WO2014092166A1 - Inhibiteur de l'activité tyrosinase et agent blanchissant - Google Patents

Inhibiteur de l'activité tyrosinase et agent blanchissant Download PDF

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Publication number
WO2014092166A1
WO2014092166A1 PCT/JP2013/083377 JP2013083377W WO2014092166A1 WO 2014092166 A1 WO2014092166 A1 WO 2014092166A1 JP 2013083377 W JP2013083377 W JP 2013083377W WO 2014092166 A1 WO2014092166 A1 WO 2014092166A1
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Prior art keywords
group
tyrosinase activity
dihydroxyphenyl
activity inhibitor
alkylresorcinol
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PCT/JP2013/083377
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English (en)
Japanese (ja)
Inventor
一郎 土黒
紗也香 森
昌久 田能村
嘉寛 徳留
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株式会社ケムジェネシス
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Priority to JP2014552092A priority Critical patent/JPWO2014092166A1/ja
Publication of WO2014092166A1 publication Critical patent/WO2014092166A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/62—Three oxygen atoms, e.g. ascorbic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a tyrosinase activity inhibitor and a whitening agent using a resorcin derivative.
  • Tyrosinase is an oxidoreductase and catalyzes various pigment formation reactions in animals and plants. For example, in skin melanocytes that have been irradiated with ultraviolet rays, tyrosine is a starting material, and tyrosinase acts to produce dopa and dopaquinone, which further undergoes an oxidation reaction to ultimately produce a melanin pigment. Inhibiting tyrosinase activity that functions in the initial stage of this melanin production reaction leads to suppression of melanin production.
  • tyrosinase activity inhibitors are used in pharmaceuticals and cosmetics based on their melanin production inhibitory action.
  • ascorbic acid derivatives such as ascorbyl magnesium phosphate and ascorbic acid glucoside having an inhibitory action on tyrosinase activity are blended in many cosmetics and the like for use as a whitening agent.
  • lucinol (generic name: 4-butylresorcinol), which is a resorcinol derivative, exhibits a particularly high tyrosinase activity inhibitory action (Patent Document 1).
  • Patent Document 1 compounds in which the 4-position alkyl group of the resorcinol skeleton of lucinol is substituted with a branched alkyl group or a cycloalkyl group are also disclosed as having a whitening effect (for example, Patent Documents 2 to 5).
  • Patent Document 7 manufactures a phosphoric ester in which a hydrogen atom of a phenolic hydroxyl group is substituted for resorcinol, and is working to improve these problems.
  • Patent Document 7 4- (hydroxyalkyl) resorcinol is produced as a compound having low cytotoxicity, and this compound exhibits an activity comparable to weakly active arbutin even when used at a high concentration of 200 ⁇ M or more. Not too much. Further, the 4- (carboxyalkyl) resorcinol derivative shown as a comparative example in this document shows much weaker activity than arbutin (Patent Document 7). On the other hand, Non-Patent Document 1 and Patent Document 8 report enhanced tyrosinase inhibitory activity in a 4- (carboxyalkyl) resorcinol derivative substituted with a hydrophobic residue at the 4-position, but its cytotoxicity is low. Is not shown.
  • tyrosinase activity inhibitors have been reported to be used as discoloration inhibitors for foods such as fruits and vegetables (for example, Patent Document 9) and as pharmaceuticals (for example, Patent Documents 2 and 3). .
  • An object of the present invention is to provide a tyrosinase activity inhibitor having high safety and good activity.
  • the present invention includes the following.
  • a tyrosinase activity inhibitor comprising a 4-alkylresorcinol derivative having a hydrophilic ester or ether substituent in the 4-alkyl chain or a salt thereof.
  • the 4-alkylresorcinol derivative is represented by the following general formula (I): X— (CH 2 ) n CO 2 —R 1 (I) (Wherein X represents a 1,3-dihydroxyphenyl group, n is an integer of 2 to 5, and R 1 represents an alcohol residue having 1 to 3 hydroxyl groups)
  • the tyrosinase activity inhibitor of [1] represented by:
  • the 4-alkylresorcinol derivative is represented by the following general formula (II): X— (CH 2 ) n CO 2 —R 2 (II) (Wherein X represents a 1,3-dihydroxyphenyl group, n is an integer of 2 to 5, and R 2 represents an ascorbyl group)
  • the tyrosinase activity inhibitor of [1] represented by:
  • the 4-alkylresorcinol derivative is represented by the following general formula (III): X— (CH 2 ) n CH 2 O—R 3 (III) (In the formula, X represents a 1,3-dihydroxyphenyl group, n is an integer of 2 to 5, and R 3 represents an ascorbyl group)
  • the tyrosinase activity inhibitor of [1] represented by:
  • the alcohol residue having 1 to 3 hydroxyl groups is a hydroxybutyl group, a hydroxymethylbutyl group, a hydroxycyclohexylmethyl group, a glyceryl group, or a diglyceryl group, [2], [5], [6 Or a tyrosinase activity inhibitor of [7].
  • a cosmetic comprising a tyrosinase activity inhibitor of [1] to [8] or a whitening agent of [10].
  • the alcohol residue having 1 to 3 hydroxyl groups is a hydroxybutyl group, a hydroxymethylbutyl group, a hydroxycyclohexylmethyl group, a glyceryl group, or a diglyceryl group, [12], [15], [16 ] Or a 4-alkylresorcinol derivative of [17] or a salt thereof.
  • a highly safe tyrosinase activity inhibitor can be provided.
  • the present invention relates to a 4-alkylresorcinol derivative having an ester or ether substituent on a 4-alkyl chain and a salt thereof.
  • a preferred example of the 4-alkylresorcinol derivative having an ester substituent on the 4-alkyl chain according to the present invention is a compound represented by the following formula (A).
  • Another preferred example of the 4-alkylresorcinol derivative having an ether substituent on the 4-alkyl chain according to the present invention is a compound represented by the following formula (B).
  • the “4-alkyl chain” represents a linear alkyl chain at the 4-position of the resorcin skeleton, wherein the number of carbon chains is n in the formula (A) and the number of carbon chains is n + 1 in the formula (B).
