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WO2025134879A1 - Inhibiteur de la mélanogenèse - Google Patents

Inhibiteur de la mélanogenèse Download PDF

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Publication number
WO2025134879A1
WO2025134879A1 PCT/JP2024/043728 JP2024043728W WO2025134879A1 WO 2025134879 A1 WO2025134879 A1 WO 2025134879A1 JP 2024043728 W JP2024043728 W JP 2024043728W WO 2025134879 A1 WO2025134879 A1 WO 2025134879A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
compounds
skin
fragrance
melanin production
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/JP2024/043728
Other languages
English (en)
Japanese (ja)
Inventor
善行 和田
謙次 足立
甲悟 飯田
晃典 長田
公輔 畑野
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ogawa and Co Ltd
Original Assignee
Ogawa and Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ogawa and Co Ltd filed Critical Ogawa and Co Ltd
Publication of WO2025134879A1 publication Critical patent/WO2025134879A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • 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
    • A61K8/35—Ketones, e.g. benzophenone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q13/00—Formulations or additives for perfume preparations
    • 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
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
    • C11B9/00—Essential oils; Perfumes

Definitions

  • the present invention relates to a melanin production inhibitor and a skin topical preparation containing the same.
  • Non-Patent Document 1 only describes this compound as an intermediate product in a synthetic reaction, and does not disclose any biological activity of the compound itself or any application of the compound to topical skin preparations.
  • the search for new natural or synthetic compounds that are non-cytotoxic and have strong melanin production inhibitory activity continues.
  • the objective of the present invention is to provide a melanin production inhibitor that is more effective and safer than existing skin whitening agents.
  • the present invention provides a compound represented by formula (1) [(4aR,8aS)-4a-methyl-8-methyleneoctahydronaphthalene-2(1H)-one] (hereinafter, sometimes referred to as "compound (1)”), a compound represented by formula (2) [(4aR,8aR)-4a-methyloctahydronaphthalene-1,7-dione] (hereinafter, sometimes referred to as “compound (2)”), a compound represented by formula (3) [(4aR,8aS)-4a,8-dimethyloctahydronaphthalene-2(1H)-one] (hereinafter, sometimes referred to as “compound (3)”), ] (hereinafter, sometimes referred to as "compound (3)”), a compound represented by formula (4) [(4aR)-4a,8-dimethyl-4,4a,5,6,7,8-hexahydronaphthalene-2(3H)-one] (hereinafter, sometimes referred to
  • compounds (1) to (5) have their own fragrance and are excellent for harmonizing with other fragrance raw materials. Harmonization refers to the process of incorporating any of compounds (1) to (5) as one of the components of a fragrance composition to transform the fragrance of the composition into an even more pleasant fragrance, or to the process of adding desirable properties (such as a luxurious or natural feel) without changing the original fragrance characteristics or strength.
  • the present invention includes the following configurations.
  • a melanin production inhibitor comprising one or more of the compounds represented by the compounds (1) to (5) as active ingredients.
  • a skin whitening agent comprising one or more of the compounds represented by the compounds (1) to (5) as active ingredients.
  • a skin external preparation comprising one or more of the compounds represented by the compounds (1) to (5) as an active ingredient.
  • a fragrance composition for external use on the skin comprising one or more of the compounds represented by the compounds (1) to (5) as active ingredients.
  • a method for whitening skin comprising the step of administering to an individual a cosmetic composition containing one or more of the compounds represented by the compounds (1) to (5) as an active ingredient.
  • a fragrance composition containing a compound represented by any one of (1) to (5).
  • An oral composition comprising the flavor composition according to [6].
  • a cosmetic product (excluding external skin preparations) containing the fragrance composition according to [6] above.
  • Compounds (1) to (5) used in the present invention have excellent whitening effects, are useful as melanin production inhibitors, and are also highly safe, making it possible to provide topical skin preparations with good whitening effects.
  • FIG. 1 is a graph showing the melanin production inhibitory effect of the use of compound (1).
  • FIG. 1 shows cell viability as a result of using compound (1).
  • % means % by mass and ppm means ppm by mass.
  • the compounds (1) to (5) of the present invention can be produced by known methods described in the above-mentioned Patent Documents 2 to 8, etc.
  • Compounds (1) to (5) of the present invention have excellent melanin production inhibitory effects as shown in the Examples below, and are useful as melanin production inhibitors and skin whitening agents. In addition, since they are not cytotoxic, they can be effectively and safely incorporated into various preparations as topical skin agents, particularly whitening cosmetics intended for skin whitening.
  • compound (1) itself has an indole-like animalic and floral scent, making compound (1) suitable as a fragrance material.
