1,3-Bisbenzylphenol derivatives, methods for producing them, and their applications

Abstract

This application relates to the application of a compound represented by formula I. The compound represented by formula I is as follows: Each R1, R2, and R3 is independently one or more combinations selected from the group consisting of hydrogen, hydroxyl group, halogen, phenyl group, halogenated methoxy group, methylamino group, methyl group, and linear or branched, saturated or unsaturated hydrocarbon groups having 2 to 4 carbon atoms; each R4, R5, R6, and R7 is independently one or more combinations selected from the group consisting of hydrogen, methyl group, and linear or branched, saturated or unsaturated hydrocarbon groups having 2 to 5 carbon atoms; and each m, n, and k is independently an integer from 1 to 3.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to the Chinese patent application filed on June 5, 2023, application number 2023106574780, with the title of the invention "1,3-Bisbenzylphenol compound, method of production, and application thereof to whitening and anti-aging cosmetics," the entire contents of which are incorporated into this application by reference.

[0002] (Technical field) This application relates to the field of cosmetics and pharmaceuticals, and concerns 1,3-bisbenzylphenol derivatives, methods for producing them, and their applications. [Background technology]

[0003] Oxygen free radicals generated during cellular metabolic processes cause cumulative damage to intracellular biomolecules, leading to cellular aging and loss of proliferative capacity. This imbalance between oxidation and antioxidant systems is considered a major cause of skin aging. Tyrosinase, also known as polyphenol oxidase, is an oxidoreductase widely present in plants, animals, microorganisms, and the human body. It is the rate-limiting enzyme in melanin synthesis and is closely related to the development of melanin hyperdeposition such as freckles and brown spots on human skin. In recent years, its application in fields such as medicine and cosmetics has attracted attention. Currently, many commercially available skin whitening and tone-up products achieve their whitening effect based on inhibition of tyrosinase by α-arbutin, kojic acid, 4-butylresorcinol, etc., or based on the antioxidant effect of vitamin C, vitamin E, and their derivatives. α-arbutin belongs to the hydroquinone derivatives and is cytotoxic to melanocytes and highly irritating to the skin. Because long-term use can cause permanent vitiligo, it is listed as a prohibited cosmetic ingredient in many countries. Kojic acid inhibits the catalytic activity of tyrosinase by chelating its copper ions, and when used in commercially available skin and hair tone-up products, it is likely to cause contact allergies and may even induce skin lesions and liver cancer. Vitamins C and E are important antioxidants for humans, but they do not directly inhibit tyrosinase; instead, they act by reducing colored intermediates in the melanin biosynthesis process, resulting in insufficient whitening and tone-up effects on the skin. Due to these disadvantages, the widespread application of these ingredients in the whitening and blemish-removing cosmetics market is limited.

[0004] In a previous study, the Xu Gang project team isolated a series of diarylheptolipphenol compounds from Ottelia acuminata var. acuminata, an aquatic plant and edible vegetable of the Bai ethnic group in Dali, Yunnan Province, China. These compounds exhibited significant α-glucosidase inhibitory activity and possess potential therapeutic value for diabetes (Liu HX, Ma JZ, Ye YS, Zhao JJ, Wan SJ, Hu XY, Xu G. α-Glucosidase inhibitory diarylheptanoids from Ottelia acuminata var. acuminata, a traditional vegetable of Bai Nationality in Yunnan, Natural Products and Bioprospecting 2022, 12: 22). As research has shown, tyrosinase is a glycosylated protein, and in its maturation process, the original glycans must undergo a series of modifications and cleavages to be converted into mature tyrosinase with normal biological function. α-glucosidase I and α-glucosidase II are important enzymes in the modification and cleavage of glycans (Mehta A, Zitzmann N, Rudd PM, Block TM, Dwek RA. α-Glucosidase inhibitors as potential broad-based antiviral agents, FEBS Letters, 1998, 430(1):17-22). When α-glucosidase is inhibited, glycosylation in glycoproteins is suppressed, preventing the production of active tyrosinase, and consequently, melanin formation is also reduced accordingly (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).Therefore, inhibiting α-glucosidase reduces tyrosinase maturation, thereby achieving the goal of reducing melanin production and skin pigmentation, representing a novel approach with potential for skin whitening and spot removal. However, naturally derived diarylheptomepolyphenol compounds have low content, their structural characteristics include a cis-transolefin structure, poor molecular stability, susceptibility to positional isomerization of double bonds via ene reactions, difficulty in synthesis, and high molecular flexibility. [Overview of the project] [Problems that the invention aims to solve]

[0005] Several embodiments of this application provide 1,3-bisbenzylphenol derivatives, methods for producing them, and their applications. [Means for solving the problem]

[0006] The first aspect of the present invention relates to an application of a compound represented by formula I, wherein the compound represented by formula I is as follows: [ka] Equation I Each R1, R2, and R3 is independently one or more combinations selected from the group consisting of hydrogen, hydroxyl group, halogen, phenyl group, halogenated methoxy group, methylamino group, methyl group, and linear or branched, saturated or unsaturated hydrocarbon groups having 2 to 4 carbon atoms. R4, R5, R6, and R7 are each independently one or more combinations selected from the group consisting of hydrogen, a methyl group, and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms. m, n, and k are each independent integers between 1 and 3. The aforementioned applications include applications in one or more of the following: the manufacture of tyrosinase inhibitors, α-glucosidase inhibitors, pharmaceuticals for the treatment of diabetes, skin whitening products, anti-oxidative skin products, anti-aging products, skincare products that reduce melanin production, pharmaceuticals for the treatment of skin diseases that reduce melanin production, skincare products that prevent pigmentation disorders, pharmaceuticals for the treatment of skin diseases that prevent pigmentation disorders, skincare products that treat pigmentation disorders, pharmaceuticals for the treatment of skin diseases that treat pigmentation disorders, and the suppression of browning of food.

[0007] In some embodiments, at least one of each R1 and each R3 is a hydroxyl group.

[0008] In some embodiments, at least one of each R1 is a hydroxyl group, and at least one of each R3 is a hydroxyl group.

[0009] In some embodiments, the compound represented by formula I is [ka] and [ka] It is one or more species selected from the group consisting of the following structures.

[0010] The aforementioned applications include applications in one or more of the following: the manufacture of α-glucosidase inhibitors, the manufacture of pharmaceuticals for the treatment of diabetes, the manufacture of anti-oxidative skin products, the manufacture of anti-aging products, the manufacture of skincare products that reduce melanin production, the manufacture of pharmaceuticals for the treatment of skin diseases that reduce melanin production, the manufacture of skincare products that prevent pigmentation disorders, the manufacture of pharmaceuticals for the treatment of skin diseases that prevent pigmentation disorders, the manufacture of skincare products that treat pigmentation disorders, and the manufacture of pharmaceuticals for the treatment of skin diseases that treat pigmentation disorders.

[0011] In some embodiments, the compound represented by formula I is [ka] Selected from among, the aforementioned applications include applications in the production of tyrosinase inhibitors.

[0012] In some embodiments, the compound represented by formula I is [ka] Selected from the above, the applications include applications in one or more of the following: the manufacture of tyrosinase inhibitors, the manufacture of α-glucosidase inhibitors, the manufacture of pharmaceuticals for the treatment of diabetes, the manufacture of anti-oxidative skin products, the manufacture of anti-aging products, the manufacture of skincare products that reduce melanin production, the manufacture of pharmaceuticals for the treatment of skin diseases that reduce melanin production, the manufacture of skincare products that prevent pigmentation disorders, the manufacture of pharmaceuticals for the treatment of skin diseases that prevent pigmentation disorders, the manufacture of skincare products that treat pigmentation disorders, and the manufacture of pharmaceuticals for the treatment of skin diseases that treat pigmentation disorders.

[0013] In some embodiments, the pigmentation disorder is one or more selected from the group consisting of freckles, brown spots, stretch marks, senile lentigines, and malignant melanoma.

[0014] In some embodiments, the anti-skin oxidation and anti-aging effects refer to the scavenging of reactive oxygen species and free radicals within cells.

[0015] A second aspect of the present application provides a 1,3-bisbenzylphenol compound, wherein its structural formula is one or more selected from the group consisting of the structural formulas of Compound 2 and Compound 3 below.

[0016] [ka] A third aspect of the present invention provides a method for producing a 1,3-bisbenzylphenol compound, the method comprising the steps of: mixing raw material A selected from 1,3-bis(bromomethyl)benzene, 1,3-bis(chloromethyl)benzene and combinations thereof, and raw material B selected from o-cresol, 1,2-benzenediphenol and combinations thereof in a molar ratio of 1:(5~10); reacting the mixture by heating it at 100~120°C for a certain period of time under the protection of nitrogen gas with aluminum trichloride as a catalyst; and further purifying it by column chromatography.

[0017] A fourth aspect of the present application is a composition having one or more effects of whitening, anti-skin oxidation, anti-aging, and inhibition of browning of food, wherein the composition comprises a compound represented by formula I and a carrier, the compound represented by formula I being as follows: [ka] Equation I Each R1, R2, and R3 is independently one or more combinations selected from the group consisting of hydrogen, hydroxyl group, halogen, phenyl group, halogenated methoxy group, methylamino group, methyl group, and linear or branched, saturated or unsaturated hydrocarbon groups having 2 to 4 carbon atoms. R4, R5, R6, and R7 are each independently one or more combinations selected from the group consisting of hydrogen, a methyl group, and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms. m, n, and k are each independent integers between 1 and 3. The present invention provides a composition in which the carrier is selected from one or more carriers that are permissible in the fields of cosmetics, pharmaceuticals, food, and combinations thereof.

[0018] In some embodiments, at least one of each R1 and each R3 is a hydroxyl group.

[0019] In some embodiments, at least one of each R1 is a hydroxyl group, and at least one of each R3 is a hydroxyl group.

[0020] In some embodiments, the compound represented by formula I is [ka] , JPEG2026518474000010.jpg1025 and [ka] It is one or more species selected from the group consisting of the following structures.

[0021] In some examples, the composition has at least one of the effects of skin whitening, anti-skin oxidation, and anti-aging, and the compound 1 is used in an effective amount as an active ingredient. [ka] , compound 2 [ka] , compound 3 [ka] It includes at least one of the following and one or more carriers permitted in the field of cosmetics.

[0022] In some embodiments, skin whitening refers to one or more of the following: inhibition of tyrosinase activity, inhibition of α-glucosidase activity, inhibition of cellular melanin production, and inhibition of pigmentation disorders; and anti-skin oxidation and anti-aging refer to the scavenging of reactive oxygen species and free radicals within cells.

[0023] In some embodiments, the pigmentation disorder is one or more selected from the group consisting of freckles, brown spots, stretch marks, senile lentigines, and malignant melanoma.

[0024] In some embodiments, the composition is one or more selected from the group consisting of tyrosinase inhibitor compositions and α-glucosidase inhibitor compositions.

[0025] In some embodiments, the carrier comprises one or more of the following: an essence, a compound for skin care, a compound for skin cleansing, and a UV absorber.

[0026] In some embodiments, the composition comprises an essence and a compound represented by formula I, wherein the essence is present in an amount that effectively provides a sensory effect, and the compound represented by formula I is present in an amount that has one or two of the following effects: tyrosinase inhibitory activity and α-glucosidase inhibitory activity.

[0027] In some embodiments, the compound represented by formula I is present in the composition at a mass percentage of about 3% to about 30%.

[0028] In some embodiments, the composition comprises an ultraviolet absorber and a compound represented by formula I, wherein the amount of the ultraviolet absorber effectively provides ultraviolet protection with a protection factor of at least 2, and the amount of the compound represented by formula I has one or two of the following effects: tyrosinase inhibitory activity and α-glucosidase inhibitory activity.

[0029] In some embodiments, the composition comprises one or more compounds for skin care and compounds for skin cleansing, and a compound represented by formula I, wherein the amount of the compound represented by formula I has one or two of the following effects: tyrosinase inhibitory activity and α-glucosidase inhibitory activity.

[0030] A fifth aspect of the present application provides applications of the above composition in the manufacture of whitening skincare products, pharmaceuticals for treating whitening skin diseases, anti-aging skincare products, pharmaceuticals for treating anti-aging skin diseases, and combinations thereof.

[0031] In some examples, the composition is one selected from the group consisting of skincare product compositions and pharmaceutical compositions, and the composition contains an effective amount of compound 1 as an active ingredient. [ka] , compound 2 [ka] , and compound 3 [ka] Includes one or more of the following.

[0032] In some embodiments, skin whitening refers to one or more of the following: inhibition of tyrosinase activity, inhibition of α-glucosidase activity, inhibition of cellular melanin production, and inhibition of pigmentation disorders; and anti-skin oxidation and anti-aging refer to the scavenging of reactive oxygen species and free radicals within cells.

[0033] In some embodiments, the pigmentation disorder is one or more selected from the group consisting of freckles, brown spots, stretch marks, senile lentigines, and malignant melanoma.

[0034] A sixth aspect of the present application is a product, the product being one of cosmetics and pharmaceuticals for the treatment of skin diseases, the product comprising the above composition or a compound represented by formula I, [ka] Equation I, Each R1, R2, and R3 is independently one or more combinations selected from the group consisting of hydrogen, hydroxyl group, halogen, phenyl group, halogenated methoxy group, methylamino group, methyl group, and linear or branched, saturated or unsaturated hydrocarbon groups having 2 to 4 carbon atoms. R4, R5, R6, and R7 are each independently one or more combinations selected from the group consisting of hydrogen, a methyl group, and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms. The present invention provides a product in which m, n, and k are each independently integers between 1 and 3. In some embodiments, the mass percentage of the compound represented by formula I in the product is between 0.0001% and 10%.

[0035] In some embodiments, the mass percentage of the compound represented by formula I in the product is 0.01% to 2%.

[0036] In some embodiments, the mass percentage of the compound represented by formula I in the product is 0.1% to 1%.

[0037] A seventh aspect of this application is a pharmaceutical composition for the treatment of diabetes, comprising an effective amount of a compound as an active ingredient and a carrier, wherein the effective amount of the compound as an active ingredient is one or more compounds selected from the group consisting of compounds represented by formula I, and the compounds represented by formula I are as follows: [ka] Equation I Each R1, R2, and R3 is independently one or more combinations selected from the group consisting of hydrogen, hydroxyl group, halogen, phenyl group, halogenated methoxy group, methylamino group, methyl group, and linear or branched, saturated or unsaturated hydrocarbon groups having 2 to 4 carbon atoms. R4, R5, R6, and R7 are each independently one or more combinations selected from the group consisting of hydrogen, a methyl group, and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms. m, n, and k are each independent integers between 1 and 3. The aforementioned carrier is selected from one or more carriers acceptable in the field of pharmacy, providing a pharmaceutical composition for the treatment of diabetes.

[0038] In some examples, the effective amount of compound used as the active ingredient was compound 1 [ka] , compound 2 [ka] , and compound 3 [ka] It is one or more species selected from the group consisting of the following.

[0039] A seventh aspect of this application provides an application of the above-mentioned pharmaceutical composition in the manufacture of a pharmaceutical for the treatment of diabetes.

[0040] In some examples, the amount of compound used as the active ingredient was compound 1. [ka] , compound 2 [ka] , and compound 3 [ka] It is one or more species selected from the group consisting of the following.

[0041] The ninth aspect of the present application is a pharmaceutical preparation comprising one or more compounds for treating diabetes and one or more compounds represented by formula I in an amount having α-glucosidase inhibitory activity, wherein the compounds represented by formula I are as follows: [ka] Equation I Each R1, R2, and R3 is independently one or more combinations selected from the group consisting of hydrogen, hydroxyl group, halogen, phenyl group, halogenated methoxy group, methylamino group, methyl group, and linear or branched, saturated or unsaturated hydrocarbon groups having 2 to 4 carbon atoms. R4, R5, R6, and R7 are each independently one or more combinations selected from the group consisting of hydrogen, a methyl group, and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms. m, n, and k are each independent integers between 1 and 3.

[0042] In some embodiments, at least one of each R1 and each R3 is a hydroxyl group.

[0043] In some embodiments, at least one of each R1 is a hydroxyl group, and at least one of each R3 is a hydroxyl group.

[0044] In some embodiments, the compound represented by formula I is [ka] , JPEG2026518474000028.jpg1127 and [ka] It is one or more species selected from the group consisting of the following structures.

[0045] A tenth aspect of the present application provides a method for the whitening of human skin and the treatment of age spots on human skin, comprising the step of administering an effective amount of the above composition or product to a person in need.

[0046] An eleventh aspect of the present application provides a method for inhibiting browning of food, comprising the step of administering an effective amount of the above composition to food.

[0047] A twelfth aspect of the present application provides a method for treating diabetes, comprising the step of administering an effective amount of the above-mentioned pharmaceutical composition or pharmaceutical preparation to a person in need.

[0048] Details of one or more embodiments of the present application will be described below. Other features, purposes, and advantages of the present application will become apparent from the specification and claims.