  • n is not limited, it is, for example, 2 to 10, preferably 2 to 5.
  • the 4-alkylresorcinol derivative according to the present invention is more preferably a 4-alkylresorcinol derivative having a hydrophilic ester or ether substituent on the 4-alkyl chain.
  • the “hydrophilic ester or ether substituent” in the present invention is a hydrocarbon chain residue having one or more hydroxyl groups and may or may not contain elements other than carbon and hydrogen atoms such as oxygen atoms.
  • R or R ′ in the above formula (A) or (B) refers to a substituent having an ester or ether bond. Even when the 4-alkylresorcinol derivative is produced without directly passing through an ester or etherification reaction, R or R ′ in the above formula (A) or (B) is converted to a 4-alkyl chain by an ester or ether bond.
  • hydrophilic ester or ether substituent does not include a carboxyl group alone in which R is a proton.
  • R or R ′ in the above formula (A) or (B) is not limited, but alcohol residues having 1 to 3 hydroxyl groups, or organic acid residues having one or more hydroxyl groups (for example, an ascorbyl group) is preferable.
  • alcohol residue having one or more hydroxyl groups means a residue generated by losing one hydroxyl group of alcohol by an ester or ether bond, and still having one or more hydroxyl groups. The thing which has.
  • an alcohol is a group in which one or more hydrogen atoms in a hydrocarbon which may or may not contain elements other than carbon atoms and hydrogen atoms (oxygen atoms, nitrogen atoms, etc.) constitute a hydroxyl group (carboxyl group).
  • the alcohol in the present invention may be an aliphatic alcohol, an alicyclic alcohol or an aromatic alcohol.
  • the alcohol of the present invention may or may not be a sugar alcohol.
  • the “hydroxyl group” in the alcohol residue or organic acid residue does not include those constituting a carboxyl group.
  • R or R ′ in formula (A) or (B), which is an alcohol residue having 1 to 3 hydroxyl groups, is preferably an alcohol residue similar to that exemplified for R 1 in formula (I) described later. It is a group.
  • R or R ′ in the formula (A) or (B) which is an ascorbyl group is preferably an ascorbyl group similar to those exemplified for R 2 in the general formula (II) and R 3 in the general formula (III) described later. It is.
  • 4-alkylresorcinol derivative of the present invention is represented by the following general formula (I): X— (CH 2 ) n CO 2 —R 1 (I) (In the formula, X represents a 1,3-dihydroxyphenyl group, n is an integer of 2 to 5, and R 1 represents an alcohol residue having one or more (preferably 1 to 3) hydroxyl groups. )
  • the alcohol residue having one or more (preferably 1 to 3) hydroxyl groups corresponding to R 1 in the general formula (I) is not limited, but for example, has 2 to 10 carbon atoms, preferably carbon atoms. 3 to 10, for example, 3 to 7 carbon atoms.
  • Examples of the alcohol residue having one hydroxyl group in the present invention include butanediol (for example, 1,3-butanediol, 3-methyl-1,3-butanediol), hydroxymethylcyclohexanol (for example, 4- (hydroxy Methyl) cyclohexanol), ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, tripropylene glycol and other residues derived from dihydric alcohols.
  • butanediol for example, 1,3-butanediol, 3-methyl-1,3-butanediol
  • hydroxymethylcyclohexanol for example, 4- (hydroxy Methyl) cyclohexanol
  • ethylene glycol propylene glycol
  • butylene glycol diethylene glycol
  • triethylene glycol tetraethylene glycol
  • dipropylene glycol
  • hydroxyethyl group 2-hydroxyethyl group
  • hydroxybutyl group eg, 3-hydroxybutyl group
  • hydroxymethylbutyl group eg, 3-hydroxy-3-methylbutyl group
  • hydroxy Hexyl methyl group e.g., 4-hydroxy - cyclohexylmethyl group
  • the alcohol residue having two or more hydroxyl groups in the present invention include residues derived from trivalent or higher alcohols such as glycerol, diglycerol, erythritol, pentaerythritol, triglycerol, xylitol, sorbitol, and the like. Particularly preferred are glyceryl and diglyceryl groups.
  • the 4-alkylresorcinol derivative of the above general formula (I) includes 4- (carboxyalkyl) resorcinol and a polyhydric alcohol having a linear or branched alkyl chain or a cycloalkanealkyl chain (preferably having 2 to 10 carbon atoms) or 2 It can be an ester compound with an organic acid having one or more hydroxyl groups (eg ascorbic acid).
  • Preferable examples of the 4-alkylresorcinol derivative of the above general formula (I) having an alcohol residue having one hydroxyl group for R 1 include the following compounds.
  • the ascorbyl group corresponding to R 2 is not limited, but is preferably a 6-ascorbyl group or a 2-ascorbyl group, and more preferably a 6-ascorbyl group.
  • the ascorbyl group corresponding to R 2 may further have a substituent as long as it retains one or more, preferably two or more hydroxyl groups.
  • the 4-alkylresorcinol derivative of the general formula (II) can be an ester compound of 4- (carboxyalkyl) resorcinol (preferably having 2 to 10 carbon atoms) and ascorbic acid.
  • 4-alkylresorcinol derivative of the general formula (II) include the following compounds.
  • the ascorbyl group corresponding to R 3 is not limited, but a 3-ascorbyl group is preferable.
  • the ascorbyl group corresponding to R 3 may further have a substituent as long as it retains one or more, preferably two or more hydroxyl groups.
  • the 4-alkylresorcinol derivative of the general formula (III) can be an ether compound of 4- (hydroxyalkyl) resorcinol (preferably having 2 to 10 carbon atoms) and ascorbic acid.
  • 4-alkylresorcinol derivative of the general formula (III) include the following compounds.
  • the 4-alkylresorcinol derivative according to the present invention can be derivatized with a phosphonooxylation of the hydroxyl group of the resorcinol skeleton in the 4-alkylresorcinol derivative. Such derivatives are also included in the 4-alkylresorcinol derivatives according to the present invention.
  • the salt of the 4-alkylresorcinol derivative of the present invention may be any salt, and examples thereof include salts of alkali metals or alkaline earth metals such as sodium, potassium, calcium and magnesium. preferable.
