WO2023151291A1

WO2023151291A1 - 1,3-disubstituted indole derivative as hyaluronidase inhibitor and use thereof in cosmetic product

Info

Publication number: WO2023151291A1
Application number: PCT/CN2022/123989
Authority: WO
Inventors: 姜燕飞
Original assignee: 北京青颜博识健康管理有限公司
Priority date: 2022-02-11
Filing date: 2022-10-09
Publication date: 2023-08-17
Also published as: CN114478354B; CN114478354A

Abstract

Disclosed in the present invention are a 1,3-disubstituted indole derivative, and a preparation method therefor and the use thereof as a hyaluronidase inhibitor and in the preparation of an anti-aging cosmetic product. Specifically, disclosed in the present invention is the preparation of a class of 1,3-disubstituted indole derivatives. In-vitro activity test detection shows that the 1,3-disubstituted indole derivatives have strong hyaluronidase inhibition activity, and IC₅₀ is about 1-10 μg/mL. In addition, the 1,3-disubstituted indole derivatives have very low cytotoxicity and strong fat solubility, are easily absorbed by skin tissues, and can be used as an anti-aging component for the preparation of a cosmetic product. Further disclosed in the present invention is the use of the 1,3-disubstituted indole derivatives as a cosmetic component in the preparation of an anti-skin aging facial mask.

Description

1,3-Disubstituted indole derivatives as hyaluronidase inhibitors and their use in cosmetic products

Cross References to Related Applications

This application claims the benefit of Chinese application number 202210130214.5 filed on February 11, 2022. Said application number 202210130214.5 is hereby incorporated herein by reference in its entirety.

technical field

The invention relates to a class of 1,3-disubstituted indole derivatives and a preparation method thereof, as well as its inhibitory effect on hyaluronidase and its use in making cosmetic products, belonging to the field of cosmetics.

Background technique

Hyaluronidase is the key enzyme for degrading hyaluronic acid. Hyaluronidase catalyzes the reaction of hyaluronic acid degradation to form monosaccharides by cleaving the glycosidic bond of hyaluronic acid. Hyaluronidases can be classified into different types according to their origin and mechanism of action. According to the mechanism of action of hyaluronidase, it is divided into three categories: the first category is mainly derived from mammals, which is endo-β-N-acetylglucosaminidase, which acts on β-1,4-glucosidic bonds Form tetrasaccharides; the second type is mainly derived from bacteria, which is endo-β-N-acetylglucosaminidase, which acts on β-1,4-glucosidic bonds to obtain 4,5-unsaturated disaccharides through β-elimination mechanism Sugar; the third type is mainly derived from leech, which is endo-β-glucuronidase, which acts on β-1,3-glucosidic bonds. Hyaluronic acid is one of the main components of the extracellular matrix (ECM) system of the skin. It is a three-dimensional network with important physiological functions such as maintaining skin structure and retaining water molecules. Published dermatological studies suggest that abnormal overactivity of hyaluronidase may lead to increased degradation of epidermal hyaluronic acid in the skin, a histochemical hallmark of aging skin. Hyaluronan-hyaluronidase homeostasis is a key factor mediating various physiological events associated with skin aging, including ECM structural integrity, wrinkle formation, and skin hydration. Therefore, hyaluronidase inhibitors are considered as promising cosmeceuticals with potential anti-aging effects on the skin, thus attracting considerable research interest.

So far, most of the hyaluronidase inhibitors reported are natural products and their analogs. There are relatively few synthetic hyaluronidase small molecule inhibitors reported so far. Several synthetic indole, benzoxazole and benzimidazole derivatives have been reported to have some hyaluronidase inhibitory activity (Fig. 1), but their inhibitory activity basically remained at _IC50 of tens of micromolar. Such compounds are rationally modified to improve their inhibition of hyaluronidase, and the indole compounds that enhance the inhibitory activity of hyaluronidase can be used to prepare cosmetics and serve as active ingredients for anti-aging skin.

Contents of the invention

In view of the literature reports that some indole, benzoxazole and benzimidazole compounds have weak hyaluronidase inhibitory activity (Figure 1), using indole as the core, optimize its structure to enhance the activity of its derivatives Inhibitory activity against hyaluronidase. The main purpose of the present invention is to provide a class of 1,3-disubstituted indole derivatives and its preparation method and application. The present invention develops a class of 1,3-disubstituted indole derivatives, which have significantly enhanced hyaluronidase inhibitory activity and can be used to develop anti-aging cosmetic products.