[0049] To more clearly explain the embodiments of the present application or the technical solutions in the prior art, the following is a brief introduction of the drawings necessary for describing the embodiments or the prior art. Clearly, the drawings in the following description are merely embodiments of the present application, and those skilled in the art can obtain other drawings based on these without any creative work. [Brief explanation of the drawing]

[0050] [Figure 1] This is the 1H NMR spectrum (500 MHz, DMSO-d6) of compound 1 according to the embodiment of the present application. [Figure 2] This is the 13C NMR spectrum (125 MHz, DMSO-d6) of compound 1 according to the embodiment of the present application. [Figure 3] This is the 1H NMR spectrum (600 MHz, DMSO-d6) of compound 2 according to the embodiment of the present application. [Figure 4] This is the 13C NMR spectrum (150 MHz, DMSO-d6) of compound 2 according to the embodiment of the present application. [Figure 5] This is the 1H NMR spectrum (500 MHz, DMSO-d6) of compound 3 according to the embodiment of the present application. [Figure 6] This is the 13C NMR spectrum (125 MHz, DMSO-d6) of compound 3 according to the embodiment of the present application. [Figure 7] This is the 1H NMR spectrum (600 MHz, DMSO-d6) of compound 4 according to the embodiment of the present application. [Figure 8] This is the 13C NMR spectrum (150 MHz, DMSO-d6) of compound 4 according to the embodiment of the present application. [Figure 9] This is the 1H NMR spectrum (500 MHz, DMSO-d6) of compound 5 according to the embodiment of the present application. [Figure 10] This is the 13C NMR spectrum (125 MHz, DMSO-d6) of compound 5 according to the embodiment of the present application. [Figure 11] This is the 1H NMR spectrum (600 MHz, MeOD) of compound 6 according to the embodiment of the present application. [Figure 12] This is the 13C NMR spectrum (150 MHz, MeOD) of compound 6 according to the embodiment of the present application. [Figure 13] This is the 1H NMR spectrum (500 MHz, CDCl3) of compound 7 according to the embodiment of the present application. [Figure 14] This is the 13C NMR spectrum (125 MHz, CDCl3) of compound 7 according to the embodiment of the present application. [Figure 15] This is the 1H NMR spectrum (500 MHz, CDCl3) of compound 8 according to the examples of this application. [Figure 16] This is the 13C NMR spectrum (125 MHz, CDCl3) of compound 8 according to the examples of this application. [Figure 17] This is the 1H NMR spectrum (500 MHz, CDCl3) of compound 9 according to the examples of this application. [Figure 18] This is the 13C NMR spectrum (125 MHz, CDCl3) of compound 9 according to the examples of this application. [Figure 19] This is the 1H NMR spectrum (500 MHz, CDCl3) of compound 10 according to the embodiment of the present application. [Figure 20] This is the 13C NMR spectrum (125 MHz, CDCl3) of compound 10 according to the examples of the present application. [Figure 21] This is the 1H NMR spectrum (600 MHz, CDCl3) of compound 11 according to the embodiment of the present application. [Figure 22] This is the 13C NMR spectrum (150 MHz, CDCl3) of compound 11 according to the examples of the present application. [Figure 23] This is the 1H NMR spectrum (500 MHz, CDCl3) of compound 12 according to the examples of the present application. [Figure 24] This is the 13C NMR spectrum (125 MHz, CDCl3) of compound 12 according to the examples of this application. [Figure 25] This is the 1H NMR spectrum (600 MHz, MeOD) of compound 13 according to the embodiment of the present application. [Figure 26] This is the 13C NMR spectrum (150 MHz, MeOD) of compound 13 according to the embodiment of the present application. [Figure 27] This is the 1H NMR spectrum (500 MHz, CDCl3) of compound 14 according to the examples of the present application. [Figure 28] This is the 13C NMR spectrum (125 MHz, CDCl3) of compound 14 according to the examples of this application. [Figure 29] This is the 1H NMR spectrum (600 MHz, CDCl3) of compound 15 according to the examples of the present application. [Figure 30] This is the 13C NMR spectrum (150 MHz, CDCl3) of compound 15 according to the examples of the present application. [Figure 31] This is the 1H NMR spectrum (600 MHz, CDCl3) of compound 16 according to the examples of the present application. [Figure 32] This is the 13C NMR spectrum (150 MHz, CDCl3) of compound 16 according to the examples of the present application. [Figure 33] This is the 1H NMR spectrum (500 MHz, DMSO-d6) of compound 17 according to the embodiment of the present application. [Figure 34]This is the 13C NMR spectrum (125 MHz, DMSO-d6) of compound 17 according to the embodiment of the present application. [Figure 35] This is the 1H NMR spectrum (500 MHz, CDCl3) of compound 18 according to the examples of the present application. [Figure 36] This is the 13C NMR spectrum (125 MHz, CDCl3) of compound 18 according to the examples of this application. [Figure 37] This is the 1H NMR spectrum (600 MHz, CDCl3) of compound 19 according to the examples of this application. [Figure 38] This is the ¹H NMR spectrum (600 MHz, CDCl3) of compound 20 according to the examples of the present application. [Figure 39] This is the 1H NMR spectrum (600 MHz, MeOD) of compound 21 according to the examples of this application. [Figure 40] This is the 13C NMR spectrum (150 MHz, MeOD) of compound 21 according to the embodiment of the present application. [Figure 41] This is the 1H NMR spectrum (600 MHz, CDCl3) of compound 22 according to the examples of the present application. [Figure 42] This is the 13C NMR spectrum (150 MHz, CDCl3) of compound 22 according to the examples of the present application. [Figure 43] This is the 1H NMR spectrum (600 MHz, CDCl3) of compound 23 according to the examples of the present application. [Figure 44] This is the 13C NMR spectrum (150 MHz, CDCl3) of compound 23 according to the examples of this application. [Figure 45] This is the 1H NMR spectrum (600 MHz, CDCl3) of compound 24 according to the examples of the present application. [Figure 46] This is the 13C NMR spectrum (150 MHz, CDCl3) of compound 24 according to the examples of the present application. [Figure 47] This is the 1H NMR spectrum (500 MHz, DMSO-d6) of compound 25 according to the examples of the present application. [Figure 48]This is the 13C NMR spectrum (125 MHz, CDCl3) of compound 25 according to the examples of this application. [Figure 49] This is the 1H NMR spectrum (500 MHz, DMSO-d6) of compound 26 according to the examples of the present application. [Figure 50] This is the 13C NMR spectrum (125 MHz, DMSO-d6) of compound 26 according to the examples of this application. [Figure 51] This is the 1H NMR spectrum (600 MHz, DMSO-d6) of compound 27 according to the examples of this application. [Figure 52] This is the 13C NMR spectrum (150 MHz, DMSO-d6) of compound 27 according to the embodiment of the present application. [Figure 53] This is the 1H NMR spectrum (500 MHz, DMSO-d6) of compound 28 according to the examples of this application. [Figure 54] This is the 13C NMR spectrum (125 MHz, DMSO-d6) of compound 28 according to the examples of this application. [Figure 55] This is the 1H NMR spectrum (600 MHz, DMSO-d6) of compound 29 according to the examples of the present application. [Figure 56] This is the 13C NMR spectrum (150 MHz, DMSO-d6) of compound 29 according to the examples of this application. [Figure 57] This is the 1H NMR spectrum (500 MHz, DMSO-d6) of compound 30 according to the embodiment of the present application. [Figure 58] This is the 13C NMR spectrum (125 MHz, DMSO-d6) of compound 30 according to the embodiment of the present application. [Figure 59] This is the 1H NMR spectrum (600 MHz, DMSO-d6) of compound 31 according to the embodiment of the present application. [Figure 60] This is the 13C NMR spectrum (150 MHz, DMSO-d6) of compound 31 according to the embodiment of the present application. [Figure 61] This figure shows the effect of three types of compounds according to the examples of this application and kojic acid, a positive drug, on tyrosinase activity. [Figure 62] This figure shows the inhibitory effect of three compounds and the positive drug acarbose on α-glucosidase activity according to the examples of this application. [Figure 63] This figure shows the scavenging effect of three types of compounds according to the embodiments of this application and vitamin E, a positive drug, on ABTS free radicals. [Figure 64] This figure shows the effects of three compounds related to the examples of this application and phenylethyl resorcinol, a positive drug, on B16 cell activity. [Figure 65] This figure shows the effects of Compound 1, Compound 2, Compound 3, and phenylethyl resorcinol according to the examples of the present application on B16 cell melanin synthesis. [Figure 66] This is a typical diagram showing the skin whitening effect on zebrafish by compounds 1 and 2 according to the embodiments of the present application (the dashed lines indicate the quantitative region). [Figure 67] This diagram shows the location of hair removal areas on animal skin. [Modes for carrying out the invention]

[0051] The technical solutions in the embodiments of this application will be described clearly and completely below with reference to the drawings of the embodiments. Clearly, the embodiments described are only a selection of the embodiments of this application, not all of them. All other embodiments that a person skilled in the art could obtain without creative work based on the embodiments of this application are all within the scope of protection of this application.

[0052] In this specification, room temperature refers to a temperature between 10°C and 30°C. For example, the temperature is 10°C, 12°C, 15°C, 18°C, 20°C, 22°C, 25°C, 28°C, 30°C, or any two of these values. Preferably, room temperature refers to a temperature between 20°C and 30°C, for example, room temperature refers to a temperature between 20°C and 25°C.

[0053] As described in the background information, diarylheptomepolyphenol compounds possess significant α-glucosidase inhibitory activity. By inhibiting α-glucosidase, they reduce tyrosinase maturation, thereby achieving the goal of reducing melanin production and skin pigmentation, representing a novel approach with potential for skin whitening and spot removal. However, naturally derived diarylheptopolyphenol compounds have problems such as low content, poor molecular stability, susceptibility to positional isomerization of double bonds via ene reactions, difficulty in synthesis, and high molecular flexibility. To solve these problems with drug sources, this invention uses such natural products as lead compounds and templates, utilizing conformational constraint and bioelectron equisequence strategies to simplify their open-chain flexible molecular structure and substitute it with a rigid benzene ring polyphenol structural analog. Simultaneously, to improve antioxidant activity, the number of phenolic hydroxyl groups on the benzene ring is increased, and a series of 1,3-bisbenzylphenol derivatives are synthesized. Studies are then conducted on their tyrosinase inhibitory activity, α-glucosidase inhibitory activity, antioxidant activity, and cellular melanin production inhibitory activity. Compound 1 is a known compound (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), but there are no reports on its biological activity. The antioxidant activity, tyrosinase inhibitory activity, and α-glucosidase inhibitory activity of Compounds 1, 2, and 3 have been discovered for the first time, and Compounds 2 and 3 are novel compounds. These components show a higher inhibition rate of cellular melanin synthesis than phenylethyl resorcinol, a representative skin-whitening ingredient on the market, and their potential applications in skin whitening, anti-aging, and diabetes treatment are very promising.

[0054] The first aspect is an application of a compound represented by formula I, the compound represented by formula I being as follows: [ka] Equation I Each R1, R2, and R3 is independently one or more combinations selected from the group consisting of hydrogen, hydroxyl group, halogen, phenyl group, halogenated methoxy group, methylamino group, methyl group, and linear or branched, saturated or unsaturated hydrocarbon groups having 2 to 4 carbon atoms. R4, R5, R6, and R7 are each independently one or more combinations selected from the group consisting of hydrogen, a methyl group, and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms. m, n, and k are each independent integers between 1 and 3. The aforementioned applications include applications in one or more of the following: the manufacture of tyrosinase inhibitors, α-glucosidase inhibitors, pharmaceuticals for the treatment of diabetes, skin whitening products, anti-oxidative skin products, anti-aging products, skincare products that reduce melanin production, pharmaceuticals for the treatment of skin diseases that reduce melanin production, skincare products that prevent pigmentation disorders, pharmaceuticals for the treatment of skin diseases that prevent pigmentation disorders, skincare products that treat pigmentation disorders, pharmaceuticals for the treatment of skin diseases that treat pigmentation disorders, and the suppression of browning of food.

[0055] In the general formula represented by Equation I, (R1) m (R2) indicates that m R1 groups are linked to a benzene ring, where m is 1, 2, or 3. Each R1 group may be the same or different, and each is independently selected from the group consisting of hydrogen, hydroxyl, halogen, methyl, and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 4 carbon atoms. Furthermore, the m R1 groups may be linked to any position on the benzene ring and are not particularly limited. n and (R3) kThese terms have similar meanings, and their explanation will be omitted here.

[0056] Active studies of compounds represented by formula I by the applicant have demonstrated that compounds represented by formula I and mixtures containing one or more compounds represented by formula I possess strong tyrosinase inhibitory and α-glucosidase inhibitory activity, making them highly suitable as skin whitening agents and anti-senile pigmentation agents. Furthermore, because they have high stability to light, they are highly suitable as skin whitening agents in products such as cosmetics, as they can be used as substitutes or auxiliary agents for known skin whitening active compounds (e.g., hydroquinone, arbutin, or ascorbic acid). Tyrosinase inhibitory activity usually occurs in cosmetic applications, but in some cases it may also have therapeutic characteristics, and for this reason, compounds represented by formula I can also be used in the drug treatment of skin diseases. For example, when compounds represented by formula I are used, especially as skin whitening agents or anti-senile pigmentation agents, they are often used topically in the form of solutions, face creams, emulsions, gels, sprays, or similar dosage forms.

[0057] Furthermore, the compound represented by formula I can be used in the food industry as an anti-browning additive. α-glucosidase inhibition inhibits the production of active tyrosinase through glycosylation on glycoproteins, thereby significantly reducing melanin formation. The compound represented by formula I can also be used in the pharmaceutical industry as an antidiabetic drug. For example, it can be used as an oral antidiabetic drug.

[0058] In some embodiments, the pigmentation disorder is one or more selected from the group consisting of freckles, brown spots, stretch marks, senile lentigines, and malignant melanoma.

[0059] In some embodiments, the anti-skin oxidation and anti-aging effects refer to the scavenging of reactive oxygen species and free radicals within cells.

[0060] In some embodiments, at least one of each R1 and each R3 is a hydroxyl group.

[0061] In some embodiments, R4, R5, R6, and R7 are each independently selected from hydrogen or a methyl group.

[0062] In some embodiments, the compound represented by formula I is [ka] , JPEG2026518474000032.jpg1637 It is one or more types selected from the group consisting of the general structural formulas of the following:

[0063] In the formula, at least one of each R1 is a hydroxyl group, at least one of each R3 is a hydroxyl group, and R4, R5, R6, and R7 are each independently selected from hydrogen or a methyl group.

[0064] In some embodiments, the compound represented by formula I is [ka] and [ka] It is one or more species selected from the group consisting of the following structures.

[0065] In some embodiments, the compound represented by formula I is [ka] , JPEG2026518474000036.jpg1026 and [ka] It is one or more compounds selected from the group consisting of the following structures. The name of compound 1 is 4,4'-(1,3-phenylenebis(methylene))diphenol, the name of compound 2 is 4,4'-(1,3-phenylenebis(methylene))bis2-methylphenol, and the name of compound 3 is 3,3'-(1,3-phenylenebis(methylene))bis1,2-benzenediphenol.

[0066] In some examples, the applications of the compound represented by formula I include the following applications (1) to (5). (1) Application of one or two of Compound 2 and Compound 3 in the manufacture of α-glucosidase inhibitors. (2) Application of one or two of Compound 2 and Compound 3 in the manufacture of pharmaceuticals for the treatment of diabetes. (3) Application of one or two of Compound 2 and Compound 3 in the manufacture of anti-oxidant skin products, anti-aging products, and combinations thereof. The term "antioxidant" primarily refers to the scavenging of reactive oxygen species and free radicals within cells. (4) Application of one or two of Compound 2 and Compound 3 in the manufacture of skincare products that reduce melanin production, pharmaceuticals for treating skin diseases that reduce melanin production, skincare products that prevent pigmentation disorders, pharmaceuticals for treating skin diseases that prevent pigmentation disorders, skincare products that treat pigmentation disorders, pharmaceuticals for treating skin diseases that treat pigmentation disorders, and combinations thereof. The pigmentation disorders are selected from freckles, brown spots, stretch marks, senile lentigines, malignant melanoma, and combinations thereof. (5) Application of compound 2 in the production of tyrosinase inhibitors.

[0067] In some other examples, applications of the compound represented by formula I include the following applications (1) to (5). (1) Application of compound 1 in the production of tyrosinase inhibitors. (2) Application of compound 1 in the production of α-glucosidase inhibitors. (3) Application of compound 1 in the manufacture of pharmaceuticals for the treatment of diabetes. (4) Application of compound 1 in the manufacture of anti-oxidant skin products, anti-aging products, and combinations thereof. The term "antioxidant" primarily refers to the scavenging of reactive oxygen species and free radicals within cells. (5) Application of Compound 1 in the manufacture of skincare products that reduce melanin production, pharmaceuticals for treating skin diseases that reduce melanin production, skincare products that prevent pigmentation disorders, pharmaceuticals for treating skin diseases that prevent pigmentation disorders, skincare products that treat pigmentation disorders, pharmaceuticals for treating skin diseases that treat pigmentation disorders, and combinations thereof. The pigmentation disorders are selected from freckles, brown spots, stretch marks, senile lentigines, malignant melanoma, and combinations thereof.

[0068] Compounds 1, 2, and 3 have excellent tone-up and whitening effects (i.e., they exhibit strong α-glucosidase and / or tyrosinase inhibitory activity in a cell in vitro test system, reducing intracellular melanin production), and also have excellent antioxidant effects (i.e., they exhibit strong free radical scavenging activity in a cell in vitro test system).

[0069] In some examples, as described above, compounds 1 and 2 exhibit high tyrosinase inhibitory activity, α-glucosidase inhibitory activity, and antioxidant activity, showing a significantly higher inhibition rate of cellular melanin synthesis than phenylethyl resorcinol, a representative whitening ingredient on the market. Compound 3 exhibits extremely excellent α-glucosidase inhibitory activity and antioxidant activity, showing a slightly better inhibition rate of cellular melanin synthesis than phenylethyl resorcinol, a representative whitening ingredient on the market. Compounds 1, 2, and 3 can be manufactured in high purity, are dermatologically and toxicologically acceptable, and exhibit good stability against photoactivity, making them suitable for use as active ingredients in whitening and anti-aging cosmetics.

[0070] Experiments demonstrated that compounds 1 and 2 can effectively inhibit tyrosinase in specific cell-free or cell-based in vitro test systems, as well as in zebrafish in vivo experiments. For example, zebrafish experiments showed that compound 1 exhibited a whitening effect and inhibited melanin production at concentrations of 0.0002% and 0.0001%, while compound 2 at a concentration of 0.0001%. In contrast, phenylethyl resorcinol 377, a typical whitening ingredient, did not exhibit a whitening effect at a concentration of 0.0002%.

[0071] The applicant has found that compounds represented by formula I, particularly compound 1 and compound 2, have stronger tyrosinase inhibitory activity than kojic acid, a known skin-whitening compound, and are therefore usable in cosmetics at particularly low concentrations and are toxicologically and dermatologically acceptable. Compound 1 has tyrosinase inhibitory activity, which is about four times stronger than that of kojic acid. Compound 2 has tyrosinase inhibitory activity, which is about ten times stronger than that of kojic acid.

[0072] In vitro micronucleus studies using mammalian cells demonstrated that neither compound 1 nor compound 2 exhibits potential genotoxicity. Bacterial reverse mutation studies detected compounds 1 and 2 in standard strains TA97a, TA98, TA100, and TA102, demonstrating that they do not exhibit potential genotoxicity. Skin phototoxicity studies using guinea pigs demonstrated that neither compound 1 nor compound 2 exhibits skin phototoxicity.

