WO2024251138A1 - 1,3-双苄基苯酚类衍生物、制备方法及其应用 - Google Patents

1,3-双苄基苯酚类衍生物、制备方法及其应用 Download PDF

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Publication number
WO2024251138A1
WO2024251138A1 PCT/CN2024/097453 CN2024097453W WO2024251138A1 WO 2024251138 A1 WO2024251138 A1 WO 2024251138A1 CN 2024097453 W CN2024097453 W CN 2024097453W WO 2024251138 A1 WO2024251138 A1 WO 2024251138A1
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Prior art keywords
compound
skin
formula
preparing
composition
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English (en)
French (fr)
Inventor
刘吉开
郑永胜
王献
黄蓉
田宇婷
李正辉
陈乾
董智慧
伍兴
杨会祥
涂亮
吕晓
陈琼
沈慧慧
邓婷婷
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Shenzhen Moore Vaporization Health and Medical Technology Co Ltd
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Shenzhen Moore Vaporization Health and Medical Technology Co Ltd
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Priority to CN202480032693.4A priority Critical patent/CN121219257A/zh
Priority to KR1020257043916A priority patent/KR20260019560A/ko
Publication of WO2024251138A1 publication Critical patent/WO2024251138A1/zh
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23B—PRESERVATION OF FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES; CHEMICAL RIPENING OF FRUIT OR VEGETABLES
    • A23B2/00—Preservation of foods or foodstuffs, in general
    • A23B2/70—Preservation of foods or foodstuffs, in general by treatment with chemicals
    • A23B2/725—Preservation of foods or foodstuffs, in general by treatment with chemicals in the form of liquids or solids
    • A23B2/729—Organic compounds; Microorganisms; Enzymes
    • A23B2/742—Organic compounds containing oxygen
    • A23B2/746—Organic compounds containing oxygen with singly-bound oxygen
    • 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
    • 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
    • A61K8/34—Alcohols
    • 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
    • A61K8/34—Alcohols
    • A61K8/347—Phenols
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/18—Antioxidants, e.g. antiradicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • 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
    • A61Q19/08—Anti-ageing preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
    • C07C37/18—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms by condensation involving halogen atoms of halogenated compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
    • C07C39/15—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings with all hydroxy groups on non-condensed rings, e.g. phenylphenol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
    • A61K2800/782—Enzyme inhibitors; Enzyme antagonists

Definitions

  • the present application belongs to the field of cosmetics and pharmaceutical technology, and relates to a 1,3-bisbenzylphenol derivative, a preparation method and an application thereof.
  • Oxygen free radicals produced during cell metabolism can cause cumulative damage to intracellular biomacromolecules, causing cell aging and loss of proliferation capacity. This imbalance of oxidation and antioxidant systems is considered to be an important cause of skin aging.
  • Tyrosinase also known as polyphenol oxidase, is an oxidoreductase widely found in animals, plants, microorganisms and the human body. It is the key rate-limiting enzyme in melanin synthesis and is closely related to the occurrence of excessive melanin deposition such as freckles and brown spots on human skin. In recent years, its application in the fields of medicine and beauty has attracted widespread attention.
  • ⁇ -arbutin is a hydroquinone derivative, which has a cytotoxic effect on melanocytes and a strong irritant to the skin. Long-term use may cause permanent white spots on the skin and has been included in the list of banned ingredients for cosmetics in many countries.
  • Kojic acid inhibits the catalytic activity of tyrosinase by chelating the copper ions of tyrosinase.
  • Vitamin C and vitamin E are important antioxidants for the human body. They do not directly inhibit tyrosinase, but reduce the colored intermediates in the biosynthesis of melanin, and have only an insufficient whitening and brightening effect on the skin. These unfavorable factors limit their widespread application in the whitening and anti-freckle cosmetics market.
  • Xu Gang's research group isolated a series of diarylheptanoids from Ottelia acuminata var. acuminata, an edible vegetable of the Bai nationality in Dali, Yunnan, China, which have significant ⁇ -glucosidase inhibitory activity and potential therapeutic value for diabetes (Liu HX, Ma JZ, Ye YS, Zhao JJ, Wan SJ, Hu XY, Xu G. ⁇ -Glucosidase inhibitory diarylheptanoids from Ottelia acuminata var. acuminata, a traditional vegetable of Bai Nationality in Yunnan, Natural Products and Bioprospecting 2022, 12:22). Studies have shown that tyrosinase is a protein with sugar chains.
  • ⁇ -glucosidase I and ⁇ -glucosidase II are the key enzymes in the sugar chain modification and cleavage process (Mehta A, Zitzmann N, Rudd PM, Block TM, Dwek RA. ⁇ -Glucosidase inhibitors as potential broad-based anti-viral agents, FEBS Letters, 1998, 430(1): 17-22).
  • diarylheptene polyphenol compounds from natural sources is low, and its structural characteristics are cis- and trans-olefin structures, poor molecular stability, easy double bond shift isomerization through ene reaction, difficult to synthesize, and relatively flexible molecules.
  • Some embodiments of the present application provide a 1,3-bisbenzylphenol derivative, a preparation method and application thereof.
  • the first aspect of the technical solution of the present application is to provide an application of a compound represented by formula I, wherein the compound represented by formula I is as follows:
  • Each R 1 , each R 2 and each R 3 is independently selected from one or a combination of hydrogen, hydroxyl, halogen, phenyl, halomethoxy, methylamino, methyl and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 4 carbon atoms;
  • R 4 , R 5 , R 6 and R 7 are each independently selected from one or a combination of hydrogen, methyl and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms;
  • n and k are each independently an integer from 1 to 3;
  • the applications include one or more of the following: preparing tyrosinase inhibitors, preparing ⁇ -glucosidase inhibitors, preparing drugs for treating diabetes, preparing whitening products, preparing anti-skin oxidation products, preparing anti-aging products, preparing skin care products for reducing melanin production, preparing drugs for treating skin diseases that reduce melanin production, preparing skin care products for preventing pigmentation diseases, preparing drugs for treating skin diseases that prevent pigmentation diseases, preparing skin care products for treating pigmentation diseases, preparing drugs for treating skin diseases that treat pigmentation diseases, and inhibiting food browning.
  • each R 1 and each R 3 is hydroxyl.
  • each R 1 is a hydroxyl group
  • at least one of each R 3 is a hydroxyl group.
  • the compound represented by formula I is selected from one or more of the following structures:
  • the application includes one or more of the following: preparing ⁇ -glucosidase inhibitors, preparing drugs for treating diabetes, preparing anti-skin oxidation, preparing anti-aging products, preparing skin care products that reduce melanin production, preparing drugs for treating skin diseases that reduce melanin production, preparing skin care products that prevent pigmentation diseases, preparing drugs for treating skin diseases that prevent pigmentation diseases, preparing skin care products for treating pigmentation diseases, and preparing drugs for treating skin diseases for treating pigmentation diseases.
  • the compound represented by formula I is selected from The application includes the preparation of tyrosinase inhibitors.
  • the compound represented by formula I is selected from The application includes one or more of the following: preparing tyrosinase inhibitors, preparing ⁇ -glucosidase inhibitors, preparing drugs for treating diabetes, preparing anti-skin oxidation products, preparing anti-aging products, preparing skin care products for reducing melanin production, preparing drugs for treating skin diseases that reduce melanin production, preparing skin care products for preventing pigmentation diseases, preparing drugs for treating skin diseases that prevent pigmentation diseases, preparing skin care products for treating pigmentation diseases, and preparing drugs for treating skin diseases that treat pigmentation diseases.
  • the pigmentation disease is selected from one or more of freckles, chloasma, stretch marks, age spots and melanoma.
  • the anti-skin oxidation and anti-aging effects refer to the removal of active oxygen free radicals in cells.
  • the second aspect of the present application provides a 1,3-bis-benzylphenol compound, the structural formula of which is selected from one or more of the following structural formulas of compound 2 and compound 3:
  • the third aspect of the present application provides a method for preparing 1,3-bis-benzylphenol compounds, the preparation method comprising the following steps: mixing raw material A and raw material B in a substance amount ratio of 1:(5-10), the raw material A being selected from 1,3-di(bromomethyl)benzene, 1,3-di(chloromethyl)benzene and a combination thereof, the raw material B being selected from o-cresol, 1,2-benzenediol and a combination thereof, using aluminum chloride as a catalyst, heating the reaction at 100-120°C under nitrogen protection for a period of time, and then purifying by column chromatography to obtain the compound.
  • the fourth aspect of the present application provides a composition, wherein the composition has one or more of the effects of whitening, anti-skin oxidation, anti-aging and inhibition of food browning, and the composition comprises a compound shown in formula I and a carrier, and the compound shown in formula I is as follows:
  • Each R 1 , each R 2 and each R 3 is independently selected from one or a combination of hydrogen, hydroxyl, halogen, phenyl, halomethoxy, methylamino, methyl and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 4 carbon atoms;
  • R 4 , R 5 , R 6 and R 7 are each independently selected from one or a combination of hydrogen, methyl and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms;
  • n and k are each independently an integer from 1 to 3;
  • the carrier is selected from one or more acceptable carriers in the cosmetics field, the pharmaceutical field, the food field and combinations thereof.
  • each R 1 and each R 3 is hydroxyl.
  • each R 1 is a hydroxyl group
  • at least one of each R 3 is a hydroxyl group.
  • the compound represented by formula I is selected from one or more of the following structures:
  • the composition has at least one of whitening, anti-skin oxidation and anti-aging effects, including an effective amount of compound 1 as an active ingredient.
  • Compound 2 Compound 3 At least one of, and one or more acceptable carriers in the field of cosmetics.
  • whitening refers to one or more of inhibiting tyrosinase activity, inhibiting ⁇ -glucosidase activity, inhibiting cellular melanin production and inhibiting pigmentation; anti-skin oxidation and anti-aging refer to removing active oxygen free radicals in cells.
  • the pigmentation is selected from one or more of freckles, chloasma, stretch marks, age spots and melanoma.
  • the composition is selected from one or more of a tyrosinase inhibitor composition and an ⁇ -glucosidase inhibitor composition.
  • the carrier includes one or more of a fragrance, a compound for skin care, a compound for skin cleansing, and an ultraviolet absorber.
  • the composition includes a flavor and a compound of formula I, wherein the flavor is present in an amount effective to provide a sensory effect, and the compound of formula I is present in an amount having one or both of the effects of inhibiting tyrosinase and inhibiting ⁇ -glucosidase.
  • the compound represented by Formula I is present in an amount of about 3% to about 30% by weight.
  • the composition includes a UV absorber and a compound shown in Formula I, wherein the amount of the UV absorber is effective to provide UV protection with a protection factor of at least greater than 2, and the amount of the compound shown in Formula I has one or both of the effects of inhibiting tyrosinase and inhibiting ⁇ -glucosidase.
  • the composition includes one or more of a compound for skin care and a compound for skin cleansing, and a compound of formula I, wherein the amount of the compound of formula I has one or both of the effects of inhibiting tyrosinase and inhibiting ⁇ -glucosidase.
  • the fifth aspect of the present application provides a use of the above-mentioned composition in the preparation of whitening skin care products, whitening skin disease treatment drugs, anti-aging skin care products, anti-aging skin disease treatment drugs and combinations thereof.
  • whitening refers to one or more of inhibiting tyrosinase activity, inhibiting ⁇ -glucosidase activity, inhibiting cellular melanin production and inhibiting pigmentation; anti-skin oxidation and anti-aging refer to removing active oxygen free radicals in cells.
  • the sixth aspect of the present application provides a product, which is one of a cosmetic and a drug for treating skin diseases, and which comprises the above-mentioned composition or a compound represented by formula I,
  • Each R 1 , each R 2 and each R 3 is independently selected from one or a combination of hydrogen, hydroxyl, halogen, phenyl, halomethoxy, methylamino, methyl and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 4 carbon atoms;
  • R 4 , R 5 , R 6 and R 7 are each independently selected from one or a combination of hydrogen, methyl and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms;
  • the mass percentage of the compound represented by formula I in the product is 0.01% to 2%.
  • the mass percentage of the compound represented by formula I in the product is 0.1% to 1%.
  • the seventh aspect of the present application provides a pharmaceutical composition for treating diabetes, which comprises an effective amount of a compound used as an active ingredient and a carrier, wherein the effective amount of the compound used as an active ingredient is selected from one or more of the compounds shown in Formula I, and the compound shown in Formula I is as follows:
  • R 4 , R 5 , R 6 and R 7 are each independently selected from one or a combination of hydrogen, methyl and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms;
  • n and k are each independently an integer from 1 to 3;
  • the carrier is selected from one or more acceptable carriers in the pharmaceutical field.
  • the effective amount of the compound used as the active ingredient is selected from compound 1 Compound 2 and compound 3 One or more of the .
  • the seventh aspect of the present application provides a use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating diabetes.
  • an effective amount of a compound selected from compound 1 is used as an active ingredient.
  • Compound 2 and compound 3 One or more of the .
  • the ninth aspect of the present application provides a pharmaceutical preparation, which includes one or more compounds for treating diabetes and one or more compounds of formula I in an amount that has an ⁇ -glucosidase inhibitory effect; the compounds of formula I are as follows:
  • Each R 1 , each R 2 and each R 3 is independently selected from one or a combination of hydrogen, hydroxyl, halogen, phenyl, halomethoxy, methylamino, methyl and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 4 carbon atoms;
  • R 4 , R 5 , R 6 and R 7 are each independently selected from one or a combination of hydrogen, methyl and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms;
  • n, k are each independently an integer of 1-3.
  • each R 1 and each R 3 is hydroxyl.
  • each R 1 is a hydroxyl group
  • at least one of each R 3 is a hydroxyl group.
  • the compound represented by formula I is selected from one or more of the following structures:
  • the tenth aspect of the present application provides a method for whitening human skin and combating age spots on human skin, comprising administering an effective amount of the above composition or the above product to a person in need.
  • the eleventh aspect of the present application provides a method for inhibiting browning of food, comprising applying an effective amount of the composition as described above to the food.
  • the twelfth aspect of the present application provides a method for treating diabetes, comprising administering an effective amount of the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation to a person in need.
  • FIG1 1 H NMR spectrum of compound 1 provided in the examples of the present application (500 MHz, DMSO-d 6 ).
  • FIG2 13 C NMR spectrum of compound 1 provided in the examples of the present application (125 MHz, DMSO-d 6 ).
  • FIG3 1 H NMR spectrum of compound 2 provided in the examples of the present application (600 MHz, DMSO-d 6 ).
  • FIG4 13 C NMR spectrum of compound 2 provided in the examples of the present application (150 MHz, DMSO-d 6 ).
  • FIG5 1 H NMR spectrum of compound 3 provided in the examples of the present application (500 MHz, DMSO-d 6 ).
  • FIG6 13 C NMR spectrum of compound 3 provided in the examples of the present application (125 MHz, DMSO-d 6 ).
  • FIG. 7 1 H NMR spectrum (600 MHz, DMSO-d 6 ) of compound 4 provided in the examples of the present application.
  • FIG8 13 C NMR spectrum of compound 4 provided in the examples of the present application (150 MHz, DMSO-d 6 ).
  • FIG9 1 H NMR spectrum of compound 5 provided in the examples of the present application (500 MHz, DMSO-d 6 ).
  • FIG10 13 C NMR spectrum of compound 5 provided in the examples of the present application (125 MHz, DMSO-d 6 ).
  • FIG. 11 1 H NMR spectrum (600 MHz, MeOD) of compound 6 provided in the Examples of the present application.
  • FIG. 12 13 C NMR spectrum (150 MHz, MeOD) of compound 6 provided in the examples of the present application.
  • FIG. 13 1 H NMR spectrum (500 MHz, CDCl 3 ) of compound 7 provided in the examples of the present application.
  • FIG. 14 13 C NMR spectrum (125 MHz, CDCl 3 ) of compound 7 provided in the examples of the present application.
  • FIG. 15 1 H NMR spectrum (500 MHz, CDCl 3 ) of compound 8 provided in the examples of the present application.
  • FIG. 16 13 C NMR spectrum (125 MHz, CDCl 3 ) of compound 8 provided in the examples of the present application.
  • FIG. 17 1 H NMR spectrum (500 MHz, CDCl 3 ) of compound 9 provided in the examples of the present application.
  • FIG. 18 13 C NMR spectrum (125 MHz, CDCl 3 ) of compound 9 provided in the examples of the present application.
  • FIG. 19 1 H NMR spectrum (500 MHz, CDCl 3 ) of compound 10 provided in the examples of the present application.
  • FIG. 20 13 C NMR spectrum (125 MHz, CDCl 3 ) of compound 10 provided in the examples of the present application.
  • FIG. 21 1 H NMR spectrum (600 MHz, CDCl 3 ) of compound 11 provided in the examples of the present application.
  • FIG. 22 13 C NMR spectrum (150 MHz, CDCl 3 ) of compound 11 provided in the examples of the present application.
  • FIG. 23 1 H NMR spectrum (500 MHz, CDCl 3 ) of compound 12 provided in the examples of the present application.
  • FIG. 24 13 C NMR spectrum (125 MHz, CDCl 3 ) of compound 12 provided in the examples of the present application.
  • FIG. 25 1 H NMR spectrum (600 MHz, MeOD) of compound 13 provided in the Examples of the present application.
  • FIG. 26 13 C NMR spectrum (150 MHz, MeOD) of compound 13 provided in the Examples of the present application.
  • FIG. 27 1 H NMR spectrum (500 MHz, CDCl 3 ) of compound 14 provided in the examples of the present application.
  • FIG. 28 13 C NMR spectrum (125 MHz, CDCl 3 ) of compound 14 provided in the examples of the present application.
  • FIG. 29 1 H NMR spectrum (600 MHz, CDCl 3 ) of compound 15 provided in the examples of the present application.
  • FIG30 13 C NMR spectrum (150 MHz, CDCl 3 ) of compound 15 provided in the examples of the present application.
  • FIG31 1 H NMR spectrum (600 MHz, CDCl 3 ) of compound 16 provided in the examples of the present application.
  • FIG32 13 C NMR spectrum (150 MHz, CDCl 3 ) of compound 16 provided in the examples of the present application.
  • FIG33 1 H NMR spectrum of compound 17 provided in the examples of the present application (500 MHz, DMSO-d 6 ).
  • FIG34 13 C NMR spectrum of compound 17 provided in the examples of the present application (125 MHz, DMSO-d 6 ).
  • FIG35 1 H NMR spectrum (500 MHz, CDCl 3 ) of compound 18 provided in the examples of the present application.
  • FIG36 13 C NMR spectrum (125 MHz, CDCl 3 ) of compound 18 provided in the examples of the present application.
  • FIG37 1 H NMR spectrum (600 MHz, CDCl 3 ) of compound 19 provided in the examples of the present application.
  • FIG38 1 H NMR spectrum (600 MHz, CDCl 3 ) of compound 20 provided in the examples of the present application.
  • FIG39 1 H NMR spectrum (600 MHz, MeOD) of compound 21 provided in the Examples of the present application.
  • FIG40 13 C NMR spectrum (150 MHz, MeOD) of compound 21 provided in the Examples of the present application.
  • FIG41 1 H NMR spectrum (600 MHz, CDCl 3 ) of compound 22 provided in the examples of the present application.
  • FIG. 42 13 C NMR spectrum (150 MHz, CDCl 3 ) of compound 22 provided in the examples of the present application.
  • FIG. 43 1 H NMR spectrum (600 MHz, CDCl 3 ) of compound 23 provided in the examples of the present application.
  • FIG. 44 13 C NMR spectrum (150 MHz, CDCl 3 ) of compound 23 provided in the examples of the present application.
  • FIG. 45 1 H NMR spectrum (600 MHz, CDCl 3 ) of compound 24 provided in the examples of the present application.
  • FIG. 46 13 C NMR spectrum (150 MHz, CDCl 3 ) of compound 24 provided in the examples of the present application.
  • FIG. 47 1 H NMR spectrum of compound 25 provided in the Examples of the present application (500 MHz, DMSO-d 6 ).
  • FIG. 48 13 C NMR spectrum (125 MHz, CDCl 3 ) of compound 25 provided in the examples of the present application.
  • FIG. 49 1 H NMR spectrum of compound 26 provided in the Examples of the present application (500 MHz, DMSO-d 6 ).
  • FIG50 13 C NMR spectrum of compound 26 provided in the examples of the present application (125 MHz, DMSO-d 6 ).
  • FIG51 1 H NMR spectrum of compound 27 provided in Examples of the present application (600 MHz, DMSO-d 6 ).
  • FIG52 13 C NMR spectrum of compound 27 provided in Examples of the present application (150 MHz, DMSO-d 6 ).
  • FIG53 1 H NMR spectrum of compound 28 provided in the examples of the present application (500 MHz, DMSO-d 6 ).
  • FIG54 13 C NMR spectrum of compound 28 provided in Examples of the present application (125 MHz, DMSO-d 6 ).
  • FIG55 1 H NMR spectrum of compound 29 provided in the examples of the present application (600 MHz, DMSO-d 6 ).
  • FIG57 1 H NMR spectrum of compound 30 provided in Examples of the present application (500 MHz, DMSO-d 6 ).
  • FIG58 13 C NMR spectrum of compound 30 provided in Examples of the present application (125 MHz, DMSO-d 6 ).
  • FIG59 1 H NMR spectrum (600 MHz, DMSO-d 6 ) of compound 31 provided in the Examples of the present application.
  • FIG60 13 C NMR spectrum of compound 31 provided in Examples of the present application (150 MHz, DMSO-d 6 ).
  • Figure 61 Effects of the three compounds provided in the examples of the present application and the positive drug kojic acid on tyrosinase activity.
  • Figure 62 Inhibitory effects of the three compounds provided in the examples of the present application and positive acarbose on ⁇ -glucosidase activity.
  • Figure 63 The scavenging effects of the three compounds provided in the examples of the present application and the positive drug vitamin E on ABTS free radicals.
  • Figure 64 Effects of the three compounds provided in the examples of the present application and the positive drug phenethylresorcinol on the activity of B16 cells.
  • Figure 65 Effects of Compound 1, Compound 2, Compound 3 and phenethylresorcinol provided in the Examples of the present application on melanin synthesis in B16 cells.
  • Figure 66 Typical images of zebrafish whitening of Compound 1 and Compound 2 provided in the Examples of the present application (the dotted line area is the quantitative area).
  • Figure 67 Schematic diagram of the location of the hair removal area on animal skin.
  • diarylheptene polyphenol compounds have significant ⁇ -glucosidase inhibitory activity, and reduce the maturation of tyrosinase by inhibiting ⁇ -glucosidase, so as to achieve the purpose of reducing the production of melanin and skin pigmentation, which is a new possible way to whiten and remove spots.
  • diarylheptene polyphenol compounds from natural sources have low content, poor molecular stability, easy double bond shift isomerization through ene reaction, difficult to synthesize, and large molecular flexibility.
  • this application uses this type of natural product as a lead compound, and uses it as a template to simplify and replace its open-chain flexible molecular structure with a rigid benzene ring polyphenol structure analog by using conformational restriction and bioelectronic isosteric replacement strategy.
  • the phenolic hydroxyl group on the benzene ring is increased, and a series of 1,3-bisbenzylphenol derivatives are synthesized, and their tyrosinase inhibitory activity, ⁇ -glucosidase inhibitory activity, antioxidant activity and inhibition of cell melanogenesis activity are studied.
  • compound 1 is a known compound (Larry Q.
  • Each R 1 , each R 2 and each R 3 is independently selected from one or a combination of hydrogen, hydroxyl, halogen, phenyl, halomethoxy, methylamino, methyl and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 4 carbon atoms;
  • R 4 , R 5 , R 6 and R 7 are each independently selected from one or a combination of hydrogen, methyl and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms;
  • n and k are each independently an integer from 1 to 3;
  • (R 1 ) m represents that m R 1 groups are connected to the benzene ring, m is 1, 2 or 3, each R 1 can be the same or different, and each is independently selected from one or a combination of hydrogen, hydroxyl, halogen, methyl and a straight chain or branched, saturated or unsaturated hydrocarbon group having 2 to 4 carbon atoms. And the m R 1 groups can be connected to any position on the benzene ring without special limitation.
  • (R 2 ) n and (R 3 ) k have similar meanings and are not repeated here.
  • the applicant's activity study on the compound shown in Formula I confirms that the compound shown in Formula I and a mixture containing one or more compounds shown in Formula I have strong tyrosinase inhibition and ⁇ -glucosidase inhibition, and are therefore very suitable for use as skin whitening agents and anti-senile plaque agents, etc. And due to their high stability to light, they are very suitable for use as skin whitening agents in products such as cosmetics, as a substitute or supplement for known skin whitening active compounds (such as hydroquinone, arbutin or ascorbic acid). Tyrosinase inhibition usually occurs in beauty, but in some cases it can also have therapeutic characteristics, therefore, the compound shown in the above Formula I can also be used in dermatological drug treatment. For example, the compound shown in Formula I, especially when they are used as skin whitening agents or anti-senile plaque agents, is usually applied topically in the form of a solution, cream, lotion, gel, spray or the like.
  • the compound shown in formula I can also be used as an anti-browning additive in the food industry. ⁇ -glucosidase inhibition can also block the modification of sugar chains on glycoproteins to produce active tyrosinase, and melanin formation is correspondingly reduced.
  • the compound shown in formula I can also be used as an antidiabetic drug in the pharmaceutical industry. For example, it is used as an oral antidiabetic drug.
  • the pigmentation disease is selected from one or more of freckles, chloasma, stretch marks, age spots and melanoma.
  • the anti-skin oxidation and anti-aging effects refer to the removal of active oxygen free radicals in cells.
  • each R 1 and each R 3 is hydroxyl. In some embodiments, at least one of each R 1 is hydroxyl, and at least one of each R 3 is hydroxyl.
  • R 4 , R 5 , R 6 and R 7 are each independently selected from hydrogen or methyl.
  • the compound represented by Formula I is selected from one or more of the following structural formulas:
  • At least one of each R 1 is a hydroxyl group
  • at least one of each R 3 is a hydroxyl group
  • R 4 , R 5 , R 6 and R 7 are each independently selected from hydrogen or methyl.
  • the compound represented by formula I is selected from one or more of the following structures:
  • the compound represented by formula I is selected from one or more of the following structures:
  • compound 1 is 4,4’-(1,3-phenylenebis(methylene))diphenol
  • the name of compound 2 is 4,4’-(1,3-phenylenebis(methylene))bis-2-methylphenol
  • compound 3 is 3,3’-(1,3-phenylenebis(methylene))bis-1,2-benzenediphenol.
