DMSO (final concentration 0.1%) was used as a control.

[0087] 2. Cell culture PHK16-0b human keratinocytes (JCRB0141) were obtained from the JCRB Cell Bank and cultured at 37°C and 5% CO2. The medium was KGM-Gold ＴＭ BulletKit ＴＭ A T-25 cell culture flask was used, containing 6.0 × 10 4 Cells were seeded at 1000 cells / mL and cultured for 5 days. Sample solution or control solution was then added and cultured for 48 hours. The medium in the T-25 cell culture flask was removed, washed with 1 mL of PBS, and then removed again. 0.25% Trypsin-EDTA was added to detach the cells, and the flask was centrifuged at 1,000 rpm at 4°C for 5 minutes. The supernatant was removed, and the pellet was resuspended in PBS and centrifuged again at 1,000 rpm at 4°C for 5 minutes. This process was repeated twice. PBS was added to the resulting cell pellet, and the cells were lysed by sonication for 10 minutes. The protein concentration of the cell lysate was measured using Pierce ＴＭ Measurement was performed using BCA Protein Assay Kits.

[0088] 3. Western blot analysis. Samples were prepared by adding sample buffer to the cell lysate. This was then heated at 100°C for 15 minutes to denature the proteins. Electrophoresis was performed on a 10% acrylamide gel at a constant voltage of 80 V. Tris-glycine was used as the running buffer. After electrophoresis, the gel was equilibrated with transfer buffer and transferred to a nitrocellulose membrane equilibrated with the same transfer buffer by applying a constant current of 150 mA for 1 hour. The membrane was then immersed in skim milk, blocked on a rotary shaker for 3 hours at room temperature, and then left overnight at 4°C. The skim milk was removed, and the membrane was washed with skim milk. It was then coated with anti-cathepsin V antibody diluted in 1% skim milk and left to stand at room temperature for 90 minutes. After the reaction, the membrane was washed three times with skim milk and coated with HRP Doneky anti-rabbit IgG diluted in skim milk, followed by leaving it at room temperature for 90 minutes. After the reaction, the membrane was washed four times with skim milk and then twice with PBS-T. ＴＭ The luminescence obtained with West Pico PLUS Chemiluminescent Substrate was detected using a Fuji Image Analyzer LAS4000. GAPDH was used as an internal standard, and band quantification was performed using Image J. The results are shown in Table 2-1.

[0089] The details of the compounds used in the examples are as follows: Kojic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) 4-butylresorcinol (manufactured by Tokyo Chemical Industry Co., Ltd.) 4-chlororesorcinol (manufactured by Tokyo Chemical Industry Co., Ltd.) 4-phenylresorcinol (manufactured by Nacalai Tesque) 4-bromoresorcinol (manufactured by Nacalai Tesque) 2,4,4'-trihydroxybiphenyl (manufactured by Nacalai Tesque) 4'-bromo-[1,1'-biphenyl]-2,4-diol (manufactured by Nacalai Tesque) 4-(α-methylbenzyl)resorcinol (manufactured by Tokyo Chemical Industry Co., Ltd.) 2-fluoro-4-biphenylboronic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) Phenylboronic acid (Tokyo Chemical Industry Co., Ltd.) 3-hydroxyphenylboronic acid (Tokyo Chemical Industry Co., Ltd.) 3-fluorophenylboronic acid (Tokyo Chemical Industry Co., Ltd.) 3-chlorophenylboronic acid (Tokyo Chemical Industry Co., Ltd.) 3-Bromophenylboronic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) 3-Fluoro-4-methylphenylboronic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) 3-Fluoro-4-hydroxyphenylboronic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) 4-Biphenylboronic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) 4-Cyclohexylresorcinol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.)