[0073] This invention has the following advantages and beneficial effects.

[0074] 1. Using diarylheptopolyphenol compounds with α-glucosidase inhibitory activity found in seaweed as a base, we designed and synthesized for the first time a series of 1,3-bisbenzylphenol derivatives, including but not limited to 4,4'-(1,3-phenylenebis(methylene))bis(2-methylphenol) (compound 2) and 3,3'-(1,3-phenylenebis(methylene))bis(1,2-benzenediphenol) (compound 3).

[0075] 2,1,3-Bisbenzylphenol compounds 1-3 exhibit significant activity in inhibiting α-glucosidase and scavenging free radicals, compounds 1 and 2 exhibit significant activity in inhibiting tyrosinase, and it has been disclosed for the first time that compounds 1, 2 and 3 show a higher inhibition rate of cellular melanin synthesis than phenylethyl resorcinol, a representative skin-whitening ingredient on the market.

[0076] 3. Compounds 1, 2, and 3 reported in this application have simple synthesis steps, high yield, low manufacturing cost, and excellent safety and stability, and have good potential for development and application in the field of whitening, tone-up, and anti-aging cosmetics.

[0077] A second aspect of the present invention provides a 1,3-bisbenzylphenol compound whose structural formula is one or more selected from the group consisting of the structural formulas of Compound 2 and Compound 3 below. [ka]

[0078] The name of compound 2 is 4,4'-(1,3-phenylenebis(methylene))bis-2-methylphenol.

[0079] The name of compound 3 is 3,3'-(1,3-phenylenebis(methylene))bis1,2-benzenediphenol.

[0080] A third aspect of the present invention provides a method for producing a 1,3-bisbenzylphenol compound, the method comprising the steps of: mixing raw material A selected from 1,3-bis(bromomethyl)benzene, 1,3-bis(chloromethyl)benzene and combinations thereof, and raw material B selected from o-cresol, 1,2-benzenediphenol and combinations thereof in a molar ratio of 1:(5~10); reacting the mixture by heating it at 100~120°C for a certain period of time under the protection of nitrogen gas with aluminum trichloride as a catalyst; and further purifying it by column chromatography.

[0081] In some examples, the reaction is carried out by heating at 110°C for 2 hours.

[0082] A fourth aspect of the present application is a composition having one or more effects of whitening, anti-skin oxidation, anti-aging, and inhibition of browning of food, wherein the composition comprises a compound represented by formula I and a carrier, the compound represented by formula I being as follows: [ka] Equation I Each R1, R2, and R3 is independently one or more combinations selected from the group consisting of hydrogen, hydroxyl group, halogen, phenyl group, halogenated methoxy group, methylamino group, methyl group, and linear or branched, saturated or unsaturated hydrocarbon groups having 2 to 4 carbon atoms. R4, R5, R6, and R7 are each independently one or more combinations selected from the group consisting of hydrogen, a methyl group, and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms. m, n, and k are each independent integers between 1 and 3. The present invention provides a composition in which the carrier is selected from one or more carriers that are permissible in the fields of cosmetics, pharmaceuticals, food, and combinations thereof.

[0083] In some embodiments, at least one of each R1 and each R3 is a hydroxyl group.

[0084] In some embodiments, at least one of each R1 is a hydroxyl group, and at least one of each R3 is a hydroxyl group.

[0085] In the context of this specification, compounds represented by formula I that have different substituted phenyl free radicals and simultaneously have different R4, R5, R6, and R7 include pure S-configuration enantiomers, R-configuration enantiomers, and any mixture of S-configuration and R-configuration enantiomers. In some examples, racemic mixtures of compounds represented by formula I are used in the treatment of skin whitening and / or senile lentigines because they are readily obtainable by synthesis, and in some other examples, pure enantiomers or non-racemic mixtures of these enantiomers are also applicable to the treatment of skin whitening and / or senile lentigines.

[0086] In some embodiments, the compound represented by formula I is [ka] , JPEG2026518474000041.jpg1026 and [ka] It is one or more species selected from the group consisting of the following structures.

[0087] In some embodiments, the composition has at least one of the following effects: whitening, anti-skin oxidation, and anti-aging. The composition is selected from skincare product compositions, pharmaceutical compositions, and combinations thereof, and the composition contains an effective amount of compound 1 used as an active ingredient. [ka] , compound 2 [ka] , compound 3 [ka] It includes at least one of the following and one or more carriers permitted in the field of cosmetics.

[0088] In some examples, the above-mentioned pharmaceutical composition refers to a pharmaceutical composition for the treatment of skin diseases.

[0089] Skin care product compositions or pharmaceutical compositions for treating skin diseases relate to skin whitening, anti-oxidation of skin, anti-aging, and combinations thereof. Skin whitening refers to inhibition of tyrosinase activity, inhibition of α-glucosidase activity, inhibition of cellular melanin production, inhibition of pigmentation, and combinations thereof, while anti-oxidation of skin and anti-aging refer to the scavenging of reactive oxygen species free radicals within cells. In some examples, anti-oxidation of skin and anti-aging refer to the scavenging of reactive oxygen species free radicals generated by ultraviolet irradiation within cells.

[0090] In some embodiments, the carriers permitted in the field of cosmetics refer to ordinary cosmetic carriers in the field of cosmetics, and these carriers include emulsifiers (e.g., oil in water, water in oil, silicone in water in oil, silicone oil in water, water in oil in water, oil in water in oil, silicone oil in water in oil, etc.), creams, skincare solutions, liquids (e.g., aqueous solutions or water-alcohol solutions), anhydrous substrates (e.g., lip balm or powders, etc.), gels, oil creams, milk lotions, ointments, sprays, solids, eye creams, etc.

[0091] In some embodiments, the cosmetic composition of the present application can be used to manufacture various forms of cosmetics, including sunscreen creams, sunless tanning products, hair care products (e.g., shampoos, conditioners, hair dyes, bleaches, straightening agents, and permanent wave agents), nail polish, moisturizing creams, skincare liquids and creams, lipsticks and lip balms, facial cleansers, lotions, masks, deodorants, antiperspirants, exfoliants, shaving products (creams, aftershaves), wet wipes, self-tanning lotions, body soaps, body oils, foot care products (powder, spray), foundations, blushes, eyeshadows and eyeliners, lip glosses, mascaras, and infant products (infant skincare creams, body oils, shampoos, baby powders, and wet wipes). These cosmetics can also be used as long-lasting cosmetics and cleansing creams.

[0092] In some embodiments, the pharmaceutically acceptable carriers include one or more anesthetics, antiallergens, antifungals, antimicrobials, anti-inflammatory agents, antioxidants, preservatives, chelating agents, colorants, decolorizers, softeners, emulsifiers, release agents, film-forming agents, fragrances, wetting agents, anthelmintics, lubricants, humectants, drugs, light stabilizers, preservatives, skin protectants, skin penetration enhancers, sunscreens, stabilizers, surfactants, thickeners, viscosity modifiers, vitamins, or any combination thereof.

[0093] In some embodiments, skin whitening refers to one or more of the following: inhibition of tyrosinase activity, inhibition of α-glucosidase activity, inhibition of cellular melanin production, and inhibition of pigmentation disorders; and anti-skin oxidation and anti-aging refer to the scavenging of reactive oxygen species and free radicals within cells.

[0094] In some embodiments, the pigmentation disorder is one or more selected from the group consisting of freckles, brown spots, stretch marks, senile lentigines, and malignant melanoma.

[0095] In some embodiments, the composition is one or more selected from the group consisting of a tyrosinase inhibitor composition and an α-glucosidase inhibitor composition.

[0096] In some embodiments, the carrier includes one or more of essence, a compound for skin care, a compound for skin cleansing, and an ultraviolet absorber.

[0097] In some embodiments, the composition includes an essence and the compound represented by Formula I, the essence is present in an amount that effectively provides a sensory effect, and the compound represented by Formula I is present in an amount having one or both of a tyrosinase inhibitory action and an α-glucosidase inhibitory action. In some embodiments, in the composition, the compound represented by Formula I is present at a mass percentage of about 3% to about 30%. Preferably, the above composition may further include one or more excipients, additives, etc. In fact, it has been proven that the substance of the compound represented by Formula I itself has no odor or no odor at all, and due to this property, it has been determined that they can be used in perfume compositions. Since the content of the perfume composition in the final cosmetic product is usually within the range of about 1% (m / m), in the perfume composition containing the compound represented by Formula I, the compound represented by Formula I of about 3% to 30% (m / m) is included. In one embodiment, the perfume composition contains 3% to 20% (m / m) of the compound represented by Formula I.

[0098] In some embodiments, the composition includes an ultraviolet absorber and the compound represented by Formula I, the amount of the ultraviolet absorber effectively provides ultraviolet protection with a protection factor greater than at least 2, and the amount of the compound represented by Formula I has one or both of a tyrosinase inhibitory action and an α-glucosidase inhibitory action. In some embodiments, the amount of the ultraviolet absorber effectively provides ultraviolet protection with a protection factor greater than at least 5.

[0099] In some embodiments, the composition comprises one or more of a compound for skin care and a compound for skin cleansing, and a compound represented by Formula I, and the amount of the compound represented by Formula I has one or two of a tyrosinase inhibitory action and an α-glucosidase inhibitory action.

[0100] In addition, the composition containing the compound represented by Formula I of the present application can also be used in foods, particularly in foods containing natural phenolic compounds that are likely to undergo a natural browning reaction under the influence of endogenous polyphenol oxidase during the processing process. For example, the foods include fruit and vegetable products, particularly apples, pears or potatoes, or crustaceans, particularly crabs, lobsters or shrimps. As can be understood, the above are some examples of common foods and are not limited thereto.

[0101] The fifth aspect of the present application provides an application of the above composition in the production of whitening skin care products, pharmaceuticals for treating whitening skin diseases, anti-aging skin care products, pharmaceuticals for treating anti-aging skin diseases and combinations thereof.

[0102] In some embodiments, the composition is one selected from the group consisting of a skin care product composition and a pharmaceutical composition, and the composition contains a compound 1 in an effective amount for use as an active ingredient

Chemical formula

Chemical formula

Chemical formula

[0103] Skin care products or pharmaceuticals for treating skin diseases relate to skin whitening, anti-oxidation of skin, anti-aging, and combinations thereof. Skin whitening refers to inhibition of tyrosinase activity, inhibition of α-glucosidase activity, inhibition of cellular melanin production, inhibition of pigmentation, and combinations thereof, while anti-oxidation of skin and anti-aging refer to the scavenging of reactive oxygen species free radicals within cells. In some embodiments, anti-oxidation of skin and anti-aging refer to the scavenging of reactive oxygen species free radicals generated by ultraviolet irradiation within cells.

[0104] The aforementioned skincare product or pharmaceutical for treating skin diseases can improve the aesthetic and / or cosmetic appearance of the skin. These improvements include a reduction in dermatological aging symptoms due to aging, hormonal aging, and / or photoaging; a reduction in skin fragility; a reduction in pore size; prevention and / or reversal of collagen and / or elastin loss; improvement of estrogen deficiency; prevention of skin atrophy; prevention and / or reduction of the appearance and / or depth of fine lines and / or wrinkles; prevention, reduction and / or treatment of excessive pigmentation; improvement of skin tone clarity and / or skin firmness; prevention, reduction and improvement of skin sagging; promotion of antioxidant activity; improvement of skin toughness, elasticity, softness and / or suppleness; increased production of procollagen and / or collagen; improvement of skin texture and / or restoration of the original skin texture; repair and / or promotion of skin barrier function; improvement of skin contour appearance; restoration of skin luster and / or radiance; and minimization of dermatological symptoms due to fatigue and stress responses, such as skin breakouts and / or environmental impacts. This is evident in any of the following: resistance to stress responses (pollution, temperature changes), replenishment of essential nutrients and / or components in the skin that have decreased due to aging and / or menopause, strengthening of intercellular communication, increased cell proliferation and / or multiplication, strengthening of skin cell metabolism that has decreased due to aging and / or menopause, delay of cellular senescence, inhibition of enzymes that accelerate the aging of skin cells in the skin, minimization of skin dryness and / or increase of skin moisture, minimization of skin discoloration including dark circles under the eyes, promotion and / or acceleration of cell renewal, increase of skin thickness, increase of skin elasticity and / or resilience, increased epidermal exfoliation with or without the use of alpha-hydroxy acids or other exfoliants, prevention and reversal of loss of glycosaminoglycans (GAGs), collagen and / or elastin, improvement of microcirculation, reduction and / or prevention of cellulite formation, reduction of acne formation, and use as a skin and hair glossing agent or anti-senile pigment agent.

[0105] In particular, the pharmaceutical compositions of the present application can improve the aesthetic appearance, health, and vitality of the skin. Such improvements are evident in at least one of the following: a reduction in melanin production; treatment of pigmentation disorders including freckles, brown spots, stretch marks, senile lentigines, or malignant melanoma; prevention and / or reversal of collagen and / or elastin loss; improvement of skin texture; improvement of skin color, clarity, and / or skin firmness; promotion / acceleration of cell renewal; and an increase in skin thickness.

[0106] In some embodiments, skin whitening refers to one or more of the following: inhibition of tyrosinase activity, inhibition of α-glucosidase activity, inhibition of cellular melanin production, and inhibition of pigmentation disorders; and anti-skin oxidation and anti-aging refer to the scavenging of reactive oxygen species and free radicals within cells.

[0107] In some embodiments, the pigmentation disorder is one or more selected from the group consisting of freckles, brown spots, stretch marks, senile lentigines, and malignant melanoma.

[0108] A sixth aspect of the present application provides a product which is one of cosmetics and pharmaceuticals for the treatment of skin diseases, the product comprising the composition described in the fourth aspect above, or a compound represented by formula I.

[0109] In some examples, the mass percentage of the compound represented by formula I in the product (particularly in topical application products) is 0.0001% to 10%. Alternatively, the mass percentage of the compound represented by formula I in the product is 0.01% to 2%. Alternatively, the mass percentage of the compound represented by formula I in the product is 0.1% to 1%. In the product, the compound represented by formula I, which is a tyrosinase inhibitory compound, can be used prophylactically or as needed. For example, the concentration of the active compound used daily will vary depending on the physiological state of the subject and individual parameters such as age or weight. The compound represented by formula I can be used alone or in combination with other tyrosinase inhibitors.

[0110] The compound represented by formula I used in this application can be used in ordinary cosmetics or pharmaceuticals for treating skin diseases, and includes, but is not limited to, pump sprays, aerosol sprays, face creams, ointments, tinctures, emulsions, and nail care products (e.g., nail polish, nail polish cleaner, nail balm). In some embodiments, the compound represented by formula I used in this application can also be used in combination with other active compounds, such as other substances having skin whitening effects or activity against senile lentigines, in the above products. In this case, products containing the compound represented by formula I can be used for skin treatment as a dermatological treatment or as a skin care cosmetic. Of course, it can also be used as a decorative cosmetic in makeup products.

[0111] In some embodiments, products containing the compound represented by formula I further include active compounds having a whitening effect. As can be understood, the active compounds having a whitening effect are not particularly limited, and any skin whitening active compound suitable for or conventionally used in cosmetic and / or dermatological applications can be used. For example, active compounds having a whitening effect include kojic acid, kojic acid derivatives, arbutin, ascorbic acid, ascorbic acid derivatives, aloin, ellagic acid, azelaic acid, thiamidol, 4-n-butylresorcinol, diphenylmethane derivatives, sulfur-containing molecules (e.g., glutathione, l-ergothioneine), α-hydroxy acids (e.g., citric acid, lactic acid, malic acid) and their derivatives, nitrogen oxide synthesis inhibitors (e.g., l-nitroarginine and its derivatives). Examples of synthetic or natural active compounds used for skin whitening include metal chelating agents (e.g., c-hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin, humic acid, bile acids, bile extract, bilirubin, biliverdin, EDTA, EGTA and their derivatives), flavonoids, chalcones, phenylpropanoids, coumarins, retinoid A, alkaloids (e.g., diacetylcholine), nicotinamide, soy milk, serine protease inhibitors, lipoic acid, or other synthetic or natural active compounds used for skin whitening. Natural active compounds used for skin whitening may also be used in the form of plant extracts, such as bearberry extract, licorice root extract or components such as glabridin and atranolin A concentrated therefrom, cinnamon extract, Polygonaceae and Gamboldaceae plant extracts, Pinus (pine) extract and Vitis plant extract or stilbene derivatives concentrated therefrom.

