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WO2025225705A1 - Promoteur de décomposition de mélanine et inhibiteur de production de mélanine - Google Patents

Promoteur de décomposition de mélanine et inhibiteur de production de mélanine

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Publication number
WO2025225705A1
WO2025225705A1 PCT/JP2025/015968 JP2025015968W WO2025225705A1 WO 2025225705 A1 WO2025225705 A1 WO 2025225705A1 JP 2025015968 W JP2025015968 W JP 2025015968W WO 2025225705 A1 WO2025225705 A1 WO 2025225705A1
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WO
WIPO (PCT)
Prior art keywords
group
halogen
carbon atoms
extract
substituent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/JP2025/015968
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English (en)
Japanese (ja)
Inventor
敦 加藤
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University of Toyama NUC
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University of Toyama NUC
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Publication of WO2025225705A1 publication Critical patent/WO2025225705A1/fr
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Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/69—Boron compounds
    • 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
    • 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
    • A61K8/58—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing atoms other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur or phosphorus
    • 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

Definitions

  • the present invention relates to a novel melanin decomposition promoter and/or a novel melanin production inhibitor, as well as cosmetic compositions, pharmaceutical compositions, and topical skin preparations containing these.
  • Melanin a black pigment, is produced and stored in melanosomes within melanocytes, which are pigment cells, in the basal layer, the lowest layer of the epidermis. Melanosomes containing accumulated melanin migrate to epidermal keratinocytes and are distributed above the cell nuclei within the epidermal keratinocytes.
  • melanin plays a role in protecting the skin from UV damage, it can also cause cosmetic problems such as age spots and freckles. Age spots and freckles are caused by the excessive accumulation of melanin, and excessive melanin production due to UV rays and external stimuli is a major contributing factor.
  • Tyrosinase is known as a melanin-producing enzyme. Tyrosinase acts in two processes: a reaction to produce dopa from the amino acid tyrosine, 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 because the reactions following 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. Tyrosinase is activated by ultraviolet rays and external stimuli, so in order to prevent excessive melanin production, it is important to suppress excessive tyrosinase activity.
  • kojic acid and 4-butylresorcinol are known as tyrosinase inhibitors.
  • Kojic acid is a compound discovered in koji rice, 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 that is known to have much greater inhibition than kojic acid (Non-Patent Document 5), (Non-Patent Document 6).
  • Melanin is produced in small vesicles called melanosomes within melanocytes.
  • the melanosomes that store melanin are transported to surrounding keratinocytes via the dendrites of melanocytes.
  • the transported melanosomes cover the apical nuclei of keratinocytes (called the melanin cap), which plays a role in preventing DNA damage caused by harmful ultraviolet rays while also promoting skin darkening (Non-Patent Document 7).
  • Non-Patent Document 8 Melanosomes are normally broken down and excreted as keratinocytes turnover. However, if turnover does not occur normally and melanosomes accumulate in keratinocytes, melanin pigment is deposited, appearing as age spots. Furthermore, it has been reported that excessive accumulation of melanosomes may reduce keratinocyte cell division and slow turnover, and it is thought that this vicious cycle escalates pigmentation (Non-Patent Document 8).
  • promoting the breakdown of melanosomes not only improves pigmentation such as blemishes and freckles that have already formed, but also helps prevent the development of further blemishes, making it a very important factor in terms of whitening.
  • 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, and this characteristic is unique to cathepsin V among the several types of cathepsins present, so cathepsin V is thought to be involved in the degradation of melanosomes and melanin (Non-Patent Document 12).
  • the present invention relates to providing a novel melanin decomposition promoter and/or a novel melanin production inhibitor, as well as cosmetic compositions, pharmaceutical compositions, and topical skin preparations containing these.
  • a melanin decomposition promoter comprising a compound represented by the following formula (1):
  • R 1 is OH, B(OH) 2 , B(OCH 3 ) 2 , B(OCH 2 CH 3 ) 2 , or B(OCH 2 CH 2 CH 3 ) 2
  • R2 and R3 each independently represent 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;
  • R4 is H, OH, or halogen.
  • R 1 is 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 is OH and the other is a phenyl group which may have a substituent
  • R 2 , R 3 , and R 4 are all H.
  • R 1 is OH, B(OH) 2 , B(OCH 3 ) 2 , B(OCH 2 CH 3 ) 2 , or B(OCH 2 CH 2 CH 3 ) 2
  • R2 and R3 each independently represent 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;
  • R4 is H, OH, or halogen.
  • R 1 is 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 is OH and the other is a phenyl group which may have a substituent
  • R 2 , R 3 , and R 4 are all H.
  • R 1 is OH, B(OH) 2 , B(OCH 3 ) 2 , B(OCH 2 CH 3 ) 2 , or B(OCH 2 CH 2 CH 3 ) 2
  • R2 and R3 each independently represent 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;