In order to achieve this purpose, the present invention includes the following technical solutions:

In the first aspect, the present invention provides a 1,3-disubstituted indole compound, the structure of which is shown in general formula (I):

Wherein, R _a , R _b , R _c , R _d , Re _are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, methoxy, trifluoromethyloxy, formylamino, methyl Sulfonyl, isopropylsulfonyl, mesylate, isopropylsulfonate, trifluoromethyl, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl.

The above C _1-8 means that the number of carbon atoms in the substituent is 1, 2, 3, 4, 5, 6, 7, or 8; C _2-8 means that the number of carbon atoms in the substituent 2, 3, 4, 5, 6, 7, 8.

The 1,3-disubstituted indole compound involved in the present invention is a class of compounds with a new structure, and has significantly enhanced hyaluronidase inhibitory activity compared with oleanolic acid in vitro. Therefore, it can be used to prepare anti-aging cosmetics.

Preferably, in general formula (I), R _a , R _b , R _c , R _d , Re _are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, trifluoromethyl, C _1-4 alkyl , C _2-4 alkenyl.

The above C _1-4 means that the number of carbon atoms in the substituent is 1, 2, 3, or 4; C _2-4 means that the number of carbon atoms in the substituent is 2, 3, or 4.

Further preferably, the 1,3-disubstituted indole compound is selected from the following compound structures:

In the second aspect, the present invention provides a compound composition, which comprises the 1,3-disubstituted indole compound as described in the first aspect above, its stereoisomers, and its chemically acceptable One or more indole salts; Preferably, the compound composition also includes cosmetically acceptable excipients, such as carriers, diluents, excipients, fillers, binders, wetting agents, disintegrating agents Agents, emulsifiers, co-solvents, solubilizers, osmotic pressure regulators, surfactants, colorants, pH regulators, antioxidants, bacteriostats or buffers, etc.

The chemically acceptable salt of the 1,3-disubstituted indole compound involved in the present invention is a salt formed by a 1,3-disubstituted indole compound and a base selected from the following: acceptable organic bases include diethanolamine , ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like; acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

In a third aspect, the present invention provides a method for preparing 1,3-disubstituted indole compounds:

Mix an equal amount of 3-((1,1'-biphenyl)-4-thio)-indole, AlMe ₃ for 1 h, add various isocyanates, such as

After reacting for 16h, it is obtained; wherein the limited ranges of the substituents R _a , R _b , R _c , R _d , and _Re are consistent with those defined in the first aspect;

Its reaction formula is as follows:

Preferably, the preparation method of 3-((1,1'-biphenyl)-4-thio)-indole compound is as follows:

Mix indole, thiol, and TBHP in a cyanide solvent, then add _I2 as a catalyst, and continue the reaction at room temperature to obtain the intermediate 3-((1,1'-biphenyl)-4-thio)-indole ,

Its reaction formula is as follows:

In the fourth aspect, the present invention provides a 1,3-disubstituted indole compound as described in the first aspect, or the indole compound composition as described in the second aspect is prepared by inhibiting the activity of hyaluronidase Use in cosmetics to delay skin aging.

In the fifth aspect, the present invention provides an anti-aging skin mask, the mask comprises the compound as described in the first aspect or the compound composition as described in the second aspect, and the formula and parts by weight of the mask are as follows:

Phase A: 92.68 parts of water, 2 parts of 1,2-butanediol, 0.1 part of methylparaben, 0.16 part of carbomer, 0.05 part of hydroxyethyl cellulose, 0.03 part of disodium EDTA, 0.05 part of sodium hyaluronate , 0.4 parts of 1,2-hexanediol, 0.1 parts of panthenol;

Phase B: 3 parts of water, 0.12 parts of triethanolamine;

Phase C: 0.1 part of the compound as described in the first aspect or the compound composition as described in the second aspect, 1 part of ethanol, and 0.1 part of phenoxyethanol

Phase D: (daily use) essence 0.01 part, PEG-40 hydrogenated castor oil 0.1 part

Description of drawings

Figure 1. Reported synthetic hyaluronidase-like small molecule inhibitors.

Detailed ways

The technical solutions of the present invention will be further described below through specific embodiments. It should be clear to those skilled in the art that the examples are only for helping to understand the present invention, and should not be regarded as specific limitations on the present invention. For all of the following examples or preparations, standard manipulations and purification methods known to those skilled in the art can be used. Unless otherwise indicated, all temperatures are in °C (Celsius) and the structures of compounds were determined by nuclear magnetic resonance spectroscopy (NMR) and/or mass spectroscopy (MS).