[0112] In some embodiments, the product may further contain preservatives. Examples of preservatives include benzoic acid, benzoic acid esters and benzoates, propionic acid and its salts, salicylic acid and its salts, 2,4-hexanoic acid (also called sorbic acid) and its salts, formaldehyde and paraformaldehyde, 2-hydroxyphenyl ether and its salts, 2-zinc pyrithione-N-oxide, inorganic sulfites and bisulfites, sodium iodate, chlorobutanol, and 4-ethylmercury-(II)5-amino-1,3-di (2-hydroxybenzoic acid) acid and its salts and esters, dehydrating acids, formic acid, 1,6-di(4-amino-2-bromophenoxy)-n-hexane and its salts, sodium ethylmercury-(II)-thiosalicylate, phenylmercury and its salts, 10-undecylenic acid and its salts, 5-amino-1,3-di(2-ethylhexyl)-5-methylhexahydropyrimidine, 5-bromo-5-nitro-1,3-dioxane, 2-bromo-2-nitro- 1,3-Propanediol, 2,4-Dichlorophenylethanol, N-(4-chloro)-N'-(3,4-dichlorophenyl)urea, 4-Chloro-m-cresol, 2,4,4'-Trichloro-2'-hydroxydiphenyl ether, 4-Chloro-3,5-dimethylphenol, 1,1'-Methylene-di(3-(1-hydroxymethyl-2,4-dioxyimidazolidined-5-yl)urea), Poly(hexamethylene biguanide) hydrochloride, 2- Phenoxyethanol, hexamethylenetetramine, 1-(3-chloropropene)-3,5,7-triaza-1-aza-chloroadamantane, 1(4-chlorophenoxy)-1(1H-imidazole-1-yl)-3,3-dimethyl-2-butanone, 1,3-bis(hydroxymethyl)-5,5-dimethyl-2,4-imidazolidinedione, benzyl alcohol, pyridoneethanolamine salt, 1,2-dibromo-2,4-dicyabutane, 2,One or more of 2'-methylenebis(6-bromo-4-chlorophenol), bromo-chlorophenol, 5-chloro-2-methyl-3(2H)-isothiazolinone and 2-methyl-3(2H) isothiazolinone and a mixture of magnesium chloride and magnesium nitrate, 2-benzyl-4-chlorophenol, 2-chloroacetamide, chlorhexidine, chlorhexidine acetate, chlorhexidine gluconate, chlorhexidine hydrochloride, 1-phenoxy-2-propanol, N-alkyltrimethylammonium bromide and chloride, 4,4-dimethyl-1,3-oxazolidine, N-hydroxymethyl-N'-hydroxymethylurea, 1,6-di(4-aminophenoxy)-n-hexane and its salts, glutaraldehyde-5-ethyl-1-aza-3,7-dioxacyclooctane, 3-(4-chlorophenoxy)-1,2-propanediol, quaternary ammonium salts, alkyl-dimethylbenzylammonium chloride, alkyl-dimethylbenzylammonium bromide, alkyl-dimethylbenzylammonium iodide, benzyl hemiformal, 3-iodo-2-propylcarbamate, sodium hydroxymethylaminoacetate and sodium hydroxymethylaminoacetate may be included.,

[0113] In use, apply the product containing the compound represented by formula I to the skin in a sufficient amount according to the conventional manner of cosmetics and skin products.,

[0114] In some embodiments, the product is a sunscreen product. The product contains one or more of a UVA blocker, a UVB blocker and an inorganic pigment. As can be understood, the sunscreen product can have various forms, for example, it is usually used in a sunscreen cream formulation. Therefore, the sunscreen product may be in the form of a solution, a water-in-oil (W / O) type or an oil-in-water (O / W) type emulsion or a multiple emulsion, for example, a water-in-oil-in-water (W / O / W) type emulsion, a gel, a hydrogen dispersion, a solid stick or an aerosol. In one example, the sunscreen product contains a UVB blocker and may be oil-soluble or water-soluble.,

[0115] In one example, to protect the skin from ultraviolet radiation, the total mass percentage of the shielding agent in the sunscreen product may be, for example, 0.01% to 20%, preferably 0.1% to 10%, and more preferably 1.0% to 5.0%.

[0116] In one example, the sunscreen product can achieve a protection factor of at least >2. Preferably, the sunscreen product can achieve a protection factor of >5.

[0117] In some embodiments, the compound represented by formula I may be used in cosmetics in combination with antioxidants, perfume oils, anti-foaming agents, colorants, pigments having coloring properties, thickeners, surfactants, emulsifiers, plasticizers, humectants, fats, oils, waxes, and other common ingredients in cosmetic formulations, such as monohydric alcohols, polyhydric alcohols, polymers, foam stabilizers, electrolytes, organic solvents, or silicone derivatives.

[0118] In some embodiments, products containing the compound represented by formula I are used for topical prophylaxis or cosmetic treatment of the skin and typically contain high concentrations of therapeutic substances. In one example, a product containing the compound represented by formula I includes one or more animal therapeutic fats and oils, plant therapeutic fats and oils, such as olive oil, sunflower oil, refined soybean oil, palm oil, sesame oil, rapeseed oil, apricot kernel oil, borage seed oil, evening primrose oil, coconut oil, shea butter, jojoba oil, whale oil, beef tallow, beef trotters oil and lard, and optionally other therapeutic components, such as aliphatic alcohols having 8 to 30 carbon atoms. The aliphatic alcohols may be saturated or unsaturated and may be linear or branched. For example, decanol, decenol, octanol, octenol, dodecanol, dodecenol, octadienol, decadienol, dodecadienol, oleyl alcohol, ricinol alcohol, cinapyl alcohol, stearyl alcohol, isostearyl alcohol, hexadecanol, dodecanol, myristyl alcohol, arachidyl alcohol, decanol, linolenyl alcohol, linolenyl alcohol, behenyl alcohol, guerbet alcohol, etc. As can be seen, aliphatic alcohols are not limited to those listed above and may be other alcohols with related chemical structures. In one example, the aliphatic alcohol is derived from a natural fatty acid and is usually produced by reducing the corresponding ester of the fatty acid. Alternatively, aliphatic alcohol fractions obtained by reducing naturally occurring fats and fatty oils such as beef tallow, peanut oil, rapeseed oil, cottonseed oil, soybean oil, sunflower oil, palm kernel oil, linseed oil, corn oil, castor oil, rapeseed oil, sesame oil, cocoa butter, and cocoa butter may be used.

[0119] In some embodiments, in a product containing a compound represented by formula I, the therapeutic substance may further include the following (1) to (4): (1) N-acylsphingosine (fatty acid amide of sphingosine) or synthetic analogs of such lipids (so-called pseudo-ceramides), which are ceramides that significantly improve the water retention of the stratum corneum; (2) Phospholipids such as soy lecithin, egg lecithin, and cephalin; (3) Petrolatum, paraffin, and silicone oil, where silicone oil includes dialkylsiloxanes and alkylarylsiloxanes, such as dimethylpolysiloxane and methylphenylpolysiloxane, as well as their alkoxylated derivatives and quaternary ammonium chloride derivatives; (4) Animal hydrolyzed proteins and plant hydrolyzed proteins such as elastin, collagen, keratin, milk protein, soy protein, oat protein, pea protein, almond protein, and wheat protein fractions or corresponding hydrolyzed proteins, and condensation products thereof with fatty acids, as well as quaternary ammonium chloride hydrolyzed proteins. In one example, plant hydrolyzed proteins are used.

[0120] In some embodiments, the product containing the compound represented by formula I may be a solution or a lotion, and the solvent may be (1) water or an aqueous solution, (2) fatty oils, fats, waxes and other natural and synthetic fats, for example, fatty acid esters formed from fatty acids and low-carbon alcohols, where the low-carbon alcohol is isopropanol, propanediol or glycerin, or fatty acid esters formed from aliphatic alcohols and low-carbon alkanoic acids or fatty acids, or (3) low-carbon monohydric alcohols, dihydric alcohols or polyhydric alcohols and their ethers, for example, ethanol, isopropanol, propanediol, glycerin, 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 analogs. To make it clear, the solvent may be a mixture of the above-mentioned solvents. When an alcoholic solvent is used, water may be included as another component.

[0121] In some embodiments, the product comprising the compound represented by formula I may further contain antioxidants, and any antioxidant suitable for or commonly used in cosmetic and / or dermatological applications can be used. For example, the antioxidants include amino acids (e.g., glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazoles (e.g., uric acid) and their derivatives, peptides (e.g., D,L-carnosine, D-carnosine, L-carnosine and their derivatives (e.g., rhizome), carotenoids, carotenes (e.g., c-carotene, β-carotene, lycopene) and their derivatives, lipoic acid and its derivatives (e.g., dihydrolipoic acid), gold thioglucose, propylthiouracil and other thio (e.g., thioredoxin, glutathione, cysteine, cystine, cystamine and its glycosyl, N-acetyl, methyl, ethyl, propyl, pentyl, butyl, dodecyl, palmitoyl, oleyl, γ-linoleyl, cholesterol and their glyceryl esters) and their salts, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and its derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts), and very Low tolerance sulfoximine compounds (e.g., butionine sulfoximine, homocysteine ​​sulfoximine, butionine sulfone, pentasulfoximine, hexasulfoximine, heptathionine sulfoximine), and (metal) chelating agents, such as α-hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin, α-hydroxy acids (e.g., citric acid, lactic acid, malic acid), humic acid, bile acids, bile extract, bilirubin, biliverdin, EDTA, EGTA and their derivatives, and unsaturated fatty acids. and its derivatives (e.g., γ-linolenic acid, linoleic acid, oleic acid), folic acid and its derivatives, ubiquinone and ubiquinol and its derivatives, vitamin C and its derivatives (e.g., ascorbyl palmitate, magnesium ascorbate phosphate, ascorbyl acetate), tocopherol and its derivatives (e.g., vitamin E acetate), vitamin A and its derivatives (vitamin A palmitate), and benzoin resin coniferyl benzoate, rutic acid and its derivatives, ferulic acid and its derivatives,The active compounds are selected from the group consisting of butylhydroxytoluene, butylhydroxyanisole, nordihydroguaiac acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose and its derivatives, zinc and its derivatives (e.g., ZnO, ZnSO4), selenium and its derivatives (e.g., seleniummethionine), stilbene and its derivatives (e.g., stilbene oxide, trans-stilbene oxide), and derivatives of the active compounds (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides, and lipids).

[0122] In some embodiments, the product comprising the compound represented by formula I may further contain vitamins and vitamin precursors, and all vitamins and vitamin precursors suitable for or conventionally used in cosmetic and / or dermatological applications can be used. Examples include tocopherol, vitamin A, nicotinic acid and nicotinamide, B vitamins such as biotin and vitamin C, pantothenyl alcohol and its derivatives, where pantothenyl alcohol and its derivatives may be esters and ethers of pantothenyl alcohol, as well as pantothenyl alcohol derivatives obtained as cations, such as pantothenyl alcohol triacetate, pantothenyl alcohol monoethyl ether and its monoacetate, and cationic pantothenyl alcohol derivatives.

[0123] In some embodiments, the product containing the compound represented by formula I may further contain a humectant. For example, humectants include hyaluronic acid, glycerin, panthenol, pyrrolidone carboxylic acid, urea, glycolic acid, salicylic acid, Brazilian flavonoid A, sodium lactate, sorbitol, propanediol, collagen, elastin, adipate diester, urocanic acid, lecithin, phytantriol, lycopene, algae extract, ceramide, cholesterol, glycolipids, chitosan, chondroitin sulfate, polyamino acids and sugars, lanolin, wool ester, amino acids, α-hydroxy acids (e.g., citric acid, lactic acid, malic acid) and their derivatives, monosaccharides, disaccharides and oligosaccharides, α-hydroxy fatty acids, plant sterols, triterpenoid saponins (e.g., betulinic acid or ursolic acid), and algae extract.

[0124] In some embodiments, a product containing the compound represented by Formula I may further contain one or more of the following: an anti-inflammatory compound, an anti-redness compound, and an anti-itch compound. Understandably, all anti-inflammatory compounds, anti-redness compounds, and anti-itch compounds suitable for or conventionally used in cosmetics and pharmaceuticals for the treatment of skin diseases can be used.

[0125] In some embodiments, a product containing the compound represented by formula I may further contain a plant extract, which is usually produced by extracting the whole plant, but in some embodiments, it may be produced by extracting only the flowers, leaves, wood, bark, or roots of the plant. The plant extract can be derived from aloe, seaweed, avocado, chamomile, coconut, green tea, ginseng, grapefruit, grapefruit seeds, rosemary, sunflower, oak bark, willow, nettle, wild nettle, hops, calendula, burdock root, hawthorn, linden flower, almond, pine needle, sandalwood, juniper, mango, apricot, orange, lemon, lime, apple, wheat, oat, barley, sage, thyme, basil, birch, mallow, vine, weeping willow bark, asparagus, okra, azalea, ginger root, and the like. In some embodiments, the plant extracts are derived from aloe, algae, avocado, chamomile, coconut, green tea, ginseng, grapefruit, grapefruit seeds, rosemary, and sunflower. For clarity, in some embodiments, the plant extract may be a mixture of two or more plant extracts. Extractants that can be used in the production of the plant extracts may be water, alcohol, and mixtures thereof.

[0126] In some embodiments, a product containing the compound represented by formula I may further contain one or more of the following: anionic surfactants, cationic surfactants, nonionic surfactants, and amphoteric surfactants. For example, surfactants can be added when crystalline or microcrystalline solids (e.g., inorganic fine pigments) are mixed into the product. Surfactants are amphiphilic substances that can dissolve organic nonpolar substances in water. In this case, the hydrophilic portion of the surfactant molecule is usually a polar functional group, such as -COO, -OSO, or -SO, and the hydrophobic portion is usually a nonpolar hydrocarbon free radical. Surfactants are generally classified according to the properties and charge of the hydrophilic group within the molecule. Here, they are classified into four types: anionic surfactants, cationic surfactants, amphoteric surfactants, and nonionic surfactants.

[0127] In some embodiments, the anionic surfactant is an acyl amino acid (and its salts), for example: (1) acyl glutamate salts, for example sodium acyl glutamate, sodium di-TEA palmitoyl aspartate, and sodium octyl / decyl glutamate; (2) acylated peptides, for example palmitoyl hydrolyzed milk protein, sodium cocoyl hydrolyzed soy protein, and sodium cocoyl hydrolyzed collagen / potassium; and (3) sarcosinates, for example myristoyl sarcosinate. (4) Taurine salts, such as sodium lauroyl sarcosinate, sodium lauroyl sarcosinate, and sodium cocoyl sarcosinate; (5) Acyl lactates, lauroyl lactates, alanine carboxylates, hexapropionyl lactates, and derivatives, such as lauric acid, aluminum stearate, magnesium alkanolate, zinc undecylenate, and ester carboxylates, such as calcium stearoyl lactate. The substances are (6) ether carboxylic acids, for example, sodium lauryl-6 citrate, sodium PEG-4 lauroyl carboxylate, (6) ether carboxylic acids, for example, sodium lauryl alcohol-13 carboxylate, sodium PEG-6 cocamide carboxylate, phosphate esters and salts, for example, DEA-10 phosphate, diurea-4 phosphate, sulfonic acids and salts, for example, acyl isosulfates, for example, cocoyl isosulfates, alkylaryl sulfonates, alkyl sulfonates, for example, sodium coconut monoglyceride sulfate, sodium colein sulfonate, sodium laurylthioacetate and magnesium PEG-3 cocamide sulfate, for example, sulfosuccinates, sodium dioctyl sulfosuccinate, disodium laureth sulfosuccinate, disodium lauryl sulfosuccinate, disodium undecylamine disodium methanesulfonate sulfonylucinate and sulfates, alkyl ether sulfates, for example, sodium sodium, ammonium sodium, magnesium sodium, MIPA, TIPA lauryl ether sulfate, mireth sulfate sodium and C 12~13 Sodium terephthalate, alkyl sulfates, such as sodium, ammonium, and TEA-dodecyl sulfate.

[0128] In some examples, the cationic surfactant is alkylamine, alkylimidazole, ethoxyamine, and quaternary ammonium salt surfactant. Quaternary ammonium salt surfactant contains at least one N atom covalently bonded to four alkyl or aryl groups. It will be positively charged at any pH value. In some examples, the cationic surfactant is one or more of alkylbetaine, alkylamidopropyl betaine, and alkylamidopropyl hydroxysulfonic acid. In some other embodiments, the cationic surfactant used may be selected from the group including quaternary ammonium salt compounds, such as phenyltrialkylammonium chloride or ammonium bromide, e.g., phenyldimethylstearylammonium chloride, and alkyltrialkylammonium salts, e.g., cetyltrimethylammonium chloride or ammonium bromide, alkyldimethylhydroxyethyl chloride or ammonium bromide, dialkyldimethyl chloride or ammonium bromide, alkylamidoethyl-trimethylammonium ether sulfate, alkylpyridinium salts, e.g., dodecyl or cetylpyridinium chloride, imidazoline derivatives, and cationic compounds, e.g., alkyldimethylamine oxide or alkylethyldimethylamine oxide. In one example, hexadecyltrimethylammonium salt is used as the cationic surfactant.

[0129] In some embodiments, the amphoteric surfactant may include (1) acyl / dialkylethylenediamines such as sodium acylamidoacetate, disodium acylamidodipropionate, disodium alkylamidodiacetate, sodium acylamidohydroxypropylsulfonate, disodium acylamidodiacetate, and sodium acylamidopropionate, and (2) N-alkylamine acids such as aminopropylalkylpentamethylenediamine, alkylaminopropionic acid, sodium alkylaminodipropionate, and lauryl amphoteric carboxyglycine.

[0130] In some examples, nonionic surfactants include alcohols, alkanolamides (e.g., cocamide MEA / DEA / MIPA), amine oxides (e.g., cocamidopropylamine oxide), esters (these esters consist of esterification of carboxylic acids with ethylene oxide, glycerin, sorbitol, or other alcohols), ethers (e.g., ethoxylated / propoxylated alcohols, ethoxylated / propoxylated esters, ethoxylated / propoxylated glyceryls, ethoxylated / propoxylated cholesterol, ethoxylated / propoxylated triglycerides, ethoxylated / propoxylated lanolin, ethoxylated / propoxylated polysiloxanes, propoxylated POE ethers, and alkyl polyglycosides, e.g., dodecyl glycosides, decyl glycosides, and cocoglucosides), sucrose esters and ethers, polyglycerides, diglycerides, monoglycerides, methyl glucose esters, hydroxy acid esters, and the like.

[0131] In some embodiments, anionic surfactants and amphoteric surfactants can be used in combination with one or more nonionic surfactants. Depending on the total weight of the product, the surfactant may be present in a mass percentage of 1% to 90% (m / m) of the product containing the compound represented by formula I.

[0132] In some embodiments, the product containing the compound represented by formula I may exist in the form of an emulsion. The oil phase may be selected from the group consisting of mineral oil, mineral wax, fat, wax and other natural and synthetic fats (e.g., fatty acid esters formed from fatty acids and low-carbon alcohols, where the low-carbon alcohol may be isopropanol, propanediol or glycerin, or fatty acid esters formed from aliphatic alcohols and low-carbon alkanoic acids or fatty acids), alkyl benzoates, and silicone oils (e.g., dimethylpolysiloxane, diethylpolysiloxane, diphenylpolysiloxane and mixtures thereof). In some embodiments, (a) esters of saturated and / or unsaturated, branched and / or straight-chain alkanecarboxylic acids with a chain length of 3 to 30 carbon atoms and saturated and / or unsaturated, branched and / or straight-chain alcohols with a chain length of 3 to 30 carbon atoms, and (b) esters of aromatic carboxylic acids with saturated and / or unsaturated, branched and / or straight-chain alcohols with a chain length of 3 to 30 carbon atoms may be used. For example, ester oils include isopropyl myristoleate, isopropyl palmitate, isopropyl stearate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl isononanoate, 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 their esters, such as jojoba oil.