  • R4 is H, OH, or halogen.
  • R 1 is 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 is OH and the other is a phenyl group which may have a substituent
  • R 2 , R 3 , and R 4 are all H.
  • R 5 is a cycloalkyl group having 3 to 10 carbon atoms, a halogen, or —X—R 6 ;
  • -X- is a single bond, -CH 2 -, or -CH(CH 3 )-; when -X- is a single bond or -CH 2 -, R 6 is a phenyl group substituted with a halogen; when -X- is -CH(CH 3 )-, 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.
  • R7 is halogen
  • R8 is a phenyl group which may have a substituent
  • 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.
  • R5 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.
  • R 5 is a cycloalkyl group having 3 to 10 carbon atoms, a halogen, or —X—R 6 ;
  • -X- is a single bond, -CH 2 -, or -CH(CH 3 )-; when -X- is a single bond or -CH 2 -, R 6 is a phenyl group substituted with a halogen; when -X- is -CH(CH 3 )-, 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.
  • R 5 is a cycloalkyl group having 3 to 10 carbon atoms, a halogen, or —X—R 6 ;
  • -X- is a single bond, -CH 2 -, or -CH(CH 3 )-; when -X- is a single bond or -CH 2 -, R 6 is a phenyl group substituted with a halogen; when -X- is -CH(CH 3 )-, 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.
  • R7 is halogen
  • R8 is a phenyl group which may have a substituent
  • 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.
  • the present invention provides a novel melanin decomposition promoter and/or a novel melanin production inhibitor, as well as cosmetic compositions, pharmaceutical compositions, and topical skin preparations containing these.
  • 10 is a fluorescent microscope image in Test Example 2. 1 is a photographed image of a culture medium in Test Example 2. 10 is a fluorescent microscope image taken in Test Example 4.
  • melanin production inhibitors or melanin degradation promoters could regulate the amount of melanin within cells, thereby reducing the amount of melanin present between the cells of the stratum corneum, and thus be effective in preventing and improving age spots and freckles caused by melanin pigment deposition, and maintaining cell turnover function. Therefore, they 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, they confirmed that these specific compounds also have the activity to reduce the amount of melanin in cells, and based on this, they completed the present invention. It was also confirmed that certain compounds have both of these effects.
  • R 1 is 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 each independently represent 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;
  • R4 is H, OH, or halogen.
  • R4 is preferably H, and when it is OH or halogen, it is preferably at position 6.
  • Examples of compounds in which OH or halogen is at position 6 include 4,6-dichlororesorcinol.
  • halogen includes fluorine, chlorine, bromine, and iodine, and from the viewpoint of promoting melanin decomposition, fluorine, chlorine, and bromine are preferred in the above formula (1).
  • an alkyl group refers to a straight- or branched-chain saturated hydrocarbon group having the specified number of carbon atoms.
  • an alkyl group having 1 to 5 carbon atoms is intended to encompass straight- or branched-chain hydrocarbon groups having 1 to 5 carbon atoms.
  • an alkoxy group refers to an -O-alkyl group having the specified number of carbon atoms.
  • R1 is B(OH) 2 or B( OCH3 ) 2
  • one of R2 and R3 is halogen and the other is H, OH, a methyl group, or an optionally substituted phenyl group
  • one is OH and the other is H or a methyl group
  • 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.
  • 2-fluoro-4-biphenylboronic acid is preferred from the viewpoint of both promoting melanin decomposition and inhibiting melanin production.
  • R1 and R2 are OH and R3 is 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'...fluoro-[1,1'-biphenyl]-2,4-diol,4'-fluoro-[1,1'-biphenyl]-2,4-diol,4'-fluoro-[1,1'-biphenyl]-2,4-diol,4'-fluoro-[1,1'-biphenyl]-2,4-dio
  • the content of the compound of formula (1) in the melanin decomposition accelerator of the present invention is typically 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, this refers to their total amount.
  • the melanin decomposition accelerator of the present invention may contain, in addition to the compound of formula (1) above, 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), ascorbyl tetra-2-hexyldecanoate EX (VC-IP EX), nicotinamide (D-melano), cetyl tranexamate hydrochloride (TXC), dexpanthen
  • the melanin decomposition promoter of the present invention can be prepared by any manufacturing method known in the art, except for the step of incorporating the compound of formula (1) above.
  • the present invention also provides a method for promoting the decomposition of melanin using the compound of formula (1) above.
  • the melanin production inhibitor of the present invention contains a compound represented by the following formula (2) and/or (3).
  • R 5 is a cycloalkyl group having 3 to 10 carbon atoms, preferably 4 to 8 carbon atoms, more preferably 6 carbon atoms, halogen or —X—R 6 ;
  • -X- is a single bond, -CH 2 -, or -CH(CH 3 )-; when -X- is a single bond or -CH 2 -, R 6 is a phenyl group substituted with a halogen;
  • 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, 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.
  • R7 is halogen
  • R8 is a phenyl group which may have a substituent
  • 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.
  • 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-( ⁇ -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.
  • examples of the compounds of formula (3) include 4-cyclohe