[0090] Synthesis Example: The following 4-phenylresorcinol derivatives (4-(4-fluorophenyl)benzene-1,3-diol, 4-(3-fluorophenyl)benzene-1,3-diol, 4-(2-fluorophenyl)benzene-1,3-diol, 4-(4-chlorophenyl)benzene-1,3-diol, 4-(3-chlorophenyl)benzene-1,3-diol, 4-(2-chlorophenyl)benzene-1,3-diol, 4-(4-hydroxyphenyl)benzene-1,3-diol, 4-(3-hydroxy ... benzene-1,3-diol, 4-(2-hydroxyphenyl)benzene-1,3-diol, 4-(4-ethylphenyl)benzene-1,3-diol, 4-(3-ethylphenyl)benzene-1,3-diol), 4-(2-ethylphenyl)benzene-1,3-diol), 4-(4-methylphenyl)benzene-1,3-diol, 4-(3-methylphenyl)benzene-1,3-diol), and 4-(2-methylphenyl)benzene-1,3-diol) were synthesized according to the following synthesis scheme.

[0091] Step 1: 4-Bromoresorcinol and potassium carbonate (3.0 eq) were dissolved in anhydrous acetone, and benzyl bromide (2.5 eq) was added under ice cooling. The mixture was stirred at room temperature for 20 hours, followed by an additional 2 hours at 50°C. The reaction mixture was concentrated, and water and ethyl acetate were added to the residue and stirred. After separating the ethyl acetate layer, the aqueous layer was extracted twice with ethyl acetate. All ethyl acetate layers were combined and washed with water and saturated brine. The ethyl acetate layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 1.

[0092] Step 2: Compound 1 and phenylboronic acid 2 (1.4 eq) bearing the substituent corresponding to the desired compound were dissolved in N,N-dimethylformamide, and 2 mol / L aqueous sodium carbonate solution was added. The mixture was stirred at room temperature for 30 minutes under an argon atmosphere. Pd(PPh3)4 (0.055 eq) was added to this solution, and the mixture was stirred at 95°C for 6 hours under an argon atmosphere. Ice water was added to the reaction mixture, and the mixture was filtered through Celite. The filtrate was extracted twice with ethyl acetate, and the combined ethyl acetate layers were washed with water and saturated brine. The ethyl acetate layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 3.

[0093] Step 3: Compound 3 was dissolved in ethyl acetate, and 10% Pd-C (10% w / w amount relative to compound 3) was added. The mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography or recrystallization to obtain the 4-phenylresorcinol derivative 4.

[0094]

[0095] 4-(4-Fluorophenyl)benzene-1,3-diol 4-(4-Fluorophenyl)benzene-1,3-diol was synthesized according to the above scheme. 1H NMR (400 MHz, acetone) δ 8.30 (bs, 2H), 7.57-7.53 (m, 2H), 7.11 (d, J = 8.3 Hz, 1H), 7.12-7.07 (m, 2H), 6.52 (d, J = 2.3 Hz, 1H), 6.44 (dd, J = 2.3 and 8.3 Hz, 1H); 13 C NMR (100 MHz, acetone) δ 163.4, 160.9, 158.8, 155.8, 136.1 (d, J = 3.2 Hz), 131.9, 131.6 (d, J = 7.8 Hz), 119.9, 115.2 (d, J = 21.0 Hz), 108.2, 103.9; 19 F NMR (376 MHz, acetone) δ -118.8; IR (KBr); 3360.0 cm -1 ; Anal. Calcd for C 12 H9O2F: C, 70.58; H, 4.44; found: C, 70.37; H, 4.49.

[0096]

[0097] 4-(3-Fluorophenyl)benzene-1,3-diol 4-(3-Fluorophenyl)benzene-1,3-diol was synthesized according to the above scheme. 1 H NMR (400 MHz, CDCl3) δ 7.44 (dt, J =1.8 and 8.0 Hz, 1H), 7.23 (dd, J = 2.4 and 7.6 Hz, 1H), 7.15 (dd, J = 2.4 and 9.8 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 7.05 (dt, J = 2.6 and 8.5 Hz, 1H), 6.49 (d, J = 6.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 164.5, 162.0, 156.8, 153.5, 131.1, 130.7 (d, J = 8.43 Hz), 124.6 (d, J = 2.8 Hz), 119.9, 116.2 (d, J = 21.4 Hz), 114.4 (d, J = 20.9 Hz), 108.3, 103.1; 19 F NMR (376 MHz, CDCl3) δ -111.9; IR (KBr) 3361.9 cm -1 ; Anal. Calcd for C 12 H9FO2: C, 70.58; H, 4.44. Found: C 70.72, H 4.62; HRMS (EI) for C 12 H9FO2, Calcd for 204.0587 (M + ), found 204.0577.