  • the salt of the 4-alkylresorcinol derivative of the present invention may be a salt acceptable for the production of food, cosmetics, pharmaceuticals or agricultural chemicals, for example, a pharmaceutically acceptable salt, depending on the use.
  • the 4-alkylresorcinol derivative of the present invention represented by the above formula (A) can be specifically synthesized through the following three steps, for example.
  • X ′ — (CH ⁇ CH) (CH 2 ) m CO 2 H with m 0
  • malonic acid is allowed to act in the presence of a base.
  • the base include an organic base such as a mixed base of pyridine and piperidine.
  • a Wittig reagent having a corresponding carboxyl group is allowed to act in the presence of a base.
  • the base include inorganic bases such as sodium hydride and potassium t-butoxy.
  • condensation conditions for example, reaction conditions for activation using a condensing agent such as dicyclohexylcarbodiimide and WSCI ⁇ HCl, and a halogenating agent such as thionyl chloride (addition of an organic base such as a tertiary amine as necessary) Or a reaction condition using a catalytic amount of a Bronsted acid such as sulfuric acid, a Lewis acid such as aluminum oxide, a mixed acid of Bronsted acid and Lewis acid, and a reaction condition using an enzyme such as lipase. .
  • a condensing agent such as dicyclohexylcarbodiimide and WSCI ⁇ HCl
  • a halogenating agent such as thionyl chloride
  • ⁇ Third step> By performing a hydrogenation reaction in a hydrogen atmosphere and in the presence of a catalyst, the synthesis of the 4-alkylresorcinol derivative of the present invention represented by the formula (A) is achieved. If the protecting group is not deprotected under these conditions, a further deprotection reaction is performed.
  • Hydrogen may be any pressure from normal pressure to high pressure, and examples of the catalyst include commonly used hydrogenation catalysts such as palladium / carbon, palladium hydroxide / carbon, and Raney nickel.
  • the phenolic hydroxyl group may be reacted without protection.
  • the 4-alkylresorcinol derivative of the present invention represented by the above formula (B) can be specifically synthesized through the following four steps, for example.
  • X ′ — (CH ⁇ CH) (CH 2 ) m CH 2 OH is synthesized by reducing the carboxyl group of X ′ — (CH ⁇ CH) (CH 2 ) m CO 2 H.
  • the reducing agent include lithium aluminum hydride.
  • X ′ — (CH ⁇ CH) (CH 2 ) m CH 2 OH is converted to X ′ — (CH ⁇ CH) (CH 2 ) m CH 2 Y
  • Y is a halogen atom such as a chlorine atom or a bromine atom, or a mesyloxy group
  • ⁇ Third step> X ′ — (CH ⁇ CH) (CH 2 ) m CH 2 Y and optionally substituted with R′—OH or ascorbic acid or a salt thereof (a base may be added if necessary)
  • R′—OH or ascorbic acid or a salt thereof a base may be added if necessary
  • To synthesize ether for example, a method in which sodium ascorbate is allowed to act in an organic solvent such as dimethyl sulfoxide.
  • Hydrogen may be any pressure from normal pressure to high pressure, and examples of the catalyst include commonly used hydrogenation catalysts such as palladium / carbon, palladium hydroxide / carbon, and Raney nickel.
  • the phenolic hydroxyl group may be reacted without protection.
  • the 4-alkylresorcinol derivative of the present invention is not limited to the above synthesis route, and can be synthesized by other synthesis procedures.
  • Tyrosinase activity inhibitory action of 4-alkylresorcinol derivative or salt thereof of the present invention and use thereof has a high tyrosinase activity inhibitory action (tyrosinase inhibitory activity).
  • tyrosinase inhibitory activity tyrosinase inhibitory activity
  • some of the 4-alkylresorcinol derivatives of the present invention exhibit a higher tyrosinase inhibitory activity than lucinol, which has a particularly high activity among the tyrosinase activity inhibitors currently on the market.
  • the level of this tyrosinase inhibitory activity corresponds to about 1000 times that of ascorbic acid derivatives such as ascorbyl phosphate magnesium and ascorbic acid glucoside, which are existing whitening agents based on the tyrosinase activity inhibitory action.
  • ascorbic acid derivatives such as ascorbyl phosphate magnesium and ascorbic acid glucoside
  • the salt of the 4-alkylresorcinol derivative of the present invention has the same effect.
  • the tyrosinase activity inhibitory action of the 4-alkylresorcinol derivative of the present invention or a salt thereof can be evaluated by a conventionally known method.
  • a test compound solution having a target final concentration for example, final concentration of 1 ⁇ M
  • a tyrosinase solution for example, mushroom tyrosinase solution
  • 2 mM L-DOPA (L- 3,4-dihydroxyphenylalanine) solution is added to the tyrosinase solution in an equal amount to make a test sample, and the remaining amount (relative value) of the substrate (L-DOPA) can be measured by measuring the absorbance at 37 ° C.
  • L-DOPA L- 3,4-dihydroxyphenylalanine
  • the obtained value can be compared with the L-DOPA measurement value of the test compound-free group (control) to determine the level of change in tyrosinase activity.
  • a tyrosinase activity inhibitory action is observed if it is reduced to 80% or less compared to the test compound-free group, and a fairly high tyrosinase activity inhibitory action is observed if it is reduced to 50% or less, which is reduced to 30% or less. If so, it can be judged that a very high tyrosinase activity inhibitory action is observed.
  • the details of the test can refer to the examples described later.
  • the 4-alkylresorcinol derivative of the present invention is further safer because of low cytotoxicity.
  • the 4-alkylresorcinol derivative of the present invention is also excellent in stability.
  • Conventional tyrosinase activity inhibitors are often recognized to have high cytotoxicity or low stability when tyrosinase inhibitory activity is high.
  • the 4-alkylresorcinol derivative of the present invention has a high tyrosinase inhibitory activity even if it has high tyrosinase inhibitory activity. Because of its low toxicity, it is very useful for use in foods, cosmetics and pharmaceuticals.