For all of the following examples or preparations, the structures of the compounds were determined by proton nuclear magnetic resonance spectroscopy (1H NMR) or mass spectroscopy (MS). Proton NMR shifts (δ) are given in parts per million (ppm). NMR spectrum is measured with Mercury-400 type NMR instrument, deuterated chloroform (CDCl3) is made solvent, tetramethylsilane (TMS) or 3-(trimethylsilyl) deuterated sodium propionate (TSM) is internal standard .

The electronic balance adopts the Japanese Yanaco LY-300 electronic balance.

Column chromatography uses 200-300 mesh or 300-400 mesh silica gel as the carrier.

Anhydrous solvents were all worked up by standard methods. Other reagents were commercially available analytical grades were purchased from Sigma-Aldrich Sigma Aldrich (Shanghai) Trading Co., Ltd., Beijing Yinuokai Technology Co., Ltd., Alfa Aisha (China) Chemical Co., Ltd., Shanghai Aladdin Biochemical Technology Co., Ltd. Ltd.

Preparation 1: 3-((1,1'-biphenyl)-4-thio)-indole

This preparation example prepares 3-((1,1'-biphenyl)-4-thio)-indole, and the synthetic route is:

Indole (0.5 mmol), thiol (0.505 mmol) and TBHP (0.51 mmol) were mixed and dissolved in MeCN (2.0 mL), and heated to 60° C. with stirring. Iodine (0.10 mmol, 10 mol%) was then added to the reaction solution. The reaction was stirred at room temperature for 1 hour until complete consumption of starting material as monitored by TLC. The reaction _was quenched by _adding saturated _Na2S2O3 . Then extracted with EtOAc, the combined organic layers were separated, dried over MgSO ₄ , filtered and concentrated in vacuo, the crude product was purified by column chromatography using petroleum ether/ethyl acetate as eluent to give 3-((1,1'- Biphenyl)-4-thio)-indole, white solid pure product 91.5 mg (61%). The product was characterized as follows: ¹ H NMR (400MHz, CDCl ₃ ): δ.d 8.98(br s,1H),7.79(d,J=8.0Hz,1H),7.64-7.54(m,1H),7.55- 7.41(m,6H),7.38-7.28(m,4H),7.06-7.02(m,1H),6.92-6.84(m,1H);HR-MS(ESI):[M+H]+C20H15NS calculated value 301.4070, the measured value is 301.4021.

Example 1: This example prepares 3-([1,1'-biphenyl]-4-sulfanyl)-N-(phenyl-carboxamido)-indole , whose structural formula is as follows:

At 0°C, 3 mL, 6.0 mmol of AlMe ₃ (2M in toluene) was added dropwise to a solution containing 3-((1,1'-biphenyl)-4-thio)-indole (600 mg, 2.0 mmol) Anhydrous toluene (6 mL). Toluene isocyanate (577 mg, 2.2 mmol) was slowly added thereto. The reaction was continued for 4 hours with TLC monitoring, then quenched with saturated NaHCO ₃ solution (8 mL), and the product was purified by column chromatography to give compound 302 mg (36%) as a white solid. The product was characterized as follows: ¹ H NMR (400MHz, CDCl ₃ ): δ9.97(br s, 1H), 7.79(d, J=5.0Hz, 1H), 7.65(m, 1H), 7.63-7.41(m ,8H),7.38-7.12(m,7H),7.09-7.05(m, 1H),7.03-6.95(m,1H); HR-MS(ESI):[M+H]+C27H21N2OS calculated value 421.5380, measured Value 421.5361.

Example 2: This example prepares 3-([1,1'-biphenyl]-4-sulfanyl)-N-([3-fluoro-phenyl]-formyl Amino)-indole, its structural formula is as follows:

At 0°C, 3 mL, 6.0 mmol of AlMe ₃ (2M in toluene) was added dropwise to a solution containing 3-((1,1'-biphenyl)-4-thio)-indole (600 mg, 2.0 mmol) Anhydrous toluene (6 mL). 3-Fluorophenylisocyanate (301 mg, 2.2 mmol) was slowly added thereto. The reaction was continued for 4 hours with TLC monitoring, then quenched with saturated NaHCO ₃ solution (8 mL), and the product was purified by column chromatography to give compound 302 mg (36%) as a white solid. The product was characterized as follows: ¹ H NMR (400MHz, CDCl ₃ ): δ9.97(br s, 1H), 7.78(d, J=5.0Hz, 1H), 7.66(m, 1H), 7.61-7.43(m ,8H),7.38-7.12(m,6H),7.09-7.05(m,1H),7.03-6.94(m,1H); HR-MS(ESI): [M+H]+C27H20FN2OS calculated value 439.5284, measured Value 439.5236.