[0133] The oil phase may also be selected from the group consisting of branched-chain and straight-chain hydrocarbons and waxes, silicone oils, dialkyl ethers, saturated or unsaturated, branched-chain or straight-chain alcohols, and fatty acid triglycerides, specifically, triglycerides of saturated and / or unsaturated, branched-chain and / or straight-chain alkanecarboxylic acids having 8 to 24 carbon atoms (e.g., 12 to 18 carbon atoms). The fatty acid triglycerides may be selected from the group consisting of synthetic oils, semi-synthetic oils, and natural oils such as olive oil, sunflower oil, soybean oil, peanut oil, rapeseed oil, apricot kernel oil, palm oil, coconut oil, and palm kernel oil. In other examples, any mixture of such oils and wax components may also be used. In some embodiments, a wax (e.g., cetyl palmitate) may be used as the sole lipid component of the oil phase. For example, the oil phase may be selected from the group consisting of 2-ethylhexyl isostearate, octyldodecanol, isotricetyl isodecanoate, isoeicosane, 2-ethylhexyl cocoate, C2-s alkylbenzoate, capric triglyceride, and dialkyl ether. For example, a mixture of c2-s-alkylbenzoate and 2-ethylhexyl isostearate, a mixture of c2-s-alkylbenzoate and isotricetyl isononanoate, or a mixture of c2-s-alkylbenzoate, 2-ethylhexyl isostearate, and isotricetyl isononanoate. Hydrocarbon compounds such as paraffin oil, squalane, and squalene are also applicable as the oil phase of this application. In some embodiments, the oil phase may further contain cyclic or straight silicone oil, or may consist entirely of such oil, but other oil phase components in additional amounts other than silicone oil or silicone oil-based substances may also be used. The silicone oil may be, for example, cyclomethylsiloxane (e.g., decamethylcyclopentasiloxane).

[0134] However, other silicone oils, such as undecamethylcyclotrisiloxane, polydimethylsiloxane, and polymethylphenylsiloxane, can also be used. Furthermore, the oil phase may be a mixture of cyclomethylsiloxane and isotrialkyl isononanoate, and a mixture of cyclomethylsiloxane and 2-ethylhexyl isostearate.

[0135] In some embodiments, the product containing the compound represented by formula I exists in the form of an emulsion, and the aqueous phase may contain one or more thickeners selected from the group consisting of low carbon number monohydric alcohols, dihydric alcohols or polyhydric alcohols and their ethers, such as ethanol, isopropanol, propanediol, glycerin, 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 analogs, as well as silica, aluminum silicate, polysaccharides and their derivatives, such as hyaluronic acid, xanthan gum, and hydroxypropyl methylcellulose. For example, the thickener may be selected from the group consisting of polyacrylates, and in one example, the polyacrylate may be selected from polyacrylates including so-called carbomers.

[0136] In some embodiments, the product containing the compound represented by formula I exists in the form of an emulsion and may further contain one or more emulsifiers. For example, an O / W emulsifier may be selected from a group including polyethoxylation or polypropoxylation, polyethoxylation and polypropoxylation products, for example, the emulsifier may be aliphatic alcohol ethoxylate, ethoxylanolin alcohol, polyethylene glycol ether, fatty acid ethoxylate, polyethylene glycol glycerin fatty acid ester, polyethoxylated sorbitol ester, cholesterol ethoxylate, polyethoxylated triglyceride, alkyl ether carboxylic acid, alkyl ether sulfate, aliphatic alcohol propoxylate, or polypropylene glycol ether. In some embodiments, an aliphatic alcohol ethoxyether is selected from the group consisting of ethoxystearyl alcohol, hexadecylstearyl alcohol, and hexadecylstearyl alcohol (cetyl alcohol).

[0137] As oil / water emulsifiers, monoglycerides of saturated and / or unsaturated aliphatic alcohols having 8 to 30 carbon atoms, diglycerides of branched and / or linear saturated and / or unsaturated alkanecarboxylic acids having 8 to 24 carbon atoms (e.g., 12 to 18 carbon atoms), monoglyceryl ethers of branched and / or linear saturated and / or unsaturated alkanecarboxylic acids having 8 to 24 carbon atoms (e.g., 12 to 18 carbon atoms), diglyceryl ethers of branched and / or linear saturated or unsaturated alcohols having 8 to 24 carbon atoms (e.g., 12 to 18 carbon atoms), propylene glycol esters of branched and / or linear saturated or unsaturated alkanecarboxylic acids having 8 to 24 carbon atoms (e.g., 12 to 18 carbon atoms), and sorbitol esters of branched and / or linear saturated or unsaturated alkanecarboxylic acids having 8 to 24 carbon atoms (e.g., 12 to 18 carbon atoms) can be used.

[0138] In some examples, the oil / water emulsifier includes glyceryl monostearate, glyceryl monoisostearate, glyceryl monomyristate, glyceryl monooleate, diglyceryl monostearate, propylene glycol monostearate, propylene glycol monoisostearate, propylene glycol monooctanoate, propylene glycol monolaurate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monocaprylate, sorbitan monoisostearate, sucrose distearate, cetyl alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol, isobehenyl alcohol, cerakyl alcohol, chymyl alcohol, glyceryl monolaurate, glyceryl monocaprate, and glyceryl monocaprylate.

[0139] A seventh aspect of this application is a pharmaceutical composition for the treatment of diabetes, comprising an effective amount of a compound as an active ingredient and a carrier, wherein the effective amount of the compound as an active ingredient is one or more compounds selected from the group consisting of compounds represented by formula I, and the compounds represented by formula I are as follows: [ka] Equation I Each R1, R2, and R3 is independently one or more combinations selected from the group consisting of hydrogen, hydroxyl group, halogen, phenyl group, halogenated methoxy group, methylamino group, methyl group, and linear or branched, saturated or unsaturated hydrocarbon groups having 2 to 4 carbon atoms. R4, R5, R6, and R7 are each independently one or more combinations selected from the group consisting of hydrogen, a methyl group, and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms. m, n, and k are each independent integers between 1 and 3. The aforementioned carrier is selected from one or more carriers acceptable in the field of pharmacy, providing a pharmaceutical composition for the treatment of diabetes.

[0140] In some examples, the effective amount of compound used as the active ingredient was compound 1 [ka] , compound 2 [ka] , and compound 3 [ka] It is one or more species selected from the group consisting of the following.

[0141] In some embodiments, the pharmaceutical composition for treating diabetes exerts its effects by inhibiting the activity of α-glucosidase.

[0142] An eighth aspect of the present application provides an application of the above-mentioned diabetic drug composition in the manufacture of a pharmaceutical drug for the treatment of diabetes.

[0143] In some examples, the amount of compound used as an active ingredient was compound 1. [ka] , compound 2 [ka] , and compound 3 [ka] It is one or more species selected from the group consisting of the following.

[0144] The ninth aspect of the present application is a pharmaceutical preparation comprising one or more compounds for treating diabetes and one or more compounds represented by formula I in an amount having α-glucosidase inhibitory activity, wherein the compounds represented by formula I are as follows: [ka] Equation I Each R1, R2, and R3 is independently one or more combinations selected from the group consisting of hydrogen, hydroxyl group, halogen, phenyl group, halogenated methoxy group, methylamino group, methyl group, and linear or branched, saturated or unsaturated hydrocarbon groups having 2 to 4 carbon atoms. R4, R5, R6, and R7 are each independently one or more combinations selected from the group consisting of hydrogen, a methyl group, and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms. The present invention provides a pharmaceutical formulation in which m, n, and k are each independently integers between 1 and 3.

[0145] In some embodiments, at least one of each R1 and each R3 is a hydroxyl group.

[0146] In some embodiments, at least one of each R1 is a hydroxyl group, and at least one of each R3 is a hydroxyl group.

[0147] In some embodiments, the compound represented by formula I is [ka] , JPEG2026518474000058.jpg1126 and [ka] It is one or more species selected from the group consisting of the following structures.

[0148] A tenth aspect of the present application provides a method for the whitening of human skin and the treatment of age spots on human skin, comprising the step of administering an effective amount of the composition described in the fourth aspect or the product described in the sixth aspect to a person in need.

[0149] An eleventh aspect of the present application provides a method for inhibiting browning of food, comprising the step of administering an effective amount of the composition described in the fourth aspect to food.

[0150] A twelfth aspect of the present application provides a method for treating diabetes, comprising the step of administering an effective amount of the pharmaceutical composition described in the seventh aspect or the pharmaceutical preparation described in the ninth aspect to a person in need.

[0151] The following are examples of implementation.

[0152] Example 1: Compound Synthesis 1. Synthesis of Compound 1: 1,3-bis(bromomethyl)benzene (1.5 g, 5.73 mmol / L), phenol (6.2 mL, 70 mmol / L), and aluminum trichloride (195 mg, 1.5 mmol / L) were weighed in order. Under the protection of nitrogen gas, the mixture was heated at 110°C until the starting materials were consumed and reacted for 2 hours. After cooling to room temperature, the mixture was extracted three times each with saturated sodium carbonate aqueous solution and ethyl acetate. The mixture was then dried over sodium sulfate, filtered by suction and rotary dried, passed through a silica gel column, and purified with ethyl acetate / petroleum ether (EA:PE = 1:200, v / v) to obtain the product Compound 1 (473.3 mg, yield 42%, white solid). [ka]

[0153] 4,4'-(1,3-phenylenebis(methylene))diphenol (compound 1): white solid, 1 H NMR (600 MHz, 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). 1313C NMR (150 MHz, 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 C 20 H 17 O2 [M-H] - = 289.1234, found 289.1246. 1 1H NMR spectrum, 13 13C NMR spectra are shown in Figures 1-2.

[0154] 2. Synthesis of Compound 2: 1,3-Bis(bromomethyl)benzene (0.3 g, 1.15 mmol / L), o-cresol (0.6 g, 5.75 mmol / L), and aluminum trichloride (39 mg, 0.29 mmol / L) were weighed in order. Under the protection of nitrogen gas, they were heated at 110 °C until the raw materials were consumed, reacted for 2 hours, cooled to room temperature, and directly purified by silica gel column chromatography using ethyl acetate / petroleum ether (EA:PE = 1:7.5, v / v) as the eluent to obtain the product Compound 2 (40.7 mg, yield 26%, brown solid). [Chemical formula]

[0155] 4,4’-(1,3-phenylenebis(methylene))bis(2-methylphenol) (Compound 2): Brown solid, 1 1H NMR (600 MHz, DMSO-d6, δ, ppm, J / Hz): 9.05 (s, 2H), 7.15 (t, J = 7.6 Hz, 1H), 7.05 (s, 1H), 6.97 (d, J = 7.6 Hz, 2H), 6.87 (s, 2H), 6.80 (dd, J = 8.2, 2.3 Hz, 2H), 6.67 (d, J = 8.1 Hz, 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 C 22 H 21 O2[MH] - =317.1547, found 317.1561. 1 H NMR spectrum, 13 The 13C NMR spectra are shown in Figures 3-4.

[0156] 3. Synthesis of Compound 3: 1,3-bis(bromomethyl)benzene (1.5 g, 5.73 mmol / L), 1,2-benzenediphenol (0.63 g, 5.72 mmol / L), and aluminum trichloride (195 mg, 1.5 mmol / L) were weighed in order. Under the protection of nitrogen gas, the mixture was heated at 110°C until all the starting materials were used, reacted for 2 hours, cooled to room temperature, and purified directly by silica gel column chromatography. Ethyl acetate / petroleum ether (EA:PE = 1:2, v / v) was used as the eluent to obtain the product, Compound 3 (124.8 mg, yield 32%, pale yellow solid). [ka]

[0157] 3,3'-(1,3-phenylenebis(methylene))bis(benzene-1,2-diol) (compound 3): pale yellow solid, 1 H NMR (500 MHz, DMSO-d6,δ, ppm, J / Hz): 8.74 (s, 2H), 8.64 (s, 2H), 7.15 (t, J = 7.6 Hz, 1H), 7.01 (s, 1H), 6.95 (dd, J = 7.6, 1.7 Hz, 2H), 6.61 (d, J = 8.0 Hz, 2H), 6.53 (d, J = 2.1 Hz, 2H), 6.44 (dd, J = 8.0, 2.1 Hz, 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 C 20 H 18 NaO4[M + Na] + =345.1097, found 345.1097. 1 H NMR spectrum, 13 The 13C NMR spectra are shown in Figures 5-6.

[0158] 4. Synthesis of compounds 4-22: In a dry round-bottom flask, a phenolic compound (5.0 equiv) was dissolved in a methanol-water mixture (volume ratio of 2:1). H2SO4 (0.3 equiv) was slowly added dropwise to the solution, and then 2-hydroxy-5-methylmetaxylene glycol was added to the flask. The mixture was heated to 45°C under nitrogen gas conditions and the reaction was carried out. The reaction was monitored by thin-layer chromatography until the starting materials were completely reacted. After cooling to room temperature, the product was purified by direct silica gel column chromatography using ethyl acetate / petroleum ether (EA:PE = 1:20-1:1, v / v) as the eluent. [ka]

[0159] 5,5'-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(benzene-1,2,3-triol) (Compound 4): white solid, 1 H NMR (600 MHz, DMSO-d6,δ, ppm, J / Hz): 8.80 (s, 3H), 8.20 (s, 4H), 6.53 (s, 2H), 6.30 (d, J = 8.3 Hz, 2H), 6.21 (d, J = 8.2 Hz, 2H), 3.68 (s, 4H), 2.02 (s, 3H); 1313C NMR (150 MHz, 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。 1 1H NMR spectrum, 13 The 13C NMR spectra are shown in Figures 7 - 8.

Chemical formula

[0160] 4,4’-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene) diphenol (Compound 5): White solid, 1 1H NMR (500 MHz, DMSO-d6,δ, ppm, J / Hz): 9.23 (s, 2H), 8.15 (s, 1H), 6.98 (d, J = 8.5 Hz, 4H), 6.65 (d, J = 8.5 Hz, 4H), 6.61 (s, 2H), 3.77 (s, 4H), 2.07 (s, 3H); 13 13C NMR (125 MHz, DMSO-d6, δ, ppm): 155.81, 150.25, 131.66, 130.07, 129.41, 128.90, 128.16, 115.44, 35.10, 20.77。 1 1H NMR spectrum, 13 The 13C NMR spectra are shown in Figures 9 - 10.

Chemical formula

[0161] 4,4’-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(benzene-1,3-diol) (Compound 6): White solid, 11H NMR (600 MHz, MeOD, δ, ppm, J / Hz): 6.87 (d, J = 8.2 Hz, 2H), 6.72 (s, 2H), 6.31 (d, J = 2.5 Hz, 2H), 6.24 (dd, J = 8.2, 2.4 Hz, 2H), 3.75 (s, 4H), 2.12 (s, 3H). 13 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 C 21 H 21 O5353.1389, found 353.1382。 1 1H NMR spectrum, 13 13C NMR spectra are shown in Figures 11 to 12. [Chemical formula]

[0162] 2-(3-bromo-2-hydroxybenzyl)-6-(3-bromo-4-hydroxybenzyl)-4-methylphenol (Compound 7): Yellow solid, 1 1H NMR (500 MHz, CDCl3, δ, ppm, J / Hz): 7.36 - 7.29 (m, 2H), 7.19 (dd, J = 7.6, 1.6 Hz, 1H), 7.07 (dd, J = 8.3, 2.1 Hz, 1H), 6.94 - 6.91 (m, 2H), 6.81 - 6.74 (m, 2H), 6.19 (d, J = 19.0 Hz, 2H), 5.43 (s, 1H), 3.92 (s, 2H), 3.86 (s, 2H), 2.22 (s, 3H). 1313C NMR (125 MHz, 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 C 21 H 19 Br2O3 476.9701, found 476.9551。 1 1H NMR spectrum, 13 13C NMR spectra are shown in Figures 13 to 14. [Chemical formula]

[0163] 4,4’-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(2-bromophenol) (Compound 8): Yellow solid, 1 1H NMR (500 MHz, CDCl3, δ, ppm, J / Hz): 7.32 - 7.29 (m, 2H), 7.06 (dd, J = 8.2, 2.1 Hz, 2H), 6.94 (d, J = 8.3 Hz, 2H), 6.85 (s, 2H), 5.66 (s, 2H), 4.57 (s, 1H), 3.86 (s, 4H), 2.28 (d, J = 3.1 Hz, 3H). 13 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 C 21 H 19Br2O3476.9701, found 476.9551. 1 H NMR spectrum, 13 The 13C NMR spectra are shown in Figures 15-16. [ka]

[0164] 2-(2-hydroxy-3-methylbenzyl)-6-(4-hydroxy-3-methylbenzyl)-4-methylphenol (Compound 9): white solid, 1 H NMR (500 MHz, CDCl3, δ, ppm, J / Hz): 7.15 (d, J = 7.5 Hz, 1H), 7.03 - 6.94 (m, 3H), 6.91 (dd, J = 8.0 and 2.3 Hz, 1H), 6.82 (t, J = 4.4 Hz, 2H), 6.68 (dd, J = 8.1 and 1.9 Hz, 1H), 5.87 (s, 1H), 5.12 (s, 1H), 3.87 (d, J = 9.0 Hz, 4H), 2.25 (s, 3H), 2.22 (d, J = 6.1 Hz, 6H). 13 C 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: [MH] - Calcd for C 21 H 23 O3347.1647, found 347.1669. 1 H NMR spectrum, 13 The 13C NMR spectra are shown in Figures 17-18. [ka]

[0165] 4,4’-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(2-methylphenol) (Compound 10): White solid, 1 H NMR (500 MHz, CDCl3, δ, ppm, J / Hz): δ 6.99 (s, 2H), 6.94 - 6.87 (m, 4H), 6.65 (d, J = 8.1 Hz, 2H), 5.53 (s, 2H), 4.78 (s, 1H), 3.87 (s, 4H), 2.30 (s, 3H), 2.21 (s, 6H). 13 C 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 C 23 H 23 O3347.1647, found 347.1669。 1 1H NMR spectrum, 13 13C NMR spectra are shown in Figures 19 - 20.