  • the content of the compounds of formula (2) and/or (3) in the melanin production inhibitor of the present invention is typically 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 (2) and/or (3) are used, this refers to their total amount.
  • the melanin production inhibitor of the present invention may contain, in addition to the compounds of formula (2) and/or (3) above, whitening ingredients known in the art, such as laurel wreath 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 EX), nicotinamide (D-melano), cetyl tranexamate hydrochloride (TXC), dexpan
  • oleic acid 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 glutinosa root extract, asparagus stem extract, acerola fruit extract, aloe vera juice, knotweed extract, knotweed root extract, turmeric extract, turmeric rhizome extract, scutellaria root extract, scutellaria root extract, hypericum extract, hypericum flower/leaf/stem extract, pueraria root extract, canina rose fruit extract,
  • 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.
  • 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 allows the melanin degradation promoter of the present invention and/or the melanin production inhibitor of the present invention to be taken up into cells.
  • Examples of the composition include an external composition from the perspective of exerting its effects, and an internal composition from the perspective of easy ingestion.
  • the topical or oral composition can be provided as a pharmaceutical composition, quasi-drug composition, cosmetic composition, etc. (hereinafter, these will also be referred to as “compositions of the present invention"), and is preferably used as a topical skin composition.
  • Topical compositions can be in the form of solid, semi-solid, or liquid preparations for transdermal or transmucosal (oral or nasal) administration.
  • they can be 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; bath additives, etc.
  • Cosmetic compositions can 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.
  • 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
  • bath additives such as colognes, deodorants, and perfumes.
  • oral compositions include those that can be easily formulated (e.g., powders and granules), and those that can be easily taken in tablets or liquid forms. Specifically, they can be used in any form, including 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.
  • composition of the present invention contains the melanin degradation promoter of the present invention and/or the melanin production inhibitor of the present invention, it can be prepared in accordance with conventional methods by appropriately blending carriers, bases, and/or additives commonly used in the pharmaceutical and cosmetic fields, etc., within the scope that achieves the objectives of the present invention.
  • Examples of carriers, bases, and/or additives used in the pharmaceutical field include excipients (glucose, lactose, sucrose, sodium chloride, starch, calcium carbonate, kaolin, crystalline cellulose, cocoa butter, hardened vegetable oil, talc, etc.), binders (distilled water, 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, gum arabic powder, gelatin, ethanol, etc.), disintegration inhibitors (sucrose, stearin, cocoa butter, hydrogenated oil, etc.), absorption enhancers (quaternary ammonium base, sodium lauryl sulfate, etc.), adsorbents (glycer
  • Carriers, bases, and/or additives used in the cosmetics industry 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), alcohol, stearyl alcohol, oleyl alcohol, behenyl alcohol, hexadecyl alcohol, etc.), fatty acids (caprylic acid, capric acid,
  • 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 amido sulfates, alkyl phosphates, alkyl trimethyl ammonium chloride, stearyl trimethyl ammonium chloride, stearyl trimethyl ammonium 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
  • suitable additives include cellulose acetate (ethylene glycol, di
  • compositions can be prepared according to known manufacturing methods for pharmaceuticals, quasi-drugs, or cosmetics.
  • the melanin decomposition promoter and/or melanin production inhibitor of the present invention can be mixed with a highly water-soluble solvent or compound such as purified water, ethanol, or glycerin, and the resulting solution can be slowly mixed with a pre-mixed mixture of a highly fat-soluble substance such as squalane, jojoba oil, or glycerin monostearate to prepare a cosmetic liquid and/or a cosmetic cream.
  • the melanin decomposition promoter and/or melanin production inhibitor of the present invention can be dried, made into various solutions, or pastes, and then blended with various additives, carriers, base materials, etc. to be formulated into solid preparations such as tablets, granules, powders, powders, and capsules, or liquid preparations such as regular liquids, suspensions, and emulsions, according to conventional methods in the art.
  • composition of the present invention may 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, 4-methoxysalicylic acid potassium salt, 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 EX), nicotinamide (D-melano), cetyl tranexamate hydrochloride (TXC), dexpanthenol W (PCE-DP), retinol, caprylyl 2-
  • Disodium Tearyl 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, Artichoke Extract, Rehmannia Root Extract, Asparagus Stem Extract, Acerola Fruit Extract, Aloe 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 Extract, Cham
  • composition of the present invention can also contain an antioxidant.
  • Antioxidants are not particularly limited, but examples include tocopherol, tocopherol acetate, propyl gallate, butylhydroxyanisole, dibutylhydroxytoluene, coenzyme Q10, alpha-lipoic acid, fullerene, astaxanthin, organic germanium, dimethylaminoethanol, hydroxytyrosol, and platinum nanocolloid.
  • the content of the melanin decomposition 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 manner and method of use.