Example 3: This example prepares 3-([1,1'-biphenyl]-4-sulfanyl)-N-([3,4-difluoro-phenyl]- Formamido)-indole, its structural formula is as follows:

At 0°C, 3 mL, 6.0 mmol of AlMe ₃ (2M in toluene) was added dropwise to a solution containing 3-((1,1'-biphenyl)-4-thio)-indole (600 mg, 2.0 mmol) Anhydrous toluene (6 mL). 3,4-Difluorophenylisocyanate (341 mg, 2.2 mmol) was slowly added thereto. The reaction was continued for 4 hours with TLC monitoring, then quenched with saturated NaHCO ₃ solution (8 mL), and the product was purified by column chromatography to give compound 255 mg (28%) as a white solid. The product was characterized as follows: ¹ H NMR (400MHz, CDCl ₃ ): δ9.97(br s, 1H), 7.78(d, J=5.0Hz, 1H), 7.66(m, 1H), 7.60-7.44(m ,8H), 7.40-7.11(m,5H), 7.09-7.05(m,1H), 7.03-6.94(m,1H); HR-MS(ESI): [M+H]+C27H20FN2OS calculated value 439.5284, measured Value 439.5236.

Example 4: This example prepares 3-([1,1'-biphenyl]-4-sulfanyl)-N-([3-chloro, 4-fluoro-phenyl]- Formamido)-indole, its structural formula is as follows:

At 0°C, 3 mL, 6.0 mmol of AlMe ₃ (2M in toluene) was added dropwise to a solution containing 3-((1,1'-biphenyl)-4-thio)-indole (600 mg, 2.0 mmol) Anhydrous toluene (6 mL). 3-Chloro,4-fluorophenylisocyanate (376 mg, 2.2 mmol) was slowly added thereto. The reaction was continued for 4 hours and monitored by TLC, then quenched with saturated NaHCO ₃ solution (8 mL), and the product was purified by column chromatography to give compound 236 mg (25%) as a white solid. The product was characterized as follows: ¹ H NMR (400MHz, CDCl ₃ ): δ9.97(br s, 1H), 7.78(d, J=5.0Hz, 1H), 7.66(m, 1H), 7.60-7.46(m ,8H), 7.42-7.11(m,5H), 7.09-7.05(m,1H), 7.03-6.96(m,1H); HR-MS(ESI): [M+H]+C27H19ClFN2OS calculated value 473.9703, measured Value 473.9725.

Example 5: This example prepares 3-([1,1'-biphenyl]-4-sulfanyl)-N-([3-trifluoromethyl-phenyl]- Formamido)-indole, its structural formula is as follows:

At 0°C, 3 mL, 6.0 mmol of AlMe ₃ (2M in toluene) was added dropwise to a solution containing 3-((1,1'-biphenyl)-4-thio)-indole (600 mg, 2.0 mmol) Anhydrous toluene (6 mL). 3-Trifluoromethylphenylisocyanate (411 mg, 2.2 mmol) was slowly added thereto. The reaction was continued for 4 hours with TLC monitoring, then quenched with saturated NaHCO ₃ solution (8 mL), and the product was purified by column chromatography to give compound 370 mg (38%) as a white solid. The product was characterized as follows: ¹ H NMR (400MHz, CDCl ₃ ): δ9.97(br s, 1H), 7.78(d, J=5.0Hz, 1H), 7.69(m, 1H), 7.64-7.43(m ,8H),7.38-7.10(m,6H),7.09-7.05(m,1H),7.03-6.96(m,1H); HR-MS(ESI): [M+H]+C27H20FN2OS calculated value 489.1248, measured Value 489.1259.

Example 6: This example prepares 3-([1,1'-biphenyl]-4-sulfanyl)-N-([3-methyl-phenyl]-methanol Amido)-indole, its structural formula is as follows:

At 0°C, 3 mL, 6.0 mmol of AlMe ₃ (2M in toluene) was added dropwise to a solution containing 3-((1,1'-biphenyl)-4-thio)-indole (600 mg, 2.0 mmol) Anhydrous toluene (6 mL). 3-Methylphenylisocyanate (292 mg, 2.2 mmol) was slowly added thereto. The reaction was continued for 4 hours with monitoring by TLC, then quenched with saturated NaHCO ₃ solution (8 mL), and the product was purified by column chromatography to give compound 234 mg (27%) as a white solid. The product was characterized as follows: ¹ H NMR (400MHz, CDCl ₃ ): δ9.97(br s, 1H), 7.75(d, J=5.0Hz, 1H), 7.64(m, 1H), 7.56-7.39(m ,8H),7.27-7.09(m,6H),7.05-7.01(m,1H),6.95-6.89(m,1H),2.29(s,3H); HR-MS(ESI):[M+H] The calculated value of +C28H23N2OS is 435.5650, and the measured value is 435.5621.