Chemical Structure

[0166] 3-(2-hydroxy-3-((6-hydroxy-[1,1’-biphenyl]-3-yl)methyl)-5-methylbenzyl)-[1,1’-biphenyl]-2-ol (Compound 11): White solid, 11H NMR (600 MHz, 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 = 7.6 and 1.7 Hz, 1H), 7.14 - 7.10 (m, 3H), 7.00 (d, J = 2.2 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 2.2 Hz, 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). 13 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 C 33 H 27 O3471.1960, found 471.1988。 1 1H NMR spectrum, 13 13C NMR spectra are shown in Figures 21 - 22.

Chemical Structure

[0167] 5,5’’-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(([1,1’-biphenyl]-2-ol)) (Compound 12): White solid, 11H NMR (500 MHz, 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 = 14.6 Hz, 2H), 4.60 (s, 1H), 3.92 (s, 4H), 2.25 (s, 3H). 13 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 C 33 H 27 O3471.1960, found 471.1988。 1 1H NMR spectrum, 13 13C NMR spectra are shown in Figures 23 - 24.

Chemical Structure

[0168] 4,4’-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(benzene-1,2-diol) (Compound 13): White solid, 1 1H NMR (500 MHz, MeOD, δ, ppm, J / Hz): 6.68 - 6.64 (m, 4H), 6.61 (d, J = 2.1 Hz, 2H), 6.53 (dd, J = 8.0 and 2.1 Hz, 2H), 3.78 (s, 4H), 2.12 (s, 3H). 1313C NMR (125 MHz, 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 C 21 H 21 O5353.1389, found 353.1381。 1 1H NMR spectrum, 13 13C NMR spectra are shown in Figs. 25-26.

Chemical formula

[0169] 2-(2-hydroxy-3-(trifluoromethoxy)benzyl)-6-(4-hydroxy-3-(trifluoromethoxy)benzyl)-4-methylphenol (Compound 14): Yellow solid, 1 1H NMR (500 MHz, CDCl3, δ, ppm, J / Hz): 7.07 - 7.04 (m, 2H), 7.01 (dd, J = 8.4 and 2.1 Hz, 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). 13 13C NMR (125 MHz, 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。 1 1H NMR spectrum, 13 13C NMR spectra are shown in Figs. 27-28.

Chemical formula

[0170] 2-(3-Ethyl-2-hydroxybenzyl)-6-(3-ethyl-4-hydroxybenzyl)-4-methylphenol (Compound 15): White solid, 1 H NMR (600 MHz, CDCl3, δ, ppm, J / Hz): 7.15 (dt, J = 7.6 and 1.2 Hz, 1H), 7.01 (td, J = 10.5, 10.0, 2.0 Hz, 3H), 6.90 (dd, J = 8.1and 2.3 Hz, 1H), 6.84 (ddd, J = 16.1, 8.1, 1.6 Hz, 2H), 6.68 (d, J = 8.1 Hz, 1H), 6.64 (s, 1H), 5.70 (s, 1H), 5.02 (s, 1H), 3.88 (d, J = 3.2 Hz, 3H), 2.61 (p, J = 7.4 Hz, 4H), 2.25 (s, 3H), 1.21 (td, J = 7.5 and 2.0 Hz, 6H). 13 C 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 C 25 H 29 O3377.2117, found 377.2112。 1 1H NMR spectrum, 13 13C NMR spectrum are shown in Figures 29 - 30.

Chemical formula

[0171] 4,4’-((2-Hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(2-ethylphenol) (Compound 16): White solid, 1 H NMR (500 MHz, CDCl3, δ, ppm, J / Hz): 7.01 (d, J = 2.2 Hz, 2H), 6.89 (dd, J = 8.1 and 2.3 Hz, 2H), 6.86 (s, 2H), 6.65 (d, J = 8.0 Hz, 2H), 4.96 (s, 1H), 4.64 (s, 1H), 3.87 (s, 4H), 2.60 (d, J = 7.5 Hz, 4H), 2.26 (d, J = 6.6 Hz, 3H), 1.21 (t, J = 7.6 Hz, 6H). 13 C 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。 1 1H NMR spectrum, 13 13C NMR spectra are shown in Figs. 31 - 32.

Chemical Structure

[0172] 2-(3-Allyl-2-hydroxybenzyl)-6-(3-allyl-4-hydroxybenzyl)-4-methylphenol (Compound 17): White solid, 11H NMR (500 MHz, DMSO-d6, δ, ppm, J / Hz): 9.14 (s, 1H), 8.45 (d, J = 55.5 Hz, 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 = 6.6 and 1.6 Hz, 2H), 3.22 (dd, J = 6.6 and 1.6 Hz, 2H), 2.05 (s, 3H). 13 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 C 27 H 29 O3401.2117, found 401.2115。 1 1H NMR spectrum, 13 13C NMR spectra are shown in Figures 33 - 34.

Chemical Structure

[0173] 4,4’-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(2-allylphenol) (Compound 18): White solid, 11H NMR (500 MHz, CDCl3, δ, ppm, J / Hz): 6.98 (d, J = 2.3 Hz, 2H), 6.95 (dd, J = 8.2 and 2.4 Hz, 2H), 6.84 (s, 2H), 6.72 (d, J = 8.2 Hz, 2H), 6.05 - 5.95 (m, 2H), 5.32 (s, 1H), 5.16 (dd, J = 6.9 and 1.7 Hz, 2H), 5.13 (t, J = 1.6 Hz, 2H), 3.86 (s, 4H), 3.37 (dt, J = 6.4, Hz, 4H), 2.26 (s, 3H). 13 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 C 27 18 29 24H34O3401.2117, found 401.2112。 1 1H NMR spectrum, 13 13C NMR spectra are shown in Figures 35 - 36.

Chemical formula

[0174] 4,4’-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(2-(methylamino)phenol) (Compound 19): White solid, 11H NMR (600 MHz, 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 = 13.2 Hz, 2H), 6.56 (d, J = 9.1 Hz, 1H), 4.07 - 3.76 (m, 4H), 2.58 (d, J = 10.8 Hz, 3H), 2.28 - 2.13 (m, 6H). HRMS(ESI) m / z: [M+H] + Calcd for C 23 H 27 N2O3 379.2022, found 379.2016。 1 The 1H NMR spectrum is shown in Figure 37.

Chemical Structure

[0175] 2-(2-hydroxy-3-(methylamino)benzyl)-6-(4-hydroxy-3-(methylamino)benzyl)-4-methylphenol (Compound 20): Yellow solid, 1 1H NMR (600 MHz, CDCl3, δ, ppm, J / Hz): 6.86 (d, J = 2.1 Hz, 2H), 6.77 (d, J = 7.9 Hz, 2H), 6.73 (s, 2H), 6.58 (d, J = 7.9 Hz, 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 C 23 H 27 N2O3 379.2022, found 379.2017。 1 The 1H NMR spectrum is shown in Figure 38.

Chemical Structure

[0176] 2-(4-(tert-butyl)-2-hydroxybenzyl)-6-(2-(tert-butyl)-4-hydroxybenzyl)-4-methylphenol (Compound 21): White solid, 1 H NMR (600 MHz, MeOD, δ, ppm, J / Hz): 7.05 (d, J = 7.9 Hz, 1H), 6.90 (d, J = 2.6 Hz, 1H), 6.86 (d, J = 1.9 Hz, 1H), 6.82 - 6.79 (m, 2H), 6.76 (d, J = 8.3 Hz, 1H), 6.54 (dd, J = 8.3 and 2.6 Hz, 1H), 6.28 (d, J = 2.2 Hz, 1H), 4.09 (s, 2H), 3.82 (s, 2H), 2.04 (s, 3H), 1.33 (s, 9H), 1.25 (s, 9H). 13 C 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 C 29 H 37 O3433.2743, found 377.2736。 1 1H NMR spectrum, 13 13C NMR spectra are shown in Figures 39 - 40.

Chemical Structure

[0177] 4,4’-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(2-ethylphenol) (Compound 22): White solid, 1 H NMR (600 MHz, CDCl3, δ, ppm, J / Hz): 7.01 (d, J = 2.2 Hz, 2H), 6.89 (dd, J = 8.1 and 2.3 Hz, 2H), 6.86 (s, 2H), 6.65 (d, J = 8.0 Hz, 2H), 4.96 (s, 1H), 4.64 (s, 1H), 3.87 (s, 4H), 2.60 (d, J = 7.5 Hz, 4H), 2.26 (d, J = 6.6 Hz, 3H), 1.21 (t, J = 7.6 Hz, 6H). 13 C 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 C 25 H 29 O3377.2117, found 377.2112。 1 1H NMR spectrum, 13 13C NMR spectrum are shown in Figs. 41 - 42.

Chem.

[0178] 5. Synthesis of Compounds 23 - 31: Phenylboronic acid compound (2.4 eq) and 1,3-bis(bromomethyl)benzene (1 eq) were added to a dry round-bottom flask and dissolved in 25 mL of 1,4-dioxane. Potassium carbonate (4.8 eq) and 13 mL of water were added, and the mixture was degassed by bubbling. Tetrakis(triphenylphosphine)palladium (0.025 eq) was added under the protection of nitrogen gas, and the mixture was heated to 100°C. The mixture was monitored by TLC thin-layer chromatography until the starting materials had completely reacted. After cooling to room temperature, the solvent was removed by rotation, and the mixture was purified by direct silica gel column chromatography. Ethyl acetate / petroleum ether (EA:PE = 1:20-1:1, v / v) was used as the eluent to obtain the product of Step 1. The product (1 eq) from Step 1 was dissolved in dichloromethane, cooled to 0°C, and BBr3 (1 M, 4.8 eq) was slowly added dropwise under the protection of nitrogen gas. The reaction was monitored by TLC thin-layer chromatography until the starting materials were completely reacted. The reaction was quenched by injection into water, extracted three times with DCM and water, the organic phases were combined, dried, and rotary dried. The product was purified by silica gel column chromatography using ethyl acetate / petroleum ether (EA:PE = 1:5, v / v) as the eluent to obtain the product. [ka]

[0179] 2,2'-(1,3-phenylenebis(methylene))diphenol (compound 23): white solid, 1 H NMR (600 MHz, CDCl3, δ, ppm, J / Hz): 7.23 (t, J = 7.6 Hz, 1H), 7.18 (s, 1H), 7.17 - 7.11 (m, 4H), 7.08 (d, J = 7.8 Hz, 2H), 6.94 - 6.89 (m, 2H), 6.77 (d, J = 7.8 Hz, 2H), 5.10 (s, 2H), 3.98 (s, 4H). 13C NMR (150 MHz, 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. 1 H NMR spectrum, 13 The 13C NMR spectra are shown in Figures 43-44. [ka]

[0180] 3,3'-(1,3-phenylenebis(methylene))diphenol (compound 24): white solid, 1 H NMR (600 MHz, CDCl3, δ, ppm, J / Hz): 7.19 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 7.8 Hz, 2H), 7.04 (s, 1H), 7.02 (dd, J = 7.5 and 1.8 Hz, 2H), 6.78 (d, J = 7.5 Hz, 2H), 6.68 (dd, J = 8.2 and 2.3 Hz, 2H), 6.61 (t, J = 2.0 Hz, 2H), 6.22 (s, 2H), 3.88 (s, 4H). 13 C NMR (150 MHz, 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. 1 H NMR spectrum, 13 The 13C NMR spectra are shown in Figures 45-46. [ka]

[0181] 4,4’-(1,3-phenylenebis(methylene))bis(benzene-1,3-diol) (Compound 25): White solid, 1 H NMR (500 MHz, DMSO-d6, δ, ppm, J / Hz): 9.15 (s, 2H), 8.99 (s, 2H), 7.08 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 6.90 (dd, J = 7.5, 1.9 Hz, 2H), 6.73 (dd, J = 8.2, 1.7 Hz, 2H), 6.27 (s, 2H), 6.11 (dt, J = 8.2, 2.2 Hz, 2H), 3.67 (s, 4H); 13 C 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。 1 1H NMR spectrum, 13 13C NMR spectrum are shown in Figures 47 - 48.

Chem.

[0182] 4,4’-(1,3-phenylenebis(ethane-1,1-diyl))bis(benzene-1,3-diol) (Compound 26): White solid, 1 H NMR (500 MHz, DMSO-d6, δ, ppm, J / Hz): 9.11 (d, J = 5.0 Hz, 2H), 8.96 (s, 2H), 7.15 - 7.04 (m, 2H), 6.93 (d, J = 7.5 Hz, 2H), 6.79 (dd, J = 8.4, 3.9 Hz, 2H), 6.23 (s, 2H), 6.13 (d, J = 8.3 Hz, 2H), 4.31 - 4.22 (m, 2H), 3.35 (s, 6H), 1.40 (d, J = 7.6 Hz, 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. 1 H NMR spectrum, 13 The 13C NMR spectra are shown in Figures 49-50. [ka]

[0183] 4,4'-(1,3-phenylenebis(methylene))bis(2,6-dimethylphenol) (Compound 27): white solid, 1 H NMR (600 MHz, DMSO-d6, δ, ppm, J / Hz): 8.01 (s, 2H), 7.14 (t, J = 7.6 Hz, 1H), 7.05 (s, 1H), 6.96 (dd, J = 7.6, 1.3 Hz, 2H), 6.73 (s, 4H), 3.70 (s, 4H), 2.11 (s, 12H); 13 C 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. 1 H NMR spectrum, 13 The 13C NMR spectra are shown in Figures 51-52. [ka]

[0184] 4,4’-(1,3-phenylenebis(methylene))bis(3,5-dimethylphenol) (Compound 28): White solid, 1 H NMR (500 MHz, DMSO-d6, δ, ppm, J / Hz): 9.01 (s, 2H), 7.06 (t, J = 7.6 Hz, 1H), 6.76 (s, 1H), 6.70 (d, J = 7.5 Hz, 2H), 6.45 (s, 4H), 3.79 (s, 4H), 2.06 (s, 12H); 13 C NMR (125 MHz, DMSO-d6) δ 155.59, 140.82, 137.90, 128.67, 127.98, 127.76, 125.23, 115.23, 34.14, 20.45。 1 1H NMR spectrum, 13 13C NMR spectrum are shown in Figs. 53 - 54.

Chemical Structure

[0185] 5,5’-(1,3-phenylenebis(methylene))bis(2-methylphenol) (Compound 29): White solid, 1 H NMR (600 MHz, DMSO-d6, δ, ppm, J / Hz): 9.13 (s, 2H), 7.18 (t, J = 7.5 Hz, 1H), 7.05 (s, 1H), 6.99 (d, J = 7.3 Hz, 2H), 6.94 (d, J = 7.4 Hz, 2H), 6.63 - 6.51 (m, 4H), 3.76 (s, 4H), 2.06 (s, 6H); 13 C 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。 1 1H NMR spectrum, 13The \(^{13}\)C NMR spectra are shown in Figures 55 to 56.

Chemical formula

[0186] 6,6’-(1,3-phenylenebis(methylene))bis(2-methylphenol) (Compound 30): White solid, 1 \(^{1}\)H NMR (500 MHz, DMSO-d6, δ, ppm, J / Hz): 8.27 (s, 2H), 7.18 - 7.09 (m, 2H), 6.95 (d, J = 7.4 Hz, 2H), 6.91 (d, J = 6.9 Hz, 2H), 6.83 (d, J = 7.4 Hz, 2H), 6.65 (t, J = 7.4 Hz, 2H), 3.86 (s, 4H), 2.16 (s, 6H); 13 \(^{13}\)C 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. 1 The \(^{1}\)H NMR spectrum, 13 The \(^{13}\)C NMR spectra are shown in Figures 57 to 58.

Chemical formula

[0187] 3,3’-(1,3-phenylenebis(methylene))bis(2-methylphenol) (Compound 31): White solid, 1H NMR (600 MHz, DMSO-d6,δ, ppm, J / Hz): 9.21 (s, 2H), 7.14 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 12.8 Hz, 1H), 6.95 - 6.87 (m, 4H), 6.69 (d, J = 7.9 Hz, 2H), 6.57 (d, J = 7.4 Hz, 2H), 3.85 (s, 4H), 1.99 (s, 6H); 13 C 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. 1 H NMR spectrum, 13 The 13C NMR spectra are shown in Figures 59-60. [ka]

[0188] Example 2: Study on tyrosinase activity inhibition by compound 1, compound 2, and compound 3 1. Preparation of the solution Phosphate buffer (0.2M, pH 6.8): 2.84 g of Na2HPO4 and 2.4 g of NaH2PO4 were precisely weighed, dissolved in purified water to a final volume of 100 mL, and then mixed in equal volumes. The pH was then adjusted to 6.8.

[0189] L-DOPA solution: 3.95 mg of L-DOPA was precisely weighed and dissolved in 10 mL of phosphate buffer (0.2 M, pH 6.8) to prepare a 2 mmol / L L-DOPA solution.

[0190] Tyrosinase solution: 1 mg of tyrosinase (enzyme activity 500 U / mg) was precisely weighed and dissolved 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.

[0191] Sample working solution: Compound 1, Compound 2, Compound 3, and kojic acid were each accurately weighed to 10 mg and placed in 500 μL of ultrapure water. Then, 1 M NaOH was slowly added dropwise until the solution became clear, and finally, purified water was added to a final volume of 1 mL to prepare a mother liquor of 10 mg / mL. Furthermore, the test compounds and the positive control drug, kojic acid, were diluted with the above phosphate buffer to produce sample working solutions with concentrations of 31.2 μg / mL, 62.5 μg / mL, 125 μg / mL, 250.00 μg / mL, and 500.00 μg / mL.

[0192] 2. Measurement of tyrosinase activity Four test groups were established: sample group A1, sample-negative control group A2, enzyme standard group B1, and enzyme-negative control group B2. Three parallel tests were set up for each sample, and 200 μL reaction systems were prepared according to Table 1. In a 96-well plate, the corresponding volume of phosphate buffer, test sample solutions at various concentrations (final concentrations of 3.12 μg / mL, 6.25 μg / mL, 12.5 μg / mL, 25 μg / mL, and 50 μg / mL), tyrosinase solution (final concentration of 20 U / mL), and the reaction substrate L-DOPA (final concentration of 1.2 mmol / L) were added in order. The systems were incubated for 30 minutes in a microplate incubator at 37°C, and then the absorbance at 475 nm for each test group was measured using a multifunctional microplate reader (SPARK 10M, TECAN). The formula for calculating the inhibition rate of the test compound against tyrosinase is as follows. Tyrosinase inhibition rate (%) = [1 - (A1 - A2) / (B1 - B2)] × 100.