  • the 4-alkylresorcinol derivatives of the present invention have the very advantageous effect that cytotoxicity remains low, especially when used at higher concentrations (eg, final concentrations of 50 ⁇ M to 500 ⁇ M). Play. This is an advantage over the existing tyrosinase activity inhibitor lucinol, whose cytotoxicity increases rapidly at high concentrations.
  • the salt of the 4-alkylresorcinol derivative of the present invention has the same effect.
  • the cytotoxicity of the 4-alkylresorcinol derivative or a salt thereof of the present invention can be evaluated by a conventionally known method.
  • a test compound is added to a culture medium containing cultured mouse B16 melanoma cells (for example, 0.3 ⁇ 10 5 cells / well) in an amount that provides a final concentration of interest (for example, a final concentration of 10 ⁇ M or 100 ⁇ M). Incubate for 72 hours, for example. The medium is collected and washed (with PBS or the like), and then the cells are collected using 0.025% trypsin / PBS or the like.
  • the cell pellet is collected, resuspended in a medium (for example, DMEM medium supplemented with 10% FBS), and the number of cells is counted by trypan blue staining.
  • the measured number of cells can be compared with the test compound-free group (control) to determine the level of change in the number of cells.
  • a certain degree of cytotoxicity was observed when the number of cells decreased to 90% or less, and considerably higher cytotoxicity was observed when the number decreased to 80% or less, which decreased to 70% or less. In this case, particularly high cytotoxicity is observed, and when it is reduced to 60% or less, it can be determined that extremely high cytotoxicity is observed.
  • the details of the test can be referred to the examples described later. When the number of cells exceeds 100% or around 100% as compared with the test compound-free group, it can be determined that the test compound has little cytotoxicity.
  • the 4-alkylresorcinol derivative or a salt thereof of the present invention may be evaluated for melanin production inhibitory action.
  • the melanin production inhibitory action can be evaluated by a conventionally known method. For example, a test compound is added to a culture medium containing cultured mouse B16 melanoma cells (for example, 0.3 ⁇ 10 5 cells / well) in an amount that provides a final concentration of interest (for example, a final concentration of 10 ⁇ M or 100 ⁇ M). Incubate for 72 hours, for example.
  • the medium is collected and washed (with PBS or the like), and then the cells are collected using 0.025% trypsin / PBS or the like.
  • the culture supernatant and the cell pellet are each collected, resuspended in a medium (for example, 10% FBS-added DMEM medium), and the absorbance at a wavelength of 405 nm is measured, and the total is used as the measured amount of melanin.
  • a medium for example, 10% FBS-added DMEM medium
  • the absorbance at a wavelength of 405 nm is measured, and the total is used as the measured amount of melanin.
  • the 4-alkylresorcinol derivative of the present invention or a salt thereof, or a tyrosinase activity inhibitor containing it can be used as a melanin production inhibitor because it has a melanin production inhibitory action.
  • the stability of the 4-alkylresorcinol derivative of the present invention or a salt thereof can also be evaluated by a conventionally known method such as a photostability test.
  • a photostability test For example, an ethanol / water solution of a test compound (eg, 0.1 wt% concentration) is exposed to sunlight, observed changes in the appearance of the liquid during sun exposure, and the results of other whitening agents or tyrosinase activity inhibitors Compare.
  • a colorless transparent liquid is converted into (2) slightly red transparent, (3) light red transparent, (4) light orange transparent as the decomposition proceeds.
  • the degree of decomposition can be determined from the appearance. Furthermore, when it becomes a suspension in the same coloring stage, it can be determined that the decomposition is more advanced than the transparent liquid.
  • lucinol becomes a suspension in (4) and subsequent stages.
  • the 4-alkylresorcinol derivative of the present invention or a salt thereof preferably exhibits superior light stability in determining the color change of the liquid as compared with lucinol, which is a great practical advantage. It can be.
  • the 4-alkylresorcinol derivative or salt thereof of the present invention can be advantageously used as a tyrosinase activity inhibitor in foods, cosmetics, pharmaceuticals and the like.
  • the present invention provides a tyrosinase activity inhibitor containing the 4-alkylresorcinol derivative or a salt thereof according to the present invention.
  • the 4-alkylresorcinol derivative of the present invention or a salt thereof as a tyrosinase activity inhibitor is used in cosmetics and pharmaceuticals (for example, external medicines or quasi-drugs for external use) intended for application to the skin.
  • the pharmaceutical agent include a pharmaceutical agent for treating or preventing hyperpigmentation of the skin.
  • Hyperpigmentation of the skin is a skin disorder in which the accumulation of melanin due to familial predisposition, hormones, exposure to sunlight, skin aging, etc. appears as brown or colored spots on the skin.
  • the 4-alkylresorcinol derivative of the present invention or a salt thereof as a tyrosinase activity inhibitor can be added to foods as an anti-discoloration agent for foods such as vegetables and fruits, or as a whitening functional ingredient.
  • the present invention also provides a skin external preparation or whitening agent containing the 4-alkylresorcinol derivative or salt thereof according to the present invention or the tyrosinase activity inhibitor of the present invention.
  • the external preparation for skin of the present invention can be used for treatment or prevention of diseases associated with skin pigmentation.
  • the whitening agent of the present invention can be used for the improvement and prevention of skin spots, freckles, dullness and the like.
  • the blending amount of the 4-alkylresorcinol derivative of the present invention or a salt thereof into the external preparation for skin or whitening agent is not particularly limited to the following, but is usually 0.0001 to 20% by mass, preferably 0.001 to It is 10% by mass, and more preferably 0.005 to 5% by mass.
  • the tyrosinase activity inhibitor, skin external preparation and whitening agent of the present invention comprise a pharmaceutically acceptable excipient, carrier, and inert additive.
  • excipients, carriers, and inert additives include solvents (water, saline, etc.), emulsifiers, diluents, humectants, thickeners, antioxidants, preservatives, neutralizing agents, Buffering agents, dispersing agents, gelling agents, lubricants, coating agents, pH adjusting agents, chelating agents, fragrances, pigments and the like can be mentioned.
  • the tyrosinase activity inhibitor, external preparation for skin and whitening agent of the present invention may further contain other medicinal ingredients.