  • the content of the melanin decomposition 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 perspective of achieving the desired effects.
  • 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 melanin decomposition promoters and/or melanin production inhibitors of the present invention are used, the content refers to the total amount of these.
  • composition of the present invention is used in an appropriate manner depending on the embodiment. Specifically, it can be used, for example, internally, externally, or by injection.
  • 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 who will be using the composition.
  • the amount is typically preferably about 1 ⁇ g to 1000 mg/day in dry weight per adult weighing approximately 50 kg, and may be used once or in several divided doses within the desired range within a day.
  • the period of use is also optional.
  • "use” includes not only “use” but also "administration” and "ingestion.”
  • reaction was carried out using the following four combinations of inhibitor, substrate and enzyme.
  • A DMSO + L-tyrosine solution + tyrosinase solution
  • B DMSO + phosphate buffer + tyrosinase solution
  • C Sample solution + L-tyrosine solution + tyrosinase solution
  • D Sample solution + phosphate buffer + tyrosinase solution
  • the absorbances of reaction systems A, B, C, and D were designated A abs , B abs , C abs , and D abs , respectively, and the inhibition rate (%) was calculated using the following formula.
  • Test Example 2 Melanin Production Inhibition Test B16F10 mouse melanoma cells (RCB2630) were obtained from Riken Briccell Bank and cultured at 37°C and 5% CO2 . RPMI-1640 containing 10% BS was used as the culture medium. 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. This was diluted with culture medium to prepare a final sample concentration of 100 ⁇ M (or a specified concentration less than this) and a final DMSO concentration of 0.1%.
  • Culture medium containing DMSO (final concentration 0.1%) was used as a control.
  • a 100 ⁇ M ⁇ -MSH solution was diluted with culture medium to prepare a final concentration of 0.1 ⁇ M.
  • 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.
  • Cells were seeded into a 24-well plate at 2.0 x 10 cells/ cm2 and pre-cultured for 24 hours at 37°C and 5% CO2 .
  • D-MEM containing 2 mM L-glutamine, 10% BS, and 1 mM sodium pyruvate was used. Penicillin-streptomycin was added as an antibiotic.
  • ⁇ -MSH solution and the sample solution or control were then added, and the cells were cultured for 72 hours at 37°C and 5% CO2 . After culturing, the cell morphology was photographed using an inverted fluorescence microscope ( Figure 1). After a further 48 hours of culture, the state of the culture medium was photographed ( Figure 2).
  • HMV-II human melanoma cells (RCB0777) were obtained from RIKEN BRCCELL BANK. Cells were seeded into T-25 cell culture flasks at 5.0 x 10 cells/ cm2 and cultured for 7 days under conditions of 37°C and 5% CO2 . D-MEM/Ham's F-12 containing 10% BS was used as the culture medium. Penicillin-streptomycin was added as an antibiotic.
  • PLL-coated culture coverslips were placed in a 24-well plate, and the keratinocytes were seeded at 2.0 x 104 cells/ cm2 and cultured at 37°C and 5% CO2 for 7 days.
  • the melanosome pellet extracted as described above was then suspended in 100 ⁇ L of medium and added to the keratinocytes. 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, membrane permeabilization was performed with 0.2% Triton X-100/PBS for 20 minutes.
  • 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 completion of the secondary antibody reaction, the samples were washed with PBS, and the PLL-Coated culture cover glass was mounted on a FINE FROST® microslide using PBS. The test samples were then observed and photographed using an upright fluorescent microscope, and the images were analyzed. Quantification of intracellular cathepsin V was performed using a cathepsin V ELISA kit according to the protocol.
  • 4-chlororesorcinol, 4-phenylresorcinol, and 2,4,4'-trihydroxybiphenyl also demonstrated the melanin production inhibitory effect shown in Table 1, demonstrating that they can both promote melanin degradation and inhibit melanin production.
  • 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).
  • 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 then diluted with medium to prepare a final sample concentration of 100 ⁇ M and a final DMSO concentration of 0.1%. Medium containing DMSO (final concentration 0.1%) was used as a control.
  • PHK16-0b human keratinocytes (JCRB0141) were obtained from the JCRB Cell Bank and cultured at 37°C and 5% CO2 in KGM-Gold TM BulletKit TM medium. Cells were seeded into T-25 cell culture flasks at a density of 6.0 ⁇ 104 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 and washed with 1 mL of PBS. Cells were detached by adding 0.25% Trypsin-EDTA and 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 lysates was measured using Pierce TM BCA Protein Assay Kits.
  • Anti-Cathepsin V antibody diluted with 1% skim milk was then applied and allowed to stand at room temperature for 90 minutes. After the reaction, the membrane was washed three times with skim milk, and HRP Doneky anti-rabbit IgG diluted with skim milk was applied and allowed to stand at room temperature for 90 minutes. After the reaction, the membrane was washed four times with skim milk and twice with PBS-T. Luminescence obtained with SuperSignal TM 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.
  • Process 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. After stirring at room temperature for 20 hours, the mixture was stirred at 50°C for an additional 2 hours. 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.
  • Process 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.