  • Compound (1) has the effect of enhancing the natural feel of fragrances when used in combination with the fragrances, so simply adding it to cosmetics or topical skin preparations as a melanin production inhibitor can dramatically improve the commercial value of cosmetics and other products.
  • compound (1) by adding compound (1) to a fragrance composition having a flavor and aroma reminiscent of a specific natural material, the flavor and aroma of the component in the fragrance composition having the flavor and aroma pronounced of the natural material can be enhanced, and the scent of the flavor and aroma component can be improved to a complex, rich scent specific to natural materials that differs from synthetic fragrances (imparting a natural feel). Therefore, compound (1) can be suitably used as a fragrance material itself.
  • the effect of enhancing the natural feel of a fragrance and the effect of imparting a natural feel to a fragrance will be collectively referred to as the "natural feel enhancing effect.”
  • compounds (2) to (5) themselves have a fragrant odor and can bring about harmonization in a fragrance composition.
  • the natural sensation enhancing effect is also one form of harmonization.
  • Inhibition of melanin production occurs through inhibition of melanin-producing enzymes, inhibition of the production of melanin-producing enzymes, enhanced degradation of enzymes, inhibition of structural scaffolding involved in melanin production or melanosome biosynthesis, or inhibition of melanosome transport, thereby inhibiting melanin production itself.
  • Compounds covered by the scope of protection of this application exert their melanin production inhibitory effect through one or more of these mechanisms.
  • the compounds (1) to (5) of the present invention may be administered orally, by injection, inhalation, transdermal, or topical administration depending on the condition of the individual, but are preferably used as external skin preparations.
  • they may be formulated into an appropriate dosage unit form containing pharma- ceutically acceptable carriers, additives, and vehicles depending on the route of administration.
  • “individual” means a subject that produces melanin, and more specifically may be a mammal such as a human or non-human primate, mouse, rat, dog, cat, horse, or cow, but is not limited thereto.
  • administration means providing a specific compound (1) to (5) of the present invention to an individual by any appropriate method.
  • External skin preparations include, but are not limited to, milk lotions, soaps, facial cleansers, bath additives, creams, milk lotions, skin toners, colognes, shaving creams, shaving lotions, cosmetic oils, sunscreen lotions, face powders, foundations, perfumes, packs, nail creams, enamel, enamel removers, eyebrow inks, blushers, eye creams, eye shadows, mascaras, eyeliners, lipsticks, lip balms, shampoos, rinses, hair dyes, dispersions, cleansers and the like.
  • the content of compounds (1) to (5) in the topical skin preparation is not particularly limited as long as the desired effect of each embodiment is achieved, but the total amount of compounds (1) to (5) is usually 0.00001 to 15 mass%, preferably 0.0001 to 10 mass%, and more preferably 0.0003 to 5 mass%.
  • the content of compounds (1) to (5) in the skin topical preparation is not particularly limited as long as the desired effect of each embodiment is achieved, but the total amount of compounds (1) to (5) is usually 0.00001 to 15 mass%, preferably 0.0001 to 10 mass%, and more preferably 0.0003 to 5 mass%.
  • the skin topical preparation of the present invention is capable of suppressing melanin production, making it possible to prevent and improve skin blemishes, freckles, dullness, melasma, senile pigmentation, darkening due to physical irritation, etc., and is therefore suitable for use as a topical composition for whitening.
  • the content of compounds (1) to (5) in the fragrance composition according to the present invention is not particularly limited. From the viewpoint of obtaining a sufficient fragrance-imparting effect, the content of compounds (1) to (5) in the fragrance composition according to the present invention is preferably 0.000001 (0.01 ppm) to 40 mass%, more preferably 0.00001 (0.1 ppm) to 10.0 mass%, and even more preferably 0.0001 (1 ppm) to 2.0 mass%, based on the total amount (mass) of the fragrance composition. If the content of compounds (1) to (5) in the fragrance composition is less than 0.01 ppm, a sufficient effect may not be obtained, and if it exceeds 40 mass%, the flavor of compounds (1) to (5) themselves may be perceived as strange.
  • Compounds (1) to (5) are flavor compositions according to the present invention that can enhance the flavor of an oral composition by adding them to the oral composition.
  • Compounds (1) to (5) or the flavor composition according to the present invention can be added to an oral composition in the same manner as other food flavors.
  • the oral compositions to which the compounds (1) to (5) or the flavoring composition of the present invention are applied are products that are taken orally or used in the oral cavity, and include foods and beverages, quasi-drugs, medicines, oral hygiene products, etc.