  • other whitening ingredients or tyrosinase activity inhibitors antioxidants, moisturizers, UV absorbers, UV scattering agents, extracts from animals or plants or microorganisms, anti-inflammatory agents, astringents, antiseborrheic agents, cell activators, It can contain keratolytic agents, enzymes, hormones, vitamins, minerals and the like.
  • the tyrosinase activity inhibitor, external skin preparation and whitening agent of the present invention can be formulated into any dosage form.
  • the tyrosinase activity inhibitor, skin external preparation and whitening agent of the present invention are liquid preparations such as liquids, suspensions and syrups, and solid preparations such as gels, tablets, granules, powders, pills and capsules. And can be formulated into dosage forms such as powders.
  • the external preparation for skin and the whitening agent of the present invention are aqueous solutions, solubilization systems, emulsification systems, powder systems, gel systems, ointment systems, creams, water / oil two-layer systems, water / oil / powder three-layer systems, and the like.
  • the present invention also provides a cosmetic comprising the 4-alkylresorcinol derivative of the present invention or a salt thereof, or a whitening agent containing the same.
  • the tyrosinase activity of a subject can be inhibited by administering to the subject a tyrosinase activity inhibitor, a skin external preparation or a whitening agent containing the 4-alkylresorcinol derivative of the present invention or a salt thereof.
  • This inhibition can treat or prevent diseases or disorders caused by tyrosinase activity such as hyperpigmentation of the skin.
  • an external preparation for skin or a whitening agent containing an effective amount of the 4-alkylresorcinol derivative of the present invention or a salt thereof melanin production is suppressed, or skin pigmentation is reduced or Can be prevented.
  • the tyrosinase activity inhibitor, external preparation for skin or whitening agent of the present invention can be administered to the skin or mucous membrane (external use), but may be administered by other administration routes such as oral.
  • the dose of the 4-alkylresorcinol derivative of the present invention or a salt thereof varies depending on the age and weight of the administration subject, the administration route, and the number of administrations, and can be widely changed at the discretion of those skilled in the art.
  • the tyrosinase activity inhibitor, external preparation for skin or whitening agent of the present invention may be administered once or repeatedly.
  • the target to which the tyrosinase activity inhibitor, the skin external preparation or the whitening agent of the present invention is administered is preferably, but not limited to, mammals including humans, domestic animals, pets, experimental (test) animals and the like.
  • Example 5 Synthesis of 3-hydroxy-3-methylbutyl 3- (2,4-dihydroxyphenyl) propionate A procedure similar to that in Example 1 (2) was followed except that (E) -3- [2,4- By using 90 mg (0.25 mmol) of bis (benzyloxy) phenyl] acrylic acid and replacing 1,3-butanediol with 3-methyl-1,3-butanediol, the synthesis has the following NMR spectrum: The title compound (18.8 mg, 28% yield over two steps) was obtained as a viscous product.
  • Example 6 Synthesis of 3-hydroxy-3-methylbutyl 4- (2,4-dihydroxyphenyl) butanoate A procedure similar to that in Example 1 (2) except that (E) -3- [2,4- 90 mg (0.25 mmol) of bis (benzyloxy) phenyl] acrylic acid and 1,3-butanediol were combined with 94 mg of (E) -4- [2,4-bis (benzyloxy) phenyl] but-3-enoic acid ( 0.25 mmol) and 3-methyl-1,3-butanediol were synthesized respectively to give the title compound (27.4 mg, two-step yield 39%) having the following NMR spectrum as a viscous product. It was.
  • Example 7 Synthesis of 3-hydroxy-3-methylbutyl 5- (2,4-dihydroxyphenyl) pentanoate
  • (E) -3- [2,4- Bis (benzyloxy) phenyl] acrylic acid 90 mg (0.25 mmol) and 1,3-butanediol were combined with 97 mg of (E) -5- [2,4-bis (benzyloxy) phenyl] pent-4-enoic acid ( 0.25 mmol) and 3-methyl-1,3-butanediol were synthesized respectively to give the title compound (20.6 mg, two-step yield 28%) having the following NMR spectrum as a viscous substance. It was.
  • Example 8 Synthesis of 3-hydroxy-3-methylbutyl 6- (2,4-dihydroxyphenyl) hexanoate
  • (E) -3- [2,4- Bis (benzyloxy) phenyl] acrylic acid 90 mg (0.25 mmol) and 1,3-butanediol were combined with (E) -6- [2,4-bis (benzyloxy) phenyl] hex-5-enoic acid 101 mg ( 0.250 mmol) and 3-methyl-1,3-butanediol were synthesized, and the title compound (25.2 mg, two-step yield 33%) having the following NMR spectrum was obtained as a viscous product by synthesis. It was.
  • Example 9 Synthesis of 4-hydroxycyclohexylmethyl 3- (2,4-dihydroxyphenyl) propionate
  • the title compound (34.9 mg, two-step yield 47%) having the following NMR spectrum was obtained as a viscous substance by substitution and synthesis.
  • Example 10 Synthesis of 4- (2,4-dihydroxyphenyl) butanoic acid 4-hydroxycyclohexylmethyl
  • (E) -3- [2,4-bis ( Benzyloxy) phenyl] acrylic acid 90 mg (0.25 mmol) and 1,3-butanediol were combined with (E) -4- [2,4-bis (benzyloxy) phenyl] but-3-enoic acid 94 mg (0.
  • Example 11 Synthesis of 5- (2,4-dihydroxyphenyl) pentanoic acid 4-hydroxycyclohexylmethyl A procedure similar to that in Example 1 (2) was followed except that (E) -3- [2,4-bis ( Benzyloxy) phenyl] acrylic acid 90 mg (0.25 mmol) and 1,3-butanediol were combined with (E) -5- [2,4-bis (benzyloxy) phenyl] pent-4-enoic acid 97 mg (0.
  • Example 12 Synthesis of 4-hydroxycyclohexylmethyl 6- (2,4-dihydroxyphenyl) hexanoate According to the same procedure as in Example 1 (2), except that (E) -3- [2,4-bis ( Benzyloxy) phenyl] acrylic acid 90 mg (0.25 mmol) and 1,3-butanediol were combined with (E) -6- [2,4-bis (benzyloxy) phenyl] hex-5-enoic acid 101 mg (0.