[0193] [Table 1]

[0194] As shown in Figure 61, when the concentrations are 3.12 μg / mL, 6.25 μg / mL, 12.5 μg / mL, and 25 μg / mL, there are four sets of data for each concentration, corresponding from left to right to Compound 3, kojic acid, Compound 1, and Compound 2. When the concentration is 50 μg / mL, there are three sets of data, corresponding from left to right to Compound 3, kojic acid, and Compound 1. As can be seen from Figure 61, Compound 1, Compound 2, and the positive control drug kojic acid all show dose-dependent inhibitory effects on tyrosinase activity. After performing nonlinear fitting using Graphpad Prism 8.0 software, the half-inhibitory concentration IC of Compound 1, Compound 2, and kojic acid against tyrosinase was obtained. 50 The calculated concentrations were 10.43 μg / mL (i.e., 35.96 μmol / L), 4.36 μg / mL (i.e., 13.68 μmol / L), and 18.61 μg / mL (i.e., 131.6 μmol / L), respectively. On the other hand, no relevant activity was observed for compound 3 within the measured concentration range (IC). 50 (>50 μg / mL). As is clear from the results, compounds 1 and 2 showed excellent inhibitory activity against tyrosinase, with tyrosinase inhibitory effects reaching 3.7 times and 9.6 times that of kojic acid, respectively, and are expected to be used as browning inhibitors for skin whitening and tone-up.

[0195] Example 3: Study on the inhibition of α-glucosidase activity by compound 1, compound 1, and compound 3. 1. Preparation of the solution Phosphate buffer (0.2M, pH 6.8): 2.84 g of Na2HPO4 and 2.4 g of NaH2PO4 were precisely weighed, dissolved in purified water to a final volume of 100 mL, and then mixed in equal volumes. The pH was then adjusted to 6.8.

[0196] α-glucosidase solution: α-glucosidase powder derived from Saccharomyces cerevisiae was prepared as a 1 U / mL α-glucosidase solution in phosphate buffer (0.2 M, pH 6.8) and stored at 20°C.

[0197] Substrate PNPG solution: 211 mg of 4-nitrobenzene-α-D-glucopyranoside (PNPG) was precisely weighed using an analytical balance, and 70 mL of the above phosphate buffer was added to dissolve it uniformly. A 10 mmol / L substrate storage solution was prepared and stored in the dark at 20°C. In this application, "mmol / L" means millimoles / liter, and "μmol / L" means micromoles / liter.

[0198] Positive control activator: In this experiment, acarbose was selected as the positive control. 103.3 mg of acarbose powder was precisely weighed, thoroughly dissolved in 1 mL of the above phosphate buffer, and mixed uniformly to prepare a 160 mmol / L acarbose mother liquor. Furthermore, the mother liquor was diluted with the above phosphate buffer to produce positive control activators with concentrations of 2.5 mmol / L, 5 mmol / L, 10 mmol / L, 20 mmol / L, 40 mmol / L, 80 mmol / L, and 160 mmol / L.

[0199] Test compound working solution: Compound 1 (2.90 mg), Compound 2 (3.19 mg), and Compound 3 (3.23 mg) were precisely weighed and dissolved in 500 μL of ultrapure water. 1 M NaOH was slowly added dropwise until the solution became clear, and finally, purified water was added to a final volume of 1 mL to prepare a 10 mmol / L compound mother liquor. Furthermore, the compounds were diluted with the above phosphate buffer to produce compound 1 working solutions with concentrations of 0.062 mmol / L, 0.125 mmol / L, 0.25 mmol / L, 0.5 mmol / L, 1 mmol / L, and 2 mmol / L; compound 2 working solutions with concentrations of 0.025 mmol / L, 0.05 mmol / L, 0.1 mmol / L, 0.2 mmol / L, 0.4 mmol / L, and 0.8 mmol / L; and compound 3 working solutions with concentrations of 3.12 μmol / L, 6.25 μmol / L, 12.5 μmol / L, 25 μmol / L, 50 μmol / L, and 100 μmol / L.

[0200] 2. Measurement of α-glucosidase activity Four test groups were established: blank control group A, enzyme standard group B, sample-negative control group C, and sample group D. Three parallel tests were set up for each sample. 600 μL of reaction system was prepared according to Table 2. The corresponding volume of phosphate buffer, test sample working solution at each concentration (the final concentration being a 20-fold dilution of the test compound working solution), α-glucosidase solution (final concentration 0.005 U / mL), and reaction substrate PNPG (final concentration 0.5 mmol / L) were added sequentially to a 96-well plate and mixed thoroughly and uniformly. After incubating the reaction system at 37°C for 50 minutes, the reaction was stopped by adding 60 μL of 0.1 mol / L Na2CO3 solution. The test 96-well plates were placed on a multifunctional microplate reader (SPARK 10M, TECAN) and the absorbance at 405 nm was measured for each test group. The formula for calculating the α-glucosidase inhibition rate is as follows. α-glucosidase inhibition rate (%) = [1 - (DC) / (BA)] × 100.

[0201] [Table 2]

[0202] As shown in Figure 62, all three compounds and the positive control drug acarbose exhibit dose-dependent inhibitory effects on α-glucosidase activity. In Figure 62, the α-glucosidase inhibition rates at different concentrations of compound 1, compound 2, compound 3, and acarbose are shown from left to right, respectively. After nonlinear fitting using Graphpad Prism 8.0 software, the half-inhibitory concentration IC of compound 1, compound 2, compound 3, and acarbose against α-glucosidase was obtained. 50The calculated concentrations were 21.77 μmol / L, 8.91 μmol / L, 0.95 μmol / L, and 481.7 μmol / L, respectively. As can be seen from the experimental results above, all three compounds exhibited excellent inhibitory activity against α-glucosidase, and their inhibitory effect was significantly superior to that of the positive control drug acarbose. It is expected that by efficiently inhibiting α-glucosidase, the production of mature active tyrosinase will decrease, thereby achieving the goal of reducing skin pigmentation.

[0203] Example 4: Study of antioxidant activity of compound 1, compound 2, and compound 3 Equivolutes of 7.4 mmol / L ABTS solution and 2.6 mmol / L K2S2O8 solution were mixed and allowed to stand at room temperature in the dark for 16 hours to prepare ABTS free radical storage solution. The ABTS free radical storage solution was diluted with phosphate buffer solution (pH 7.4, 10 mmol / L) to adjust the absorbance at a wavelength of 734 nm to 0.70 ± 0.05 to prepare ABTS working solution. 200 μL of ABTS working solution was mixed with 10 μL of phosphate buffer solution (pH 7.4, 10 mmol / L), and the absorbance at 734 nm was measured and determined as A0. 10 mg of compound 1 was precisely weighed and dissolved in 500 μL of purified water. 1 mol / L of NaOH was slowly added dropwise until the solution became clear, and finally, purified water was added to a final volume of 1 mL to prepare a 10 mg / mL mother liquor. Furthermore, the test mother liquor was diluted to the corresponding concentration with a phosphate buffer solution (pH 7.4, 10 mmol / L). The positive control drug, Trolox (water-soluble vitamin E), was prepared in a mother liquor at a concentration of 10 mg / mL using pure water, and then diluted with water to the specified concentration. 10 μL of sample solutions of different concentrations were mixed with 200 μL of ABTS working solution to obtain final concentrations of the positive agent, vitamin E, of 0.9 μg / mL, 1.79 μg / mL, 3.58 μg / mL, 7.15 μg / mL, 10.73 μg / mL, 14.30 μg / mL, 25 μg / mL, and 50 μg / mL. The final concentrations of compound 1 were 0.62 μg / mL, 1.25 μg / mL, 2.50 μg / mL, 5.00 μg / mL, 10 μg / mL, 20 μg / mL, 40 μg / mL, and 50 μg / mL. The final concentrations of compounds 2 and 3 were 0.78 μg / mL, 1.56 μg / mL, 3.12 μg / mL, 6.25 μg / mL, 12.5 μg / mL, 25 μg / mL, and 50 μg / mL. The mixed sample solution was allowed to stand at room temperature for 10 minutes, and its absorbance (Ai) was measured at a wavelength of 734 nm. Simultaneously, 10 μL of a sample solution of a predetermined concentration was mixed with 200 μL of a 10 mmol / L, pH 7.4 phosphate buffer solution, and its background absorbance Aj at 734 nm was measured. Three parallel tests were set up for each sample concentration. The formula for calculating the scavenging rate of the sample against ABTS free radicals is as follows. JPEG2026518474000095.jpg12164

[0204] As shown in Figure 63, within the test concentration range, all test compounds exhibited good scavenging activity against ABTS free radicals. Nonlinear fitting was performed using Graphpad Prism 8.0 software, and the IC20 50 The half maximal inhibitory concentrations (IC) were calculated to be 6.78 μg / mL (i.e., 23.22 μmol / L), 2.56 μg / mL (i.e., 8.02 μmol / L), and 2.10 μg / mL (i.e., 6.49 μmol / L), respectively, and the IC of the positive control drug, vitamin E. 50 The value is 4.75 μg / mL (i.e., 11.05 μmol / L). As is clear from the experimental results above, compounds 1, 2, and 3 have good free radical scavenging ability, and the antioxidant activity of compounds 2 and 3 is superior to that of the positive control drug vitamin E, suggesting that cells will resist oxidative stress damage and skin aging will be delayed.

[0205] [Table 3]

[0206] Example 5: Cell activity test using Compound 1, Compound 2, and Compound 3 Processing of test samples: Sample group: Compound 1, Compound 2, Compound 3, and phenylethyl resorcinol were each dissolved in DMSO, then diluted with 1640 culture medium to a mother liquor of 38.6 μmol / L, and further diluted with 1640 culture medium to samples of concentrations of 19.3 μmol / L, 9.65 μmol / L, 4.825 μmol / L, and 2.413 μmol / L in preparation for use. Negative control group: 1640 basal medium.

[0207] Cell activity test: B16 cells were seeded in 96-well plates, the culture medium was discarded after 24 hours, and basal medium containing different concentrations of test samples was added. After 24 hours, the OD490nm was measured by the MTT method, and the effect of the test samples on B16 cell activity was analyzed by t-tests.

[0208] The statistical analysis software used was SPSS, and independent sample t-tests were employed to compare the test samples with the negative control group. All statistical analyses above were two-tailed tests, with a significance level of α=0.05. *P<0.05 indicates that the test samples showed a statistically significant difference compared to the negative control group under the effect of the concentration, and the experimental results are shown in Figure 64. Each group corresponding to the horizontal axis in Figure 64 contains four sets of data. The four sets of data, from left to right, correspond to cell viability data for compound 1, compound 2, compound 3, and phenylethyl resorcinol.

[0209] As can be seen from Figure 64, when the concentration of the three compounds is 19.3 μmol / L, cell activity is >90%, and no cytotoxicity is observed.

[0210] Example 6: Experiment on inhibition of cell melanin synthesis by compound 1, compound 2, and compound 3 Compounds 1, 2, and 3, along with phenylethyl resorcinol, were used as experimental samples at a concentration of 19.3 μmol / L. 1640 basal medium was used as a negative control. B16 cells were seeded in a 6-well plate and cultured for 24 hours. After this, the medium was changed to 1640 basal medium containing different concentrations of the test samples, followed by two more medium changes. The cells were then washed twice with PBS, and 200 μL of 0.25% pancreatin was added to each well to digest the cells. The cells were collected in centrifuge tubes and centrifuged for 5 minutes. 200 μL of 1M NaOH containing 10% DMSO was added to each centrifuge tube to lyse the cells, which were then shaken thoroughly. The cells were transferred to a 96-well plate, and the absorbance at 405 nm in each well was detected using a microplate reader. The formula for calculating the cellular melanin synthesis inhibition rate is as follows:

number

[0211] As can be seen from Figure 65, the inhibition rates of compound 1, compound 2, compound 3, and phenylethyl resorcinol on B16 cell melanin synthesis at 19.3 μmol / L were 52.230%, 40.881%, 34.798%, and 32.791%, respectively. These compounds showed a significant inhibitory effect (P<0.05) on cell melanin synthesis, and the inhibition rates of compound 1, compound 2, and compound 3 on B16 cell melanin synthesis were significantly higher than those of phenylethyl resorcinol, a representative whitening ingredient on the market, indicating that compound 1, compound 2, and compound 3 have excellent whitening effects.

[0212] Example 7: Testing the skin whitening effect of compound 1 and compound 2 on zebrafish. Zebrafish have transparent bodies in the early stages of development, and melanin production begins in the retinal pigment epithelium 24 hours after the start of embryonic development. Pigment cells originate from neural crest cells, which are a group of cells that differentiate from the dorsal ectoderm, and then differentiate into chromatoblasts through proliferation and migration. Melanin formation can be inhibited by intervening in the melanin formation process. The whiteness of zebrafish skin is used as an indicator to evaluate the skin-whitening effect of a sample.

[0213] The experimental system uses wild-type AB zebrafish. The zebrafish used are 6 hpf (6 hours post-fertilization). The sample size for each group is 15 fish (N=10). Adult fish rearing is carried out according to a standard laboratory breeding protocol that conforms to international AAALAC certification standards.

[0214] Randomly selected zebrafish were placed in a 6-well plate, with 15 fish in each well. The samples were prepared as suspensions that could be uniformly dispersed in water, with concentrations as shown in Table 4. A normal control group was also established, with a volume of 3 mL in each well. The samples were incubated at 28°C for 45 hours in the dark. After incubation, 10 zebrafish were randomly selected from each sample group and photographed under a stereomicroscope. The data was analyzed and collected using advanced image analysis software. The melanin signal intensity (S) of the zebrafish heads was analyzed, and the presence or absence of a skin-whitening effect of the samples was calculated and determined based on the following formula. The calculation formula is as follows: Whitening effect = S (normal control group) - S (sample group) / S (normal control group) × 100%.

[0215] As can be seen from the observation results in Table 4 and Figure 66, the melanin signal intensity in the zebrafish heads of sample compound 1 (0.0002%), compound 1 (0.0001%), and compound 2 (0.0001%) was significantly reduced compared to the normal control group, indicating that the samples have a whitening effect. On the other hand, the melanin signal intensity in the zebrafish heads of sample compound 1 (0.00001%), compound 2 (0.00001%), and phenylethyl resorcinol 377 group was similar to that of the normal control group, indicating that the samples do not have a whitening effect at these concentrations. Therefore, under the experimental conditions of this study, Compound 1 (0.0002%), Compound 1 (0.0001%), and Compound 2 (0.0001%) have a whitening effect, but Compound 1 (0.00001%), Compound 2 (0.00001%), and Phenylethyl Resorcinol 377 (0.0002%) do not have a whitening effect.

[0216] [Table 4] Note: In statistical analysis, efficacy is determined when p < 0.05 and efficacy value ≥ 20%.

[0217] Example 8: In vitro micronucleus test using mammalian cells The in vitro micronucleus (MNvit) test is a genotoxicity test used to detect micronuclei that develop in the cytoplasm during interphase of cell division.

[0218] The testing process is as follows:

[0219] Using DMSO as the solvent, a fixed amount of sample is weighed and dissolved. It is then added to serum-containing DMEM medium at a 1% concentration, and the final concentration of the sample in the medium is determined by IC. 50 , 1 / 2 IC 50 and 1 / 4 IC 50 That is the case.

[0220] A cell suspension was prepared using mouse lymphoma cells L5178Y that had not exceeded 32 passages. The prepared cell suspension was seeded into a 24-well cell culture plate at a seeding rate of 1 mL / well, with a cell count of 4 × 10⁶. 5 Each well contained one sample. The samples were placed in a carbon dioxide incubator and incubated for 24 hours at 37°C and 5% CO2.

[0221] One mL of a prepared solvent control solution containing cells and culture medium, a positive control solution, and different doses of test sample solution were added to the corresponding wells of the culture plate. The solvent control solution was identical in composition to the test sample solution, except that it did not contain the test sample. The positive control solution consisted of 0.25 g / mL mitomycin, 10 g / mL cyclophosphamide, and 0.3 g / mL colchicine. Cells in the cell culture plate were exposed in three ways: short-term exposure without the metabolic activator (S9 mixture), short-term exposure with the metabolic activator (S9 mixture), and long-term exposure without the metabolic activator (S9 mixture). The culture plates were incubated in a carbon dioxide incubator according to the requirements of the different groups.

[0222] After incubation, the cell suspension in the cell culture plate was collected in a centrifuge tube and subjected to hypotonic treatment. Cell fixation was performed after hypotonic treatment was complete. The fixed cell suspension was dropped onto glass slides, and one slide was prepared for each well of culture. After staining the prepared micronucleus sample slides, 1000 cells were observed under a microscope, and the number of cells containing micronuclei was recorded.

[0223] Criteria for evaluating results: (1) Positive result determination (1) The micronucleus rate at at least one test dose showed a statistically significant increase compared to the solvent control group (a p-value < 0.05 is considered a significant increase), (2) the increase in the micronucleus rate was dose-dependent, and (3) the test results at any dose were not within the distribution range (95% range) of previous negative control data.

[0224] (2) Negative result determination (1) Compared to the solvent control group, no statistically significant increase in the micronucleus rate was observed at any test dose, (2) no dose-dependent relationship was observed in the micronucleus rate, and (3) all test results were within the range (95% confidence interval) of previous solvent control data.

[0225] Experimental conclusion: In the micronucleus test, compound 1 and compound 2 showed higher IC values ​​compared to the solvent control group. 50 (22.5, 19.76 μg / mL), 1 / 2 IC 50 (11.28, 9.88 μg / mL) and 1 / 4 IC2 50 Under the respective concentration conditions of (5.64 and 4.96 μg / mL), the micronucleus rate did not show a statistically significant increase, and no dose-dependent relationship was observed, indicating that neither compound 1 nor compound 2 exhibits potential genotoxicity.