  • the application of the compound represented by Formula I includes:
  • the anti-oxidation mainly refers to the removal of intracellular reactive oxygen free radicals
  • Compound 2 and Compound 3 Use of one or both of Compound 2 and Compound 3 in the preparation of skin care products for reducing melanin production, skin care products for preventing pigmentation diseases, skin care products for preventing pigmentation diseases, skin care products for treating pigmentation diseases, skin care products for treating pigmentation diseases, and skin care products for treating pigmentation diseases, and combinations thereof.
  • the pigmentation diseases are selected from freckles, chloasma, stretch marks, age spots, melanoma, and combinations thereof.
  • the application of the compound represented by Formula I includes:
  • pigmentation diseases are selected from freckles, chloasma, stretch marks, age spots, melanoma, and combinations thereof.
  • Compound 1, Compound 2 and Compound 3 have good skin lightening and whitening effects (i.e., for example, they have strong ⁇ -glucosidase and/or tyrosinase inhibitory effects in an in vitro cell test system, reducing the production of cellular melanin); they also have good antioxidant effects (i.e., for example, they have strong free radical scavenging effects in an in vitro cell test system).
  • the above effects are manifested as follows: Compound 1 and Compound 2 have high tyrosinase inhibitory activity, ⁇ -glucosidase inhibitory activity and antioxidant activity, and also have a significantly higher cell melanin synthesis inhibition rate than the classic whitening ingredient phenethyl resorcinol on the market; Compound 3 has extremely excellent ⁇ -glucosidase inhibitory activity and antioxidant activity, and also has a slightly better cell melanin synthesis inhibition rate than the classic whitening ingredient phenethyl resorcinol on the market. Compound 1, Compound 2 and Compound 3 can be prepared in a highly pure form; are acceptable to dermatology and toxicology; and also show good stability to light effects, so they can be used as functional ingredients of whitening and anti-aging cosmetics.
  • the compounds in Formula I especially Compound 1 and Compound 2 have stronger tyrosinase inhibitory activity than the known whitening active compound kojic acid, so they can be used in cosmetics at particularly low concentrations and are therefore toxicologically and dermatologically acceptable.
  • Compound 1 has a tyrosinase inhibitory effect that is about 4 times stronger than kojic acid.
  • Compound 2 has a tyrosinase inhibitory effect that is about 10 times stronger than kojic acid.
  • the in vitro mammalian cell micronucleus test proved that neither compound 1 nor compound 2 showed potential genetic toxicity.
  • the bacterial reverse mutation test proved that compound 1 and compound 2 were tested with standard strains TA97a, TA98, TA100, and TA102, and the results showed no potential genetic toxicity.
  • the skin phototoxicity test proved that compound 1 and compound 2 did not show skin phototoxicity in the guinea pig phototoxicity test.
  • 1,3-bisbenzylphenol derivatives were designed and synthesized for the first time, including but not limited to: 4,4'-(1,3-phenylenebis(methylene))bis-2-methylphenol (Compound 2), 3,3'-(1,3-phenylenebis(methylene))bis-1,2-benzenediol (Compound 3).
  • 1,3-bisbenzylphenol compounds 1-3 have significant activity in inhibiting ⁇ -glucosidase and scavenging free radicals, compounds 1 and 2 have significant activity in inhibiting tyrosinase, and compounds 1, 2 and 3 have a higher cell melanin synthesis inhibition rate than the classic whitening ingredient phenethyl resorcinol on the market.
  • the second aspect of the present application provides a 1,3-bis-benzylphenol compound, the structural formula of which is selected from one or more of the following structural formulas of compound 2 and compound 3:
  • compound 2 is 4,4'-(1,3-phenylenebis(methylene))bis-2-methylphenol.
  • compound 3 is 3,3'-(1,3-phenylenebis(methylene))bis-1,2-benzenediol.
  • the third aspect of the present application provides a method for preparing 1,3-bis-benzylphenol compounds, the preparation method comprising the following steps: mixing raw material A and raw material B in a substance amount ratio of 1:(5-10), the raw material A being selected from 1,3-di(bromomethyl)benzene, 1,3-di(chloromethyl)benzene and a combination thereof, the raw material B being selected from o-cresol, 1,2-benzenediol and a combination thereof, using aluminum chloride as a catalyst, heating the reaction at 100-120°C under nitrogen protection for a period of time, and then purifying by column chromatography to obtain the compound.
  • the reaction is heated at 110° C. for 2 h.
  • the fourth aspect of the present application provides a composition, wherein the composition has one or more of the effects of whitening, anti-skin oxidation, anti-aging and inhibiting food browning, and the composition comprises a compound shown in formula I and a carrier, and the compound shown in formula I is as follows:
  • Each R 1 , each R 2 and each R 3 is independently selected from one or a combination of hydrogen, hydroxyl, halogen, phenyl, halomethoxy, methylamino, methyl and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 4 carbon atoms;
  • R 4 , R 5 , R 6 and R 7 are each independently selected from one or a combination of hydrogen, methyl and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms;
  • n and k are each independently an integer from 1 to 3;
  • the carrier is selected from one or more acceptable carriers in the cosmetics field, the pharmaceutical field, the food field and combinations thereof.
  • each R 1 and each R 3 is hydroxyl.
  • each R 1 is a hydroxyl group
  • at least one of each R 3 is a hydroxyl group.
  • the compound represented by formula I is selected from one or more of the following structures:
  • the composition has at least one of whitening, anti-skin oxidation and anti-aging effects, and the composition is selected from a skin care composition, a pharmaceutical composition and a combination thereof, and the composition includes an effective amount of compound 1 as an active ingredient.
  • Compound 2 Compound 3 At least one of, and one or more acceptable carriers in the field of cosmetics.
  • the above-mentioned pharmaceutical composition is a pharmaceutical composition for treating skin diseases.
  • the skin care composition or the skin disease treatment pharmaceutical composition is related to whitening, anti-skin oxidation, anti-aging and their combination effects.
  • whitening refers to inhibiting tyrosinase activity, inhibiting ⁇ -glucosidase activity, inhibiting cellular melanin production, inhibiting pigmentation and their combination
  • anti-skin oxidation and anti-aging refer to removing active oxygen free radicals in cells.
  • anti-skin oxidation and anti-aging refer to removing active oxygen free radicals generated in cells due to ultraviolet light.
  • acceptable carriers in the cosmetic field refer to conventional cosmetic carriers in the cosmetic field, including emulsifiers (e.g., oil-in-water, water-in-oil, water-in-silicone oil, water-in-water silicone oil, water-in-oil-in-water, oil-in-water-in-oil, silicone oil-in-water-in-oil, etc.), creams, lotions, liquids (e.g., aqueous or aqueous-alcoholic solutions), anhydrous bases (e.g., lipsticks or powders, etc.), gels, ointments, milks, creams, sprays, solids, eye creams, etc.
  • emulsifiers e.g., oil-in-water, water-in-oil, water-in-silicone oil, water-in-water silicone oil, water-in-oil-in-water, oil-in-water-in-oil, silicone oil-in-water-in-oil, etc.
  • creams
  • the cosmetic composition of the present application can be made into various forms of cosmetics, including sunscreen, sunless tanning products, hair care products (such as shampoo, conditioner, hair dye, bleach, hair straightener and perm), nail polish, moisturizer, skin lotion and skin cream, lipstick and lip balm, cleanser, toner, mask, deodorant, antiperspirant, keratin exfoliant, shaving products (cream, aftershave), wet wipes, tanning lotion, bath gel, body oil, foot care products (powder, spray), foundation cream, rouge, eye shadow and eyeliner, lip gloss, mascara, baby products (baby skin cream, body oil, shampoo, talcum powder, wet wipes).
  • these cosmetics can also be used as resident cosmetics or makeup remover cream.
  • the pharmaceutically acceptable carrier comprises one or more anesthetics, antiallergens, antifungals, antimicrobials, anti-inflammatory agents, antioxidants, preservatives, chelating agents, colorants, decolorizing agents, softeners, emulsifiers, exfoliants, film formers, fragrances, wetting agents, insect repellents, lubricants, moisturizers, pharmaceutical agents, photostabilizers, preservatives, skin protectants, skin penetration enhancers, sunscreens, stabilizers, surfactants, thickeners, viscosity regulators, vitamins, or any combination thereof.
  • whitening refers to one or more of inhibiting tyrosinase activity, inhibiting ⁇ -glucosidase activity, inhibiting cellular melanin production and inhibiting pigmentation; anti-skin oxidation and anti-aging refer to removing active oxygen free radicals in cells.
  • the pigmentation is selected from one or more of freckles, chloasma, stretch marks, age spots and melanoma.
  • the composition is selected from one or more of a tyrosinase inhibitor composition and an ⁇ -glucosidase inhibitor composition.
  • the carrier includes one or more of a fragrance, a compound for skin care, a compound for skin cleansing, and an ultraviolet absorber.
  • the composition includes a fragrance and a compound shown in formula I
  • the fragrance is present in an amount effective to provide a sensory effect
  • the compound shown in formula I is present in an amount having one or both of the effects of inhibiting tyrosinase and inhibiting ⁇ -glucosidase.
  • the compound shown in formula I is present in a mass percentage of about 3% to about 30%.
  • one or more excipients, additives, etc. may also be included in the above composition. It has been proven that the substances in the compounds shown in formula I have no odor themselves, or no odor at all, and this property determines that they can be used in perfume compositions.
  • the perfume composition containing the compound shown in formula I contains about 3% to 30% (m/m) of the compound shown in formula I. In one embodiment, the perfume composition contains 3% to 20% (m/m) of the compound shown in formula I.
  • the composition includes a UV absorber and a compound of formula I, the amount of the UV absorber is effective to provide UV protection with a protection factor of at least greater than 2, and the amount of the compound of formula I has one or both of the effects of inhibiting tyrosinase and inhibiting ⁇ -glucosidase. In some embodiments, the amount of the UV absorber is effective to provide UV protection with a protection factor of at least greater than 5.
  • the composition includes one or more of a compound for skin care and a compound for skin cleansing, and a compound of formula I, wherein the amount of the compound of formula I has one or both of the effects of inhibiting tyrosinase and inhibiting ⁇ -glucosidase.
  • composition containing the compound shown in Formula I of the present application can also be used in foods, especially those foods that are prone to spontaneous browning reactions during processing due to their naturally occurring phenolic compound content under the influence of endogenous polyphenol oxidase.
  • foods include fruit and vegetable products, especially apples, pears or potatoes, or crustaceans, especially crabs, lobsters or shrimps. It will be understood that the above only lists some common foods, but is not limited to this.
  • the fifth aspect of the present application provides a use of the above-mentioned composition in the preparation of whitening skin care products, whitening skin disease treatment drugs, anti-aging skin care products, anti-aging skin disease treatment drugs and combinations thereof.
  • the composition is selected from one of a skin care composition and a pharmaceutical composition, and the composition includes an effective amount of compound 1 as an active ingredient.
  • Compound 2 and compound 3 One or more of the .
  • Skin care products or skin disease treatment drugs are related to whitening, anti-skin oxidation, anti-aging and their combination effects.
  • whitening refers to inhibiting tyrosinase activity, inhibiting ⁇ -glucosidase activity, inhibiting cellular melanin production, inhibiting pigmentation and their combination
  • anti-skin oxidation and anti-aging refer to removing active oxygen free radicals in cells.
  • anti-skin oxidation and anti-aging refer to removing active oxygen free radicals generated in cells due to ultraviolet light.
  • the skin care products or dermatological treatments described herein can improve the aesthetic and/or cosmetic appearance of the skin. These improvements can be manifested in any of the following ways: reduction of dermatological aging symptoms, which are attributed to, for example, chronological aging, hormonal aging and/or photoaging; reduction of skin fragility; reduction of pore size; prevention and/or reversal of collagen and/or elastin loss; improvement of the effects of estrogen imbalance; prevention of skin atrophy; prevention and/or reduction of the appearance and/or depth of lines and/or wrinkles, including fine lines and/or wrinkles; prevention, reduction and/or treatment of hyperpigmentation; improvement of liver color, skin clarity and/or firmness; prevention, reduction and improvement of skin sagging; promotion of antioxidant activity; improvement of skin toughness, plumpness, elasticity, suppleness and/or softness; increase of procollagen and/or collagen production; improvement of skin texture and/or promotion of restoration of original texture state; promotion of skin barrier repair and/or function; improvement of skin contour appearance; restoration of skin radi
  • the pharmaceutical composition of the present application can improve the aesthetic appearance, health and vitality of the skin.
  • Such an improvement can be manifested in at least one of the following: reduction of melanin production, treatment of pigmentation diseases, including freckles, melasma, stretch marks, age spots or melanoma; prevention and/or reversal of collagen and/or elastin loss; improvement of skin texture; improvement of skin tone, clarity, and/or firmness; promotion/acceleration of cell renewal; and increase of skin thickness.
  • whitening refers to one or more of inhibiting tyrosinase activity, inhibiting ⁇ -glucosidase activity, inhibiting cellular melanin production and inhibiting pigmentation; anti-skin oxidation and anti-aging refer to removing active oxygen free radicals in cells.
  • the pigmentation is selected from one or more of freckles, chloasma, stretch marks, age spots and melanoma.
  • the sixth aspect of the present application provides a product, which is one of a cosmetic and a skin disease treatment drug, and the product includes the composition of the fourth aspect or includes the compound shown in Formula I.
  • the mass percentage of the compound shown in Formula I in the product (especially the product for local application) is 0.0001% to 10%. Or the mass percentage of the compound shown in Formula I in the product is 0.01% to 2%. Or the mass percentage of the compound shown in Formula I in the product is 0.1% to 1%.
  • Tyrosinase inhibitory active compounds such as compounds shown in Formula I in the product can be used preventively or as needed. For example, the concentration of active compounds used daily varies, depending on the physiological condition of the test subject and personal parameters such as age or weight. The compound shown in Formula I can be used alone or in combination with other tyrosinase inhibitors.
  • the compound shown in the formula I used in the present application can be used in conventional cosmetics or dermatological treatment drugs, such as but not limited to: pump sprays, aerosol sprays, creams, ointments, tinctures, lotions, nail care products (such as nail polish, nail polish remover, nail balm) etc.
  • the compound shown in the formula I used in the present application can also be combined with other active compounds, such as with skin whitening effects or other substances active against senile plaques.
  • the product containing the compound shown in the formula I can be used for skin treatment in the sense of dermatological treatment or treatment in the sense of nursing cosmetics. Of course, it can also be used for decorative cosmetics in makeup products.
  • the product containing the compound shown in Formula I also contains an active compound with whitening effect. It can be understood that there is no particular limitation on the active compound with whitening effect, and all skin whitening active compounds suitable or customarily used for cosmetic and/or dermatological applications can be used.
  • active compounds with whitening effects include kojic acid, kojic acid derivatives, arbutin, ascorbic acid, ascorbic acid derivatives, aloesin, ellagic acid, azelaic acid, thiamine, 4-n-butylresorcinol, diphenylmethane derivatives, sulfur-containing molecules (e.g., glutathione, l-ergothioneine), ⁇ -hydroxy acids (e.g., citric acid, lactic acid, malic acid) and their derivatives, nitrogen oxide synthesis inhibitors (e.g., l-nitroarginine and its derivatives), metal chelators (e.g., c-hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin, humic acid, bile acid, bile extracts, bilirubin, biliverdin, EDTA, EGTA and its derivatives), flavonoids, chalcones, phenylpropanoids, cous,
  • natural active compounds for whitening may also be used in the form of plant extracts, for example, bearberry extract, licorice root extract or components enriched therein, such as glycyrrhizin or lychee A, cinnamon extract, Polygonaceae and Garcinia plant extracts, Pinus (pine) extracts and Vitis plant extracts or stilbene derivatives enriched therein.
  • plant extracts for example, bearberry extract, licorice root extract or components enriched therein, such as glycyrrhizin or lychee A, cinnamon extract, Polygonaceae and Garcinia plant extracts, Pinus (pine) extracts and Vitis plant extracts or stilbene derivatives enriched therein.
  • the product may also contain preservatives, such as benzoic acid, benzoic acid esters and benzoic acid salts, propionic acid and its salts, salicylic acid and its salts, 2,4-hexanoic acid (also known as sorbic acid) and its salts, formaldehyde and polyformaldehyde, 2-hydroxyphenyl ether and its salts, 2-zincthiopyridine-N-oxide, inorganic sulfites and bisulfites, sodium iodate, chlorobutanol, 4-ethylmercury-(II) 5-amino-1,3-bis(2-hydroxybenzoic acid) acid and its salts and esters, dehydrated acid, formic acid, 1,6-bis(4-amino-2-bromo-phenoxy)-n-hexane and its salts, ethylmercury-(II)-thiosalicylic acid sodium salt, phenylmercury and its salt
  • the product containing the compound represented by formula I is applied to the skin in a sufficient amount according to the usual manner of cosmetics and skin products.
  • the total mass percentage of the filter is, for example, 0.01% to 20%, optionally 0.1% to 10%, optionally 1.0% to 5.0%, so that the sunscreen product can protect the skin from ultraviolet radiation.
  • the sunscreen product is capable of achieving a protection factor of at least > 2.
  • the sunscreen product is capable of achieving a protection factor of > 5.
  • the compound shown in Formula I can also be combined with cosmetic adjuvants, for example, antioxidants, perfume oils, anti-foaming agents, colorants, pigments with coloring effects, thickeners, surfactants, emulsifiers, plasticizers, humectants, fats, oils, waxes, and other conventional ingredients of cosmetic formulations, such as monohydric alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives.
  • cosmetic adjuvants for example, antioxidants, perfume oils, anti-foaming agents, colorants, pigments with coloring effects, thickeners, surfactants, emulsifiers, plasticizers, humectants, fats, oils, waxes, and other conventional ingredients of cosmetic formulations, such as monohydric alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives.
  • the product containing the compound shown in Formula I is used for local prevention or cosmetic treatment of the skin, and generally contains a high content of therapeutic substances.
  • the product containing the compound shown in Formula I contains one or more animal therapeutic fats and oils, plant therapeutic fats and oils, such as olive oil, sunflower seed oil, purified soybean oil, palm oil, sesame oil, rapeseed oil, almond oil, borage oil, evening primrose oil, coconut oil, shea butter, jojoba oil, whale oil, tallow, neatsfoot oil and lard, and optionally contains other therapeutic ingredients, such as fatty alcohols with 8-30 carbon atoms.
  • the fatty alcohol can be saturated or unsaturated, and can be straight chain or branched.
  • fatty alcohols are not limited to those listed above, and can also be alcohols related to other structural chemistry.
  • the fatty alcohols are derived from natural fatty acids, usually prepared by reduction of the corresponding esters of the fatty acids.
  • the fatty alcohol fractions formed by reduction of naturally occurring fats and fatty oils can be used, for example, tallow, peanut oil, rapeseed oil, cottonseed oil, soybean oil, sunflower seed oil, palm kernel oil, linseed oil, corn oil, castor oil, rapeseed oil, sesame oil, cocoa butter and cocoa butter.
  • the therapeutic substance may also include: (1) ceramide, which is understood to be N-acyl sphingosine (fatty acid amide of sphingosine) or synthetic analogs of such lipids (so-called pseudoceramides), which significantly improve the water retention of the stratum corneum.
  • ceramide which is understood to be N-acyl sphingosine (fatty acid amide of sphingosine) or synthetic analogs of such lipids (so-called pseudoceramides), which significantly improve the water retention of the stratum corneum.
  • phospholipids such as soybean lecithin, egg lecithin and cephalin.
  • petrolatum, paraffin and silicone oil includes dialkyl and alkyl aryl siloxanes, such as dimethyl polysiloxane and methylphenyl polysiloxane, and their alkoxylated and quaternized derivatives.
  • animal hydrolyzed protein and plant hydrolyzed protein such as elastin, collagen, keratin, milk protein, soy protein, oat protein, pea protein, almond protein and wheat protein fractions or corresponding hydrolyzed proteins, and their condensation products with fatty acids, and quaternized hydrolyzed proteins.
  • plant hydrolyzed protein is used.
  • Formed fatty acid esters (3) monohydric alcohols, dihydric alcohols or polyhydric alcohols with a low carbon number, and ethers thereof, such as ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monobutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether and the like.
  • the solvent can be a mixture of the above-mentioned multiple solvents. In the case of an alcohol solvent, water may be another component.
  • the product containing the compound shown in Formula I may also contain an antioxidant, and all antioxidants suitable or customary for cosmetic and/or dermatological applications may be used.
  • the antioxidant is selected from the following substances: amino acids (e.g., glycine, histidine, tyrosine, tryptophan) and derivatives thereof, imidazoles (e.g., uric acid) and derivatives thereof, peptides such as D, L-carnosine, D-carnosine, L-carnosine and derivatives thereof (e.g., pilose antler), carotenoids, carotenes (e.g., c-carotene, b-carotene, lycopene) and derivatives thereof, lipoic acid and derivatives thereof (e.g., dihydrolipoic acid), gold thioglucose, propylthiouracil and other thiols (e.g., thioredoxime, thiourea ...
  • amino acids e.g
  • ascorbyl palmitate ascorbyl phosphate, ascorbyl acetate
  • tocopherol and its derivatives e.g. vitamin E acetate
  • vitamin A and its derivatives vitamin A palmitate
  • coniferyl benzoate of benzoin resin rutinic acid and its derivatives, ferulic acid and its derivatives, butylated hydroxytoluene, butylated hydroxyanisole, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose and its derivatives, zinc and its derivatives (e.g. ZnO, ZnSO 4 ), selenium and its derivatives (e.g.
  • stilbene and its derivatives e.g. stilbene oxide, trans-stilbene oxide
  • derivatives salts, esters, ethers, sugars, nucleotides, nucleosides, peptides and lipids
  • the product containing the compound of formula I may also contain vitamins and vitamin precursors, and all vitamins and vitamin precursors suitable or customary for cosmetic and/or dermatological applications may be used.
  • vitamins and vitamin precursors suitable or customary for cosmetic and/or dermatological applications may be used.
  • the product containing the compound shown in Formula I can also contain a wetting agent.
  • the wetting agent used is the following material: hyaluronic acid, glycerol, panthenol, pyrrolidone carboxylic acid, urea, glycolic acid, salicylic acid, brazilflavonoid class A, sodium lactate, sorbitol, propylene glycol, collagen, elastin, diester of adipic acid, urocanic acid, lecithin, phytantriol, lycopene, algae extract, ceramide, cholesterol, glycolipid, chitosan, chondroitin sulfate, polyamino acids and sugars, lanolin, lanolin, amino acids, alpha-hydroxy acids (e.g., citric acid, lactic acid, malic acid) and derivatives thereof, monodisaccharides and oligosaccharides, alpha-hydroxy fatty acids, phytosterols, triterpene
  • the product containing the compound shown in Formula I may also contain one or more of an anti-inflammatory active compound, an active compound that reduces redness, and an active compound that reduces itching. It is understood that all anti-inflammatory active compounds, active compounds that reduce redness, and active compounds that reduce itching that are suitable or customary for use in cosmetics and dermatological treatment drugs can be used.
  • the product containing the compound shown in Formula I can also contain plant extract, which is usually prepared by extracting complete plants, but in certain embodiments, it is also possible to extract and prepare separately from the flower, leaf, timber, bark or root of plants.
  • Plant extract can come from aloe, seaweed, avocado, chamomile, coconut, green tea, ginseng, grapefruit, grapefruit seed, rosemary, sunflower, oak bark, willow herb, stinging nettle, wild nettle, hops, marigold, burdock root, hawthorn, linden flower, almond, pine needle, sandalwood, juniper, mango, apricot, orange, lemon, lime, apple, wheat, oat, barley, sage, thyme, basil, birch, mallow, vallisneria, willow bark, asparagus, okra, azalea, ginger root etc.
  • plant extract comes from aloe, algae, avocado, chamomile, coconut, green tea, ginseng, grapefruit, grapefruit, grapefruit,
  • the product containing the compound shown in Formula I can also contain one or more of anionic surfactants, cationic surfactants, nonionic surfactants and amphoteric surfactants.
  • anionic surfactants cationic surfactants
  • nonionic surfactants nonionic surfactants
  • amphoteric surfactants when crystallization or microcrystalline solids (such as inorganic micro-pigment) are incorporated into the product, a surfactant can be added.
  • Surfactant is an amphipathic substance that can dissolve organic non-polar substances in water.
  • the hydrophilic part of the surfactant molecule is generally a polar functional group, such as-COO,-OSO,-SO, and the hydrophobic part is generally a non-polar hydrocarbon radical.
  • Surfactant is generally classified according to the properties and charge of the hydrophilic part of the molecule. Here can be divided into four categories: anionic surfactants, cationic surfactants, amphoteric surfactants and nonionic surfactants.
  • the anionic surfactant is an acyl amino acid (and its salts), such as: (1) acyl glutamate, such as sodium acyl glutamate, sodium bis-TEA-palmitoyl aspartate, and sodium octyl/decyl glutamate; (2) acyl peptides, such as palmitoyl hydrolyzed milk protein, sodium coconut hydrolyzed soy protein, and sodium/potassium coconut hydrolyzed collagen; (3) sarcosinate, such as myristoyl sarcosine, TEA lauroyl sarcosinate, sodium lauroyl sarcosinate, and sodium coconut sarcosinate; (4) taurate, such as sodium lauroyl taurate and sodium methyl cocoyl taurate; (5) acyl lactylates, lauroyl lactylates, alanine carboxylates, capryloyl lactylates and derivatives, such as lauric acid,
  • the cationic surfactant is an alkylamine, an alkylimidazole, an ethoxylated amine and a quaternary ammonium salt surfactant.
  • the quaternary ammonium salt surfactant contains at least one N atom covalently bonded to 4 alkyl or aryl groups. Regardless of the pH value, this will result in a positive charge.
  • the cationic surfactant is one or more of alkyl betaine, alkyl amidopropyl betaine and alkyl amidopropyl hydroxysulfonic acid.
  • the cationic surfactant used can also be selected from the group comprising quaternary ammonium compounds, such as benzene trialkyl ammonium chloride or ammonium bromide, such as phenyl dimethyl stearyl ammonium chloride, and alkyl trialkyl ammonium salts, such as hexadecyl trimethyl ammonium chloride or ammonium bromide, alkyl dimethyl hydroxyethyl chloride or ammonium bromide, dialkyl dimethyl chloride or ammonium bromide, alkyl amidoethyl-trimethyl ammonium ether sulfate, alkyl pyridinium salt, such as dodecyl or hexadecyl pyridinium chloride, imidazoline derivatives and compounds of cationic nature, such as alkyl dimethylamine oxide or alkyl ethyl dimethylamine oxide.