[0098]

[0099] 4-(2-Fluorophenyl)benzene-1,3-diol 4-(2-Fluorophenyl)benzene-1,3-diol was synthesized according to the above scheme. 1 H NMR (400 MHz, acetone) δ 8.30 (bs, 2H), 7.37 (dt, J = 1.8 and 7.7 Hz, 1H), 7.23-7.26 (m, 1H), 7.17 (dt, J = 1.2 and 7.1 Hz, 1H), 7.11 (dt, J = 1.2 and 7.1 Hz, 1H), 7.02 (dd, J = 1.2 and 8.3 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.44 (dd, J = 2.4 and 8.3 Hz, 1H); 13C NMR (100 MHz, acetone) δ 162.3, 159.8, 159.3, 156.5, 133.1 (d, J = 4.0 Hz), 132.7, 129.2 (d, J = 8.0 Hz), 127.3 (d, J = 15.9 Hz), 124.5 (d, J = 3.5 Hz), 116.1, 115.3, 107.7, 103.6; 19 F NMR (376 MHz, acetone) δ 115.3; IR (KBr) 3396.6 cm -1 ; Anal. Calcd for C 12 H9O2F: C, 70.58; H, 4.44. found: C, 70.72; H, 4.62; HRMS (EI) for C 12 H9FO2, Calcd for 204.0587 (M + ), found 204.0585.

[0100]

[0101] 4-(4-Chlorophenyl)benzene-1,3-diol 4-(4-Chlorophenyl)benzene-1,3-diol was synthesized according to the above scheme. 1 H NMR (400 MHz, acetone) δ 8.20 (bs, 2H), 7.43 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 2.4 Hz, 1H), 6.32 (dd, J = 2.4 and 8.4 Hz, 1H); 13 IR (neat) 3138.1 cm -1 ; HRMS (EI) for C 12 H9O2Cl Calcd 220.0291 (M + ), found 220.0895.

[0102]

[0103] 4-(3-chlorophenyl)benzene-1,3-diol 4-(3-chlorophenyl)benzene-1,3-diol was synthesized according to the above scheme. 1 H NMR (400 MHz, CDCl3) δ 7.44-7.41 (m, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.35-7.31 (m, 2H), 7.09 (dd, J = 1.5 and 7.1 Hz, 1H), 6.50-6.48 (m, 2H); 13 IR (KBr) 2337.7 cm -1 ; HRMS (EI) for C 12 H9O2Cl, Calcd for 220.0291 (M + ), found 220.0290.

[0104]

[0105] 4-(2-chlorophenyl)benzene-1,3-diol 4-(2-chlorophenyl)benzene-1,3-diol was synthesized according to the above scheme. 1 H NMR (400 MHz, CDCl3) δ 7.53-7.51 (m, 1H), 7.36-7.33 (m, 3H), 7.03 (dd, J = 1.2 and 8.5 Hz, 1H), 6.51 (s, 1H), 6.49 (d, J = 6.0 Hz, 1H); 13 IR (KBr) 2337.7 cm -1 ; HRMS (EI) for C12 H9O2Cl, Calcd for 220.0291 (M + ), found 220.0286.

[0106]

[0107] 4-(4-Hydroxyphenyl)benzene-1,3-diol was synthesized according to the above scheme. mp 217-219°C; 1 H NMR (400 MHz, acetone) δ8.20 (bs, 1H), 7.99 (bs, 1H), 7.37 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 6.50 (d, J = 2.4 Hz, 1H), 6.42 (dd, J = 2.4 and 8.3 Hz, 1H); 13 IR (KBr) 3255.8 cm -1 ; Anal. Calcd for C 12 H 10 O3: C, 71.28; H, 4.98. found: C, 71.17; H, 5.10; HRMS (EI) for C 12 H 10 O3, Calcd for 202.0630 (M + ), found 202.0625.