  • Example 14 Synthesis of 1-O- [4- (2,4-dihydroxyphenyl) butanoyl] glycerol
  • (E) -3- [2,4-bis (benzyloxy) ) Phenyl] acrylic acid 108 mg (0.300 mmol) is replaced with 112 mg (0.300 mmol) of (E) -4- [2,4-bis (benzyloxy) phenyl] but-3-enoic acid.
  • Example 15 Synthesis of 1-O- [5- (2,4-dihydroxyphenyl) pentanoyl] glycerol
  • (E) -3- [2,4-bis (benzyloxy) ) Phenyl] acrylic acid 108 mg (0.300 mmol) is replaced with (E) -5- [2,4-bis (benzyloxy) phenyl] pent-4-enoic acid 116 mg (0.300 mmol)
  • Gave the title compound (30.7 mg, two-step yield 36%) having the following NMR spectrum as a viscous product.
  • Example 16 Synthesis of 1-O- [6- (2,4-dihydroxyphenyl) hexanoyl] glycerol
  • (E) -3- [2,4-bis (benzyloxy) ) Phenyl] acrylic acid 108 mg (0.300 mmol) is replaced with (E) -6- [2,4-bis (benzyloxy) phenyl] hex-5-enoic acid 121 mg (0.300 mmol)
  • Example 17 Synthesis of 1-O- [3- (2,4-dihydroxyphenyl) propanoyl] diglycerol
  • (E) -3- [2,4-bis (benzyl Oxy) phenyl] acrylic acid 108 mg (0.300 mmol) was used, and glycerol (3 equivalents) was replaced with diglycerol (3 equivalents) to perform synthesis to give the title compound (37.8 mg, 2 A process yield of 38%) was obtained as a viscous product.
  • Example 18 Synthesis of 6-O- [3- (2,4-dihydroxyphenyl) propanoyl] -L-ascorbic acid
  • Example 19 Synthesis of 6-O- [4- (2,4-dihydroxyphenyl) butanoyl] -L-ascorbic acid
  • (E) -3- [2,4- Bis (benzyloxy) phenyl] acrylic acid 108 mg (0.300 mmol) and glycerol (3 equivalents) were added to (E) -4- [2,4-bis (benzyloxy) phenyl] but-3-enoic acid 193 mg (0 .515 mmol) and 2,3-O-dibenzyl-L-ascorbic acid (1.5 equivalents), respectively, and further diisopropylethylamine (2.5 equivalents) was added during the condensation reaction to carry out the synthesis.
  • the title compound (47.1 mg, two-step yield 26%) having the following NMR spectrum was obtained as a viscous product.
  • Example 20 Synthesis of 6-O- [5- (2,4-dihydroxyphenyl) pentanoyl] -L-ascorbic acid
  • (E) -3- [2,4- Bis (benzyloxy) phenyl] acrylic acid 108 mg (0.300 mmol) and glycerol (3 equivalents) were added to (E) -5- [2,4-bis (benzyloxy) phenyl] pent-4-enoic acid 200 mg (0 .515 mmol) and 2,3-O-dibenzyl-L-ascorbic acid (1.5 equivalents), respectively, and further diisopropylethylamine (2.5 equivalents) was added during the condensation reaction to carry out the synthesis.
  • the title compound (87.8 mg, two-step yield 46%) having the following NMR spectrum was obtained as a viscous product.
  • Example 21 Synthesis of 6-O- [6- (2,4-dihydroxyphenyl) hexanoyl] -L-ascorbic acid
  • (E) -3- [2,4- Bis (benzyloxy) phenyl] acrylic acid 108 mg (0.300 mmol) and glycerol (3 equivalents) were combined with (E) -6- [2,4-bis (benzyloxy) phenyl] hex-5-enoic acid 207 mg (0 .514 mmol) and 2,3-O-dibenzyl-L-ascorbic acid (1.5 equivalents), respectively, and further diisopropylethylamine (2.5 equivalents) was added during the condensation reaction to carry out the synthesis.
  • the title compound (83.4 mg, two-step yield 42%) having the following NMR spectrum was obtained as a viscous product.
  • Example 23 Evaluation of Tyrosinase Activity Inhibitory Action The tyrosinase activity inhibitory action of the compounds finally synthesized in the above Examples and Comparative Examples was evaluated.
  • Each compound was prepared as a solution diluted with 0.1 M phosphate buffer (pH 6.8) so as to have a final concentration of 1 ⁇ M (including 0.1% DMSO).
  • the tyrosinase activity rate (%) was calculated for the test compound added group as a relative value with respect to the test compound non-added group (control).
  • Tyrosinase activity rate (%) [(absorbance of test sample (10 min) ⁇ absorbance of test sample (0 min)] / [(absorbance of control sample (10 min) ⁇ absorbance of control sample (0 min)]) ⁇ 100
  • the smaller the tyrosinase activity rate the lower the tyrosinase activity compared to the control, that is, the higher the tyrosinase activity inhibitory action of the test compound.
  • the compound of the present invention has a high tyrosinase activity inhibitory action.
  • the calculated tyrosinase activity rate is exemplified in Table 1 below.
  • Example X The compounds of the present invention finally synthesized in Examples 2, 3, 4, 6, 7, 8, 10, 11, 12, 14, 15, 16, 20 shown in Table 1 (hereinafter referred to as “Example X
  • Example X The compound “denoted as“ compound ”) showed a tyrosinase activity inhibitory action over that of lucinol, which is known for its high tyrosinase activity inhibitory action.
  • the compounds of Examples 3, 4, 7, 8, 10, 11, 12, 15, and 16 had very high inhibitory activity.
  • mouse B16 melanoma cells were seeded at 0.3 ⁇ 10 5 cells / well in a 6-well plate, and then in a DMEM medium supplemented with 10% FBS under conditions of 37 ° C. and 5% CO 2 for 24 hours. Cultured. The medium was removed, and a 0.1% DMSO solution in which the compound of each example was dissolved to a final concentration of 10 ⁇ M or 100 ⁇ M was added to each well, and cultured for 72 hours. The medium in each well was dispensed into a microtube, washed with PBS, and then cells were collected using 0.025% trypsin / PBS.