  • the amphoteric surfactant may include: (1) acyl/dialkylethylenediamines, such as sodium acylamide acetate, disodium acylamide dipropionate, disodium alkylamide diacetate, sodium acylamide hydroxypropyl sulfonate, disodium acylamide diacetate and sodium acylamide propionate; (2) N-alkylamino acids, such as aminopropyl alkylpentanediamine, alkylaminopropionic acid, sodium alkylaminodipropionate and laurin ampoulecarboxyglycine.
  • acyl/dialkylethylenediamines such as sodium acylamide acetate, disodium acylamide dipropionate, disodium alkylamide diacetate, sodium acylamide hydroxypropyl sulfonate, disodium acylamide diacetate and sodium acylamide propionate
  • N-alkylamino acids such as aminoprop
  • the nonionic surfactant is an alcohol, an alkanolamide (e.g., cocamide MEA/DEA/MIPA), an amine oxide (e.g., cocamide propylamine oxide), an ester (these esters are esterified by carboxylic acids with ethylene oxide, glycerol, sorbitol or other alcohols), an ether (e.g., ethoxylated/propoxylated alcohols, ethoxylated/propoxylated esters, ethoxylated/propoxylated glycerides, ethoxylated/propoxylated cholesterol, ethoxylated/propoxylated triglycerides, ethoxylated/propoxylated lanolin, ethoxylated/propoxylated silicones, propoxylated POE ethers and alkyl polyglycosides such as dodecyl glucoside, decyl glucoside and coconut gluco
  • anionic surfactants and amphoteric surfactants can be used in combination with one or more nonionic surfactants.
  • the surfactant can be present in the product containing the compound shown in Formula I in a mass percentage of 1% to 90% (m/m), based on the total weight of the product.
  • the product containing the compound shown in Formula I can also exist in the form of emulsion.Oil phase can be selected from the following material groups: mineral oil, mineral wax, fat, wax and other natural and synthetic fat bodies, such as fatty acid and the fatty acid ester formed by alcohol with low carbon number, wherein, the alcohol with low carbon number can be isopropanol, propylene glycol or glycerine, or fatty alcohol and the fatty acid ester formed by alkane acid or fatty acid with low carbon number; Alkyl benzoate; Silicone oil, such as dimethylpolysiloxane, diethylpolysiloxane, diphenylpolysiloxane and mixed form thereof.
  • (a) chain length can be used for saturated and/or unsaturated, branched and/or straight-chain alkane carboxylic acid with 3 to 30 carbon atoms and ester formed by saturated and/or unsaturated, branched and/or straight-chain alcohol with
  • the ester oils include isopropyl myristate, isopropyl palmitate, isopropyl stearate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl isononyl, 2-ethylhexyl palmitate, 2-ethylhexyl laurate, 2-hexyldecyl stearate, 2-octyldodecyl palmitate, oleyl oleate, oleyl erucate, erucyl erucate, and synthetic, semi-synthetic, and natural mixtures of these esters, such as jojoba oil.
  • the oil phase can be selected from the set consisting of branched and straight-chain hydrocarbons and waxes, silicone oils, dialkyl ethers, saturated or unsaturated, branched or straight-chain alcohols and fatty acid triglycerides, specifically, triglycerides of saturated and/or unsaturated, branched and/or straight-chain alkane carboxylic acids with 8 to 24 carbon atoms, for example, 12 to 18 carbon atoms.
  • Fatty acid triglycerides can be selected from the group including synthetic, semi-synthetic and natural oils, such as olive oil, sunflower seed oil, soybean oil, peanut oil, rapeseed oil, almond oil, palm oil, coconut oil, palm kernel oil, etc.
  • any mixture of this oil and wax component can also be used.
  • wax e.g., hexadecyl palmitate
  • the oil phase is selected from the set consisting of 2-ethylhexyl isostearate, octyl dodecanol, isononanoic acid isotriadecanoate, isoeicosane, 2-ethylhexyl coconut acid ester, C2-s alkyl benzoate, capric acid triglyceride and dialkyl ether.
  • a mixture of C2-S-alkyl benzoate and 2-ethylhexyl isostearate a mixture of C2-S-alkyl benzoate and isotriacontanoic acid isotriacontanoic acid and a mixture of C2-S-alkyl benzoate, 2-ethylhexyl isostearate and isotriacontanoic acid isotriacontanoic acid.
  • Hydrocarbon paraffin oil, squalane and squalene can also be used in the oil phase of the present application.
  • the oil phase can also contain cyclic or linear silicone oil or be composed of such oils completely, however, the additional content of other oil phase components except silicone oil or silicone oil-like substances can also be used.
  • Silicone oil can for example be cyclomethicone (for example, decamethylcyclopentasiloxane).
  • silicone oils may also be used, such as undecamethylcyclotrisiloxane, polydimethylsiloxane and polymethylphenylsiloxane.
  • the oil phase may also be a mixture of cyclomethicone with isotrialkyl isononanoate and cyclomethicone with 2-ethylhexyl isostearate.
  • the product containing the compound shown in Formula I exists in the form of emulsion, and water may include: monohydric alcohol, dihydric alcohol or polyhydric alcohol and ether thereof with low carbon number, such as ethanol, isopropanol, propylene glycol, glycerine, ethylene glycol, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, propylene glycol monoethyl ether, propylene glycol monobutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether and analogue, and one or more thickeners, the thickener may be selected from the group comprising silicon dioxide, aluminum silicate, polysaccharide and derivatives thereof, such as hyaluronic acid, xanthan gum, hydroxypropyl methylcellulose.
  • polyacrylate may be selected from the polyacrylate comprising so-called carbomer
  • the product containing the compound shown in Formula I exists in emulsion form can also contain one or more emulsifiers.
  • O/W emulsifier for example emulsifier can be: fatty alcohol ethoxylate, ethoxylated wool wax alcohol, polyethylene glycol ether, fatty acid ethoxylate, polyethylene glycol glycerol fatty acid ester, polyethoxylated sorbitol ester, cholesterol ethoxylate, polyethoxylated triglyceride, alkyl ether carboxylic acid, alkyl ether sulfate, fatty alcohol propoxylate, polypropylene glycol ether.
  • fatty alcohol ethoxy ether is selected from the group consisting of ethoxylated stearyl alcohol, hexadecyl steary
  • the seventh aspect of the present application provides a pharmaceutical composition for treating diabetes, wherein, including a compound and a carrier used as an effective ingredient, the compound used as an effective ingredient is selected from one or more of the compounds shown in Formula I, and the compound shown in Formula I is as follows:
  • Each R 1 , each R 2 and each R 3 is independently selected from one or a combination of hydrogen, hydroxyl, halogen, phenyl, halomethoxy, methylamino, methyl and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 4 carbon atoms;
  • R 4 , R 5 , R 6 and R 7 are each independently selected from one or a combination of hydrogen, methyl and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms;
  • n and k are each independently an integer from 1 to 3;
  • the carrier is selected from one or more acceptable carriers in the pharmaceutical field.
  • the effective amount of the compound used as the active ingredient is selected from compound 1 Compound 2 and compound 3 One or more of the .
  • the pharmaceutical composition for treating diabetes exerts its effect by inhibiting the activity of ⁇ -glucosidase.
  • the eighth aspect of the present application provides a use of the above-mentioned pharmaceutical composition for treating diabetes in the preparation of a drug for treating diabetes.
  • an effective amount of a compound selected from compound 1 is used as an active ingredient.
  • Compound 2 and compound 3 One or more of the .
  • the ninth aspect of the present application provides a pharmaceutical preparation, which includes one or more compounds for treating diabetes and one or more compounds of formula I in an amount that has an ⁇ -glucosidase inhibitory effect; the compounds of formula I are as follows:
  • Each R 1 , each R 2 and each R 3 is independently selected from one or a combination of hydrogen, hydroxyl, halogen, phenyl, halomethoxy, methylamino, methyl and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 4 carbon atoms;
  • R 4 , R 5 , R 6 and R 7 are each independently selected from one or a combination of hydrogen, methyl and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms;
  • n, k are each independently an integer of 1-3.
  • each R 1 and each R 3 is hydroxyl.
  • each R 1 is a hydroxyl group
  • at least one of each R 3 is a hydroxyl group.
  • the compound represented by formula I is selected from one or more of the following structures:
  • the tenth aspect of the present application provides a method for whitening human skin and combating age spots on human skin, comprising administering an effective amount of the composition of the fourth aspect or the product of the sixth aspect to a person in need.
  • the eleventh aspect of the present application provides a method for inhibiting browning of food, comprising applying an effective amount of the composition according to the fourth aspect to the food.
  • the twelfth aspect of the present application provides a method for treating diabetes, comprising administering an effective amount of the pharmaceutical composition of the seventh aspect or the pharmaceutical preparation of the ninth aspect to a person in need thereof.
  • phenylboronic acid compounds (2.4 eq) and 1,3-dibromomethylbenzene (1 eq) were added and dissolved in 25 mL of 1,4-dioxane, potassium carbonate (4.8 eq) and 13 mL of water were added, and after bubbling degassing, tetrakis(triphenylphosphine)palladium (0.025 eq) was added under nitrogen protection, and the mixture was heated to 100° C. and monitored by TLC spot plate until the raw material disappeared.
  • the first step product (1 eq) was dissolved in dichloromethane, cooled to 0°C, and BBr 3 (1M, 4.8 eq) was slowly added dropwise under nitrogen protection. The TLC spot plate was monitored until the raw material disappeared, and the reaction was quenched in water.
  • Example 2 Study on the inhibition of tyrosinase activity by compound 1, compound 2 and compound 3
  • Phosphate buffer (0.2M, pH 6.8): Accurately weigh 2.84 g of Na 2 HPO 4 and 2.4 g of NaH 2 PO 4 , dissolve them in purified water to make up to 100 mL respectively, mix them in equal volumes and adjust the pH to 6.8.
  • L-DOPA solution Accurately weigh 3.95 mg of L-DOPA and dissolve it in 10 mL of phosphate buffer (0.2 M, pH 6.8) to prepare a 2 mmol/L L-DOPA solution.
  • Tyrosinase solution Accurately weigh 1 mg of tyrosinase (enzyme activity is 500 U/mg) and dissolve it in 5 mL of phosphate buffer (0.2 M, pH 6.8) to prepare a tyrosinase solution with an enzyme activity of 100 U/mL.
  • Sample working solution Accurately weigh 10 mg each of compound 1, compound 2, compound 3, and kojic acid and place them in 500 ⁇ L of ultrapure water. Then slowly add 1 M NaOH until the solution is clear and transparent. Finally, make up to 1 mL with purified water to prepare a 10 mg/mL stock solution. Then use the above-mentioned phosphate buffer to dilute the test compounds and the positive control drug kojic acid to the concentrations of 31.2 ⁇ g/mL, 62.5 ⁇ g/mL, 125 ⁇ g/mL, 250.00 ⁇ g/mL and 500.00 ⁇ g/mL of sample working solution.
  • test groups were set up: sample group A 1 , sample negative control group A 2 , enzyme standard group B 1 and enzyme negative control group B 2 ; 3 parallels were set for each sample, and a 200 ⁇ L reaction system was prepared according to Table 1.
  • the corresponding volume of phosphate buffer, the sample solution of each concentration (final concentration was 3.12 ⁇ g/mL, 6.25 ⁇ g/mL, 12.5 ⁇ g/mL, 25 ⁇ g/mL and 50 ⁇ g/mL), tyrosinase solution (final concentration was 20 U/mL) and reaction substrate L-DOPA (final concentration was 1.2 mmol/L) were added to the 96-well plate in sequence, and incubated in a microplate constant temperature oscillator at 37°C for 30 minutes, and then the absorbance of each test group at 475 nm was measured in a multifunctional microplate reader (SPARK 10M, TECAN).
  • SPARK 10M, TECAN multifunctional microplate reader
  • each concentration contains four groups of data, and the four groups of data are compound 3, kojic acid, compound 1 and compound 2 from left to right; when the concentration is 50 ⁇ g/mL, there are three groups of data, and from left to right they are compound 3, kojic acid and compound 1.
  • compound 1, compound 2 and the positive control drug kojic acid all exhibit a dose-dependent inhibitory effect on tyrosinase activity.
  • Example 3 Study on the inhibition of ⁇ -glucosidase activity by compound 1, compound 1 and compound 3
  • Phosphate buffer (0.2M, pH 6.8): Accurately weigh 2.84 g of Na 2 HPO 4 and 2.4 g of NaH 2 PO 4 , dissolve them in purified water to 100 mL respectively, mix equal volumes of the two and adjust the pH to 6.8.
  • ⁇ -Glucosidase solution ⁇ -glucosidase powder from Saccharomyces cerevisiae was prepared into 1U/mL ⁇ -glucosidase solution with phosphate buffer (0.2M, pH 6.8) and stored at -20°C.
  • Substrate PNPG solution 211 mg of 4-nitrobenzene- ⁇ -D-pyranoglucoside (PNPG) was accurately weighed using an analytical balance, and 70 mL of the above phosphate buffer was added to dissolve evenly, and a 10 mmol/L substrate storage solution was prepared and stored at -20°C away from light.
  • mmol/L in this application refers to millimoles per liter
  • ⁇ mol/L in this application refers to micromoles per liter.
  • Positive control working solution Acarbose was selected as the positive control in this experiment. 103.3 mg of acarbose powder was accurately weighed and fully dissolved and mixed with 1 mL of the above phosphate buffer to prepare a 160 mmol/L acarbose mother solution. The mother solution was then diluted with the above phosphate buffer to a positive control working solution with a concentration of 2.5 mmol/L, 5 mmol/L, 10 mmol/L, 20 mmol/L, 40 mmol/L, 80 mmol/L and 160 mmol/L.
  • Test compound working solution Accurately weigh 2.90 mg of compound 1, 3.19 mg of compound 2, and 3.23 mg of compound 3, respectively, and place them in 500 ⁇ L of ultrapure water. Slowly add 1 M NaOH until the solution becomes clear and transparent. Finally, fill up to 1 mL with purified water to prepare a 10 mmol/L compound stock solution.
  • a working solution of compound 1 with a concentration of 0.062mmol/L, 0.125mmol/L, 0.25mmol/L, 0.5mmol/L, 1mmol/L and 2mmol/L
  • a working solution of compound 2 with a concentration of 0.025mmol/L, 0.05mmol/L, 0.1mmol/L, 0.2mmol/L, 0.4mmol/L and 0.8mmol/L
  • a working solution of compound 3 with a concentration of 3.12 ⁇ mol/L, 6.25 ⁇ mol/L, 12.5 ⁇ mol/L, 25 ⁇ mol/L, 50 ⁇ mol/L and 100 ⁇ mol/L.
  • test groups were set up: blank group A, enzyme standard group B, sample negative control group C, sample group D; 3 parallels were set for each sample.
  • 600 ⁇ L of reaction system was prepared, and the corresponding volume of phosphate buffer, working solution of each concentration of the sample to be tested (the final concentration was 20 times diluted by the working solution of the test compound), ⁇ -glucosidase solution (final concentration 0.005U/mL) and reaction substrate PNPG (final concentration 0.5mmol/L) were added to the 96-well plate in turn, and mixed thoroughly.
  • the 96-well plate to be tested was placed in a multifunctional microplate reader (SPARK 10M, TECAN) to measure the absorbance of each test group at 405nm.
  • the inhibition rate of ⁇ -glucosidase was calculated as follows:
  • ⁇ -Glucosidase inhibition rate (%) [1-(D-C)/(B-A)] ⁇ 100.
  • the three compounds and the positive control drug acarbose all have a dose-dependent inhibitory effect on the activity of ⁇ -glucosidase.
  • the ⁇ -glucosidase inhibition rates of compound 1, compound 2, compound 3 and acarbose at different concentrations are respectively corresponding.
  • the half-inhibitory concentration IC 50 of compound 1, compound 2, compound 3 and acarbose on ⁇ -glucosidase were 21.77 ⁇ mol/L, 8.91 ⁇ mol/L, 0.95 ⁇ mol/L and 481.7 ⁇ mol/L, respectively.
  • the mixed sample solution was allowed to stand at room temperature for 10 minutes, and the absorbance (Ai) was measured at a wavelength of 734 nm.
  • 10 ⁇ L of the sample solution of the corresponding concentration was mixed with 200 ⁇ L of 10 mmol/L pH 7.4 phosphate buffer solution, and the background absorbance Aj at a wavelength of 734 nm was measured.
  • Three parallels were set for each sample concentration.
  • the formula for calculating the scavenging rate of the sample for ABTS free radicals is as follows:
  • Example 5 Cell activity test of compound 1, compound 2 and compound 3
  • Sample group Compound 1, Compound 2, Compound 3 and phenethyl resorcinol were respectively dissolved in DMSO and diluted with 1640 culture medium to form a mother solution with a concentration of 38.6 ⁇ mol/L. The mother solution was then diluted with 1640 culture medium to form a series of concentration samples of 19.3 ⁇ mol/L, 9.65 ⁇ mol/L, 4.825 ⁇ mol/L and 2.413 ⁇ mol/L for use.
  • Negative control group 1640 basal culture medium.
  • B16 cells were plated in 96-well plates. After 24 hours, the culture medium was discarded and basal culture medium containing test samples at different concentrations was added. After 24 hours, OD490 nm was detected by MTT method, and the effects of test samples on B16 cell activity were analyzed by t-test.
  • the statistical analysis software was SPSS, and the comparison between the test sample and the negative control was performed using an independent sample t-test.
  • the four groups of data are, from left to right, the cell survival rate data of compound 1, compound 2, compound 3, and phenethylresorcinol.
  • T absorbance of test sample well
  • the statistical analysis software was SPSS, and the comparison between the test sample and the negative control was performed using the independent sample t test.
  • the inhibition rates of 19.3 ⁇ mol/L of compound 1, compound 2, compound 3 and phenethyl resorcinol on B16 cell melanin synthesis were 52.230%, 40.881%, 34.798% and 32.791%, respectively, which had a significant effect on inhibiting cellular melanin synthesis (P ⁇ 0.05).
  • the inhibition rates of compound 1, compound 2 and compound 3 on B16 cell melanin synthesis were significantly higher than that of phenethyl resorcinol, a classic whitening ingredient on the market, indicating that compound 1, compound 2 and compound 3 have excellent whitening effects.
  • Example 7 Whitening efficacy experiment of compound 1 and compound 2 in zebrafish
  • Zebrafish are transparent in the early stages of development, and melanin begins to grow from the retinal epithelium at 24 hours of embryonic development.
  • Pigment cells originate from neural crest cells, which are a group of cells differentiated from the dorsal ectoderm, and then proliferate, migrate, and differentiate into pigment stem cells. Intervention in the melanin formation process can inhibit the formation of melanin.
  • the whiteness of zebrafish skin can be used to evaluate the whitening effect of the sample.
  • the experimental system uses wild AB zebrafish.
  • the zebrafish used are 6 hpf (6 hours after fertilization).
  • the adult fish are raised and bred according to laboratory standard methods, which meet the requirements of international AAALAC certification.
  • compound 1 (0.0002%), compound 1 (0.0001%), and compound 2 (0.0001%) have a whitening effect, while compound 1 (0.00001%), compound 2 (0.00001%), and phenethylresorcinol 377 (0.0002%) do not have a whitening effect.
  • Example 8 In vitro mammalian cell micronucleus assay
  • the in vitro micronucleus (MNvit) test is a genetic toxicity test used to detect micronuclei in the cytoplasm during interphase of cell division.
  • the test process is as follows:
  • DMSO DMEM medium containing serum
  • concentrations of the sample in the medium are IC 50 , 1/2IC 50 and 1/4IC 50 , respectively.
  • Mouse lymphoma cells L5178Y with a passage number of no more than 32 were used to prepare a cell suspension, which was seeded into a 24-well cell culture plate at a seeding volume of 1 mL/well and a cell number of 4 ⁇ 10 5 /well. The plate was placed in a carbon dioxide incubator and cultured for 24 hours at 37°C and 5% CO 2 .
  • the solvent control solution is the same as the test sample solution except that it does not contain the test sample.
  • the positive control solution is 0.25 ⁇ g/mL mitomycin, 10 ⁇ g/mL cyclophosphamide, and 0.3 ⁇ g/mL colchicine.
  • the cells in the cell culture plate are exposed in three ways, including: short-term exposure without metabolic activation system (S9 mixture), short-term exposure with metabolic activation system (S9 mixture), and long-term exposure without metabolic activation system (S9 mixture).
  • the culture plate is placed in a carbon dioxide incubator for incubation according to the requirements of different groups.
  • the micronucleus rate at at least one tested dose showed a statistically significant increase (p value ⁇ 0.05 was considered a significant increase); 2 The increase in micronucleus rate was dose-dependent; 3 The test results at any dose were not within the distribution range of the historical negative control data (within 95%).
  • the bacterial reverse mutation test uses amino acid-requiring strains of Salmonella typhimurium and Escherichia coli to detect point mutations that involve the substitution, addition, or deletion of one or several DNA base pairs.
  • the principle of this bacterial reverse mutation test is that it detects the presence of the reverse mutation in the test strain and restores the functional ability of the bacteria to synthesize the essential amino acids. Reverse transfecting bacteria are detected by their ability to grow in the absence of the amino acids required by the parent test strain.
  • the test process is as follows:
  • Select Salmonella typhimurium TA97a, TA98, TA100, and TA102. Take an appropriate amount of nutrient broth medium, add it to a test tube, inoculate the main plate strain into the nutrient broth medium, shake and culture at 37°C, 150 rpm for 10 hours, and the number of viable bacteria in each milliliter of culture medium is not less than 1 ⁇ 10 9 /mL, and then measure OD 650 .
  • (1) Determination of positive results Directly count the number of reverse mutant colonies growing on the culture medium. If, under conditions of good background growth, the number of reverse mutant colonies of the test substance TA97a, TA98, TA100, and TA102 should increase by more than 1 time (i.e., the number of reverse mutant colonies is equal to or greater than 2 times that of the solvent control) in at least one or more strains, and there is a dose-response relationship, the test substance mutagenicity test can be considered positive.
  • test substance mutagenicity test can be considered positive.
  • the animal was fixed, and 0.2 mL of the sample was applied to the hair removal area 1 and hair removal area 2 of the animal as shown in Table 1 of Specification P501.
  • the left side (hair removal area 1 and hair removal area 3) was covered with aluminum foil and fixed with tape, and the right side (hair removal area 2 and hair removal area 4) was irradiated with UVA.
  • the average light intensity was about 7.011 mW/cm 2
  • the irradiation dose was 10 J/cm 2
  • the time was 1426 seconds.
  • the skin reaction was observed at 1h, 24h, 48h and 72h, and the skin reaction score of each animal was determined according to Table 2 of Specification P501-P502.