[0108]

[0109] 4-(3-Hydroxyphenyl)benzene-1,3-diol 4-(3-Hydroxyphenyl)benzene-1,3-diol was synthesized according to the above scheme. 1H NMR (400 MHz, acetone) δ 8.04 (bs, 2H), 7.12-7.09 (m, 1H), 6.97 (d, J = 8.3 Hz, 1H), 6.92 (dd, J = 1.7 and 2.4Hz, 1H), 6.86 (m,1H), 6.59 (ddd, J = 1.0, 2.4 and 9.0 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 6.29 (dd, J = 2.4 and 8.3 Hz, 1H); 13 IR (neat) 3138.1 cm -1 ; HRMS (EI) for C 12 H 10 O3, Calcd for 202.0630 (M + ), found 202.0633.

[0110]

[0111] 4-(2-Hydroxyphenyl)benzene-1,3-diol 4-(2-Hydroxyphenyl)benzene-1,3-diol was synthesized according to the above scheme. mp 145-151°C; 1 H NMR (400 MHz, acetone) δ8.23 (bs, 2H), 7.24 (dd, J = 1.6 and 7.6 Hz, 1H), 7.20-7.18 (m, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.98-6.92 (m, 2H), 6.53 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 2.4 and 8.2 Hz, 1H); 13IR (KBr): 3340 cm -1 ; Anal. Calcd. for C 12 H 10 O3: C, 71.28; H, 4.98. found: C, 71.38; H, 5.07.

[0112]

[0113] 4-(4-Ethylphenyl)benzene-1,3-diol 4-(4-Ethylphenyl)benzene-1,3-diol was synthesized according to the above scheme. 1 H NMR (400 MHz, CDCl3) δ 7.32-7.30 (m, 4H), 7.09 (d, J = 8.0 Hz, 1H), 6.49 (d, J = 2.3 Hz, 1H), 6.47 (dd, J = 2.3 and 8.0 Hz, 1H), 2.70 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H); 13 IR (KBr) 3340.7 cm -1 ; Anal. Calcd for C 14 H 14 O2: C, 78.48; H, 6.59. found: C, 78.41; H, 6.65; HRMS (EI) for C 14 H 14 O2, Calcd for 214.0994 (M + ), found 214.0995.

[0114]

[0115] 4-(3-Ethylphenyl)benzene-1,3-diol 4-(3-Ethylphenyl)benzene-1,3-diol was synthesized according to the above scheme. 1 H NMR (400 MHz, CDCl3) δ 7.39 (t, J = 5.0 Hz, 1H), 7.24-7.21 (m, 3H), 7.10 (d, J = 5.4 Hz, 1H), 6.50 (d, J = 1.6 Hz, 1H), 6.48 (dd, J = 1.6 and 5.4 Hz, 1H), 2.70 (q, J = 5.1 Hz, 2H), 1.27 (t, J = 5.1 Hz, 3H); 13 IR (KBr) 3356.1 cm -1 ; Anal. Calcd for C 14 H 14 O2: C, 78.48; H, 6.59. found: C, 78.67; H, 6.68; HRMS (EI) for C 14 H 14 O2, Calcd for 214.0994 (M + ), found 214.0996.

[0116]

[0117] 4-(2-Ethylphenyl)benzene-1,3-diol 4-(2-Ethylphenyl)benzene-1,3-diol was synthesized according to the above scheme. 1H NMR (400 MHz, CDCl3) δ 7.62-7.58 (m, 2H), 7.33 (dt, J = 1.2 and 10.7 Hz, 1H), 7.23-7.12 (m, 2H), 6.53 (dd, J = 2.5 and 8.4 Hz, 1H), 6.47 (d, J = 2.5 Hz, 1H), 5.25 (q, J = 6.6 Hz, 1H), 1.60 (d, J = 6.6 Hz, 3H); 13 IR (KBr) 3356.1, 1620.2 cm -1 ; HRMS (EI) for C 14 H 14 O2, Calcd for 214.0994 (M + ), found 214.0987.