  • foods and beverages include: (a) beverages such as tea beverages, such as green tea, black tea, and oolong tea; fruit beverages, fruit-flavored beverages (including those without fruit juice), vegetable beverages, sports drinks, nutritional drinks, dairy beverages, carbonated beverages, coffee, cocoa, and alcoholic beverages; (b) frozen desserts, such as ice cream, sorbets, and popsicles; (c) fermented dairy products, such as yogurt and cheese; (d) luxury items, such as Japanese and Western confectioneries, baked goods, jams, chewing gum, bread, and tobacco; (e) desserts, such as puddings, jellies, bavarois, and mousses; (f) soups, such as Japanese-style soups, Western-style soups, and instant food soups and stocks; (g) flavor, such
  • the amount of the compounds (1) to (5) or the flavoring composition of the present invention added to the oral composition is not particularly limited, and the amount can be appropriately adjusted so that the oral composition has a desired natural feel. In general, it is preferable to add the compounds (1) to (5) so that the content (mass) of the compounds (1) to (5) relative to the total amount (mass) of the oral composition is within the range of 0.001 ppb to 2 mass%, and more preferably within the range of 0.1 ppb to 200 ppm.
  • Compounds (1) to (5) are fragrance compositions according to the present invention that can enhance the fragrance of an oral composition by incorporating them into the oral composition.
  • the commercial value of the cosmetic product can be further increased.
  • Compounds (1) to (5) or the fragrance composition according to the present invention can be widely used in cosmetics in general.
  • cosmetics to which compounds (1) to (5) or the fragrance composition according to the present invention can be applied include (a) health and sanitary materials such as tissue paper, toilet paper, and sanitary products, and (b) fragrance and deodorizing products such as room fresheners, car fresheners, fabric mists, and deodorants.
  • the amount of the compounds (1) to (5) or the fragrance composition of the present invention added to a cosmetic product is not particularly limited, and the amount added can be adjusted appropriately so that the natural feel of the cosmetic product has the desired strength.
  • the content (mass) of the compounds (1) to (5) relative to the total amount (mass) of the cosmetic product is usually 0.0001 ppb to 15 mass%, preferably 0.001 ppb to 10 mass%, and more preferably 0.1 ppb to 5 mass%.
  • Example 6 Mellanin production inhibition test using a three-dimensional cultured skin model
  • the compound (1) obtained in the above Production Example was subjected to the melanin production inhibition test shown below.
  • kojic acid manufactured by Nacalai Tesque
  • an ascorbic acid derivative L-ascorbic acid 2-glucoside, manufactured by Chem-Impex Int'l. Inc.
  • Solvable PerkinElmer
  • the amount of melanin produced when various concentrations of compound (1) were added, measured using this method, is shown in Figure 1.
  • the control is the result when compound (1) was not added.
  • Table 1 shows the results of calculating the IC50 value of melanin production inhibition. Furthermore, the production inhibition strength is shown when the IC50 value of compound (1) is set to 1.
  • the IC50 value means the concentration at which melanin production is inhibited by 50%, and is a value indicating the effectiveness of the melanin production inhibitory action of each test substance. Therefore, a lower IC50 value means that the test substance exerts the effect of inhibiting melanin production at a lower concentration than other test substances, that is, the inhibitory effect is stronger.
  • compound (1) of the present invention has a strong melanin production inhibitory effect, and that its melanin production inhibitory effect is 100 times stronger than that of ascorbic acid derivatives and about twice stronger than that of kojic acid, both of which are known to have melanin production inhibitory effects.
  • the cell viability was measured by varying the concentration of compound (1) used, and the results are shown in FIG. As shown in Figure 2, even when compound (1) was added at a concentration of 4000 ppm, which suppresses melanin production to less than 20%, the cell viability was not affected. Therefore, it was confirmed that compound (1) has no cytotoxicity or has extremely low cytotoxicity.
  • Example 7 (Melanin production inhibition test of bicyclic compounds) The compounds (1) to (5) were subjected to a melanin production inhibition test by the following method.
  • the amount of melanin produced was measured using the method described in Example 6.
  • the amount of melanin produced is shown in the table below, assuming that the amount of melanin produced in the culture cup to which only the liquid paraffin solution was added is 100.
  • the lotions, cosmetic creams and milky lotions of the above Formulation Examples 1 to 3 containing the compounds (1) to (5) had no unpleasant appearance, properties or feel when used.
  • a rose-type fragrance was used as the fragrance, and it was confirmed that formulation examples 1 to 3 enhance the naturalness of the rose fragrance (have a naturalness enhancing effect).
  • the compounds represented by the following formulas (1) to (5) have excellent melanin production inhibitory effects and are safe, and can be applied to a wide range of dosage forms, for example, topical skin preparations such as lotions, milky lotions, and creams. In addition, since they have excellent whitening effects, they are very useful in terms of skin beauty.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Wood Science & Technology (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Cosmetics (AREA)