  • lucinol was used as a comparative compound (PC).
  • the number of cells (%) in the test compound-added group was calculated as a relative value to the test compound-free group (control). As the cell number (%) decreases from 100%, the cell death increases, that is, the cytotoxicity is high.
  • lucinol did not show cytotoxicity when a 10 ⁇ M solution was used, but showed remarkable cytotoxicity when a 100 ⁇ M solution was used.
  • mouse B16 melanoma cells were seeded in a 6-well plate at 0.3 ⁇ 10 5 cells / well, and cultured for 24 hours under conditions of 37 ° C. and 5% CO 2 in DMEM medium supplemented with 10% FBS.
  • the medium was removed, and a 0.1% DMSO solution in which the compound of each example was dissolved to a final concentration of 10 ⁇ M was added to each well, and cultured for 72 hours.
  • the medium in each well was dispensed into a microtube, washed with PBS, and then cells were collected using 0.025% trypsin / PBS.
  • the supernatant was collected, and the cell pellet was resuspended in DMEM medium supplemented with 10% FBS. The suspension was centrifuged at 1,500 rpm for 10 minutes. The supernatant was fractionated into a 96-well plate, the absorbance at a wavelength of 405 nm was measured with a microplate reader, and the amount of melanin (the amount of melanin in the cell) was calculated from the calibration curve of melanin.
  • the absorbance of the medium collected at the end of the culture for 72 hours after adding the test compound was measured at a wavelength of 405 nm, and the amount of melanin (the amount of melanin in the medium) was calculated in the same manner.
  • the total value of the calculated amount of melanin in the cell and the amount of melanin in the medium was defined as the amount of melanin produced.
  • lucinol was used as a comparative compound (PC).
  • the melanin ratio (%) of the test compound added group was calculated as a relative value to the test compound non-added group (control). It shows that melanin production is suppressed, so that the amount ratio of melanin is low.
  • the calculation results are illustrated in Table 4 below.
  • Table 4 shows that the compounds of Examples 1, 2, 3, 4, 7, 8, 14, 15, 16, and 20 have melanin production inhibitory activity.
  • the compounds of Examples 2, 3, 4, 8, 14, and 15 shown in Table 4 showed particularly high melanin production inhibitory activity.
  • Example 26 Photostability test
  • PC comparative compound
  • test samples were each 0.1% by weight solution (ethanol / water (20/80; v / v)) test samples were prepared and exposed to sunlight. All of the test samples were colorless and transparent liquids, but since the color changed according to the degree of degradation caused by sun exposure, changes in the appearance of the liquid during sun exposure were observed.
  • Table 5 shows the observation results obtained by sun exposure after 2 days, 1 week and 2 weeks.
  • the compounds synthesized in the examples are: (1) a colorless and transparent liquid, with the progress of decomposition, (2) slightly red transparent, (3) light red transparent, (4) light orange transparent, (5) yellow transparent, (6) The color of the liquid changed in the order of light yellow and transparent. About lucinol, it became a suspension in (4) and the subsequent stages. The suspension (indicated by “′” in Table 5) indicates that the decomposition progressed more than the transparent at the same coloring stage.
  • Example 27 Formulation examples of cosmetic preparations using the compounds of the present invention having a tyrosinase activity inhibitory action are shown below. The blending amount of each component is shown in wt%.
  • Formulation Example 1 (Lotion) Ingredient (wt%) 4-Alkylresorcinol derivatives 8 Propylene glycol 10 Ethanol 20 Liquid paraffin 2 Polyoxyethylene (30) hydrogenated castor oil 1 Polyethylene glycol 5 Citric acid 0.2 Sodium phosphate 0.3 Allantoin 0.05 EDTA-2Na 0.05 Antioxidant 0.02 Fragrance 0.2 Purified water 53.18
  • Formulation Example 3 (Foundation) Ingredient (wt%) 4-Alkylresorcinol derivatives 5 Fine particle titanium oxide 7 Isostearic acid triglyceride 2 2-octyl dodecyl oleate 8 Liquid paraffin 3 Cetyl alcohol 5 Candelilla wax 2 Polyoxyethylene (25) monostearate 2 Sorbitan monostearate 1 Yellow iron oxide 1.3 Petal 0.8 Polyethylene glycol 4 Methylparaben 0.2 Fragrance 0.2 Purified water 58.5
  • Formulation Example 4 (Powder) Ingredient (wt%) 4-Alkylresorcinol derivatives 3 Talc 80 Crystalline cellulose 5 Ultramarine 1 Spherical calcium silicate 3 Fine particle titanium oxide 3.5 Squalane 4.5
  • Example 28 Synthesis of 2-hydroxyethyl 3- (2,4-dihydroxyphenyl) propionate
  • (E) -3- [2,4-bis (benzyloxy) phenyl By using 90 mg (0.25 mmol) of acrylic acid and replacing glycerol (3 equivalents) with 2- (benzyloxy) ethanol (2 equivalents), the title compound (14.7 mg) having the following NMR spectrum was synthesized. , Two-step yield 26%) as a viscous product.
  • Example 29 Synthesis of 2-hydroxyethyl 4- (2,4-dihydroxyphenyl) butanoate A procedure similar to that in Example 13 except that (E) -3- [2,4-bis (benzyloxy) phenyl ] 108 mg (0.300 mmol) of acrylic acid and glycerol (3 equivalents) were combined with 94 mg (0.25 mmol) of (E) -4- [2,4-bis (benzyloxy) phenyl] but-3-enoic acid and 2- The title compound (7.0 mg, two-step yield 12%) having the following NMR spectrum was obtained as a viscous product by substituting (benzyloxy) ethanol (2 equivalents) for synthesis.
  • Example 30 Synthesis of 2-hydroxyethyl 5- (2,4-dihydroxyphenyl) pentanoate
  • (E) -3- [2,4-bis (benzyloxy) phenyl ] 108 mg (0.300 mmol) of acrylic acid and glycerol (3 equivalents) were combined with 97 mg (0.25 mmol) of (E) -5- [2,4-bis (benzyloxy) phenyl] pent-4-enoic acid and 2-
  • the title compound (22.3 mg, two-step yield 35%) having the following NMR spectrum was obtained as a white solid by synthesizing by replacing with (benzyloxy) ethanol (2 equivalents).