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Abstract

L'invention concerne un promoteur de décomposition de mélanine contenant un composé représenté par la formule (1). (Dans la formule, R1 représente OH, B(OH)2, B(OCH3)2, B(OCH2CH3)2, ou B(OCH2CH2CH3)2, R2 et R3 représentent chacun indépendamment H, OH, un groupe méthyle, un groupe cycloalkyle en C3-10, un halogène ou un groupe phényle qui peut comporter un substituant, le substituant étant au moins un substituant choisi dans le groupe constitué par OH, un halogène, un groupe alkyle en C1-5 et un groupe alcoxy en C1-5, et R4 représente H, OH ou un halogène, avec des exceptions où R1 représente B(OH)2, B(OCH3)2, B(OCH2CH3)2, ou B(OCH2CH2CH3)2, l'un parmi R2 et R3 représentant OH et l'autre représentant un groupe phényle qui peut comporter un substituant, et R2, R3 et R4 représentant tous H.) La présente invention permet de fournir un nouveau promoteur de décomposition de mélanine et/ou un nouvel inhibiteur de production de mélanine, et une composition cosmétique, une composition pharmaceutique et une préparation cutanée topique qui contiennent le promoteur de décomposition de mélanine et/ou l'inhibiteur de production de mélanine.
PCT/JP2025/015968 2024-04-25 2025-04-24 Promoteur de décomposition de mélanine et inhibiteur de production de mélanine Pending WO2025225705A1 (fr)

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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
JPH11152203A (ja) * 1997-09-23 1999-06-08 Pfizer Prod Inc レゾルシノール誘導体を含む組成物
JPH11255638A (ja) * 1998-03-13 1999-09-21 Kansai Kouso Kk チロシナーゼ活性阻害剤及び化粧料
WO2007077770A1 (fr) * 2005-12-26 2007-07-12 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Glycoside d’alkylresorcinol, son procede de production et son utilisation
JP2020015740A (ja) * 2008-07-21 2020-01-30 ユニゲン・インコーポレーテッド スキンホワイトニング（色を薄くする）化合物系列

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
JPH11152203A (ja) * 1997-09-23 1999-06-08 Pfizer Prod Inc レゾルシノール誘導体を含む組成物
JPH11255638A (ja) * 1998-03-13 1999-09-21 Kansai Kouso Kk チロシナーゼ活性阻害剤及び化粧料
WO2007077770A1 (fr) * 2005-12-26 2007-07-12 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Glycoside d’alkylresorcinol, son procede de production et son utilisation
JP2020015740A (ja) * 2008-07-21 2020-01-30 ユニゲン・インコーポレーテッド スキンホワイトニング（色を薄くする）化合物系列

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