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Abstract

本申请涉及一种式I所示的化合物的应用，其中，所述式I所示的化合物如下：式I；各R1、各R2及各R3独立地选自氢、羟基、卤素、苯基、卤代甲氧基、甲基氨基、甲基及具有2-4个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；R4、R5、R6及R7各自独立地选自氢、甲基及具有2-5个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；m、n及k各自独立地为1～3的整数。

Description

1,3-双苄基苯酚类衍生物、制备方法及其应用
相关申请
本申请要求2023年06月05日申请的，申请号为2023106574780，名称为“1,3-双苄基苯酚类化合物、制备方法及其在美白抗衰化妆品中的应用”的中国专利申请的优先权，在此将其全文引入作为参考。
技术领域
本申请属于化妆品和医药技术领域，涉及一种1,3-双苄基苯酚类衍生物、制备方法及其应用。
背景技术
细胞代谢过程中产生的氧自由基会对细胞内生物大分子产生累积性损伤，引起细胞衰老与增殖能力丧失，这种氧化与抗氧化体系的失衡被认为是引起皮肤衰老的重要诱因。酪氨酸酶又称多酚氧化酶，是一种广泛存在于动植物、微生物及人体中的氧化还原酶，是黑色素合成的关键限速酶，与人体皮肤雀斑、褐斑等黑色素过度沉积等的发生密切相关。近年来对其在医药、美容等领域的应用，引起了广泛关注。目前，市场上的皮肤美白增亮剂大多基于对酪氨酸酶的抑制，如α-熊果苷，曲酸，4-丁基间苯二酚等，亦或是基于抗氧化，如维生素C，维生素E及其衍生物，以达到美白的效果。α-熊果苷属于氢醌衍生物，对黑色素细胞具有细胞毒作用并且对皮肤有较强的刺激作用，长期使用可能引起皮肤永久性白斑，已被多国列入了化妆品禁用成分清单。曲酸通过螯合酪氨酸酶的铜离子抑制其催化活性，它用于商品化的皮肤和毛发增亮剂中易导致接触性过敏，还可能引起皮肤病变或引发肝癌。维生素C和维生素E作为人体重要的抗氧化剂，它们不直接抑制酪氨酸酶，而是减少黑色素生物合成中的有色中间体，对皮肤仅具有不充分的美白提亮作用。这些不利因素限制了它们在美白祛斑化妆品市场上的广泛应用。
前期，许刚课题组从中国云南大理白族可食用蔬菜的水生植物海菜花Ottelia acuminata var.acuminata中分离得到了一系列二芳基庚烯多酚类化合物，具有显著的α-葡萄糖苷酶抑制活性，对糖尿病具有潜在的治疗价值(Liu HX,Ma JZ,Ye YS,Zhao JJ,Wan SJ,Hu XY,Xu G.α-Glucosidase inhibitive diarylheptanoids from Ottelia acuminata var.acuminata,a traditional vegetable of Bai Nationality in Yunnan，Natural Products and Bioprospecting 2022,12:22)。研究表明，酪氨酸酶是一种带糖链的蛋白，在其成熟过程中，其原始糖链必须经过一系列修饰剪切，才能转化为成熟酪氨酸酶，并发挥其正常的生物学功效，而α-葡萄糖苷酶I、α-葡萄糖苷酶II则是糖链修饰剪切过程中的关键酶(Mehta A，Zitzmann N，Rudd PM，Block TM，Dwek RA.α-Glucosidase inhibitors as potential broad based anti-viral agents，FEBS Letters，1998，430(1)：17-22)。当α-葡萄糖苷酶受到抑制时，糖蛋白上的糖链修饰受阻，无法产生有活性的酪氨酸酶，则黑色素的形成也相应的减少了(Takahashi H，Parsons PG，Rapid and reversible inhibition of tyrosinase activity by glucosidase inhibitors in human melanoma cells，the Journal of Investigative Dermatology，1992，98(4)：481-487.)。因此，通过抑制α-葡萄糖苷酶来减少酪氨酸酶的成熟，以达到降低黑色素的生成和皮肤色素沉着的目的，是一种新型美白祛斑的可能途径。然而天然来源的二芳基庚烯多酚化合物含量低微，其结构特征为具有顺式、反式烯烃结构，分子稳定性差，易通过烯(ene)反应进行双键移位异构化，不易合成，且分子柔性较大。
发明内容
本申请一些实施例提供一种1,3-双苄基苯酚类衍生物、制备方法及其应用。
本申请技术方案的第一方面是提供一种式I所示的化合物的应用，其中，所述式I所示的化合物如下：
各R1、各R2及各R3独立地选自氢、羟基、卤素、苯基、卤代甲氧基、甲基氨基、甲基及具有2-4个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
R4、R5、R6及R7各自独立地选自氢、甲基及具有2-5个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
m、n及k各自独立地为1～3的整数；
所述应用包括在制备酪氨酸酶抑制剂、制备α-葡萄糖苷酶抑制剂、制备治疗糖尿病药物、制备美白产品、制备抗皮肤氧化产品、制备抗衰老产品、制备减少黑色素生成的护肤品、制备减少黑色素生成的皮肤病治疗药物、制备预防色素沉着疾病的护肤品、制备预防色素沉着疾病的皮肤病治疗药物、制备治疗色素沉着疾病的护肤品、制备治疗色素沉着疾病的皮肤病治疗药物及抑制食物褐变中的一种或几种中的应用。
在其中一些实施例中，各R1及各R3中至少有一个为羟基。
在其中一些实施例中，各R1中至少有一个为羟基，各R3中至少有一个为羟基。
在其中一些实施例中，所述式I所示的化合物选自如下结构中的一种或几种：
所述应用包括在制备α-葡萄糖苷酶抑制剂、制备治疗糖尿病药物、制备抗皮肤氧化、制备抗衰老产品、制备减少黑色素生成的护肤品、制备减少黑色素生成的皮肤病治疗药物、制备预防色素沉着疾病的护肤品、制备预防色素沉着疾病的皮肤病治疗药物、制备治疗色素沉着疾病的护肤品及制备治疗色素沉着疾病的皮肤病治疗药物中的一种或几种中的应用。
在其中一些实施例中，所述式I所示的化合物选自所述应用包括制备酪氨酸酶抑制剂。
在其中一些实施例中，所述式I所示的化合物选自所述应用包括在制备酪氨酸酶抑制剂、制备α-葡萄糖苷酶抑制剂、制备治疗糖尿病药物、制备抗皮肤氧化产品、制备抗衰老产品、制备减少黑色素生成的护肤品、制备减少黑色素生成的皮肤病治疗药物、制备预防色素沉着疾病的护肤品、制备预防色素沉着疾病的皮肤病治疗药物、制备治疗色素沉着疾病的护肤品及制备治疗色素沉着疾病的皮肤病治疗药物中的一种或几种中的应用。
在其中一些实施例中，所述色素沉着疾病选自雀斑、黄褐斑、妊娠纹、老年斑及黑色素瘤中的一种或几种。
在其中一些实施例中，所述抗皮肤氧化和抗衰老是指清除细胞内的活性氧自由基。
本申请的第二方面提供一种1,3-双苄基苯酚类化合物，其结构式选自以下化合物2的结构式及化合物3的结构式中的一种或几种：
本申请的第三方面提供一种1,3-双苄基苯酚类化合物的制备方法，所述制备方法包括以下步骤：将原料A与原料B按物质的量之比1：(5～10)混合，所述原料A选自1,3-二(溴甲基)苯、1,3-二(氯甲基)苯和其组合，所述原料B选自邻甲酚、1,2-苯二酚和其组合，以三氯化铝为催化剂，在氮气保护下，100-120℃加热反应一段时间，再经柱层析纯化，制得。
本申请的第四方面提供一种组合物，其中，所述组合物具有美白、抗皮肤氧化、抗衰老及抑制食物褐变中的一种或几种功效，所述组合物包括式I所示的化合物以及载体，所述式I所示的化合物如下:
各R1、各R2及各R3独立地选自氢、羟基、卤素、苯基、卤代甲氧基、甲基氨基、甲基及具有2-4个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
R4、R5、R6及R7各自独立地选自氢、甲基及具有2-5个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
m、n及k各自独立地为1～3的整数；
所述载体选自一种或多种化妆品领域、药学领域、食品领域和其组合中可接受的载体。
在其中一些实施例中，各R1及各R3中至少有一个为羟基。
在其中一些实施例中，各R1中至少有一个为羟基，各R3中至少有一个为羟基。
在其中一些实施例中，所述式I所示的化合物选自如下结构中的一种或几种：
在其中一些实施例中，所述组合物具有美白、抗皮肤氧化及抗衰老中的至少一种功效，包括作为有效成分的使用有效量的化合物1化合物2化合物3中的至少一种，和一种或多种化妆品领域中可接受的载体。
在其中一些实施例中，美白是指抑制酪氨酸酶活性、抑制α-葡萄糖苷酶活性、抑制细胞黑色素生成及抑制色素沉着中的一种或几种；抗皮肤氧化和抗衰老是指清除细胞内的活性氧自由基。
在其中一些实施例中，所述色素沉着选自雀斑、黄褐斑、妊娠纹、老年斑及黑色素瘤中的一种或几种。
在其中一些实施例中，所述组合物选自酪氨酸酶抑制剂组合物和α-葡萄糖苷酶抑制剂组合物中的一种或几种。
在其中一些实施例中，所述载体包括香精、用于皮肤护理的化合物、用于皮肤清洁的化合物和紫外线吸收剂中的一种或几种。
在其中一些实施例中，所述组合物包括香精和所述式I所示的化合物，所述香精以有效提供感官效果的量存在，所述式I所示的化合物以具有抑制酪氨酸酶作用和抑制α-葡萄糖苷酶作用中的一种或两种作用的量存在。
在其中一些实施例中，在所述组合物中，所述式I所示的化合物以约3％至约30％的质量百分比存在。
在其中一些实施例中，所述组合物包括紫外线吸收剂和式I所示的化合物，所述紫外线吸收剂的量有效地提供保护系数至少大于2的紫外线保护，所述式I所示的化合物的量具有抑制酪氨酸酶和抑制α-葡萄糖苷酶中的一种或两种作用。
在其中一些实施例中，所述组合物包括用于皮肤护理的化合物及用于皮肤清洁的化合物中的一种或几种，以及式I所示的化合物，所述式I所示的化合物的量具有抑制酪氨酸酶和抑制α-葡萄糖苷酶中的一种或两种作用。
本申请的第五方面提供一种如上述的组合物在制备美白护肤品、美白皮肤病治疗药物、抗衰老护肤品、抗衰老皮肤病治疗药物和其组合中的应用。
在其中一些实施例中，所述组合物选自护肤品组合物和药物组合物中的一种，所述组合物包括作为有效成分的使用有效量的化合物1化合物2及化合物3中的一种或几种。
在其中一些实施例中，美白是指抑制酪氨酸酶活性、抑制α-葡萄糖苷酶活性、抑制细胞黑色素生成及抑制色素沉着中的一种或几种；抗皮肤氧化和抗衰老是指清除细胞内的活性氧自由基。
在其中一些实施例中，所述色素沉着选自雀斑、黄褐斑、妊娠纹、老年斑及黑色素瘤中的一种或几种。
本申请的第六方面提供一种产品，所述产品为化妆品及皮肤病治疗药物中的一种，所述产品包括上述的组合物或包括式I所示的化合物，
各R1、各R2及各R3独立地选自氢、羟基、卤素、苯基、卤代甲氧基、甲基氨基、甲基及具有2-4个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
R4、R5、R6及R7各自独立地选自氢、甲基及具有2-5个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
m、n及k各自独立地为1～3的整数。在其中一些实施例中，所述式I所示的化合物在所述产品中的质量百分比为0.0001％～10％。
在其中一些实施例中，所述式I所示的化合物在所述产品中的质量百分比为0.01％～2％。
在其中一些实施例中，所述式I所示的化合物在所述产品中的质量百分比为0.1％～1％。
本申请的第七方面提供一种治疗糖尿病的药物组合物，其中，包括作为有效成分的使用有效量的化合物和载体，所述作为有效成分的使用有效量的化合物选自式I所示的化合物中的一种或几种，所述式I所示的化合物如下:
各R1、各R2及各R3独立地选自氢、羟基、卤素、苯基、卤代甲氧基、甲基氨基、甲基及具有2-4个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
R4、R5、R6及R7各自独立地选自氢、甲基及具有2-5个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
m、n及k各自独立地为1～3的整数；
所述载体选自一种或多种药学领域中可接受的载体。
在其中一些实施例中，所述作为有效成分的使用有效量的化合物选自化合物1化合物2和化合物3中的一种或几种。
本申请的第七方面提供一种如上述的药物组合物在制备治疗糖尿病药物中的应用。
在其中一些实施例中，作为有效成分的使用有效量的化合物选自化合物1化合物2及化合物3中的一种或几种。
本申请的第九方面提供一种药物制剂，其中，包括一种或多种治疗糖尿病的化合物，以及一种或多种具有抑制α-葡萄糖苷酶作用的量的式I所示的化合物；所述式I所示的化合物如下：
各R1、各R2及各R3独立地选自氢、羟基、卤素、苯基、卤代甲氧基、甲基氨基、甲基及具有2-4个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
R4、R5、R6及R7各自独立地选自氢、甲基及具有2-5个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
m、n及k各自独立地为1～3的整数。
在其中一些实施例中，各R1及各R3中至少有一个为羟基。
在其中一些实施例中，各R1中至少有一个为羟基，各R3中至少有一个为羟基。
在其中一些实施例中，所述式I所示的化合物选自如下结构中的一种或几种：
本申请的第十方面提供一种用于人类皮肤美白和对抗人类皮肤老年斑的方法，包括给需要的人施用有效量的如上述的组合物或上述的产品。
本申请的第十一方面提供一种用于抑制食品褐变的方法，包括将有效量的如上述的组合物施用于食品。
本申请的第十二方面提供一种治疗糖尿病的方法，包括给需要的人施用有效量的上述的药物组合物或上述的药物制剂。
本申请的一个或多个实施例的细节在下面的描述中提出。本申请的其他特征、目的和优点将从说明书以及权利要求书变得明显。
附图说明
为了更清楚地说明本申请实施例或传统技术中的技术方案，下面将对实施例或传统技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本申请的实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据公开的附图获得其他的附图。
图1：本申请实施例提供的化合物1的1H NMR谱图(500MHz,DMSO-d6)。
图2：本申请实施例提供的化合物1的13C NMR谱图(125MHz,DMSO-d6)。
图3：本申请实施例提供的化合物2的1H NMR谱图(600MHz,DMSO-d6)。
图4：本申请实施例提供的化合物2的13C NMR谱图(150MHz,DMSO-d6)。
图5：本申请实施例提供的化合物3的1H NMR谱图(500MHz,DMSO-d6)。
图6：本申请实施例提供的化合物3的13C NMR谱图(125MHz,DMSO-d6)。
图7：本申请实施例提供的化合物4的1H NMR谱图(600MHz,DMSO-d6)。
图8：本申请实施例提供的化合物4的13C NMR谱图(150MHz,DMSO-d6)。
图9：本申请实施例提供的化合物5的1H NMR谱图(500MHz,DMSO-d6)。
图10：本申请实施例提供的化合物5的13C NMR谱图(125MHz,DMSO-d6)。
图11：本申请实施例提供的化合物6的1H NMR谱图(600MHz,MeOD)。
图12：本申请实施例提供的化合物6的13C NMR谱图(150MHz,MeOD)。
图13：本申请实施例提供的化合物7的1H NMR谱图(500MHz,CDCl3)。
图14：本申请实施例提供的化合物7的13C NMR谱图(125MHz,CDCl3)。
图15：本申请实施例提供的化合物8的1H NMR谱图(500MHz,CDCl3)。
图16：本申请实施例提供的化合物8的13C NMR谱图(125MHz,CDCl3)。
图17：本申请实施例提供的化合物9的1H NMR谱图(500MHz,CDCl3)。
图18：本申请实施例提供的化合物9的13C NMR谱图(125MHz,CDCl3)。
图19：本申请实施例提供的化合物10的1H NMR谱图(500MHz,CDCl3)。
图20：本申请实施例提供的化合物10的13C NMR谱图(125MHz,CDCl3)。
图21：本申请实施例提供的化合物11的1H NMR谱图(600MHz,CDCl3)。
图22：本申请实施例提供的化合物11的13C NMR谱图(150MHz,CDCl3)。
图23：本申请实施例提供的化合物12的1H NMR谱图(500MHz,CDCl3)。
图24：本申请实施例提供的化合物12的13C NMR谱图(125MHz,CDCl3)。
图25：本申请实施例提供的化合物13的1H NMR谱图(600MHz,MeOD)。
图26：本申请实施例提供的化合物13的13C NMR谱图(150MHz,MeOD)。
图27：本申请实施例提供的化合物14的1H NMR谱图(500MHz,CDCl3)。
图28：本申请实施例提供的化合物14的13C NMR谱图(125MHz,CDCl3)。
图29：本申请实施例提供的化合物15的1H NMR谱图(600MHz,CDCl3)。
图30：本申请实施例提供的化合物15的13C NMR谱图(150MHz,CDCl3)。
图31：本申请实施例提供的化合物16的1H NMR谱图(600MHz,CDCl3)。
图32：本申请实施例提供的化合物16的13C NMR谱图(150MHz,CDCl3)。
图33：本申请实施例提供的化合物17的1H NMR谱图(500MHz,DMSO-d6)。
图34：本申请实施例提供的化合物17的13C NMR谱图(125MHz,DMSO-d6)。
图35：本申请实施例提供的化合物18的1H NMR谱图(500MHz,CDCl3)。
图36：本申请实施例提供的化合物18的13C NMR谱图(125MHz,CDCl3)。
图37：本申请实施例提供的化合物19的1H NMR谱图(600MHz,CDCl3)。
图38：本申请实施例提供的化合物20的1H NMR谱图(600MHz,CDCl3)。
图39：本申请实施例提供的化合物21的1H NMR谱图(600MHz,MeOD)。
图40：本申请实施例提供的化合物21的13C NMR谱图(150MHz,MeOD)。
图41：本申请实施例提供的化合物22的1H NMR谱图(600MHz,CDCl3)。
图42：本申请实施例提供的化合物22的13C NMR谱图(150MHz,CDCl3)。
图43：本申请实施例提供的化合物23的1H NMR谱图(600MHz,CDCl3)。
图44：本申请实施例提供的化合物23的13C NMR谱图(150MHz,CDCl3)。
图45：本申请实施例提供的化合物24的1H NMR谱图(600MHz,CDCl3)。
图46：本申请实施例提供的化合物24的13C NMR谱图(150MHz,CDCl3)。
图47：本申请实施例提供的化合物25的1H NMR谱图(500MHz,DMSO-d6)。
图48：本申请实施例提供的化合物25的13C NMR谱图(125MHz,CDCl3)。
图49：本申请实施例提供的化合物26的1H NMR谱图(500MHz,DMSO-d6)。
图50：本申请实施例提供的化合物26的13C NMR谱图(125MHz,DMSO-d6)。
图51：本申请实施例提供的化合物27的1H NMR谱图(600MHz,DMSO-d6)。
图52：本申请实施例提供的化合物27的13C NMR谱图(150MHz,DMSO-d6)。
图53：本申请实施例提供的化合物28的1H NMR谱图(500MHz,DMSO-d6)。
图54：本申请实施例提供的化合物28的13C NMR谱图(125MHz,DMSO-d6)。
图55：本申请实施例提供的化合物29的1H NMR谱图(600MHz,DMSO-d6)。
图56：本申请实施例提供的化合物29的13C NMR谱图(150MHz,DMSO-d6)。
图57：本申请实施例提供的化合物30的1H NMR谱图(500MHz,DMSO-d6)。
图58：本申请实施例提供的化合物30的13C NMR谱图(125MHz,DMSO-d6)。
图59：本申请实施例提供的化合物31的1H NMR谱图(600MHz,DMSO-d6)。
图60：本申请实施例提供的化合物31的13C NMR谱图(150MHz,DMSO-d6)。
图61：本申请实施例提供的三种化合物及阳性药曲酸对酪氨酸酶活性的影响。
图62：本申请实施例提供的三种化合物及阳性阿卡波糖对α-葡萄糖苷酶活性的抑制作用。
图63：本申请实施例提供的三种化合物及阳性药维生素E对ABTS自由基的清除效果。
图64：本申请实施例提供的三种化合物及阳性药苯乙基间苯二酚对B16细胞活性的影响。
图65：本申请实施例提供的化合物1、化合物2、化合物3及苯乙基间苯二酚对B16细胞黑素合成的影响。
图66：本申请实施例提供的化合物1和化合物2斑马鱼美白典型图(虚线部位为定量区域)。
图67：动物皮肤去毛区位置示意图。
具体实施方式
下面将结合本申请实施例中的附图，对本申请实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本申请保护的范围。
在本文中，室温指温度为10℃～30℃。例如，温度为10℃、12℃、15℃、18℃、20℃、22℃、25℃、28℃、30℃或这些取值中任意两者所组成的范围。可选地，室温指温度为20℃～30℃，例如，室温指温度为20℃～25℃。
如背景技术所述，二芳基庚烯多酚类化合物具有显著的α-葡萄糖苷酶抑制活性，通过抑制α-葡萄糖苷酶来减少酪氨酸酶的成熟，以达到降低黑色素的生成和皮肤色素沉着的目的，是一种新型美白祛斑的可能途径。但天然来源的二芳基庚烯多酚类化合物存在含量低微，分子稳定性差，易通过烯(ene)反应进行双键移位异构化，不易合成，且分子柔性较大等问题，为解决药源问题，本申请以这类天然产物为先导化合物，以此作为模板，利用构象限制和生物电子等排替换策略将其开链柔性分子结构简化及替换为刚性苯环多酚类结构类似物，同时，为了提高抗氧化活性，增加了苯环上的酚羟基，合成出了一系列1,3-双苄基苯酚类衍生物，并对其酪氨酸酶抑制活性、α-葡萄糖苷酶抑制活性、抗氧化活性及抑制细胞黑素生成活性进行了研究。其中化合物1虽然是已知化合物(Larry Q.Reyes,Salumeh Issazadeh,Jane Zhang,Buu Dao,and Russell J.Varley,Synthesis of Tri-Aryl Methane Epoxy Resin Isomers and Their Cure with Aromatic Amines,Macromolecular Materials and Engineering,Macromol.Mater.Eng.2020,305(2),1900546.)，但没有任何有关生物活性的报道，化合物1，化合物2，化合物3的抗氧化活性、酪氨酸酶抑制活性、α-葡萄糖苷酶抑制活性系首次发现，化合物2和化合物3是新化合物。这类成分具有高于市场经典美白成分苯乙基间苯二酚的细胞黑素合成抑制率，在美白、抗衰老以及糖尿病治疗方面具有很好的应用前景。
第一方面，提供一种式I所示的化合物的应用，其中，所述式I所示的化合物如下：
各R1、各R2及各R3独立地选自氢、羟基、卤素、苯基、卤代甲氧基、甲基氨基、甲基及具有2-4个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
R4、R5、R6及R7各自独立地选自氢、甲基及具有2-5个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
m、n及k各自独立地为1～3的整数；
所述应用包括在制备酪氨酸酶抑制剂、制备α-葡萄糖苷酶抑制剂、制备治疗糖尿病药物、制备美白产品、制备抗皮肤氧化产品、制备抗衰老产品、制备减少黑色素生成的护肤品、制备减少黑色素生成的皮肤病治疗药物、制备预防色素沉着疾病的护肤品、制备预防色素沉着疾病的皮肤病治疗药物、制备治疗色素沉着疾病的护肤品、制备治疗色素沉着疾病的皮肤病治疗药物及抑制食物褐变中的一种或几种中的应用。
在式I所示的通式中，(R1)m表示苯环上连接有m个R1基团，m为1、2或3，各R1可以相同，也可以不同，彼此各自独立地选自氢、羟基、卤素、甲基及具有2-4个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合。且m个R1基团可以连接在苯环上的任意位置，并无特别限定。(R2)n及(R3)k具有相似的含义，在此不再赘述。
申请人对式I所示的化合物的活性研究证实，式I所示的化合物和含有一种或多种式I所示化合物的混合物，具有强的酪氨酸酶抑制作用和α-葡萄糖苷酶抑制作用，因此非常适合用作皮肤美白剂和抗老年斑剂等。且由于它们对光的高稳定性，非常适合用作化妆品等产品中的皮肤美白剂，作为已知皮肤美白活性化合物(例如对苯二酚、熊果苷或抗坏血酸)的替代品或补充剂。酪氨酸酶抑制作用通常发生在美容方面，但在一些情况下也可以有治疗的特点，因此，上述式I所示的化合物还可以用于皮肤病药物治疗方面。例如，式I所示的化合物，特别是当它们被用作皮肤美白剂或抗老年斑剂时，通常以溶液、面霜、乳液、凝胶、喷雾剂或类似物的形式局部应用。
此外，式I所示的化合物还可用于食品工业中作为抗褐变添加剂。α-葡萄糖苷酶抑制还可阻断糖蛋白上糖链修饰产生活性酪氨酸酶，黑色素形成相应减少。此外，所述式I所示的化合物还可在制药工业中用作抗糖尿病药。例如，被用作口服抗糖尿病药物。
在其中一些实施例中，所述色素沉着疾病选自雀斑、黄褐斑、妊娠纹、老年斑及黑色素瘤中的一种或几种。
在其中一些实施例中，所述抗皮肤氧化和抗衰老是指清除细胞内的活性氧自由基。
在其中一些实施例中，各R1及各R3中至少有一个为羟基。在其中一些实施例中，各R1中至少有一个为羟基，各R3中至少有一个为羟基。
在其中一些实施例中，R4、R5、R6及R7各自独立地选自氢或甲基。
在其中一些实施例中，所述式I所示的化合物选自如下结构通式中的一种或几种：