[0118]

[0119] 4-(4-Methylphenyl)benzene-1,3-diol 4-(4-Methylphenyl)benzene-1,3-diol was synthesized according to the above scheme. 1 H NMR (400 MHz, acetone) δ 8.03 (bs, 2H), 7.29 (d, J = 8.0 Hz, 2H),7.03 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.3 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H), 6.30 (dd, J = 2.4 and 8.3 Hz, 1H), 2.20 (s, 3H); 13 IR (neat) 3373.5 cm -1 ; HRMS (EI) for C13 H 12 O2Calcd 200.0837 (M + ), found 200.0838.

[0120]

[0121] 4-(3-Methylphenyl)benzene-1,3-diol 4-(3-Methylphenyl)benzene-1,3-diol was synthesized according to the above scheme. 1 H NMR (400 MHz, acetone) δ 8.04 (bs, 2H), 7.21 (bs, 1H), 7.19 (bd, J = 8.2 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.90 (bd, J = 8.5 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H), 6.30 (dd, J = 2.4 and 8.3 Hz, 1H), 2.21 (s, 3H); 13 IR (neat) 3361.9 cm -1 ; HRMS (EI) for C 13 H 12 O2Calcd 200.0837 (M + ), found 200.0836.

[0122]

[0123] 4-(2-Methylphenyl)benzene-1,3-diol 4-(2-Methylphenyl)benzene-1,3-diol was synthesized according to the above scheme. 1H NMR (400 MHz, acetone) δ 8.05 (bs, 2H), 7.25-7.12 (m, 4H), 6.88 (d, J = 8.2 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.44 (dd, J = 2.4 and 8.2 Hz, 1H), 2.19 (s, 3H); 13 IR (neat) 3138.1cm -1 ; HRMS (EI) for C 13 H 12 O2Calcd 200.0837 (M + ), found 200.0835.

[0124]

[0125] Formulation Example 1: Topical gel

[0126] Formulation Example 2: Topical cream

[0127] Formulation Example 3: Topical lotion

[0128] Formulation Example 4: Tablets

[0129] Formulation Example 5: Oral liquid

[0130] According to the present invention, it is possible to provide a novel melanin decomposition promoter and / or a novel melanin production inhibitor, as well as a cosmetic composition, a pharmaceutical composition, and an external skin preparation containing the same.

Claims

1. A melanin decomposition promoter comprising a compound represented by the following formula (1): (In the formula, R １ OH, B(OH) ２ , B(OCH ３ ) ２ , B(OCH ２ CH ３ ) ２ , or B(OCH ２ CH ２ CH ３ ) ２ , R ２ and R ３ are each independently H, OH, a methyl group, a cycloalkyl group having 3 to 10 carbon atoms, a halogen, or a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, a halogen, an alkyl group having 1 to 5 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms; R ４ is H, OH, or halogen. １ But B(OH) ２ , B(OCH ３ ) ２ , B(OCH ２ CH ３ ) ２ , or B(OCH ２ CH ２ CH ３ ) ２ , and R ２ and R ３ and one of R is OH and the other is an optionally substituted phenyl group, and ２ , R ３ , and R ４ Except for those where all are H.) 2. R １ is B(OH) ２ or B(OCH ３ ) ２ and R ２ and R ３ is a halogen atom and the other is H, OH, a methyl group, or a phenyl group which may have a substituent, or is OH and the other is H or a methyl group, or is a phenyl group which may have a substituent and the other is H or a methyl group.

3. R ４ The melanin decomposition promoter according to claim 2, wherein is H.

4. R １ and R ２ is OH and R ３ The melanin decomposition accelerator according to claim 1, wherein is a cycloalkyl group having 3 to 10 carbon atoms, a halogen atom, or a phenyl group which may have a substituent.