[0226] Example 9: Bacterial Reverse Mutation Test Principle: Bacterial reverse mutation tests detect point mutations using amino acid-requiring Salmonella typhimurium and Escherichia coli strains. Such mutations involve the substitution, addition, or deletion of one or more DNA base pairs. The principle of such bacterial reverse mutation tests is that the detected reverse mutation is present in the test strain, restoring the bacterium's ability to synthesize essential amino acids. Reverse transcription bacteria are detected by their ability to grow when the parent test strain lacks the necessary amino acids.

[0227] The testing process is as follows:

[0228] The samples were dissolved in DMSO at concentrations of 5 mg / petri dish, 2.5 mg / petri dish, 1.6 mg / petri dish, 0.8 mg / petri dish, and 0.4 mg / petri dish, filtered, and prepared for use. Strains of Salmonella typhimurium TA97a, TA98, TA100, and TA102 were selected. An appropriate amount of nutrient broth medium was placed in a test tube, the strains obtained from the master plate were inoculated into the nutrient broth medium, and the culture was incubated with shaking at 37°C and 150 rpm for 10 hours. The number of viable cells per 1 mL of culture medium was 1 × 10⁶. 9 The level exceeds / mL, and then OD (Oral Discharge) 650 We measured it.

[0229] Lower and upper agar layers were prepared. 0.1 mL of fresh bacterial suspension of the test strain, the test substance (the specific amount of test substance to be added was determined according to the set concentration of the test substance), and 0.5 mL of 10% S9 mixture were added to 2 mL of the upper agar layer, which had been kept warm. After shaking to ensure uniform mixing, the mixture was quickly poured into the lower agar layer, the petri dish was rotated to uniformly distribute the upper agar layer into the lower agar layer, and the mixture was flattened and allowed to solidify. The test concentrations of the test substance were 5 mg / petri dish, 2.5 mg / petri dish, 1.6 mg / petri dish, 0.8 mg / petri dish, and 0.4 mg / petri dish, with three parallel tests set up for each concentration. Simultaneously, a positive control group, a solvent control group, and a blank control group were established, with three parallel tests set up for each group. The solidified plates were placed in an incubator and incubated at 37°C for 48 hours. The results were observed, and the number of colonies was recorded.

[0230] Criteria for evaluating results: (1) Determination of positive results: The number of reverse mutation colonies grown on the culture medium is directly counted. Under conditions of good background growth, the number of reverse mutation colonies of TA97a, TA98, TA100, and TA102 of the test specimen should increase by at least one time in at least one or more strains (i.e., the number of reverse mutation colonies should be at least twice that of the solvent control group), and a dose-response relationship is present. If this relationship is present, the mutagenesis test of the test specimen is considered positive. If a significant difference in the number of reverse mutation colonies is observed at at least one concentration of the test specimen in at least one or more strains, but a dose-response relationship is not present, the data is reproducible, and the test specimen shows a statistically significant positive reaction, the mutagenesis test of the test specimen is considered positive.

[0231] (2) Determination of negative results: If the results do not match any of the positive reactions described above, and regardless of the bacterial strain or the presence or absence of the S9 activation system, the number of reverse mutant colonies of the test substance does not increase significantly compared to spontaneous reverse mutations at all test substance concentrations, and no dose-response relationship is observed, then the mutagenesis test of the test substance is considered negative. Under these experimental conditions, the test substance does not induce gene mutations in the test strain.

[0232] Experimental conclusions: Compound 1 and Compound 2 were dissolved in DMSO at concentrations of 5 mg / petri dish, 2.5 mg / petri dish, 1.6 mg / petri dish, 0.8 mg / petri dish, and 0.4 mg / petri dish, respectively. The filtered samples were detected using standard bacterial strains TA97a, TA98, TA100, and TA102 and showed no potential genotoxicity.

[0233] Example 10: Detection of skin phototoxicity Adult albino guinea pigs were selected, with an equal number of males and females. Six animals were used in the formal test. Before the test, the animals were allowed to acclimate to the laboratory environment for three days. 24 hours before the formal phototoxicity test, the hair on the skin of both sides of the animals' spine was removed, ensuring that the skin at the test site was intact and free from damage or abnormalities. In accordance with Figure 1 on page 501 of the Chinese "Technical Standards for Cosmetic Safety" (2015 edition) (hereinafter referred to as the Standards), four hair removal areas (Figure 67) were prepared, with each area measuring approximately 2 cm x 2 cm.

[0234] The animals were fixed, and 0.2 mL of the sample was applied to depilation areas 1 and 2 of the animals as shown in Table 1 of P501 in the standard. After 30 minutes, the left side (depilation areas 1 and 3) was covered with aluminum foil and secured with tape, and the right side (depilation areas 2 and 4) was irradiated with UVA. The average light intensity was approximately 7.011 mW / cm². 2 The radiation dose is 10 J / cm². 2 The duration was 1426 seconds. After completion, skin reactions were observed at 1 hour, 24 hours, 48 ​​hours, and 72 hours, respectively, and the skin reaction score for each animal was determined based on Table 2 of P501-P502 in the guidelines. If no skin reaction occurred in the area where only the sample was applied and not irradiated, and if one or more animals had a total skin reaction score of 2 or higher in the area where the sample was applied and then irradiated, the sample was judged to be phototoxic.

[0235] Experimental conclusion: In phototoxicity tests using guinea pigs, compounds 1 and 2 did not exhibit skin phototoxicity.

[0236] The technical features of the embodiments described above can be combined in any way, and for the sake of brevity, not all possible combinations of the technical features in the embodiments described above have been described. However, as long as these combinations of technical features are inconsistent, they should be considered to fall within the scope described herein.

[0237] The above examples describe only a few embodiments of the present application, and although these descriptions are specific and detailed, they should not be interpreted as limiting the scope of the patent of this application. Furthermore, a person skilled in the art may make various modifications and improvements as long as they do not deviate from the spirit of this application, and both such modifications and improvements fall within the scope of protection of this application. Therefore, the scope of protection of the patent of this application should be based on the attached claims.

Claims

1. The application of the compound represented by formula I is as follows: 【Chemistry 1】 Each R １ , each R ２ and each R ３ Each of these is independently one or more combinations selected from the group consisting of hydrogen, hydroxyl group, halogen, phenyl group, halogenated methoxy group, methylamino group, methyl group, 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 Each of these is independently selected from the group consisting of hydrogen, a methyl group, and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms, and is one or more of these combinations. m, n, and k are each independent integers between 1 and 3. The aforementioned applications include applications in one or more of the following: the manufacture of tyrosinase inhibitors, the manufacture of α-glucosidase inhibitors, the manufacture of pharmaceuticals for the treatment of diabetes, the manufacture of skin whitening products, the manufacture of anti-oxidative skin products, the manufacture of anti-aging products, the manufacture of skin care products that reduce melanin production, the manufacture of pharmaceuticals for the treatment of skin diseases that reduce melanin production, the manufacture of skin care products that prevent pigmentation disorders, the manufacture of pharmaceuticals for the treatment of skin diseases that prevent pigmentation disorders, the manufacture of skin care products that treat pigmentation disorders, the manufacture of pharmaceuticals for the treatment of skin diseases that treat pigmentation disorders, and the inhibition of browning of food.

2. Each R １ and each R ３ At least one of which is a hydroxy group, the application according to claim 1.

3. Each R １ At least one of them is a hydroxyl group, and each R ３ The application according to any one of claims 1 to 2, wherein at least one of them is a hydroxyl group.

4. The compound represented by the above formula I is 【Chemistry 2】 and 【Transformation 3】 One or more types selected from the group consisting of the following structures: The application described in any one of claims 1 to 3 includes applications in one or more of the following: the manufacture of α-glucosidase inhibitors, the manufacture of pharmaceuticals for the treatment of diabetes, the manufacture of anti-oxidative skin products, the manufacture of anti-aging products, the manufacture of skincare products that reduce melanin production, the manufacture of pharmaceuticals for the treatment of skin diseases that reduce melanin production, the manufacture of skincare products that prevent pigmentation disorders, the manufacture of pharmaceuticals for the treatment of skin diseases that prevent pigmentation disorders, the manufacture of skincare products that treat pigmentation disorders, and the manufacture of pharmaceuticals for the treatment of skin diseases that treat pigmentation disorders.

5. The compound represented by the above formula I is 【Chemistry 4】 An application according to any one of claims 1 to 4, wherein the application is selected from and the application includes an application in the production of a tyrosinase inhibitor.

6. The compound represented by the above formula I is 【Transformation 5】 An application according to any one of claims 1 to 3, selected from the above, wherein the application includes one or more applications among the production of tyrosinase inhibitors, α-glucosidase inhibitors, pharmaceuticals for the treatment of diabetes, anti-oxidative skin products, anti-aging products, skincare products that reduce melanin production, pharmaceuticals for the treatment of skin diseases that reduce melanin production, skincare products that prevent pigmentation disorders, pharmaceuticals for the treatment of skin diseases that prevent pigmentation disorders, skincare products that treat pigmentation disorders, and pharmaceuticals for the treatment of skin diseases that treat pigmentation disorders.

7. The application according to any one of claims 1 to 6, wherein the pigmentation disorder is one or more selected from the group consisting of freckles, brown spots, stretch marks, senile lentigines, and malignant melanoma.

8. The use according to any one of claims 1 to 7, wherein the anti-skin oxidation and anti-aging referred to the scavenging of reactive oxygen free radicals within cells.

9. A 1,3-bisbenzylphenol compound, wherein its structural formula is one or more selected from the group consisting of the structural formulas of compound 2 and compound 3 below. 【Transformation 6】

10. A method for producing a 1,3-bisbenzylphenol compound according to claim 9, the method comprising the steps of: mixing raw material A selected from 1,3-bis(bromomethyl)benzene, 1,3-bis(chloromethyl)benzene and combinations thereof, and raw material B selected from o-cresol, 1,2-benzenediphenol and combinations thereof in a molar ratio of 1:(5 to 10); reacting the mixture by heating it at 100 to 120°C for a certain period of time under the protection of nitrogen gas with aluminum trichloride as a catalyst; and further purifying it by column chromatography.

11. A composition having one or more effects among whitening, anti-skin oxidation, anti-aging, and inhibition of browning of food, the composition comprising a compound represented by formula I and a carrier, the compound represented by formula I being as follows: 【Transformation 7】 Each R １ , each R ２ and each R ３ Each of these is independently one or more combinations selected from the group consisting of hydrogen, hydroxyl group, halogen, phenyl group, halogenated methoxy group, methylamino group, methyl group, 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 Each of these is independently selected from the group consisting of hydrogen, a methyl group, and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms, and is one or more of these combinations. m, n, and k are each independent integers between 1 and 3. The aforementioned carrier is a composition selected from one or more carriers permitted in the fields of cosmetics, pharmaceuticals, food, and combinations thereof.

12. Each R １ and each R ３ The composition according to claim 11, wherein at least one of them is a hydroxyl group.

13. Each R １ At least one of them is a hydroxyl group, and each R ３ The composition according to any one of claims 11 to 12, wherein at least one of them is a hydroxyl group.

14. The compound represented by the above formula I is 【Transformation 8】 and 【Chemistry 9】 The composition according to any one of claims 11 to 13, which is one or more selected from the group consisting of the following structures.

15. The composition has at least one of the following effects: whitening, anti-oxidation of skin, and anti-aging, and contains an effective amount of compound 1 as an active ingredient. 【Chemistry 10】 , compound 2 【Chemistry 11】 , compound 3 【Chemistry 12】 The composition according to any one of claims 11 to 14, comprising at least one of the above and one or more carriers permitted in the field of cosmetics.

16. The composition according to claim 15, wherein "whitening" refers to one or more of the following: inhibition of tyrosinase activity, inhibition of α-glucosidase activity, inhibition of cellular melanin production, and inhibition of pigmentation disorders, and "anti-skin oxidation and anti-aging" refers to the scavenging of reactive oxygen free radicals within cells.

17. The composition according to claim 16, wherein the pigmentation disorder is one or more selected from the group consisting of freckles, brown spots, stretch marks, senile lentigines, and malignant melanoma.

18. The composition according to any one of claims 11 to 17, wherein the composition is one or more selected from the group consisting of tyrosinase inhibitor compositions and α-glucosidase inhibitor compositions.

19. The composition according to any one of claims 11 to 18, wherein the carrier comprises one or more of the following: an essence, a compound for skin care, a compound for skin cleansing, and an ultraviolet absorber.

20. The composition according to claim 19, comprising an essence and a compound represented by formula I, wherein the essence is present in an amount that effectively provides a sensory effect, and the compound represented by formula I is present in an amount that has one or two of the following effects: tyrosinase inhibitory activity and α-glucosidase inhibitory activity.

21. The composition according to claim 20, wherein the compound represented by formula I is present in a mass percentage of about 3% to about 30%.

22. The composition according to claim 19, comprising an ultraviolet absorber and a compound represented by formula I, wherein the amount of the ultraviolet absorber effectively provides ultraviolet protection with a protection factor of at least 2, and the amount of the compound represented by formula I has one or two of the following effects: tyrosinase inhibitory activity and α-glucosidase inhibitory activity.

23. The composition according to claim 19, comprising one or more compounds selected from those for skin care and those for skin cleansing, and a compound represented by formula I, wherein the amount of the compound represented by formula I has one or two of the following effects: tyrosinase inhibitory activity and α-glucosidase inhibitory activity.

24. Application of the composition according to any one of claims 11 to 23 in the manufacture of a whitening skincare product, a pharmaceutical for treating whitening skin diseases, an anti-aging skincare product, a pharmaceutical for treating anti-aging skin diseases, and combinations thereof.

25. The composition is one selected from the group consisting of skincare product compositions and pharmaceutical compositions for treating skin diseases, and the composition contains an effective amount of compound 1 as an active ingredient. 【Chemistry 13】 , compound 2 【Chemistry 14】 , and compound 3 【Chemistry 15】 The application according to claim 24, which includes one or more of the above.

26. The application according to claim 25, wherein "whitening" refers to one or more of the following: inhibition of tyrosinase activity, inhibition of α-glucosidase activity, inhibition of cellular melanin production, and inhibition of pigmentation disorders, and "anti-skin oxidation and anti-aging" refers to the scavenging of reactive oxygen free radicals within cells.

27. The application according to claim 26, wherein the pigmentation disorder is one or more selected from the group consisting of freckles, brown spots, stretch marks, senile lentigines, and malignant melanoma.

28. A product, wherein the product is one of cosmetics and pharmaceuticals for the treatment of skin diseases, and the product comprises a composition according to any one of claims 11 to 23, or a compound represented by formula I. 【Chemistry 16】 Each R １ , each R ２ and each R ３ Each of these is independently one or more combinations selected from the group consisting of hydrogen, hydroxyl group, halogen, phenyl group, halogenated methoxy group, methylamino group, methyl group, 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 Each of these is independently selected from the group consisting of hydrogen, a methyl group, and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms, and is one or more of these combinations. A product in which m, n, and k are each an integer between 1 and 3, independently of each other.

29. The product according to claim 28, wherein the mass percentage of the compound represented by formula I in the product is 0.0001% to 10%.

30. The product according to claim 29, wherein the mass percentage of the compound represented by formula I in the product is 0.01% to 2%.

31. The product according to claim 30, wherein the mass percentage of the compound represented by formula I in the product is 0.1% to 1%.

32. A pharmaceutical composition for the treatment of diabetes, comprising an effective amount of a compound as an active ingredient and a carrier, wherein the effective amount of the compound as an active ingredient is one or more compounds selected from the group consisting of compounds represented by formula I, and the compounds represented by formula I are as follows: 【Chemistry 17】 Each R １ , each R ２ and each R ３ Each of these is independently one or more combinations selected from the group consisting of hydrogen, hydroxyl group, halogen, phenyl group, halogenated methoxy group, methylamino group, methyl group, 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 Each of these is independently selected from the group consisting of hydrogen, a methyl group, and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms, and is one or more of these combinations. m, n, and k are each independent integers between 1 and 3. The aforementioned carrier is selected from one or more carriers permitted in the field of pharmacy, and is a pharmaceutical composition for the treatment of diabetes.

33. The compound used in an effective amount as the active ingredient is compound 1 [Chemistry 18] , compound 2 【Chemistry 19】 , and compound 3 【Chemistry 20】 The pharmaceutical composition for treating diabetes according to claim 32, which is one or more selected from the group consisting of the following.

34. Application of the pharmaceutical composition according to any one of claims 32 to 33 in the manufacture of a pharmaceutical for the treatment of diabetes.

35. The amount of compound used as an active ingredient is compound 1. 【Chemistry 21】 , compound 2 【Chemistry 22】 , and compound 3 【Chemistry 23】 The application according to claim 34, which is one or more selected from the group consisting of the above.

36. A pharmaceutical preparation comprising one or more compounds for treating diabetes and one or more compounds represented by formula I in an amount having α-glucosidase inhibitory activity, wherein the compounds represented by formula I are as follows: 【Chemistry 24】 Each R １ , each R ２ and each R ３ Each of these is independently one or more combinations selected from the group consisting of hydrogen, hydroxyl group, halogen, phenyl group, halogenated methoxy group, methylamino group, methyl group, 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 Each of these is independently selected from the group consisting of hydrogen, a methyl group, and a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 5 carbon atoms, and is one or more of these combinations. A pharmaceutical preparation in which m, n, and k are each independently integers between 1 and 3.

37. Each R １ and each R ３ The pharmaceutical preparation according to claim 36, wherein at least one of them is a hydroxyl group.

38. Each R １ At least one of them is a hydroxyl group, and each R ３ A pharmaceutical preparation according to any one of claims 36 to 37, wherein at least one of them is a hydroxyl group.

39. The compound represented by the above formula I is 【Chemistry 25】 and 【Chemistry 26】 A pharmaceutical preparation according to any one of claims 36 to 38, which is one or more selected from the group consisting of the following structures.

40. A method for whitening human skin and treating age spots on human skin, comprising the step of administering an effective amount of the composition according to any one of claims 11 to 23, or the product according to any one of claims 28 to 31, to a person in need.

41. A method for inhibiting browning of food, comprising the step of administering an effective amount of the composition described in any one of claims 11 to 23 to food.

42. A method for treating diabetes, comprising the step of administering an effective amount of a pharmaceutical composition according to any one of claims 32 to 33, or a pharmaceutical preparation according to any one of claims 36 to 39, to a person in need.

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