各R1中至少有一个为羟基，各R3中至少有一个为羟基，R4、R5、R6及R7各自独立地选自氢或甲基。
在其中一些实施例中，所述式I所示的化合物选自如下结构中的一种或几种：
在其中一些实施例中，式I所示的化合物选自如下结构中的一种或几种：
其中，化合物1的名称为4,4’-(1,3-亚苯基双(亚甲基))二苯酚；化合物2的名称为4,4’-(1,3-亚苯基双(亚甲基))双2-甲基苯酚；化合物3的名称为3,3’-(1,3-亚苯基双(亚甲基))双1,2-苯二酚。
在其中一些实施例中，式I所示的化合物的应用包括：
(1)化合物2和化合物3中的一种或两种在制备α-葡萄糖苷酶抑制剂中的应用；
(2)化合物2和化合物3中的一种或两种在制备治疗糖尿病药物中的应用。
(3)化合物2和化合物3中的一种或两种在制备抗皮肤氧化产品、抗衰老产品和其组合中的应用。其中，所述抗氧化主要是指清除细胞内活性氧自由基；
(4)化合物2和化合物3中的一种或两种在制备减少黑色素生成的护肤品、减少黑色素生成的皮肤病治疗药物、预防色素沉着疾病的护肤品、预防色素沉着疾病的皮肤病治疗药物、治疗色素沉着疾病的护肤品、治疗色素沉着疾病的皮肤病治疗药物和其组合中的应用。其中，所述色素沉着类疾病选自雀斑、黄褐斑、妊娠纹、老年斑、黑色素瘤和其组合。
(5)上述化合物2在制备酪氨酸酶抑制剂中的应用。
在另外一些实施例中，式I所示的化合物的应用包括：
(1)化合物1在制备酪氨酸酶抑制剂中的应用。
(2)化合物1在制备α-葡萄糖苷酶抑制剂中的应用。
(3)化合物1在制备治疗糖尿病药物中的应用。
(4)化合物1在制备抗皮肤氧化产品、抗衰老产品和其组合中的应用。其中，所述抗氧化主要是指清除细胞内活性氧自由基。
(5)化合物1在制备减少黑色素生成的护肤品、减少黑色素生成的皮肤病治疗药物、预防色素沉着疾病的护肤品、预防色素沉着疾病的皮肤病治疗药物、治疗色素沉着疾病的护肤品、治疗色素沉着疾病的皮肤病治疗药物和其组合中的应用。其中，所述色素沉着类疾病选自雀斑、黄褐斑、妊娠纹、老年斑、黑色素瘤和其组合。
化合物1、化合物2和化合物3具有良好的亮肤美白效果(即，例如，在细胞体外测试系统中有较强的α-葡萄糖苷酶和/或酪氨酸酶抑制作用，减少细胞黑色素的生成)；也具有良好的抗氧化效果(即，例如，在细胞体外测试系统中有较强自由基清除作用)。
在其中一些实施例中，上述效果体现为：化合物1和化合物2具有较高的酪氨酸酶抑制活性、α-葡萄糖苷酶抑制活性以及抗氧化活性，还具有明显高于市场经典美白成分苯乙基间苯二酚的细胞黑素合成抑制率；化合物3具有极优异的α-葡萄糖苷酶抑制活性以及抗氧化活性，还具有略优于市场经典美白成分苯乙基间苯二酚的细胞黑素合成抑制率。化合物1、化合物2和化合物3可以以高纯的形式制备；是皮肤病学和毒理学可接受的；还对光作用表现出良好的稳定性，因此可以用作美白抗衰化妆品的功效成分。
实验证明，化合物1和化合物2在特定的无细胞或细胞体外测试系统中，以及在斑马鱼体内实验中，能够有效抑制酪氨酸酶。例如，通过斑马鱼实验证明，化合物1在浓度为0.0002％和浓度为0.0001％时，化合物2在浓度为0.0001％时具有美白功效，能够抑制黑色素生成，而经典美白成分苯乙基间苯二酚377在浓度为0.0002％时不具有美白功效。
申请人发现，式I中的化合物，特别是化合物1和化合物2，与已知的美白活性化合物曲酸相比，具有更强的酪氨酸酶抑制活性，因此它们可以在化妆品中以特别低的浓度使用，因此在毒理学和皮肤学上是可接受的。其中，化合物1具有酪氨酸酶抑制作用，其作用比曲酸强约4倍。化合物2具有酪氨酸酶抑制作用，其作用比曲酸强约10倍。
且通过体外哺乳动物细胞微核试验证明，化合物1和化合物2均未表现出潜在遗传毒性。细菌回复突变试验证明，化合物1和化合物2用标准菌株TA97a、TA98、TA100、TA102检测，结果显示无潜在遗传毒性。通过皮肤光毒检测试验证明，化合物1和化合物2对豚鼠光毒性实验中，未见皮肤光毒性。
本申请具有如下优点及有益效果：
1、基于海菜花中具有α-葡萄糖苷酶抑制活性的二芳基庚烯多酚类化合物为母体，首次设计并合成了一系列1,3-双苄基苯酚类衍生物，包括但不限于：4,4’-(1,3-亚苯基双(亚甲基))双2-甲基苯酚(化合物2)，3,3’-(1,3-亚苯基双(亚甲基))双1，2-苯二酚(化合物3)。
2、首次公开了1,3-双苄基苯酚类化合物1-3在抑制α-葡萄糖苷酶以及清除自由基方面具有显著活性，化合物1和化合物2在抑制酪氨酸酶方面具有显著活性，化合物1、化合物2和化合物3具有高于市场经典美白成分苯乙基间苯二酚的细胞黑素合成抑制率。
3、本申请所报道的化合物1、化合物2和化合物3，合成步骤简单，收率高，制造成本较低，有较好的安全稳定性，在美白提亮抗衰化妆品领域具有良好的开发应用前景。
本申请的第二方面提供一种1,3-双苄基苯酚类化合物，其结构式选自以下化合物2的结构式及化合物3的结构式中的一种或几种：
其中，化合物2的名称为4,4’-(1,3-亚苯基双(亚甲基))双2-甲基苯酚。
化合物3的名称为3,3’-(1,3-亚苯基双(亚甲基))双1,2-苯二酚。
本申请的第三方面提供一种1,3-双苄基苯酚类化合物的制备方法，所述制备方法包括以下步骤：将原料A与原料B按物质的量之比1：(5～10)混合，所述原料A选自1,3-二(溴甲基)苯、1,3-二(氯甲基)苯和其组合，所述原料B选自邻甲酚、1,2-苯二酚和其组合，以三氯化铝为催化剂，在氮气保护下，100-120℃加热反应一段时间，再经柱层析纯化，制得。
在一些实施例中，在110℃加热反应2h。
本申请的第四方面提供一种组合物，其中，所述组合物具有美白、抗皮肤氧化、抗衰老及抑制食物褐变中的一种或几种功效，所述组合物包括式I所示的化合物以及载体，所述式I所示的化合物如下:
各R1、各R2及各R3独立地选自氢、羟基、卤素、苯基、卤代甲氧基、甲基氨基、甲基及具有2-4个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
R4、R5、R6及R7各自独立地选自氢、甲基及具有2-5个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
m、n及k各自独立地为1～3的整数；
所述载体选自一种或多种化妆品领域、药学领域、食品领域和其组合中可接受的载体。
在其中一些实施例中，各R1及各R3中至少有一个为羟基。
在其中一些实施例中，各R1中至少有一个为羟基，各R3中至少有一个为羟基。
应指出，在本文上下文中，对于具有不同取代的苯基自由基且同时R4、R5、R6及R7不同的式I所示的化合物，包括纯S构型对映体、R构型对映体和S构型和R构型对映体的任意混合物。在一些实施例中，由于外消旋混合物容易通过合成获得，使用式I所示化合物的外消旋混合物用来美白和/或对抗老年斑中，在另一些实施例中，这些对映体的纯对映体或非外消旋混合物也适用于美白和/或对抗老年斑中。
在其中一些实施例中，所述式I所示的化合物选自如下结构中的一种或几种：
在其中一些实施例中，所述组合物具有美白、抗皮肤氧化及抗衰老中的至少一种功效，所述组合物选自护肤品组合物、药物组合物和其组合，组合物包括作为有效成分的使用有效量的化合物1化合物2化合物3中的至少一种，和一种或多种化妆品领域中可接受的载体。
在一些实施例中，上述药物组合物是指皮肤病治疗药物组合物。
护肤品组合物或皮肤病治疗药物组合物是与美白、抗皮肤氧化、抗衰老和其组合作用有关的。其中：美白是指抑制酪氨酸酶活性、抑制α-葡萄糖苷酶活性、抑制细胞黑色素生成、抑制色素沉着和其组合；抗皮肤氧化和抗衰老是指清除细胞内的活性氧自由基。在其中一些实施例中，抗皮肤氧化和抗衰老是指清除细胞内因紫外光照而产生的活性氧自由基。
在一些实施例中，化妆品领域中可接受的载体是指化妆品领域常规的化妆品载体，这些载体包括乳化剂(例如水包油、油包水、硅油包水、水包硅油、水包油包水、油包水包油、油包水包硅油等)，霜剂，护肤液，液体(例如水剂或水-醇溶液)，无水基质(例如唇膏或粉剂等)，啫喱，油膏，奶液，软膏，喷雾剂，固体剂，眼霜等。
在一些实施例中，本申请中的化妆品组合物可制成各种形式的化妆品，这些化妆品包括防晒霜、无日光美黑产品、护发产品(如洗发液、护发素、染发剂、漂白剂、直发剂和烫发剂)，指甲油、保湿霜、护肤液和护肤霜、唇膏和润唇膏、洁面乳、爽肤水、面膜、除臭剂、抑汗剂、角质剥脱剂、剃须品(霜、须后品)、湿面巾、美黑液、沐浴液、润肤油、脚部护理产品(粉剂、喷雾剂)、粉底霜、胭脂、眼影和眼线、唇彩、睫毛膏、婴幼儿产品(婴幼儿护肤霜、润肤油、洗发液、爽身粉、湿巾)。此外，这些化妆品还可作为驻留类化妆品或卸妆霜。
在一些实施例中，所述药学领域中可接受的载体包括一种或多种麻醉剂、抗变应原、抗真菌、抗微生物、抗炎剂、抗氧化剂、防腐剂、螯合剂、着色剂、脱色剂、软化剂、乳化剂、脱落剂、成膜剂、芳香剂、湿润剂、驱虫剂、润滑剂、增湿剂、药剂、光稳定剂、防腐剂、皮肤保护剂、皮肤渗透增强剂、防晒剂、稳定剂、表面活性剂、增稠剂、粘度调节剂、维生素，或者它们的任意组合。
在其中一些实施例中，美白是指抑制酪氨酸酶活性、抑制α-葡萄糖苷酶活性、抑制细胞黑色素生成及抑制色素沉着中的一种或几种；抗皮肤氧化和抗衰老是指清除细胞内的活性氧自由基。
在其中一些实施例中，所述色素沉着选自雀斑、黄褐斑、妊娠纹、老年斑及黑色素瘤中的一种或几种。
在其中一些实施例中，所述组合物选自酪氨酸酶抑制剂组合物和α-葡萄糖苷酶抑制剂组合物中的一种或几种。
在其中一些实施例中，所述载体包括香精、用于皮肤护理的化合物、用于皮肤清洁的化合物和紫外线吸收剂中的一种或几种。
在其中一些实施例中，所述组合物包括香精和所述式I所示的化合物，所述香精以有效提供感官效果的量存在，所述式I所示的化合物以具有抑制酪氨酸酶作用和抑制α-葡萄糖苷酶作用中的一种或两种作用的量存在。在其中一些实施例中，在所述组合物中，所述式I所示的化合物以约3％至约30％的质量百分比存在。可选地，在上述组合物中还可以包括一种或多种赋形剂、添加剂等。事实证明，式I所示化合物中的物质本身没有气味，或者完全没有气味，这一特性决定了它们可以用于香水组合物。由于化妆品最终产品中的香水组合物含量通常在约1％(m/m)的范围内，因此含有式I所示化合物的香水组合物中含有约3％至30％(m/m)的式I所示的化合物。在其中一个实施例中，在香水组合物中含有3％至20％(m/m)的式I所示的化合物。
在其中一些实施例中，所述组合物包括紫外线吸收剂和式I所示的化合物，所述紫外线吸收剂的量有效地提供保护系数至少大于2的紫外线保护，所述式I所示的化合物的量具有抑制酪氨酸酶和抑制α-葡萄糖苷酶中的一种或两种作用。在其中一些实施例中，紫外线吸收剂的量有效地提供保护系数至少大于5的紫外线保护。
在其中一些实施例中，所述组合物包括用于皮肤护理的化合物及用于皮肤清洁的化合物中的一种或几种，以及式I所示的化合物，所述式I所示的化合物的量具有抑制酪氨酸酶和抑制α-葡萄糖苷酶中的一种或两种作用。
此外，本申请的含有式I所示的化合物的组合物还可用于食品中，特别是那些由于其天然存在的酚类化合物含量，在内源性多酚氧化酶的影响下，在加工过程中容易发生自发褐变反应的食品。例如，食品包括水果和蔬菜产品，特别是苹果、梨或土豆，或甲壳类动物，特别是螃蟹、龙虾或虾。可以理解，以上仅列举了一些常见的食品，但并不限于此。
本申请的第五方面提供一种如上述的组合物在制备美白护肤品、美白皮肤病治疗药物、抗衰老护肤品、抗衰老皮肤病治疗药物和其组合中的应用。
在其中一些实施例中，所述组合物选自护肤品组合物和药物组合物中的一种，所述组合物包括作为有效成分的使用有效量的化合物1化合物2及化合物3中的一种或几种。
护肤品或皮肤病治疗药物是与美白、抗皮肤氧化、抗衰老和其组合作用有关的。其中：美白是指抑制酪氨酸酶活性、抑制α-葡萄糖苷酶活性、抑制细胞黑色素生成、抑制色素沉着和其组合；抗皮肤氧化和抗衰老是指清除细胞内的活性氧自由基。在其中一些实施例中，抗皮肤氧化和抗衰老是指清除细胞内因紫外光照而产生的活性氧自由基。
所述的护肤品或皮肤病治疗药物能够改善皮肤的美学和/或化妆外观。这些改善能够以以下任何方式显现：减少皮肤病学老化症状，它归因于，例如，年龄老化、激素老化和/或光老化的皮肤病学症状减少；减少皮肤脆性；减少毛孔的尺寸；胶原和/或弹性蛋白损失的预防和/或逆转；改善雌激素失调的效应；皮肤萎缩的预防；预防和/或减少包括细纹和/或皱纹的纹/或皱纹的外观和/或深度；预防、减少和/或治疗色素沉着过度；肝色、肤色清晰和/或紧缩度的改善；预防、减少和改善皮肤下垂；促进抗氧化活性；改善皮肤韧性、丰满弹性、柔度和/或柔软度；增加前胶原和/或胶原生成；改善皮肤肌理和/或促进恢复原来的肌理状态；促进皮肤屏障修复和/或功能；皮肤轮廓外观的改善；恢复皮肤光泽和/或亮度；最小化疲劳和应激性反应的皮肤病学症状，例如皮肤发疹和/或对环境影响所引起的应激性反应(污染、温度变化)的抵抗力；补充由于老化和/或绝经减少的皮肤内基本营养和/或成分；增强皮肤细胞间的联系；增加细胞增生和/或增殖；增强由于老化和/或绝经下降的皮肤细胞新陈代谢；延缓细胞老化；抑制皮肤内加速皮肤细胞老化的酶；最小化皮肤干燥和/或增加皮肤水分；最小化皮肤变色，包括黑眼圈；促进和/或加速细胞更新；增加皮肤厚度；增加皮肤弹性和/或弹力；借助于或不借助于α-羟基酸或其它剥离剂，增加表皮剥脱；预防和逆转葡糖胺聚糖(GAG)、胶原和/或弹性蛋白损失；微循环改善；减少和/或预防脂肪团形成；减少痤疮形成；可用作皮肤和毛发增亮剂或抗老年斑药剂。
尤其是，具有本申请药物组合物能够改善皮肤的美学外观、健康和活力。这样一种改善能够显现在以下的至少一种中：减少黑色素生成、治疗色素沉着类疾病，所述色素沉着类疾病包括雀斑、黄褐斑、妊娠纹、老年斑或黑色素瘤；预防和/或逆转胶原和/或弹性蛋白损失；皮肤肌理改善；肤色、透明度， 和/或紧固度改善；促进/加速细胞更新；和增加皮肤厚度。
在其中一些实施例中，美白是指抑制酪氨酸酶活性、抑制α-葡萄糖苷酶活性、抑制细胞黑色素生成及抑制色素沉着中的一种或几种；抗皮肤氧化和抗衰老是指清除细胞内的活性氧自由基。
在其中一些实施例中，所述色素沉着选自雀斑、黄褐斑、妊娠纹、老年斑及黑色素瘤中的一种或几种。
本申请的第六方面提供一种产品，产品为化妆品及皮肤病治疗药物中的一种，所述产品包括上述第四方面的组合物或包括式I所示的化合物。
在一些实施例中，式I所示的化合物在产品(特别是局部应用的产品)中的质量百分比为0.0001％～10％。或式I所示的化合物在产品中的质量百分比为0.01％～2％。或式I所示的化合物在产品中的质量百分比为0.1％～1％。在产品中酪氨酸酶抑制活性化合物如式I所示的化合物可预防性使用或根据需要使用。例如，每天使用的活性化合物的浓度不同，取决于测试者的生理状况和个人特有的参数，比如年龄或体重等。式I所示的化合物可单独使用，也可与其他酪氨酸酶抑制物质混合使用。
根据本申请使用的式I所示的化合物可以用于常规化妆品或皮肤病治疗药物中，例如包括但不限于为：泵喷雾剂、气溶胶喷雾剂、面霜、软膏、酊剂、乳液、指甲护理产品(例如指甲油、指甲油清洗剂、指甲香脂)等。在其中一些实施例中，在上述产品中，还可以将本申请使用的式I所示的化合物与其他活性化合物结合，例如与具有皮肤美白作用或对老年斑有活性的其他物质结合。在这种情况下，含有式I所示的化合物的产品可以用于皮肤学治疗意义上的皮肤治疗或护理化妆品意义上的治疗。当然，也可以用于彩妆产品中的装饰性化妆品。
在其中一些实施例中，在含有式I所示的化合物的产品中，还含有具有美白作用的活性化合物。可以理解，对具有美白作用的活性化合物并无特别限定，可以使用适合或习惯用于美容和/或皮肤病学应用的所有皮肤美白活性化合物。例如，具有美白作用的活性化合物包括曲酸、曲酸衍生物、熊果苷、抗坏血酸、抗坏血酸衍生物、芦荟素、鞣花酸、壬二酸、硫胺醇、4-正丁基间苯二酚、二苯基甲烷衍生物、含硫分子(例如谷胱甘肽、l-麦角硫因)、α-羟基酸(例如柠檬酸、乳酸、苹果酸)及其衍生物、氮氧化物合成抑制剂(例如，l-硝基精氨酸及其衍生物)、金属螯合剂(如c-羟基脂肪酸、棕榈酸、植酸、乳铁蛋白、腐殖酸、胆汁酸、胆汁提取物、胆红素、胆绿素、EDTA、EGTA及其衍生物)、类黄酮、查尔酮、苯丙素、香豆素、类维生素a、生物碱(如二乙酰胆碱)、烟酰胺、豆浆、丝氨酸蛋白酶抑制剂、硫辛酸或其他用于美白的合成或天然活性化合物。其中，用于美白的天然活性化合物也可能以植物提取物的形式使用，例如，熊果提取物、甘草根提取物或从中富集的成分，比如光甘草定或荔枝素A、桂木属提取物、蓼科植物和藤黄科植物提取物、松属植物(松树)提取物以及葡萄属植物提取物或富集其中的芪类衍生物。
在一些实施例中，在产品中，还可以含有防腐剂。其中，防腐剂例如苯甲酸、苯甲酸酯类及苯甲酸盐、丙酸及其盐、水杨酸及其盐、2,4-己酸(也称山梨酸)及其盐、甲醛及多聚甲醛、2-羟基苯基醚及其盐、2-锌硫吡啶-N-氧化物、无机亚硫酸盐和亚硫酸氢盐、碘酸钠、氯丁醇、4-乙基汞-(II)5-氨基-1,3-二(2-羟基苯甲酸)酸及其盐和酯、脱水酸、甲酸、1,6-二(4-氨基-2-溴-苯氧基)-正己烷及其盐类、乙基汞-(II)-硫代水杨酸钠盐、苯汞及其盐类、10-十一烯酸及其盐类、5-氨基-1,3-二(2-乙基己基)-5-甲基-六氢嘧啶、5-溴-5-硝基-1,3-二氧环、2-溴-2-硝基-1,3-丙二醇、2,4-二氯苯醇，N-(4-氯基)-N'-(3,4-二氯苯基)-脲，4-氯间甲酚、2,4,4'-三氯-2'-羟基二苯醚、4-氯-3,5-二甲基苯酚、1,1'-亚甲基-二(3-(1-羟甲基-2,4-二氧咪唑-5-基)脲)、聚(六亚甲基二胍)盐酸、2-苯氧乙醇、六亚甲基四胺、1-(3-氯丙烯基)-3,5,7-三氮-1-氮-氯金刚烷、1(4-氯苯氧基)-1(1H-咪唑-1-基)-3,3-二甲基-2-丁酮、1,3-二(羟甲基)-5,5-二甲基-2,4-咪唑烷二酮、苯甲醇、吡啶酮乙醇胺盐、1,2-二溴-2,4-二氰丁烷、2,2'-亚甲基双(6-溴-4-氯苯酚)、溴-氯苯酚、5-氯-2-甲基-3(2H)-异噻唑啉酮和2-甲基-3(2H)异噻唑啉酮与氯化镁和硝酸镁的混合物、2-苄基-4-氯苯酚、2-氯乙酰胺、氯己定、醋酸氯己定、葡萄糖酸氯己定、盐酸氯己定、1-苯氧基-2-丙烷醇、N-烷基三甲基溴化铵和氯化物、4,4-二甲基-1,3-恶唑烷、N-羟甲基-N'-羟甲基脲、1,6-二(4-氨基苯氧基)-正己烷及其盐类、戊二醛-5-乙基-1-氮杂-3,7-二氧基环辛烷、3-(4-氯苯氧基)-1,2-丙二醇、季铵盐、烷基-二甲基苄基氯化铵、烷基-二甲基苄基溴化铵、烷基-二甲基苄基糖化铵、甲醛苄醇半缩醛、3-碘-2-丙基氨基甲酸酯、羟甲基氨基乙酸钠及羟甲基氨基乙酸钠中的一种或几种。
使用时，按照化妆品和皮肤产品的习惯方式，将含有式I所示的化合物的产品以足够的量施用于皮肤上。
在其中一些实施例中，产品为防晒产品。产品中含有UVA滤光剂、UVB滤光剂和无机颜料中的一种或几种。可以理解，防晒产品可以具有各种形式，例如通常用于防晒霜制剂。因此，防晒产品可以是溶液、油包水(W/O)型或水包油(O/W)型的乳液或多重乳液，例如，油包水(W/O/N)型的乳液、凝胶、氢分散体、固体棒或气溶胶等形式。在其中一个示例中，在防晒产品中，含有UVB滤光剂，其可以为油溶性，也可以为水溶性的。
在其中一个示例中，在防晒产品中，滤光剂的总质量百分比例如为0.01％～20％，可选为0.1％～10％，可选为1.0％～5.0％，以使防晒产品可保护皮肤免受紫外线辐射。
在其中一个示例中，防晒产品能够实现至少>2的保护系数。可选地，防晒产品能够实现>5的保护系数。
在一些实施例中，在化妆品中，式I所示的化合物还可以与化妆品助剂组合，例如，抗氧化剂、香水油、防起泡剂、着色剂、有着色作用的颜料、增稠剂、表面活性剂、乳化剂、增塑剂、保湿剂、脂肪、油、蜡，以及化妆品配方的其他常规成分，如一元醇、多元醇、聚合物、泡沫稳定剂、电解质、有机溶剂或有机硅衍生物等。
在其中一些实施例中，含有式I所示的化合物的产品用于皮肤的局部预防或美容治疗，通常含有高含量的治疗物质。在其中一个示例中，含有式I所示的化合物的产品含有一种或多种动物治疗性脂肪和油、植物治疗性脂肪和油，例如橄榄油、葵花籽油、纯化大豆油、棕榈油、芝麻油、菜籽油、杏仁油、玻璃苣油、月见草油、椰子油、乳木果油、荷荷巴油、鲸油、牛脂、牛蹄油和猪油，以及还可选地含有其他治疗成分，例如具有8-30个碳原子的脂肪醇。其中，脂肪醇可以是饱和的或不饱和的，可以是直链的或支链的。例如，可以使用癸醇、癸烯醇、辛醇、辛烯醇、十二烷醇、十二烯醇、辛二烯醇、癸二烯醇、十二碳二烯醇、油醇、蓖麻醇、芥子醇、硬脂醇、异硬脂醇、十六烷醇、十二烷醇、肉豆醇、花生四烯醇、癸醇、亚麻醇、亚麻仁醇和二十二烷醇，以及格尔伯特醇。可以理解，脂肪醇并不限于上述所列举的，还可以为其他结构化学相关的醇。在其中一个示例中，所述脂肪醇源自天然脂肪酸，通常由所述脂肪酸的相应酯通过还原制备。此外，可以使用由天然存在的脂肪和脂肪油通过还原形成的脂肪醇馏分，例如，牛脂、花生油、菜籽油、棉籽油、大豆油、葵花籽油、棕榈仁油、亚麻籽油、玉米油、蓖麻油、油菜籽油、芝麻油、可可脂和可可油。
在一些实施例中，在含有式I所示的化合物的产品中，治疗物质还可以包括：(1)神经酰胺，神经酰胺被理解为N-酰基鞘氨醇(鞘氨醇的脂肪酸酰胺)或此类脂质的合成类似物(所谓的伪神经酰胺)，它们明显提高了角质层的保水性。(2)磷脂，如大豆卵磷脂、鸡蛋卵磷脂和脑磷脂。(3)凡士林、石蜡和硅油。其中，硅油包括二烷基和烷基芳基硅氧烷，如二甲基聚硅氧烷和甲基苯基聚硅氧烷，以及其烷氧基化和季铵盐化衍生物等。(4)动物水解蛋白和植物水解蛋白，例如弹性蛋白、胶原蛋白、角蛋白、乳蛋白、大豆蛋白、燕麦蛋白、豌豆蛋白、杏仁蛋白和小麦蛋白馏分或相应的水解蛋白，以及它们与脂肪酸的缩合产物，以及季铵化水解蛋白。在其中一个示例中，使用植物水解蛋白。
在一些实施例中，含有式I所示化合物的产品可以是溶液或洗剂，其中，溶剂可以是：(1)水或水溶液；(2)脂肪油、脂肪、蜡和其他天然和合成脂肪体，例如脂肪酸与具有低碳数的醇所形成的脂肪酸酯，其中，低碳数的醇可以为异丙醇、丙二醇或甘油等，或脂肪醇与具有低碳数的烷烃酸或脂肪酸所形成的脂肪酸酯；(3)具有低碳数的一元醇、二元醇或多元醇，以及其醚，例如乙醇、异丙醇、丙二醇、甘油、乙二醇、乙二醇单乙基醚、乙二醇单丁基醚、丙二醇单甲基醚、丙二醇单乙基醚、丙二醇单丁基醚、二甘醇单甲醚、二甘醇单乙醚以及类似物。可以理解，溶剂可以为上述多种溶剂的混合物。在酒精溶剂的情况下，水可能是另一个成分。
在一些实施例中，含有式I所示化合物的产品中也可以含有抗氧化剂，可以使用所有适合或习惯用于化妆品和/或皮肤病学应用的抗氧化剂。例如，所述抗氧化剂选自下列物质:氨基酸(例如甘氨酸、组氨酸、酪氨酸、色氨酸)及其衍生物、咪唑(例如尿酸)及其衍生物、肽例如D、L-肌肽、D-肌肽、L-肌肽及其衍生物(例如鹿茸)、类胡萝卜素、胡萝卜素(例如c-胡萝卜素、b-胡萝卜素、番茄红素)及其衍生物、硫辛酸及其衍生物(例如二氢硫辛酸)、金硫葡萄糖、丙基硫尿嘧啶和其他硫醇(例如硫氧还蛋白、谷胱甘肽、半胱氨酸、胱氨酸、半胺和其糖基、N-乙酰基、甲基、乙基、丙基、戊基、丁基、十二烷基、棕榈酰、油基、γ-亚油基、胆固醇和它们的甘油酯)及其盐类、二萘酰硫代二丙酸、二硬脂酰硫代二丙酸、硫代二丙酸及其衍生物(酯类、醚类、肽、脂类、核苷酸、核苷和盐)以及极低耐受剂量的亚砜亚胺化合物(例如丁硫氨酸亚砜、同型半胱氨酸亚砜、丁硫氨酸磺砜、五硫氨酸亚砜、六硫氨酸亚砜、七硫氨酸亚砜)，以及(金属)螯合剂，例如α-羟基脂肪酸、棕榈酸、植酸、乳铁蛋白、α-羟基酸(例如柠檬酸、乳酸、苹果酸)、腐植酸、胆汁酸、胆汁提取物、胆红素、胆绿素、EDTA、EGTA及其衍生物、不饱和脂肪酸及其衍生物(例如γ-亚麻酸、亚油酸、油酸)、叶酸及其衍生物、泛醌和泛醇及其衍生物、维生素C及其衍生物(例如抗坏血酸棕榈酸酯、抗坏血酸磷酸梅酯、抗坏血酸乙酸酯)、生育酚及其衍生物(例如维生素E醋酸酯)、维生素A及其衍生物(维生素A棕榈酸酯)和安息香树脂的苯甲酸松柏酯、芸香亭酸及其衍生物、阿魏酸及其衍生物、丁基羟基甲苯、丁基羟基茴香醚、去甲二氢愈创木酸、三羟基丁苯酮、尿酸及其衍生物、甘露糖及其衍生物、锌及其衍生物(例如ZnO、ZnSO4)、硒及其衍生物(例如蛋氨酸硒)、二苯乙烯及其衍生物(例如氧化二苯乙烯、反式氧化二苯乙烯)以及所述活性化合物的衍生物(盐、酯、醚、糖、核苷酸、核苷、肽和脂类)。
在一些实施例中，含有式I所示化合物的产品中还可以含有维生素和维生素前体，可以使用适合或习惯用于化妆品和/或皮肤病学应用的所有维生素和维生素前体。例如，生育酚、维生素A、烟酸和烟酰胺、B族维生素例如生物素和维生素C、泛酸醇及其衍生物，泛酸醇及其衍生物可以是泛酸醇的酯和醚，以及阳离子获得的泛酸醇衍生物，例如，三醋酸泛酸醇、泛酸醇、单乙醚及其单乙酸酯以及阳离子泛乙烯醇衍生物。
在一些实施例中，含有式I所示的化合物的产品还可以含有保湿剂。例如，使用的保湿剂是以下物质:透明质酸、甘油、泛醇、吡罗烷酮羧酸、尿素、乙醇酸、水杨酸、类巴西黄酮类A、乳酸钠、山梨醇、丙二醇、胶原蛋白、弹性蛋白、己二酸二酯、尿刊酸、卵磷脂、植烷三醇、番茄红素、藻类提取物、神经酰胺、胆固醇、糖脂、壳聚糖、硫酸软骨素、聚氨基酸和糖、羊毛脂、羊毛酯、氨基酸、α-羟基酸(例如柠檬酸、乳酸、苹果酸)及其衍生物、单二糖和低聚糖、α-羟基脂肪酸、植物甾醇、三萜酸如白桦酸或熊果酸、藻类提取物。
在一些实施例中，含有式I所示的化合物的产品还可以含有抗炎活性化合物、减轻发红的活性化合物及减轻瘙痒的活性化合物中的一种或几种。可以理解，所有适合或习惯用于化妆品和皮肤病治疗药物中的抗炎活性化合物、减轻发红的活性化合物及减轻瘙痒的活性化合物都可以使用。
在一些实施例中，含有式I所示的化合物的产品还可以含有植物提取物，其通常通过提取完整的植物来制备，但在一些实施例中，也可以单独从植物的花、叶子、木材、树皮或根中提取制备。植物提取物可以来自于芦荟、海藻、牛油果、甘菊、椰子、绿茶、人参、葡萄柚、葡萄柚籽、迷迭香、向日葵、橡树皮、柳草、刺荨麻、野荨麻、啤酒花、金盏花、牛蒡根、山楂、椴树花、杏仁、松针、檀香、杜松、芒果、杏、橙子、柠檬、酸橙、苹果、小麦、燕麦、大麦、鼠尾草、百里香、罗勒、桦树、锦葵、苦草、柳树皮、芦笋、秋葵、杜鹃花、姜根等。在其中一些实施例中，植物提取物来自于芦荟、藻类、牛油果、甘菊、椰子、绿茶、人参、葡萄柚、葡萄柚籽、迷迭香、向日葵。可以理解，在一些实施例中，植物提取物也可以采用两种或两种以上植物提取物的混合物。可用于制备所述植物提取物的萃取剂可为水、醇及其混合物。