5. R ４ The melanin decomposition promoter according to claim 4, wherein is H.

6. A cosmetic composition comprising the melanin decomposition accelerator according to any one of claims 1 to 5.

7. A pharmaceutical composition comprising the melanin decomposition promoter according to any one of claims 1 to 5.

8. An external skin preparation comprising the melanin decomposition accelerator according to any one of claims 1 to 5.

9. A method for producing a melanin decomposition accelerator, comprising the step of blending a compound represented by the following formula (1): (In the formula, R １ OH, B(OH) ２ , B(OCH ３ ) ２ , B(OCH ２ CH ３ ) ２ , or B(OCH ２ CH ２ CH ３ ) ２ , R ２ and R ３ are each independently H, OH, a methyl group, a cycloalkyl group having 3 to 10 carbon atoms, a halogen, or a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, a halogen, an alkyl group having 1 to 5 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms; R ４ is H, OH, or halogen. １ But B(OH) ２ , B(OCH ３ ) ２ , B(OCH ２ CH ３ ) ２ , or B(OCH ２ CH ２ CH ３ ) ２ , and R ２ and R ３ and one of R is OH and the other is an optionally substituted phenyl group, and ２ , R ３ , and R ４ Except for those where all are H.) 10. A method for promoting the decomposition of melanin using a compound represented by the following formula (1): (In the formula, R １ OH, B(OH) ２ , B(OCH ３ ) ２ , B(OCH ２ CH ３ ) ２ , or B(OCH ２ CH ２ CH ３ ) ２ , R ２ and R ３ are each independently H, OH, a methyl group, a cycloalkyl group having 3 to 10 carbon atoms, a halogen, or a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, a halogen, an alkyl group having 1 to 5 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms; R ４ is H, OH, or halogen. １ But B(OH) ２ , B(OCH ３ ) ２ , B(OCH ２ CH ３ ) ２ , or B(OCH ２ CH ２ CH ３ ) ２ , and R ２ and R ３ and one of R is OH and the other is an optionally substituted phenyl group, and ２ , R ３ , and R ４ Except for those where all are H.) 11. A melanin production inhibitor comprising a compound represented by the following formula (2) and / or (3): (In the formula, R ５ is a cycloalkyl group having 3 to 10 carbon atoms, a halogen, or -X-R ６ , where -X- is a single bond, -CH ２ - or -CH(CH ３ )-, and —X- is a single bond or —CH ２ R when - ６ is a phenyl group substituted with halogen, -X- is -CH(CH ３ )- when R ６ is a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, halogen, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms. (In the formula, R ７ is halogen, R ８ is a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, halogen, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms.

12. R ５ is a cycloalkyl group having 3 to 10 carbon atoms, a halogen, a phenyl group substituted with a halogen, a benzyl group substituted with a halogen, or a methylbenzyl group optionally substituted with a halogen.

13. A cosmetic composition comprising the melanin production inhibitor according to claim 11 or 12.

14. A pharmaceutical composition comprising the melanin production inhibitor according to claim 11 or 12.

15. A topical skin preparation comprising the melanin production inhibitor according to claim 11 or 12.

16. A method for producing a melanin production inhibitor, comprising the step of blending a compound represented by the following formula (2) and / or (3): (In the formula, R ５ is a cycloalkyl group having 3 to 10 carbon atoms, a halogen, or -X-R ６ , where -X- is a single bond, -CH ２ - or -CH(CH ３ )-, and —X- is a single bond or —CH ２ R when - ６ is a phenyl group substituted with halogen, -X- is -CH(CH ３ )- when R ６ is a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, halogen, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms. (In the formula, R ７ is halogen, R ８ is a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, halogen, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms.

17. A method for inhibiting melanin production using a compound represented by the following formula (2) and / or (3): (In the formula, R ５ is a cycloalkyl group having 3 to 10 carbon atoms, a halogen, or -X-R ６ , where -X- is a single bond, -CH ２ - or -CH(CH ３ )-, and —X- is a single bond or —CH ２ R when - ６ is a phenyl group substituted with halogen, -X- is -CH(CH ３ )- when R ６ is a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, halogen, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms. (In the formula, R ７ is halogen, R ８ is a phenyl group which may have a substituent, and the substituent is one or more substituents selected from the group consisting of OH, halogen, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms.

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