Abstract

L'invention concerne : un nouveau composé ayant une faible cytotoxicité et une forte activité inhibitrice de la mélanogenèse ; et une préparation topique pour la peau, qui contient cet inhibiteur de la mélanogenèse.　Cet inhibiteur de la mélanogenèse contient de la (4aR,8aS)-4a-méthyl-8-méthylène-octahydronaphtalén-2(1H)-one en tant que principe actif.
PCT/JP2024/043728 2023-12-18 2024-12-11 Inhibiteur de la mélanogenèse Pending WO2025134879A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2023-212614 2023-12-18
JP2023212614 2023-12-18

Publications (1)

Publication Number Publication Date
WO2025134879A1 true WO2025134879A1 (fr) 2025-06-26

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ID=96136924

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2024/043728 Pending WO2025134879A1 (fr) 2023-12-18 2024-12-11 Inhibiteur de la mélanogenèse

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WO (1) WO2025134879A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017026520A1 (fr) * 2015-08-10 2017-02-16 高砂香料工業株式会社 Inhibiteur de la mélanogenèse

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017026520A1 (fr) * 2015-08-10 2017-02-16 高砂香料工業株式会社 Inhibiteur de la mélanogenèse

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BELHASSEN, E. et al. Unravelling the Scent of Vetiver: Identification of Character-Impact Compounds. Chemistry & Biodiversity. (2014), vol. 11, no. 11, pp. 1821-1842, DOI 10.1002/cbdv.201400079 *
MALLAVARAPU, G. R. et al. Constituents of South Indian Vetiver Oils. Natural Product Communications. (2012), vol. 7, no. 2, pp. 223-225, DOI 10.1177/1934578x1200700228 *
PENG, H.-Y. et al. Effect of Vetiveria zizanioides Essential Oil on Melanogenesis in Melanoma Cells:Downregulation of Tyrosinase Expression and Suppression of Oxidative Stress. The Scientific World Journal. (2014), vol. 2014, article ID 213013, pp. 1-9, DOI http://dx.doi.org/10.1155/2014/213013 *
WEYERSTAHL, P. et al. Constituents of Haitian vetiver oil. Flavour and Fragrance Journal. (2000), vol. 15, no. 6, pp. 395-412, DOI 10.1002/1099-1026(200011/12)15:6<395::AID-FFJ930>3.0.CO;2-9 *

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