在一些实施例中，含有式I所示的化合物的产品还可以含有阴离子表面活性剂、阳离子表面活性剂、非离子表面活性剂和两性表面活性剂中的一种或几种。例如，在将结晶或微晶固体(例如无机微色素)掺入产品中时，可以加入表面活性剂。表面活性剂是两亲性物质，能够溶解水中的有机非极性物质。在这种情况下，表面活性剂分子的亲水部分通常是极性官能团，例如-COO、-OSO、-SO，而疏水部分通常是非极性烃自由基。表面活性剂一般根据分子亲水部分的性质和电荷来分类。这里可分为四类：阴离子表面活性剂、阳离子表面活性剂、两性表面活性剂和非离子表面活性剂。
在其中一些实施例中，阴离子表面活性剂是酰基氨基酸(及其盐类)，如：(1)酰基谷氨酸盐例如酰基谷氨酸钠、双TEA-棕榈酰天冬氨酸钠和辛基/癸基谷氨酸钠；(2)酰基肽，例如棕榈酰水解乳蛋白、椰基水解大豆蛋白钠和椰基水解胶原蛋白钠/钾；(3)肌氨酸盐，例如肉豆蔻酰肌氨酸、TEA月桂酰肌氨酸盐、月桂酰肌氨酸钠和椰基肌氨酸钠；(4)牛磺酸盐，例如月桂酰牛磺酸钠和甲基椰油酰牛磺酸钠； (5)酰基乳酸盐、月桂酰乳酸盐、丙氨酸羧酸盐、己丙酰乳酸盐和衍生物，例如月桂酸、硬脂酸铝、烷醇酸镁和十一烯酸锌、酯羧酸盐，例如硬脂酰乳酸钙、月桂-6柠檬酸盐和PEG-4月桂酰羧酸钠；(6)醚羧酸，例如月桂醇-13羧酸钠和PEG-6椰油酰胺羧酸钠、磷酸酯和盐，例如，DEA-10磷酸和二脲-4磷酸、磺酸和盐，例如酰基异硫酸酯，例如椰油酰异硫酸酯、烷基芳基磺酸盐、烷基磺酸盐，例如椰子单甘油酯硫酸钠、colein-磺酸钠、月桂基硫乙酸钠和PEG-3椰油酰胺硫酸镁，例如，磺基琥珀酸酯；二辛基磺酰琥珀酸钠、月桂酰磺酰琥珀酸二钠、十二烷基磺酰琥珀酸二钠和十一烷基胺二钠-甲磺酸磺酰琥珀酸酯和硫酸酯，如烷基醚硫酸盐，例如钠、铵、镁、MIPA、TIPA月桂醚硫酸盐、梅氏硫酸钠和C12～13对苯二甲酸钠、烷基硫酸盐，例如钠、铵和TEA十二烷基硫酸盐。
在其中一些实施例中，阳离子表面活性剂是烷基胺、烷基咪唑、乙氧基化胺和季铵盐表面活性剂。季铵盐表面活性剂含有至少一个与4个烷基或芳基共价键合的N原子。不管pH值如何，这都会导致带正电荷。在其中一些实施例中，阳离子表面活性剂为烷基甜菜碱、烷基酰胺丙基甜菜碱和烷基酰胺丙基羟基磺酸中的一种或几种。在另外一些实施例中，所使用的阳离子表面活性剂还可以从包含季铵化合物的组中选择，例如苯三烷基氯化铵或溴化铵，例如苯基二甲基硬脂酰氯化铵，以及烷基三烷基铵盐，例如十六烷基三甲基氯化铵或溴化铵、烷基二甲基羟基乙基氯化物或溴化铵、二烷基二甲基氯化物或溴化铵、烷基酰胺乙基-三甲基铵醚硫酸盐、烷基吡啶盐，例如十二烷基或十六烷基吡啶氯、咪唑啉衍生物和阳离子性质的化合物，例如烷基二甲胺氧化物或烷基乙基二甲胺氧化物。在其中一个示例中，使用十六烷基三甲基铵盐作为阳离子表面活性剂。
在其中一些实施例中，两性表面活性剂可包括：(1)酰基/二烷基乙二胺，例如酰基酰胺乙酸钠、酰基酰胺二丙酸二钠、烷基酰胺二乙酸二钠、酰基酰胺羟丙基磺酸钠、酰基酰胺二乙酸二钠和酰基酰胺丙酸钠；(2)N-烷基胺酸，例如氨丙基烷基戊二胺、烷基氨基丙酸、烷基氨基二丙酸钠和桂两性羧甘氨酸。
在其中一些实施例中，非离子表面活性剂是醇、烷醇酰胺(例如椰油酰胺MEA/DEA/MIPA)、胺氧化物(例如椰油酰胺丙胺氧化物)、酯(这些酯是由羧酸与环氧乙烷、甘油、山梨醇或其他醇酯化而成)、醚(例如乙氧基化/丙氧基化醇、乙氧基化/丙氧基化酯、乙氧基化/丙氧基化甘油酯、乙氧基化/丙氧基化胆固醇、乙氧基化/丙氧基化甘油三酯、乙氧基化窝丙氧基化羊毛脂、乙氧基化/丙氧基化聚硅氧烷、丙氧基化POE醚和烷基多糖苷，如十二烷基糖苷、癸基糖苷和椰油糖苷)、蔗糖酯和醚、聚甘油酯、二甘油酯、单甘油酯、甲基葡萄糖酯、羟基酸酯等。
在其中一些实施例中，阴离子表面活性剂和两性表面活性剂可以与一种或多种非离子表面活性剂的组合使用。根据产品的总重量计，表面活性物质可以在含有式I所示的化合物的产品中以1％～90％(m/m)的质量百分比存在。
在一些实施例中，含有式I所示的化合物的产品也可以以乳液的形式存在。油相可从下列物质组中选择:矿物油、矿物蜡、脂肪、蜡和其他天然和合成脂肪体，例如脂肪酸与具有低碳数的醇所形成的脂肪酸酯，其中，低碳数的醇可以为异丙醇、丙二醇或甘油等，或脂肪醇与具有低碳数的烷烃酸或脂肪酸所形成的脂肪酸酯；苯甲酸烷基酯；硅油，如二甲基聚硅氧烷、二乙基聚硅氧烷、二苯基聚硅氧烷及其混合形式。在其中一些实施例中，可以使用(a)链长为3至30碳原子的饱和和/或不饱和、支链和/或直链烷烃羧酸与链长为3至30碳原子的饱和和/或不饱和、支链和/或直链醇所形成的酯，(b)芳香羧酸与链长为3至30碳原子的饱和和/或不饱和、支链和/或直链醇所形成的酯。在一个示例中，酯类油有肉豆油酸异丙酯、棕榈酸异丙酯、硬脂酸异丙酯、硬脂酸正丁酯、月桂酸正己酯、油酸正癸酯、硬脂酸异辛酯、异壬酯异壬酯、棕榈酸2-乙基己酯、月桂酸2-乙基己酯、硬脂酸2-己基癸酯、棕榈酸2-辛基十二烷基酯、油酸油酯、芥酸油酯、芥酸芥酯和这些酯的合成、半合成和天然混合物，例如荷荷巴油。
此外，油相可以从包含支链和直链烃和蜡、硅油、二烷基醚、饱和或不饱和、支链或直链醇的以及脂肪酸甘油三酯所组成的集合中选择，具体地说，具有8至24碳原子的饱和和/或不饱和、支链和/或直链烷烃羧酸的甘油三酯，例如是12至18个碳原子。脂肪酸甘油三酯可以从包括合成、半合成和天然油的组中选择，例如橄榄油、葵花籽油、大豆油、花生油、菜籽油、杏仁油、棕榈油、椰子油、棕榈仁油等。在另一些实施例中，也可以使用这种油和蜡组分的任意混合物。在一些实施例中，使用蜡(例如十六烷基棕榈酸酯)作为油相的唯一脂质组分也是可以的；例如，油相从由2-乙基己基异硬脂酸酯、辛基十二醇、异壬酸异三十六基异癸酸酯、异廿烷、2-乙基己基椰子酸酯、C2-s烷基苯甲酸酯、癸酸甘油三酯和二烷基醚组成的集合中选择。例如，c2-s-烷基苯甲酸酯和2-乙基己基异硬脂酸酯的混合物、c2-s-烷基苯甲酸酯和异壬酸异三十六基的混合物以及c2-s-烷基苯甲酸酯、2-乙基己基异硬脂酸酯和异壬酸异三十六基的混合物。碳氢化合物石蜡油、角鲨烷和角鲨烯也可以应用在本申请的油相中。在其中一些实施例中，油相还可以含有环状或线性硅油或完全由此类油组成，然而，也可以使用除硅油或硅油类物质之外的其他油相组分的附加含量。硅油例如可以为环甲硅氧烷(例如，十甲基环戊硅氧烷)。
然而，也可以使用其他硅油，例如十一甲基环三硅氧烷、聚二甲基硅氧烷和聚甲基苯基硅氧烷。此外，油相还可以为环甲基硅氧烷与异壬酸异三烷基酯以及环甲基硅氧烷与异硬脂酸2-乙基己基酯的混合物。
在一些实施例中，含有式I所示的化合物的产品以乳液形式存在，水相可包括:具有低碳数的一元醇、二元醇或多元醇及其醚，例如乙醇、异丙醇、丙二醇、甘油、乙二醇、乙二醇单乙基醚、乙二醇单丁基醚、丙二醇单乙基醚、丙二醇单丁基醚、二乙二醇单甲基醚、二乙二醇单乙基醚和类似物，以及一种或多种增稠剂，该增稠剂可从包含二氧化硅、硅酸铝、多糖及其衍生物，例如透明质酸、黄原胶、羟丙基甲基纤维素的组中选择。例如，从包含聚丙烯酸酯的组中选择，在其中一个示例中，聚丙烯酸酯可以从包含所谓卡波姆的聚丙烯酸酯中选择。
在一些实施例中，含有式I所示的化合物的产品以乳液形式存在，还可以含有一种或多种乳化剂。例如，从包含聚乙氧基化或聚丙氧基化或聚乙氧基化和聚丙氧基化产物的集合中选择O/W乳化剂，例如乳化剂可以为:脂肪醇乙氧基化物、乙氧基羊毛蜡醇、聚乙二醇醚、脂肪酸乙氧基化物、聚乙二醇甘油脂肪酸酯、聚乙氧基化山梨醇酯、胆固醇乙氧基化物、聚乙氧基化甘油三酯、烷基醚羧酸、烷基醚硫酸盐、脂肪醇丙氧基化物、聚丙烯乙二醇醚。在其中一些实施例中，从由乙氧基硬脂醇、十六烷基硬脂醇、十六烷基硬脂醇(十六烷基醇)组成的组中选择脂肪醇乙氧基醚。
以下可作为油/水乳化剂:具有8至30个碳原子、饱和和/或不饱和脂肪醇的单甘油酯，具有8至24个碳原子(例如12至18个碳原子)的支链和/或直链、饱和和/或不饱和烷烃羧酸的二甘油酯，具有8至24个碳原子(例如12至18个碳原子)的支链和/或直链、饱和和/或不饱和烷烃羧酸的单甘油醚，具有8至24个碳原子(例如12至18个碳原子)的支链和/或直链、饱和或不饱和醇的双甘油醚，具有8至24个碳原子(例如12至18个碳原子)的支链和/或直链、饱和或不饱和烷烃羧酸的丙二醇酯以及具有8至24个碳原子(例如12至18个碳原子)的支链和/或直链、饱和或不饱和烷烃羧酸的山梨醇酯。
在其中一些实施例中，油/水乳化剂包括单硬脂酸甘油酯、单异硬脂酸甘油酯、单肉豆蔻酸甘油酯、单油酸甘油酯、单硬脂酸二甘油酯、单硬脂酸丙二醇酯、单异硬脂酸丙二醇酯、单辛酸丙二醇酯、单月桂酸丙二醇酯、山梨醇单异硬脂酸酯、山梨醇单月桂酸酯、山梨醇单辛酸酯、山梨醇单异硬脂酸酯、蔗糖二硬脂酸酯、鲸蜡醇、硬脂醇、花生醇、二十二烷醇、异二十二烷醇、鲨油醇、鲛肝醇、单月桂酸甘油酯、单癸酸甘油酯、单辛酸甘油酯。本申请的第七方面提供一种治疗糖尿病的药物组合物，其中，包括作为有效成分的使用有效量的化合物和载体，所述作为有效成分的使用有效量的化合物选自式I所示的化合物中的一种或几种，所述式I所示的化合物如下:
各R1、各R2及各R3独立地选自氢、羟基、卤素、苯基、卤代甲氧基、甲基氨基、甲基及具有2-4个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
R4、R5、R6及R7各自独立地选自氢、甲基及具有2-5个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
m、n及k各自独立地为1～3的整数；
所述载体选自一种或多种药学领域中可接受的载体。
在其中一些实施例中，所述作为有效成分的使用有效量的化合物选自化合物1 化合物2和化合物3中的一种或几种。
在一些实施例中，治疗糖尿病的药物组合物发挥效果是通过抑制α-葡萄糖苷酶活性实现的。
本申请的第八方面提供一种如上述的治疗糖尿病的药物组合物在制备治疗糖尿病药物中的应用。
在其中一些实施例中，作为有效成分的使用有效量的化合物选自化合物1化合物2及化合物3中的一种或几种。
本申请的第九方面提供一种药物制剂，其中，包括一种或多种治疗糖尿病的化合物，以及一种或多种具有抑制α-葡萄糖苷酶作用的量的式I所示的化合物；所述式I所示的化合物如下：
各R1、各R2及各R3独立地选自氢、羟基、卤素、苯基、卤代甲氧基、甲基氨基、甲基及具有2-4个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
R4、R5、R6及R7各自独立地选自氢、甲基及具有2-5个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
m、n及k各自独立地为1～3的整数。
在其中一些实施例中，各R1及各R3中至少有一个为羟基。
在其中一些实施例中，各R1中至少有一个为羟基，各R3中至少有一个为羟基。
在其中一些实施例中，式I所示的化合物选自如下结构中的一种或几种：
本申请的第十方面提供一种用于人类皮肤美白和对抗人类皮肤老年斑的方法，包括给需要的人施用有效量的如上述第四方面的组合物或施用上述第六方面的产品。
本申请的第十一方面提供一种用于抑制食品褐变的方法，包括将有效量的如上述第四方面的组合物施用于食品。
本申请的第十二方面提供一种治疗糖尿病的方法，包括给需要的人施用有效量的上述第七方面的药物组合物或权上述第九方面的药物制剂。
以下为实施例部分：
实施例1：化合物的合成
1、化合物1的合成：依次称取1,3-二(溴甲基)苯(1.5g，5.73mmol/L)、苯酚(6.2mL，70mmol/L)、三氯化铝(195mg，1.5mmol/L)，在氮气保护下，110℃加热至原料消失，反应2小时，冷至室温后依次用饱和碳酸钠水溶液和乙酸乙酯各萃取三次，然后用硫酸钠干燥，抽滤旋干，过硅胶柱、用乙酸乙酯/石油醚(EA:PE＝1:200，v/v)纯化，得到产物化合物1(473.3mg，产率42％，白色固体)。
4,4'-(1,3-phenylenebis(methylene))diphenol(化合物1):白色固体，1H NMR(600MHz,CD3OD,δ,ppm,J/Hz):9.17(s,2H),7.15(t,J＝10,1H),7.04(s,1H),6.98-6.95(m,6H),6.66-6.64(m,4H),3.76(s,4H)。13C NMR(150MHz,DMSO-d6，δ,ppm):155.9,142.4,131.8,130.0,129.3,128.8,126.5,115.6,40.7。HRMS(ESI-)calcd for C20H17O2[M-H]-＝289.1234,found 289.1246。其中1H NMR谱图、13C NMR谱图如图1～2所示。
2、化合物2的合成：依次称取1,3-二(溴甲基)苯(0.3g，1.15mmol/L)、邻甲酚(0.6g，5.75mmol/L)、三氯化铝(39mg，0.29mmol/L)，在氮气保护下，110℃加热至原料消失，反应2小时，冷至室温，直接硅胶柱层析过柱，乙酸乙酯/石油醚(EA:PE＝1:7.5，v/v)为洗脱剂，得到产物化合物2(40.7mg，产率26％，棕色固体)。
4,4'-(1,3-phenylenebis(methylene))bis(2-methylphenol)(化合物2)：棕色固体，1H NMR(600MHz,DMSO-d6,δ,ppm,J/Hz):9.05(s,2H),7.15(t,J＝7.6Hz,1H),7.05(s,1H),6.97(d,J＝7.6Hz,2H),6.87(s,2H),6.80(dd,J＝8.2,2.3Hz,2H),6.67(d,J＝8.1Hz,2H),3.73(s,4H),2.06(s,6H)。13C NMR(150MHz,DMSO-d6,δ,ppm):153.5,142.0,131.3,130.9,128.8,128.3,126.7,126.0,123.6,114.5,40.4,16.0.HRMS(ESI-)calcd for C22H21O2[M-H]-＝317.1547,found 317.1561。其中1H NMR谱图、13C NMR谱图如图3～4所示。
3、化合物3的合成：依次称取1,3-二(溴甲基)苯(1.5g，5.73mmol/L)、1,2-苯二酚(0.63g，5.72mmol/L)、三氯化铝(195mg，1.5mmol/L)，在氮气保护下，110℃加热至原料消失，反应2小时，冷至室温，直接硅胶柱层析过柱，乙酸乙酯/石油醚(EA:PE＝1:2，v/v)为洗脱剂，得到产物化合物3(124.8mg，产率32％，淡黄色固体)。
3,3'-(1,3-phenylenebis(methylene))bis(benzene-1,2-diol)(化合物3)：淡黄色固体，1H NMR(500MHz,DMSO-d6,δ,ppm,J/Hz):8.74(s,2H),8.64(s,2H),7.15(t,J＝7.6Hz,1H),7.01(s,1H),6.95(dd,J＝7.6,1.7Hz,2H),6.61(d,J＝8.0Hz,2H),6.53(d,J＝2.1Hz,2H),6.44(dd,J＝8.0,2.1Hz,2H),3.69(s,4H)。13C NMR(125MHz,DMSO-d6,δ,ppm):145.5,143.9,142.4,132.5,129.4,128.7,126.6,119.8,116.5,115.9,41.0.HRMS(ESI)calcd for C20H18NaO4[M+Na]+＝345.1097,found 345.1097。其中1H NMR谱图、13C NMR谱图如图5～6所示。
4、化合物4-22的合成：
在干燥的圆底烧瓶中，将苯酚类化合物(5.0equiv)溶解在甲醇和水的混合溶液中(两者体积比为2:1)，向溶液中缓慢滴加H2SO4(0.3equiv)，随后将2-羟基-5-甲基间苯二甲醇加入到烧瓶中，氮气条件下升至45℃反应，点板监测至原料反应完全，冷却至室温后，直接硅胶柱层析过柱，乙酸乙酯/石油醚(EA:PE＝1:20-1:1，v/v)为洗脱剂，即可得到产物。
5,5'-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(benzene-1,2,3-triol)(化合物4):白色固体，1H NMR(600MHz,DMSO-d6,δ,ppm,J/Hz):8.80(s,3H),8.20(s,4H),6.53(s,2H),6.30(d,J＝8.3Hz,2H),6.21(d,J＝8.2Hz,2H),3.68(s,4H),2.02(s,3H)；13C NMR(150MHz,DMSO-d6,δ,ppm):172.1,149.7,144.3,143.8,132.9,128.1,127.8,127.2,119.7,118.6,106.6,29.5,20.5.其中1H NMR谱图、13C NMR谱图如图7～8所示。
4,4'-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene)diphenol(化合物5):白色固体，1H NMR(500MHz,DMSO-d6,δ,ppm,J/Hz):9.23(s,2H),8.15(s,1H),6.98(d,J＝8.5Hz,4H),6.65(d,J＝8.5Hz,4H),6.61(s,2H),3.77(s,4H),2.07(s,3H)；13C NMR(125MHz,DMSO-d6,δ,ppm):155.81,150.25,131.66,130.07,129.41,128.90,128.16,115.44,35.10,20.77.其中1H NMR谱图、13C NMR谱图如图9～10所示。
4,4'-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(benzene-1,3-diol)(化合物6):白色固体，1H NMR(600MHz,MeOD,δ,ppm,J/Hz):6.87(d,J＝8.2Hz,2H),6.72(s,2H),6.31(d,J＝2.5Hz,2H),6.24(dd,J＝8.2,2.4Hz,2H),3.75(s,4H),2.12(s,3H).13C NMR(150MHz,MeOD,δ,ppm):157.60,155.93,150.33,132.00,130.20,129.66,129.42,119.99,108.06,103.32,30.67,20.72.HRMS(ESI)m/z:[M+H]+Calcd for C21H21O5 353.1389,found 353.1382.其中1H NMR谱图、13C NMR谱图如图11～12所示。
2-(3-bromo-2-hydroxybenzyl)-6-(3-bromo-4-hydroxybenzyl)-4-methylphenol(化合物7):黄色固体，1H NMR(500MHz,CDCl3,δ,ppm,J/Hz):7.36–7.29(m,2H),7.19(dd,J＝7.6,1.6Hz,1H),7.07(dd,J＝8.3,2.1Hz,1H),6.94–6.91(m,2H),6.81–6.74(m,2H),6.19(d,J＝19.0Hz,2H),5.43(s,1H),3.92(s,2H),3.86(s,2H),2.22(s,3H).13C NMR(125MHz,CDCl3,δ,ppm):150.45,149.23,148.72,134.32,131.87,130.38,130.07,129.94,129.84,129.51,128.10,127.75,125.98,122.45,115.90,110.42,110.17,35.28,31.26,20.51.HRMS(ESI)m/z:[M+H]+Calcd for C21H19Br2O3 476.9701,found 476.9551.其中1H NMR谱图、13C NMR谱图如图13～14所示。
4,4'-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(2-bromophenol)(化合物8):黄色固体，1H NMR(500MHz,CDCl3,δ,ppm,J/Hz):7.32–7.29(m,2H),7.06(dd,J＝8.2,2.1Hz,2H),6.94(d,J＝8.3Hz,2H),6.85(s,2H),5.66(s,2H),4.57(s,1H),3.86(s,4H),2.28(d,J＝3.1Hz,3H).13C NMR(125MHz,CDCl3,δ,ppm):150.65,149.46,133.43,131.73,130.06,129.89,129.23,126.73,116.11,110.30,35.31,20.50.HRMS(ESI)m/z:[M+H]+Calcd for C21H19Br2O3 476.9701,found 476.9551.其中1H NMR谱图、13C NMR谱图如图15～16所示。
2-(2-hydroxy-3-methylbenzyl)-6-(4-hydroxy-3-methylbenzyl)-4-methylphenol(化合物9):白色固体，1H NMR(500MHz,CDCl3,δ,ppm,J/Hz):7.15(d,J＝7.5Hz,1H),7.03–6.94(m,3H),6.91(dd,J＝8.0and 2.3Hz,1H),6.82(t,J＝4.4Hz,2H),6.68(dd,J＝8.1and 1.9Hz,1H),5.87(s,1H),5.12(s,1H),3.87(d,J＝9.0Hz,4H),2.25(s,3H),2.22(d,J＝6.1Hz,6H).13C NMR(125MHz,CDCl3,δ,ppm):153.07,151.89,148.84,131.66,131.48,131.29,130.87,130.14,129.87,129.60,128.57,127.54,127.37,126.78,124.79,124.73,120.85,115.50,35.89,30.66,20.16,15.73,15.37.HRMS(ESI)m/z:[M-H]-Calcd for C21H23O3 347.1647,found 347.1669.其中1H NMR谱图、13C NMR谱图如图17～18所示。
4,4'-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(2-methylphenol)(化合物10):白色固体，1H NMR(500MHz,CDCl3,δ,ppm,J/Hz):δ6.99(s,2H),6.94–6.87(m,4H),6.65(d,J＝8.1Hz,2H),5.53(s,2H),4.78(s,1H),3.87(s,4H),2.30(s,3H),2.21(s,6H).13C NMR(125MHz,CDCl3,δ,ppm):152.32,149.87,131.82,131.15,129.64,129.59,127.41,127.08,124.02,115.07,35.85,20.55,15.77.HRMS(ESI)m/z:[M-H]-Calcd for C23H23O3347.1647,found 347.1669.其中1H NMR谱图、13C NMR谱图如图19～20所示。
3-(2-hydroxy-3-((6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-5-methylbenzyl)-[1,1'-biphenyl]-2-ol(化合物11):白色固体，1H NMR(600MHz,CDCl3,δ,ppm,J/Hz):7.51–7.46(m,2H),7.46–7.42(m,6H),7.41–7.35(m,2H),7.29(dd,J＝7.6and 1.7Hz,1H),7.14–7.10(m,3H),

7.00(d,J＝2.2Hz,1H),6.96(t,J＝7.6Hz,1H),6.89(d,J＝8.9Hz,1H),6.80(d,J＝2.2Hz,1H),6.49(s,1H),6.09(s,1H),5.13(s,1H),3.95(s,2H),3.92(s,2H),2.24(s,3H).13C NMR(150MHz,CDCl3,δ,ppm):151.16,149.75,149.26,137.52,137.28,133.04,130.74,130.53,130.05,130.03,129.72,129.69,129.65,129.48,129.43,129.37,128.92,128.70,128.35,128.31,128.02,127.49,126.84,121.66,116.09,35.44,30.72,20.22.HRMS(ESI)m/z:[M-H]-Calcd for C33H27O3 471.1960,found 471.1988.其中1H NMR谱图、13C NMR谱图如图21～22所示。
5,5”-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(([1,1'-biphenyl]-2-ol))(化合物12):白色固体，1H NMR(500MHz,CDCl3,δ,ppm,J/Hz):7.51–7.35(m,10H),7.13–7.05(m,4H),6.92–6.85(m,4H),5.22(d,J＝14.6Hz,2H),4.60(s,1H),3.92(s,4H),2.25(s,3H).13C NMR(125MHz,CDCl3,δ,ppm):151.40,150.31,137.39,132.39,130.57,130.11,130.05,129.50,129.37,128.51,128.11,127.45,116.31,35.61,20.21.HRMS(ESI)m/z:[M-H]-Calcd for C33H27O3 471.1960,found 471.1988.其中1H NMR谱图、13C NMR谱图如图23～24所示。