  • Example 31 Synthesis of 2-hydroxyethyl 6- (2,4-dihydroxyphenyl) hexanoate According to the same procedure as in Example 13, except that (E) -3- [2,4-bis (benzyloxy) phenyl ] 108 mg (0.300 mmol) of acrylic acid and glycerol (3 equivalents) were combined with 101 mg (0.251 mmol) of (E) -6- [2,4-bis (benzyloxy) phenyl] hex-5-enoic acid and 2- The title compound (26.1 mg, two-step yield 39%) having the following NMR spectrum was obtained as a viscous substance by substituting (benzyloxy) ethanol (2 equivalents) for synthesis.
  • Example 32 For the compounds of Examples 28 to 31, the tyrosinase activity inhibitory action was evaluated according to the same procedure as in Example 23 using a compound solution having a final concentration of 1 ⁇ M. Further, the compounds of Examples 28 to 31 were subjected to a cytotoxicity test according to the same procedure as Example 24 using a compound solution having a final concentration of 10 ⁇ M.

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Abstract

La présente invention concerne un inhibiteur de l'activité tyrosinase hautement sûr ayant une bonne activité. La présente invention concerne : un inhibiteur de l'activité tyrosinase contenant un ou plusieurs dérivés 4-alkylrésorcinol ou des sels de ceux-ci ayant un substituant ester ou éther hydrophile dans la chaîne 4-alkyle ; une préparation externe pour la peau contenant ceux-ci ; un agent blanchissant ; et un produit cosmétique.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017057148A (ja) * 2015-09-15 2017-03-23 国立大学法人高知大学 チロシナーゼ阻害剤
WO2018043731A1 (fr) * 2016-09-05 2018-03-08 株式会社ファルネックス Agent anti-adhérence utilisant une émulsion qui contient un composant huileux
FR3067027A1 (fr) * 2017-05-31 2018-12-07 L'oreal Derives de resorcinol pour leur utilisation cosmetique
JP2020117458A (ja) * 2019-01-23 2020-08-06 国立大学法人宇都宮大学 レゾルシノール誘導体およびこれを含むチロシナーゼ活性阻害剤

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07316034A (ja) * 1993-04-29 1995-12-05 L'oreal Sa ４位、４位および５位、または４位および６位がモノ‐もしくはジ‐置換されたレゾルシノール誘導体を、色素脱失作用を有する化粧品組成物もしくは皮膚薬剤組成物に使用する方法
JP2007186445A (ja) * 2006-01-12 2007-07-26 Kyushu Univ レゾルシノール誘導体を含有するメラニン生成抑制剤
FR2991983A1 (fr) * 2012-06-19 2013-12-20 Oreal Nouveaux derives de resorcinol et leurs applications cosmetiques
WO2013189930A1 (fr) * 2012-06-19 2013-12-27 L'oreal Procédé de dépigmentation de matières kératiniques au moyen de nouveaux composés à base de résorcinol
WO2013190482A1 (fr) * 2012-06-19 2013-12-27 L'oreal Dérivés de résorcinol et utilisation cosmétique de ceux-ci

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07316034A (ja) * 1993-04-29 1995-12-05 L'oreal Sa ４位、４位および５位、または４位および６位がモノ‐もしくはジ‐置換されたレゾルシノール誘導体を、色素脱失作用を有する化粧品組成物もしくは皮膚薬剤組成物に使用する方法
JP2007186445A (ja) * 2006-01-12 2007-07-26 Kyushu Univ レゾルシノール誘導体を含有するメラニン生成抑制剤
FR2991983A1 (fr) * 2012-06-19 2013-12-20 Oreal Nouveaux derives de resorcinol et leurs applications cosmetiques
WO2013189930A1 (fr) * 2012-06-19 2013-12-27 L'oreal Procédé de dépigmentation de matières kératiniques au moyen de nouveaux composés à base de résorcinol
WO2013190482A1 (fr) * 2012-06-19 2013-12-27 L'oreal Dérivés de résorcinol et utilisation cosmétique de ceux-ci

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FICO ET AL.: "A new phenolic compound from Nigella damascena seeds", FITOTERAPIA, vol. 72, no. 4, 2001, pages 462 - 463 *
KHATIB ET AL.: "Enhanced Substituted Resorcinol Hydrophobicity Augments Tyrosinase Inhibition Potency", JOURNAL OF MEDICINAL CHEMISTRY, vol. 50, no. 11, 2007, pages 2676 - 2681 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017057148A (ja) * 2015-09-15 2017-03-23 国立大学法人高知大学 チロシナーゼ阻害剤
WO2018043731A1 (fr) * 2016-09-05 2018-03-08 株式会社ファルネックス Agent anti-adhérence utilisant une émulsion qui contient un composant huileux
FR3067027A1 (fr) * 2017-05-31 2018-12-07 L'oreal Derives de resorcinol pour leur utilisation cosmetique
WO2018220020A3 (fr) * 2017-05-31 2019-10-17 L'oreal Utilisation cosmétique de dérivés du résorcinol
CN110678454A (zh) * 2017-05-31 2020-01-10 莱雅公司 针对其化妆品用途的间苯二酚衍生物
JP2020521808A (ja) * 2017-05-31 2020-07-27 ロレアル 美容的使用のためのレゾルシノール誘導体
US11401236B2 (en) * 2017-05-31 2022-08-02 L'oreal Resorcinol derivatives for their cosmetic use
JP7128266B2 (ja) 2017-05-31 2022-08-30 ロレアル 美容的使用のためのレゾルシノール誘導体
JP2020117458A (ja) * 2019-01-23 2020-08-06 国立大学法人宇都宮大学 レゾルシノール誘導体およびこれを含むチロシナーゼ活性阻害剤
JP7376058B2 (ja) 2019-01-23 2023-11-08 国立大学法人宇都宮大学 レゾルシノール誘導体およびこれを含むチロシナーゼ活性阻害剤

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