4,4'-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(benzene-1,2-diol)(化合物13):白色固体，1H NMR(500MHz,MeOD,δ,ppm,J/Hz):6.68–6.64(m,4H),6.61(d,J＝2.1Hz,2H),6.53(dd,J＝8.0and 2.1Hz,2H),3.78(s,4H),2.12(s,3H).13C NMR(125MHz,MeOD,δ,ppm):150.97,146.02,144.24,134.04,130.19,130.15,129.90,121.26,117.10,116.15,36.23,20.73.HRMS(ESI)m/z:[M-H]-Calcd for C21H21O5 353.1389,found 353.1381.其中1H NMR谱图、13C NMR谱图如图25～26所示。
2-(2-hydroxy-3-(trifluoromethoxy)benzyl)-6-(4-hydroxy-3-(trifluoromethoxy)benzyl)-4-methylphenol(化合物14):黄色固体，1H NMR(500MHz,CDCl3,δ,ppm,J/Hz):7.07–7.04(m,2H),7.01(dd,J＝8.4and 2.1Hz,2H),6.95(s,1H),6.93(s,1H),6.83(s,2H),5.41(s,2H),4.39(s,1H),3.87(s,4H),2.25(s,3H).13C NMR(125MHz,CDCl3,δ,ppm):150.00,146.63,136.69,133.00,130.51,130.30,128.38,126.83,121.80,117.64,35.34,20.15.其中1H NMR谱图、13C NMR谱图如图27～28所示。
2-(3-ethyl-2-hydroxybenzyl)-6-(3-ethyl-4-hydroxybenzyl)-4-methylphenol(化合物15):白色固体，1H NMR(600MHz,CDCl3,δ,ppm,J/Hz):7.15(dt,J＝7.6and 1.2Hz,1H),7.01(td,J＝10.5,10.0,2.0Hz,3H),6.90(dd,J＝8.1and 2.3Hz,1H),6.84(ddd,J＝16.1,8.1,1.6Hz,2H),6.68(d,J＝8.1Hz,1H),6.64(s,1H),5.70(s,1H),5.02(s,1H),3.88(d,J＝3.2Hz,3H),2.61(p,J＝7.4Hz,4H),2.25(s,3H),1.21(td,J＝7.5and 2.0Hz,6H).13C NMR(150MHz,CDCl3,δ,ppm):152.72,151.62,148.83,131.19,130.94,130.91,130.16,129.93,129.83,128.47,127.76,127.38,127.31,127.23,126.84,120.87,115.81,36.10,30.71,22.82,22.69,20.19,13.61,13.53.HRMS(ESI)m/z:[M+H]+Calcd for C25H29O3 377.2117,found 377.2112.其中1H NMR谱图、13C NMR谱图如图29～30所示。
4,4'-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(2-ethylphenol)(化合物16):白色固体，1H NMR(500MHz,CDCl3,δ,ppm,J/Hz):7.01(d,J＝2.2Hz,2H),6.89(dd,J＝8.1and 2.3Hz,2H),6.86(s,2H),6.65(d,J＝8.0Hz,2H),4.96(s,1H),4.64(s,1H),3.87(s,4H),2.60(d,J＝7.5Hz,4H),2.26(d,J＝6.6Hz,3H),1.21(t,J＝7.6Hz,6H).13C NMR(150MHz,CDCl3,δ,ppm):151.83,149.84,131.91,130.19,129.63,129.60,129.51,127.40,126.90,115.33,35.92,22.98,20.55,14.00.HRMS(ESI)m/z:[M+H]+Calcd for C25H29O3 377.2117,found 377.2112.其中1H NMR谱图、13C NMR谱图如图31～32所示。
2-(3-allyl-2-hydroxybenzyl)-6-(3-allyl-4-hydroxybenzyl)-4-methylphenol(化合物17)：白色固体，1H NMR(500MHz,DMSO-d6,δ,ppm,J/Hz):9.14(s,1H),8.45(d,J＝55.5Hz,2H),6.92–6.87(m,2H),6.85–6.80(m,2H),6.72–6.65(m,2H),6.65–6.60(m,2H),6.02–5.86(m,2H),5.09–4.92(m,4H),3.84(s,2H),3.76(s,2H),3.34(dd,J＝6.6and 1.6Hz,2H),3.22(dd,J＝6.6and 1.6Hz,2H),2.05(s,3H).13C NMR(125MHz,DMSO-d6,

δ,ppm):152.97,152.05,149.66,137.31,137.22,131.33,130.17,128.97,128.65,128.55,128.20,128.07,127.84,127.66,127.36,126.73,125.63,119.76,115.49,115.26,114.77,34.75,34.21,34.02,30.41,20.42.HRMS(ESI)m/z:[M+H]+Calcd for C27H29O3 401.2117,found 401.2115.其中1H NMR谱图、13C NMR谱图如图33～34所示。
4,4'-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(2-allylphenol)(化合物18)：白色固体，1H NMR(500MHz,CDCl3,δ,ppm,J/Hz):6.98(d,J＝2.3Hz,2H),6.95(dd,J＝8.2and 2.4Hz,2H),6.84(s,2H),6.72(d,J＝8.2Hz,2H),6.05–5.95(m,2H),5.32(s,1H),5.16(dd,J＝6.9and 1.7Hz,2H),5.13(t,J＝1.6Hz,2H),3.86(s,4H),3.37(dt,J＝6.4,Hz,4H),2.26(s,3H).13C NMR(125MHz,CDCl3,δ,ppm):153.07,136.75,132.27,130.88,129.92,128.10,127.64,116.53,116.18,35.53,34.76,20.17.HRMS(ESI)m/z:[M+H]+Calcd for C27H29O3 401.2117,found 401.2112.其中1H NMR谱图、13C NMR谱图如图35～36所示。
4,4'-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(2-(methylamino)phenol)(化合物19):白色固体，1H NMR(600MHz,CDCl3,δ,ppm,J/Hz):7.09–7.03(m,1H),6.91–6.84(m,2H),6.83–6.75(m,2H),6.71(d,J＝13.2Hz,2H),6.56(d,J＝9.1Hz,1H),4.07–3.76(m,4H),2.58(d,J＝10.8Hz,3H),2.28–2.13(m,6H).HRMS(ESI)m/z:[M+H]+Calcd for C23H27N2O3 379.2022,found 379.2016.其中1H NMR谱图37所示。
2-(2-hydroxy-3-(methylamino)benzyl)-6-(4-hydroxy-3-(methylamino)benzyl)-4-methylphenol(化合物20):黄色固体，1H NMR(600MHz,CDCl3,δ,ppm,J/Hz):6.86(d,J＝2.1Hz,2H),6.77(d,J＝7.9Hz,2H),6.73(s,2H),6.58(d,J＝7.9Hz,2H),4.75(s,3H),3.82(s,3H),2.82(s,4H),2.20(s,3H).HRMS(ESI)m/z:[M+H]+Calcd for C23H27N2O3379.2022,found 379.2017.其中1H NMR谱图38所示。
2-(4-(tert-butyl)-2-hydroxybenzyl)-6-(2-(tert-butyl)-4-hydroxybenzyl)-4-methylphenol(化合物21):白色固体，1H NMR(600MHz,MeOD,δ,ppm,J/Hz):7.05(d,J＝7.9Hz,1H),6.90(d,J＝2.6Hz,1H),6.86(d,J＝1.9Hz,1H),6.82–6.79(m,2H),6.76(d,J＝8.3Hz,1H),6.54(dd,J＝8.3and 2.6Hz,1H),6.28(d,J＝2.2Hz,1H),4.09(s,2H),3.82(s,2H),2.04(s,3H),1.33(s,9H),1.25(s,9H).13C NMR(150MHz,MeOD,δ,ppm):155.99,154.17,151.85,150.67,150.63,135.06,131.26,131.11,130.39,129.81,129.63,129.40,128.50,125.66,118.36,114.27,113.41,112.99,36.51,35.14,35.00,31.97,31.79,31.22,20.82.HRMS(ESI)m/z:[M+H]+Calcd for C29H37O3 433.2743,found 377.2736.其中1H NMR谱图、13C NMR谱图如图39～40所示。
4,4'-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(2-ethylphenol)(化合物22):白色固体，1H NMR(600MHz,CDCl3,δ,ppm,J/Hz):7.01(d,J＝2.2Hz,2H),6.89(dd,J＝8.1and 2.3Hz,2H),6.86(s,2H),6.65(d,J＝8.0Hz,2H),4.96(s,1H),4.64(s,1H),3.87(s,4H),2.60(d,J＝7.5Hz,4H),2.26(d,J＝6.6Hz,3H),1.21(t,J＝7.6Hz,6H).13C NMR(150MHz,CDCl3,δ,ppm):151.83,149.84,131.91,130.19,129.63,129.60,129.51,127.40,126.90,115.33,35.92,22.98,20.55,14.00.HRMS(ESI)m/z:[M+H]+Calcd for C25H29O3 377.2117,found 377.2112.其中1H NMR谱图、13C NMR谱图如图41～42所示。
5、化合物23-31的合成：
在干燥的圆底烧瓶中加入苯硼酸类化合物(2.4eq)和1,3-二溴甲基苯(1eq)溶于25mL1,4-二氧六环，加入碳酸钾(4.8eq)和13mL水，鼓泡脱气后，氮气保护下加入四(三苯基膦)钯(0.025eq)，加热至100℃，TLC点板监测至原料消失，冷至室温后旋去溶剂，直接硅胶柱层析过柱，乙酸乙酯/石油醚(EA:PE＝1:20-1:1，v/v)为洗脱剂，即可得到第一步产物。第一步产物(1eq)溶于二氯甲烷中，冷至0℃后，氮气保护下，缓慢滴加BBr3(1M,4.8eq)，TLC点板监测至原料消失，倒入水中淬灭反应，用DCM和水萃取三次，合并有机相，干燥，旋干，硅胶柱层析过柱，乙酸乙酯/石油醚(EA:PE＝1:5，v/v)为洗脱剂，即可得到产物。
2,2'-(1,3-phenylenebis(methylene))diphenol(化合物23):白色固体，1H NMR(600MHz,CDCl3,δ,ppm,J/Hz):7.23(t,J＝7.6Hz,1H),7.18(s,1H),7.17–7.11(m,4H),7.08(d,J＝7.8Hz,2H),6.94–6.89(m,2H),6.77(d,J＝7.8Hz,2H),5.10(s,2H),3.98(s,4H).13C NMR(150MHz,CDCl3,δ,ppm):153.59,140.16,130.88,129.14,128.89,127.75,126.97,126.63,120.87,115.68,36.25.其中1H NMR谱图、13C NMR谱图如图43～44所示。
3,3'-(1,3-phenylenebis(methylene))diphenol(化合物24):白色固体，1H NMR(600MHz,CDCl3,δ,ppm,J/Hz):7.19(t,J＝7.6Hz,1H),7.14(t,J＝7.8Hz,2H),7.04(s,1H),7.02(dd,J＝7.5and 1.8Hz,2H),6.78(d,J＝7.5Hz,2H),6.68(dd,J＝8.2and 2.3Hz,2H),6.61(t,J＝2.0Hz,2H),6.22(s,2H),3.88(s,4H).13C NMR(150MHz,CDCl3,δ,ppm):171.94,155.66,143.02,140.80,129.77,129.50,128.57,126.79,121.14,115.74,113.03,41.51.其中1H NMR谱图、13C NMR谱图如图45～46所示。
4,4'-(1,3-phenylenebis(methylene))bis(benzene-1,3-diol)(化合物25):白色固体，1H NMR(500MHz,DMSO-d6,δ,ppm,J/Hz):9.15(s,2H),8.99(s,2H),7.08(t,J＝7.5Hz,1H),7.04(d,J＝2.1Hz,1H),6.90(dd,J＝7.5,1.9Hz,2H),6.73(dd,J＝8.2,1.7Hz,2H),6.27(s,2H),6.11(dt,J＝8.2,2.2Hz,2H),3.67(s,4H)；13C NMR(125MHz,CDCl3,δ,ppm):156.5,155.6,141.7,130.6,128.9,127.8,125.7,118.0,106.0,102.4,34.6.其中1H NMR谱图、13C NMR谱图如图47～48所示。
4,4'-(1,3-phenylenebis(ethane-1,1-diyl))bis(benzene-1,3-diol)(化合物26):白色固体，1H NMR(500MHz,DMSO-d6,δ,ppm,J/Hz):9.11(d,J＝5.0Hz,2H),8.96(s,2H),7.15–7.04(m,2H),6.93(d,J＝7.5Hz,2H),6.79(dd,J＝8.4,3.9Hz,2H),6.23(s,2H),6.13(d,J＝8.3Hz,2H),4.31–4.22(m,2H),3.35(s,6H),1.40(d,J＝7.6Hz,6H)；13C NMR(125MHz,DMSO-d6,δ,ppm):156.53,156.52,155.46,155.44,146.93,146.88,128.15,128.01,127.96,127.37,127.07,124.93,124.78,123.69,123.61,106.43,106.40,102.75,36.75,36.70,21.69,21.62.其中1H NMR谱图、13C NMR谱图如图49～50所示。
4,4'-(1,3-phenylenebis(methylene))bis(2,6-dimethylphenol)(化合物27):白色固体，1H NMR(600MHz,DMSO-d6,δ,ppm,J/Hz):8.01(s,2H),7.14(t,J＝7.6Hz,1H),7.05(s,1H),6.96(dd,J＝7.6,1.3Hz,2H),6.73(s,4H),3.70(s,4H),2.11(s,12H)；13C NMR(150MHz,DMSO-d6,δ,ppm):151.76,142.46,132.08,129.32,128.88,128.73,126.47,124.50,40.89,17.12.其中1H NMR谱图、13C NMR谱图如图51～52所示。
4,4'-(1,3-phenylenebis(methylene))bis(3,5-dimethylphenol)(化合物28):白色固体，1H NMR(500MHz,DMSO-d6,δ,ppm,J/Hz):9.01(s,2H),7.06(t,J＝7.6Hz,1H),6.76(s,1H),6.70(d,J＝7.5Hz,2H),6.45(s,4H),3.79(s,4H),2.06(s,12H)；13C NMR(125MHz,DMSO-d6)δ155.59,140.82,137.90,128.67,127.98,127.76,125.23,115.23,34.14,20.45.其中1H NMR谱图、13C NMR谱图如图53～54所示。
5,5'-(1,3-phenylenebis(methylene))bis(2-methylphenol)(化合物29):白色固体，1H NMR(600MHz,DMSO-d6,δ,ppm,J/Hz):9.13(s,2H),7.18(t,J＝7.5Hz,1H),7.05(s,1H),6.99(d,J＝7.3Hz,2H),6.94(d,J＝7.4Hz,2H),6.63–6.51(m,4H),3.76(s,4H),2.06(s,6H)；13C NMR(150MHz,DMSO-d6,δ,ppm):155.74,141.96,140.13,130.90,129.53,128.81,126.77,121.79,119.68,115.38,

41.32,16.11.其中1H NMR谱图、13C NMR谱图如图55～56所示。
6,6'-(1,3-phenylenebis(methylene))bis(2-methylphenol)(化合物30):白色固体，1H NMR(500MHz,DMSO-d6,δ,ppm,J/Hz):8.27(s,2H),7.18–7.09(m,2H),6.95(d,J＝7.4Hz,2H),6.91(d,J＝6.9Hz,2H),6.83(d,J＝7.4Hz,2H),6.65(t,J＝7.4Hz,2H),3.86(s,4H),2.16(s,6H)；13C NMR(125MHz,DMSO-d6,δ,ppm):153.18,141.48,129.72,129.09,128.47,128.46,128.41,126.52,124.96,119.78.其中1H NMR谱图、13C NMR谱图如图57～58所示。
3,3'-(1,3-phenylenebis(methylene))bis(2-methylphenol)(化合物31):白色固体，1H NMR(600MHz,DMSO-d6,δ,ppm,J/Hz):9.21(s,2H),7.14(t,J＝7.6Hz,1H),6.98(d,J＝12.8Hz,1H),6.95–6.87(m,4H),6.69(d,J＝7.9Hz,2H),6.57(d,J＝7.4Hz,2H),3.85(s,4H),1.99(s,6H)；13C NMR(150MHz,DMSO-d6,δ,ppm):155.84,141.03,140.69,129.33,128.69,126.40,126.25,122.78,121.11,113.27,39.41,11.95.其中1H NMR谱图、13C NMR谱图如图59～60所示。
实施例2：化合物1、化合物2和化合物3抑制酪氨酸酶活性研究
1、溶液配制
磷酸盐缓冲液(0.2M，pH 6.8)：精密称取Na2HPO4 2.84g、NaH2PO4 2.4g，分别用纯化水溶解定容至100mL，将其二者等体积混合后调节pH至6.8。
L-多巴溶液：精密称取L-多巴3.95mg，溶于10mL磷酸盐缓冲液(0.2M，pH 6.8)中，制成2mmol/L L-多巴溶液。
酪氨酸酶溶液：精密称取1mg酪氨酸酶(酶活为500U/mg)，溶于5mL磷酸盐缓冲液(0.2M，pH 6.8)中，制成酶活力为100U/mL的酪氨酸酶溶液。
样品工作液：精密称取化合物1、化合物2和化合物3、曲酸各10mg置于500μL超纯水中，随后缓慢滴加1M NaOH至溶液澄清透亮，最后用纯化水补齐至1mL，配制成10mg/mL母液；再用上述磷酸盐缓冲液将待测化合物及阳性对照药物曲酸稀释至浓度为31.2μg/mL、62.5μg/mL、125μg/mL、250.00μg/mL和500.00μg/mL的样品工作液。
2、酪氨酸酶活性测定
设置四个试验组：样品组A1，样品阴性对照组A2，酶标准组B1和酶阴性对照组B2；每个样品设置3个平行，按表1配制200μL反应体系。依次向96孔板中加入对应体积的磷酸盐缓冲液、各浓度待测样品溶液(终浓度为3.12μg/mL、6.25μg/mL、12.5μg/mL、25μg/mL和50μg/mL)、酪氨酸酶溶液(终浓度为20U/mL)以及反应底物L-多巴(终浓度为1.2mmol/L)，于37℃微孔板恒温振荡器中温育30min，随后在多功能酶标仪(SPARK 10M，TECAN)中测定各试验组在475nm处的吸光度。待测化合物对酪氨酸酶的抑制率计算公式如下：
酪氨酸酶抑制率(％)＝[1-(A1-A2)/(B1-B2)]×100。
表1酪氨酸酶活性抑制实验反应体系配制(体积/μL)
如图61所示，在图61中，浓度为3.12μg/mL、6.25μg/mL、12.5μg/mL和25μg/mL时，每组浓度下均含有四组数据，四组数据从左至右依次为化合物3、曲酸、化合物1和化合物2；浓度为50μg/mL下，有三组数据，从左至右依次为化合物3、曲酸、化合物1。由图61可以看出，化合物1、化合物2和阳性对照药曲酸均表现出对酪氨酸酶活性产生剂量依赖性的抑制作用，应用Graphpad Prism 8.0软件进行非线性拟合后计算得出化合物1、化合物2和曲酸对酪氨酸酶的半抑制浓度IC50分别为10.43μg/mL(即35.96μmol/L)、4.36μg/mL(即13.68μmol/L)和18.61μg/mL(即131.6μmol/L)。而化合物3在测试浓度下均无相关活性(IC50>50μg/mL)。结果表明，化合物1和化合物2对酪氨酸酶有良好的抑制活性， 酪氨酸酶抑制活性效果分别是曲酸的3.7倍和9.6倍，有望作为褐变抑制剂用于皮肤美白提亮。
实施例3：化合物1、化合物1和化合物3抑制α-葡萄糖苷酶活性研究
1、溶液配制
磷酸盐缓冲液(0.2M，pH 6.8)：精密称取Na2HPO4 2.84g、NaH2PO4 2.4g，分别用纯化水溶解定容至100mL，将二者等体积混合后调节pH至6.8。
α-葡萄糖苷酶溶液：来源于酿酒酵母的α-葡萄糖苷酶粉末，用磷酸盐缓冲液(0.2M，pH 6.8)配制成1U/mL的α-葡萄糖苷酶溶液，-20℃保存。
底物PNPG溶液：用分析天平精密称取4-硝基苯-α-D-吡喃葡萄糖苷(PNPG)211mg，加入70mL上述磷酸盐缓冲液溶解均匀，配制成10mmol/L的底物储存液，-20℃避光保存。本申请中的“mmol/L”是指毫摩尔每升，本申请中的“μmol/L”是指微摩尔每升。
阳性对照工作液：本实验选取阿卡波糖作为阳性对照，精密称取阿卡波糖粉末103.3mg，用1mL上述磷酸盐缓冲液充分溶解混匀，配制成160mmol/L的阿卡波糖母液。再用上述磷酸盐缓冲液将母液稀释至浓度为2.5mmol/L、5mmol/L、10mmol/L、20mmol/L、40mmol/L、80mmol/L和160mmol/L的阳性对照工作液。
测试化合物工作液：精密称取2.90mg化合物1、3.19mg化合物2和3.23mg化合物3，分别置于500μL超纯水中，缓慢滴加1M NaOH至溶液澄清透亮，最后用纯化水补齐至1mL，配制成10mmol/L化合物母液。再用上述磷酸盐缓冲液将其稀释至浓度为0.062mmol/L、0.125mmol/L、0.25mmol/L、0.5mmol/L、1mmol/L和2mmol/L的化合物1工作液，浓度为0.025mmol/L、0.05mmol/L、0.1mmol/L、0.2mmol/L、0.4mmol/L和0.8mmol/L的化合物2工作液，浓度为3.12μmol/L、6.25μmol/L、12.5μmol/L、25μmol/L、50μmol/L和100μmol/L的化合物3工作液。
2、α-葡萄糖苷酶活性测定
设置四个试验组：空白组A，酶标准组B，样品阴性对照组C，样品组D；每个样品设置3个平行。按表2配制600μL反应体系，依次向96孔板中加入对应体积的磷酸盐缓冲液、各浓度待测样品工作液(终浓度为测试化合物工作液稀释20倍)、α-葡萄糖苷酶溶液(终浓度0.005U/mL)以及反应底物PNPG(终浓度0.5mmol/L)，充分混匀。反应体系于37℃温育50min后，加入60μL 0.1mol/L Na2CO3溶液终止反应。将待测96孔板置于多功能酶标仪(SPARK 10M，TECAN)中测定各试验组在405nm处的吸光度。α-葡萄糖苷酶的抑制率计算公式如下：
α-葡萄糖苷酶抑制率(％)＝[1-(D-C)/(B-A)]×100。
表2α-葡萄糖苷酶活性抑制实验反应体系配制(体积/μL)
如图62所示，三种化合物和阳性对照药阿卡波糖均对α-葡萄糖苷酶活性产生剂量依赖性的抑制作用。在图62中，从左至右分别对应化合物1、化合物2、化合物3和阿卡波糖在不同浓度下的α-葡萄糖苷酶抑制率。应用Graphpad Prism 8.0软件进行非线性拟合后计算得出化合物1、化合物2、化合物3及阿卡波糖对α-葡萄糖苷酶的半抑制浓度IC50分别为21.77μmol/L、8.91μmol/L、0.95μmol/L和481.7μmol/L。上述实验结果表明，三种化合物均对α-葡萄糖苷酶有良好的抑制活性，且抑制效果显著优于阳性对照药阿卡波糖，有望通过高效抑制α-葡萄糖苷酶以减少成熟的活性酪氨酸酶的生成，达到降低皮肤色素沉着的目的。
实施例4：化合物1、化合物2和化合物3抗氧化活性研究
将7.4mmol/L ABTS溶液和2.6mmol/L K2S2O8溶液等体积混合室温避光静置16h，制备ABTS自由基储备液。用磷酸盐缓冲溶液(pH 7.4，10mmol/L)将ABTS自由基储备液稀释，使其在波长734nm处吸光度达到0.70±0.05，制成ABTS工作液。取200μL ABTS工作液与10μL磷酸盐缓冲溶液(pH7.4，10mmol/L)混合，测得734nm处的吸光度设为A0。精密称取10mg化合物1溶于500μL纯化水中，缓慢滴加1mol/L NaOH至溶液澄清透亮，最后用纯化水补齐至1mL，使其配制为10mg/mL母液。再用磷酸盐缓冲溶液(pH7.4，10mmol/L)将待测母液稀释至相应浓度。阳性对照药Trolox(水溶性维生素E)直接用纯水配制成10mg/mL母液，再用水稀释至相应浓度。将10μL不同浓度的样品溶液与200μL ABTS工作液混合，使阳性药维生素E的终浓度为0.9μg/mL、1.79μg/mL、3.58μg/mL、7.15μg/mL、10.73μg/mL、14.30μg/mL、25μg/mL和50μg/mL，化合物1的终浓度为0.62μg/mL、1.25μg/mL、2.50μg/mL、5.00μg/mL、10μg/mL、20μg/mL、40μg/mL和50μg/mL，化合物2和化合物3的终浓度为0.78μg/mL、1.56μg/mL、3.12μg/mL、6.25μg/mL、12.5μg/mL、25μg/mL和50μg/mL。混合后的样品溶液室温静置10min，于波长734nm处测量吸光度(Ai)。同时，将10μL对应浓度的样品溶液与200μL10mmol/L pH 7.4的磷酸盐缓冲溶液混合，测定其在波长734nm处的背景吸光度Aj。每个样品浓度设置3个平行。计算样品对ABTS自由基的清除率公式如下：
ABTS自由基清除率(％)＝[1-(Ai-Aj)/A0]×100。
如图63所示，在测试浓度范围内，待测化合物对ABTS自由基均表现出良好的清除作用。应用Graphpad Prism 8.0软件进行非线性拟合，计算得出化合物1、化合物2和化合物3对ABTS自由基清除的IC50(half maximal inhibitory concentration)分别为6.78μg/mL(即23.22μmol/L)、2.56μg/mL(即8.02μmol/L)和2.10μg/mL(即6.49μmol/L)；阳性对照药维生素E的IC50值为4.75μg/mL(即11.05μmol/L)。上述实验结果表明，化合物1、化合物2和化合物具有良好的自由基清除能力，其中化合物2和化合物3的抗氧化活性优于阳性对照药维生素E，有望帮助细胞抵抗氧化应激损伤，延缓皮肤衰老。
表3三种化合物相关活性的半抑制浓度IC50值
实施例5：化合物1、化合物2和化合物3细胞活性试验
试验样品的处理：
样品组：将化合物1、化合物2和化合物3、苯乙基间苯二酚分别用DMSO溶解后用1640培养液稀释成浓度为38.6μmol/L的母液，再用1640培养液将母液稀释成19.3μmol/L、9.65μmol/L、4.825μmol/L、2.413μmol/L系列浓度样品备用。
阴性对照组：1640基础培养基。
细胞活性试验：
取B16细胞铺96孔板，24h后吸弃培养基，加入含有不同浓度试验样品的基础培养基，24h后MTT法检测OD490 nm，并通过t检验分析得出试验样品对B16细胞活性的影响。
统计分析软件为SPSS，试验样品和阴性对照之间的比较采用独立样本t检验。上述统计分析均为双尾检验，显著性水平为α＝0.05。*P＜0.05，*表示试验样品在该浓度作用下与阴性对照组对比有显著性差异，实验结果如图64。在图64横坐标所对应的每组类别中，均含有四组数据。四组数据从左至右依次为化合物1、化合物2、化合物3和苯乙基间苯二酚的细胞存活率数据。
由图64可知，三种化合物浓度为19.3μmol/L时，细胞活性>90％，无细胞毒性。
实施例6：化合物1、化合物2和化合物3细胞黑素合成抑制实验
以19.3μmol/L的化合物1、化合物2和化合物3、苯乙基间苯二酚为实验样品，1640基础培养基为阴性对照，取B16细胞铺6孔板，培养24h后，更换为含有不同浓度试验样品的1640基础培养基，再经过两次换液后，用PBS洗两遍细胞，每孔加入200μL 0.25％胰酶消化细胞，将细胞收集入离心管中，离心5分钟。在每管中加入200μL的含10％DMSO的1M NaOH裂解细胞，震摇均匀，移入96孔板中，酶标仪检测各孔405nm处吸光度。细胞黑素合成抑制率计算公式为：
式中：T—试验样品孔吸光度；
C—阴性对照组吸光度的3次平均值；
统计分析软件为SPSS，试验样品和阴性对照之间的比较采用独立样本t检验。上述统计分析均为双尾检验，显著性水平为α＝0.05。*P＜0.05；**P＜0.01，*表示试验样品在该浓度作用下与阴性对照组对比有显著性差异。结果如图65。
由图65可知，19.3μmol/L的化合物1、化合物2和化合物3、苯乙基间苯二酚对B16细胞黑素合成抑制率分别为52.230％、40.881％、34.798％、32.791％，对抑制细胞黑素合成有显著作用(P<0.05)，且化合物1、化合物2和化合物3对B16细胞黑素合成抑制率显著高于市场经典美白成分苯乙基间苯二酚，表明化合物1、化合物2和化合物3有优异的美白功效。
实施例7：化合物1和化合物2斑马鱼美白功效实验
斑马鱼在发育的早期是透明的，在胚胎发育至24小时黑色素开始从视网膜上皮生长。色素细胞起源于神经嵴细胞，神经嵴细胞是由背部外胚层分化而来的一组细胞，然后经过增殖、迁移、分化为色素母细胞。在黑色素形成过程中进行干预可以抑制黑色素的形成。斑马鱼皮肤的白度可以用来评价样品的美白效果。
试验系统采用野生AB型斑马鱼。使用的斑马鱼年龄为6hpf(受精后6小时)。每组样本量为15尾鱼(N＝10)。成鱼按照实验室标准饲养繁育方法，符合国际AAALAC认证要求。
随机选取斑马鱼于6孔板中，每孔15尾。将样品制备成可均匀分散于水中的悬浮液，浓度如表4所示，同时设置正常对照组，每孔容量为3mL，28℃条件下避光孵育45h。孵育结束后，每个样品组随机选取10尾斑马鱼置于解剖显微镜下拍照，用高级图像处理软件分析并采集数据，分析斑马鱼头部黑色素信号强度(S)，根据公式计算并判断样品是否具有美白功效。计算公式为：
美白功效＝S(正常对照组)-S(样品组)/S(正常对照组)×100％。
由表4和图66观察发现，样品化合物1(0.0002％组)、化合物1(0.0001％组)、化合物2(0.0001％组)的斑马鱼头部黑色素信号强度与正常对照组相比，明显减少，揭示了样品具有美白功效；样品化合物1(0.00001％组)、化合物2(0.00001％组)、苯乙基间苯二酚377组的斑马鱼头部黑色素信号强度与正常对照组相似，揭示了样品该浓度下不具有美白功效。因此，在本次实验条件下，化合物1(0.0002％)、化合物1(0.0001％)、化合物2(0.0001％)具有美白功效，而化合物1(0.00001％)、化合物2(0.00001％)、苯乙基间苯二酚377(0.0002％)不具有美白功效。
表4斑马鱼美白功效检测结果
备注:统计学分析p<0.05且功效值≥20％，判定为有效。
实施例8：体外哺乳动物细胞微核试验
体外微核(MNvit)试验是用于检测细胞分裂间期细胞质中微核的一种遗传毒性检测方法。
试验过程如下：
以DMSO做溶剂，称量一定量样品进行溶解。按1％的加入量加入含血清的DMEM培养基中，培养基中样品的终浓度分别为IC50、1/2IC50和1/4IC50。
使用传代次数不超过32代的小鼠淋巴瘤细胞L5178Y制备成细胞悬液，将制备好的细胞悬浮液种植到24孔细胞培养板中，种植量为1mL/孔，每孔的细胞数量是4×105个/每孔。置于二氧化碳培养箱中在37℃、5％ CO2条件下培养24h。
在培养板的相应孔内分别加入含有细胞与培养基的1mL配制好的溶剂对照溶液、阳性对照溶液、不同剂量的供试品样品溶液。其中，溶剂对照溶液与供试品样品溶液除不含有供试品样品外，其他均相同。阳性对照溶液为0.25μg/mL丝裂霉素、10μg/mL环磷酰胺和0.3μg/mL秋水仙碱细胞培养板内的细胞分别进行三种方式的暴露，包括：不加代谢活化体系(S9混合液)的短期暴露、添加代谢活化体系(S9混合液)的短期暴露、不加代谢活化体系(S9混合液)的长期暴露。按不同组要求将培养板放置于二氧化碳培养箱中孵育。
孵育结束后，收集细胞培养板内的细胞悬浮液于离心管内，进行低渗处理，低渗完成后进行细胞固定。将固定后的细胞悬浮液滴在载玻片上，每一孔培养物应滴1张载玻片。制好的微核玻片染色后，于显微镜下观察1000个细胞，记录微核细胞数量。
结果评价标准：
(1)阳性结果判定
①与溶剂对照组相比，至少一种测试剂量下微核率显示出统计学意义的显著增加(p值＜0.05即视为显著增加)；②微核率的增长有剂量依赖性；③任何剂量下的测试结果都不在历史阴性对照数据的分布范围内(95％范围内)。
(2)阴性结果判定
①与溶剂对照组相比，任何测试剂量下微核率未显示出统计学意义的显著增加；②微核率无剂量依赖性；③所有测试结果均在历史溶剂对照数据的范围内(95％范围内)。
实验结论:在微核试验中，与溶剂对照组相比，化合物1和化合物2在在IC50(22.5,19.76μg/mL)、1/2 IC50(11.28,9.88μg/mL)和1/4 IC50(5.64,4.96μg/mL)各浓度条件下的微核率未显示出统计学意义的显著增加，且无剂量依赖性，说明化合物1和化合物2均未表现出潜在遗传毒性。
实施例9：细菌回复突变
试验原理：细菌回复突变试验使用需要氨基酸的鼠伤寒沙门氏菌和大肠杆菌菌株检测点突变，这种突变涉及替换、添加或删除一个或几个DNA碱基对。这种细菌回复突变试验的原理是，它检测的回复突变存在于测试菌株和恢复细菌合成必需氨基酸的功能能力。逆转录细菌是通过它们在缺乏母体测试菌株所需的氨基酸的情况下生长的能力来检测的。
试验过程如下：
将样品溶于浓度为5mg/皿、2.5mg/皿、1.6mg/皿、0.8mg/皿、0.4mg/皿的DMSO中，过滤后制成样品待用。选取鼠伤寒沙门菌TA97a、TA98、TA100、TA102。取适量营养肉汤培养基，加入试管中，将主平板菌株接种到营养肉汤培养基中，在37℃，150转/min条件下震荡培养10h，每毫升培养液中活菌数不少于1×109/mL，然后测定OD650。
配制底层培养基和顶层琼脂，于2mL保温的顶层培养基中加入测试菌株新鲜菌液0.1mL、供试品(根据供试品设定浓度决定供试品的具体加入量)、10％ S9混合液0.5mL，震荡摇晃均匀，然后迅速倒入至底层培养基上，转动平皿使顶层培养基均匀分布在底层培养基上，平放固化。受试物取5mg/皿、2.5mg/皿、1.6mg/皿、0.8mg/皿、0.4mg/皿的试验浓度，每个浓度设置3个平行。同时设置阳性对照、溶剂对照和空白对照，每组设3个平行。将固化的平板放在培养箱中于37℃条件下培养48h，观察结果并记录菌落数。
结果评价标准：
(1)阳性结果的判定:直接计数培养基上生长的回复突变菌落数的多少，如在背景生长良好的条件下，在至少1个或多个菌株，受试物的TA97a、TA98、TA100、TA102的回复突变菌落数应增加1倍以上(即回复突变菌落数等于或大于溶剂对照的2倍以上)，并存在剂量反应关系，即可认为该供试品诱变试验阳性。在至少一个或多个菌株，如果至少某一供试品浓度下，回复突变菌落的数量存在显著差异，但不具有剂量反应关系，如果数据可重复并存在统计学意义的阳性反应，则可认为该受试物诱变试验阳性。
(2)阴性结果的判定:与上述阳性反应均不符，在任何菌株或是否添加S9活化系统的条件下，任何供试品浓度下，相对于自发回变，供试品的回复突变菌落数未显著增加，并且不存在剂量反应关系，即该供试物诱变实验阴性。在该实验条件下供试品对测试菌株不诱发基因突变。
实验结论:化合物1和化合物2分别以5mg/皿、2.5mg/皿、1.6mg/皿、0.8mg/皿、0.4mg/皿的浓度溶于DMSO中，过滤后的样品用标准菌株TA97a、TA98、TA100、TA102检测，结果显示无潜在遗传毒性。
实施例10：皮肤光毒检测
选取成年白化豚鼠，雌雄各半。选用6只动物进行正式试验。试验前动物在实验动物房环境中适应3d时间。进行正式光毒性试验前24h，将动物脊柱两侧皮肤去毛，试验部位皮肤完好，无损伤及异常。按中国《化妆品安全技术规范》(2015年版)(下简称规范)P501图1备4块去毛区(图67)，每块去毛面积约为2cm×2cm。
将动物固定，按规范P501表1所示，在动物去毛区1和去毛区2涂敷0.2mL样品，30min后，左侧(去毛区1和去毛区3)用铝箔覆盖，胶带固定，右侧(去毛区2和去毛区4)用UVA进行照射。光强度平均值约为7.011mW/cm2，，照射剂量为10J/cm2，时间为1426秒。结束后分别于1h、24h、48h和72h观察皮肤反应，根据规范P501-P502表2判定每只动物皮肤反应评分。单纯涂样品而未经照射区域未出现皮肤反应，而涂样品后经照射的区域出现皮肤反应分值之和为2或2以上的动物数为1只或1只以上时，判为样品具有光毒性。
实验结论：受试物化合物1和化合物2对豚鼠光毒性实验中，未见皮肤光毒性。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本申请的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对申请专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本申请构思的前提下，还可以做出若干变形和改进，这些都属于本申请的保护范围。因此，本申请专利的保护范围应以所附权利要求为准。

Claims (42)

  1. 一种式I所示的化合物的应用，其中，所述式I所示的化合物如下：
    各R1、各R2及各R3独立地选自氢、羟基、卤素、苯基、卤代甲氧基、甲基氨基、甲基及具有2-4个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
    R4、R5、R6及R7各自独立地选自氢、甲基及具有2-5个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
    m、n及k各自独立地为1～3的整数；
    所述应用包括在制备酪氨酸酶抑制剂、制备α-葡萄糖苷酶抑制剂、制备治疗糖尿病药物、制备美白产品、制备抗皮肤氧化产品、制备抗衰老产品、制备减少黑色素生成的护肤品、制备减少黑色素生成的皮肤病治疗药物、制备预防色素沉着疾病的护肤品、制备预防色素沉着疾病的皮肤病治疗药物、制备治疗色素沉着疾病的护肤品、制备治疗色素沉着疾病的皮肤病治疗药物及抑制食物褐变中的一种或几种中的应用。
  2. 根据权利要求1所述的应用，其中，各R1及各R3中至少有一个为羟基。
  3. 根据权利要求1～2任一项所述的应用，其中，各R1中至少有一个为羟基，各R3中至少有一个为羟基。
  4. 根据权利要求1～3任一项所述的应用，其中，所述式I所示的化合物选自如下结构中的一种或几种：
    所述应用包括在制备α-葡萄糖苷酶抑制剂、制备治疗糖尿病药物、制备抗皮肤氧化、制备抗衰老产品、制备减少黑色素生成的护肤品、制备减少黑色素生成的皮肤病治疗药物、制备预防色素沉着疾病的护肤品、制备预防色素沉着疾病的皮肤病治疗药物、制备治疗色素沉着疾病的护肤品及制备治疗色素沉着疾病的皮肤病治疗药物中的一种或几种中的应用。
  5. 根据权利要求1～4任一项所述的应用，其中，所述式I所示的化合物选自所述应用包括制备酪氨酸酶抑制剂。
  6. 根据权利要求1～3任一项所述的应用，其中，所述式I所示的化合物选自所述应用包括在制备酪氨酸酶抑制剂、制备α-葡萄糖苷酶抑制剂、制备治疗糖尿病药物、制备抗皮肤氧化产品、制备抗衰老产品、制备减少黑色素生成的护肤品、制备减少黑色素生成的皮肤病治疗药物、制备预防色素沉着疾病的护肤品、制备预防色素沉着疾病的皮肤病治疗药物、制备治疗色素沉着疾病的护肤品及制备治疗色素沉着疾病的皮肤病治疗药物中的一种或几种中的应用。
  7. 根据权利要求1～6任一项所述的应用，其中，所述色素沉着疾病选自雀斑、黄褐斑、妊娠纹、老年斑及黑色素瘤中的一种或几种。
  8. 根据权利要求1～7任一项所述的应用，其中，所述抗皮肤氧化和抗衰老是指清除细胞内的活性氧自由基。
  9. 一种1,3-双苄基苯酚类化合物，其结构式选自以下化合物2的结构式及化合物3的结构式中的一种或几种：
  10. 权利要求9所述的1,3-双苄基苯酚类化合物的制备方法，其中，所述制备方法包括以下步骤：将原料A与原料B按物质的量之比1：(5～10)混合，所述原料A选自1,3-二(溴甲基)苯、1,3-二(氯甲基)苯和其组合，所述原料B选自邻甲酚、1,2-苯二酚和其组合，以三氯化铝为催化剂，在氮气保护下，100-120℃加热反应一段时间，再经柱层析纯化，制得。
  11. 一种组合物，其中，所述组合物具有美白、抗皮肤氧化、抗衰老及抑制食物褐变中的一种或几种功效，所述组合物包括式I所示的化合物以及载体，所述式I所示的化合物如下:
    各R1、各R2及各R3独立地选自氢、羟基、卤素、苯基、卤代甲氧基、甲基氨基、甲基及具有2-4个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
    R4、R5、R6及R7各自独立地选自氢、甲基及具有2-5个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
    m、n及k各自独立地为1～3的整数；
    所述载体选自一种或多种化妆品领域、药学领域、食品领域和其组合中可接受的载体。
  12. 根据权利要求11所述的组合物，其中，各R1及各R3中至少有一个为羟基。
  13. 根据权利要求11～12任一项所述的组合物，其中，各R1中至少有一个为羟基，各R3中至少有一个为羟基。
  14. 根据权利要求11～13任一项所述的组合物，其中，所述式I所示的化合物选自如下结构中的一种或几种：
  15. 根据权利要求11～14任一项所述的组合物，其中，所述组合物具有美白、抗皮肤氧化及抗衰老中的至少一种功效，包括作为有效成分的使用有效量的化合物1化合物2化合物3中的至少一种，和一种或多种化妆品领域中可接受的载体。
  16. 根据权利要求15所述的组合物，其中，美白是指抑制酪氨酸酶活性、抑制α-葡萄糖苷酶活性、抑制细胞黑色素生成及抑制色素沉着中的一种或几种；抗皮肤氧化和抗衰老是指清除细胞内的活性氧自由基。
  17. 根据权利要求16所述的组合物，其中，所述色素沉着选自雀斑、黄褐斑、妊娠纹、老年斑及黑色素瘤中的一种或几种。
  18. 根据权利要求11～17任一项所述的组合物，其中，所述组合物选自酪氨酸酶抑制剂组合物和α-葡萄糖苷酶抑制剂组合物中的一种或几种。
  19. 根据权利要求11～18任一项所述的组合物，其中，所述载体包括香精、用于皮肤护理的化合物、用于皮肤清洁的化合物和紫外线吸收剂中的一种或几种。
  20. 根据权利要求19所述的组合物，其中，所述组合物包括香精和所述式I所示的化合物，所述香精以有效提供感官效果的量存在，所述式I所示的化合物以具有抑制酪氨酸酶作用和抑制α-葡萄糖苷酶作用中的一种或两种作用的量存在。
  21. 根据权利要求20所述的组合物，其中，在所述组合物中，所述式I所示的化合物以约3％至约30％的质量百分比存在。
  22. 根据权利要求19所述的组合物，其中，所述组合物包括紫外线吸收剂和式I所示的化合物，所述紫外线吸收剂的量有效地提供保护系数至少大于2的紫外线保护，所述式I所示的化合物的量具有抑制酪氨酸酶和抑制α-葡萄糖苷酶中的一种或两种作用。
  23. 根据权利要求19所述的组合物，其中，所述组合物包括用于皮肤护理的化合物及用于皮肤清洁的化合物中的一种或几种，以及式I所示的化合物，所述式I所示的化合物的量具有抑制酪氨酸酶和抑制α-葡萄糖苷酶中的一种或两种作用。
  24. 如权利要求11～23任一项所述的组合物在制备美白护肤品、美白皮肤病治疗药物、抗衰老护肤品、抗衰老皮肤病治疗药物和其组合中的应用。
  25. 根据权利要求24所述的应用，其中，所述组合物选自护肤品组合物和皮肤病治疗药物组合物中的一种，所述组合物包括作为有效成分的使用有效量的化合物1化合物2及化合物3中的一种或几种。
  26. 根据权利要求25所述的应用，其中，美白是指抑制酪氨酸酶活性、抑制α-葡萄糖苷酶活性、抑制细胞黑色素生成及抑制色素沉着中的一种或几种；抗皮肤氧化和抗衰老是指清除细胞内的活性氧自由基。
  27. 根据权利要求26所述的应用，其中，所述色素沉着选自雀斑、黄褐斑、妊娠纹、老年斑及黑色素瘤中的一种或几种。
  28. 一种产品，其中，所述产品为化妆品及皮肤病治疗药物中的一种，所述产品包括如权利要求11～23任一项所述的组合物或包括式I所示的化合物，
    各R1、各R2及各R3独立地选自氢、羟基、卤素、苯基、卤代甲氧基、甲基氨基、甲基及具有2-4个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
    R4、R5、R6及R7各自独立地选自氢、甲基及具有2-5个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
    m、n及k各自独立地为1～3的整数。
  29. 根据权利要求28所述的产品，其中，所述式I所示的化合物在所述产品中的质量百分比为0.0001％～10％。
  30. 根据权利要求29所述的产品，其中，所述式I所示的化合物在所述产品中的质量百分比为0.01％～2％。
  31. 根据权利要求30所述的产品，其中，所述式I所示的化合物在所述产品中的质量百分比为0.1％～1％。
  32. 一种治疗糖尿病的药物组合物，其中，包括作为有效成分的使用有效量的化合物和载体，所述作为有效成分的使用有效量的化合物选自式I所示的化合物中的一种或几种，所述式I所示的化合物如下:
    各R1、各R2及各R3独立地选自氢、羟基、卤素、苯基、卤代甲氧基、甲基氨基、甲基及具有2-4个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
    R4、R5、R6及R7各自独立地选自氢、甲基及具有2-5个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
    m、n及k各自独立地为1～3的整数；
    所述载体选自一种或多种药学领域中可接受的载体。
  33. 根据权利要求32所述的治疗糖尿病的药物组合物，其中，所述作为有效成分的使用有效量的化合物选自化合物1化合物2和化合物3中的一种或几种。
  34. 权利要求32～33任一项所述的药物组合物在制备治疗糖尿病药物中的应用。
  35. 根据权利要求34所述的应用，其中，作为有效成分的使用有效量的化合物选自化合物1化合物2及化合物3中的一种或几种。
  36. 一种药物制剂，其中，包括一种或多种治疗糖尿病的化合物，以及一种或多种具有抑制α-葡萄糖苷酶作用的量的式I所示的化合物；所述式I所示的化合物如下：
    各R1、各R2及各R3独立地选自氢、羟基、卤素、苯基、卤代甲氧基、甲基氨基、甲基及具有2-4个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
    R4、R5、R6及R7各自独立地选自氢、甲基及具有2-5个碳原子的直链或支链、饱和或不饱和烃基中的一种或几种的组合；
    m、n及k各自独立地为1～3的整数。
  37. 根据权利要求36所述的药物制剂，其中，各R1及各R3中至少有一个为羟基。
  38. 根据权利要求36～37任一项所述的药物制剂，其中，各R1中至少有一个为羟基，各R3中至少有一个为羟基。
  39. 根据权利要求36～38任一项所述的药物制剂，其中，所述式I所示的化合物选自如下结构中的一种或几种：
  40. 一种用于人类皮肤美白和对抗人类皮肤老年斑的方法，其中，包括给需要的人施用有效量的如权利要求11～23任一项所述的组合物或施用权利要求28～31任一项所述的产品。
  41. 一种用于抑制食品褐变的方法，其中，包括将有效量的如权利要求11～23任一项所述的组合物施用于食品。
  42. 一种治疗糖尿病的方法，其中，包括给需要的人施用有效量的权利要求32～33任一项所述的药物组合物或权利要求36～39任一项所述的药物制剂。
PCT/CN2024/097453 2023-06-05 2024-06-05 1,3-双苄基苯酚类衍生物、制备方法及其应用 Ceased WO2024251138A1 (zh)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2730551A (en) * 1952-03-24 1956-01-10 Monsanto Chemicals Halogenated tris-phenols
JPH09278695A (ja) * 1996-04-16 1997-10-28 Honshu Chem Ind Co Ltd 新規なトリスフェノール化合物
US20070276034A1 (en) * 2002-05-31 2007-11-29 Luke Esposito Compounds, compositions and methods for the treatment of synucleinopathies
CN101953820A (zh) * 2010-07-16 2011-01-26 暨南大学 一种苯乙烯苯酚类化合物作为制备胰岛素增敏剂的用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2730551A (en) * 1952-03-24 1956-01-10 Monsanto Chemicals Halogenated tris-phenols
JPH09278695A (ja) * 1996-04-16 1997-10-28 Honshu Chem Ind Co Ltd 新規なトリスフェノール化合物
US20070276034A1 (en) * 2002-05-31 2007-11-29 Luke Esposito Compounds, compositions and methods for the treatment of synucleinopathies
CN101953820A (zh) * 2010-07-16 2011-01-26 暨南大学 一种苯乙烯苯酚类化合物作为制备胰岛素增敏剂的用途

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