Example 7: This example prepares 3-([1,1'-biphenyl]-4-sulfanyl)-N-([3,4-dimethyl-phenyl]- Formamido)-indole, its structural formula is as follows:

At 0°C, 3 mL, 6.0 mmol of AlMe ₃ (2M in toluene) was added dropwise to a solution containing 3-((1,1'-biphenyl)-4-thio)-indole (600 mg, 2.0 mmol) Anhydrous toluene (6 mL). 3,5-Dimethylphenylisocyanate (323 mg, 2.2 mmol) was slowly added thereto. The reaction was continued for 4 hours with TLC monitoring, then quenched with saturated NaHCO ₃ solution (8 mL), and the product was purified by column chromatography to give compound 179 mg (20%) as a white solid. The product was characterized as follows: ¹ H NMR (400MHz, CDCl ₃ ): δ9.97(br s, 1H), 7.75(d, J=5.0Hz, 1H), 7.64(m, 1H), 7.59-7.32(m ,6H),7.29-7.09(m,7H),7.05-7.01(m,1H),6.95-6.89(m,1H),2.29(s,6H); HR-MS(ESI):[M+H] The calculated value of +C29H25N2OS is 449.5920, and the measured value is 449.5965.

Example 8: This example prepares 3-([1,1'-biphenyl]-4-sulfanyl)-N-([4-tert-butyl-phenyl]- Formamido)-indole, its structural formula is as follows:

At 0°C, 3mL, 6.0mmol of AlMe3 (2M in toluene) was added dropwise to a solution containing 3-((1,1'-biphenyl)-4-thio)-indole (600mg, 2.0mmol) water toluene (6 mL). Thereto was slowly added 4-(tert-butyl)phenylisocyanate (385 mg, 2.2 mmol). The reaction was continued for 4 hours with monitoring by TLC, then quenched with saturated NaHCO ₃ solution (8 mL), and the product was purified by column chromatography to give compound 233 mg (26%) as a white solid. The product was characterized as follows: ¹ H NMR (400MHz, CDCl ₃ ): δ9.98(br s, 1H), 7.79(d, J=5.0Hz, 1H), 7.65(m, 1H), 7.63-7.41(m ,8H),7.34-7.11(m,6H),7.07-7.01(m,1H),6.95-6.84(m,1H),2.28(s,9H); HR-MS(ESI):[M+H] The calculated value of +C31H29N2OS is 477.6460, and the measured value is 477.6453.

Example 9: Screening test for hyaluronidase inhibitory activity

Experimental method: Hyaluronidase is derived from bovine testes, and the hyaluronidase inhibitory activity is screened for references (Molecules, 2020; 25:1923). It is worth noting that under low negative ion conditions, long-chain hyaluronic acid and hyaluronidase tend to form inactive complexes, which will hinder the catalytic activity of hyaluronidase and interfere with the screening assay for hyaluronidase inhibitory activity. Therefore, it should be avoided to add too much positively charged protein to interfere with the negative ion concentration in the buffer system, which will restore the activity of hyaluronidase. In a specific test, bovine serum albumin was added to 20 mM PBS, pH 3.75, to a final concentration of 0.01%, which was a prepared reaction buffer. Mix 5 μL of the sample (with a concentration range of 1-400 μg/mL) and 95 μL of the reaction solution containing hyaluronidase (7.5 U/mL), and incubate at 37°C for 10 minutes. Then 100 μL of hyaluronic acid was added to the above reaction solution, and incubated at 37° C. for 45 minutes. After the degradation reaction, 1 mL of stop solution (containing 0.1% BSA, 24 mM sodium acetate and 79 mM acetic acid, pH=3.75) was added, and after mixing for 10 minutes, non-degraded hyaluronic acid was removed by precipitation. Use a PE microplate reader to detect the absorbance at a wavelength of 600 nm. Each sample was tested at least three times. The compound Vcpal (L-ascorbicacid 6-hexadecanoate) is a control compound for activity screening.

Calculate the inhibitory activity of the sample to hyaluronidase by the following formula:

Inhibitory activity (%)=[1–(OD hyaluronic acid–OD sample)/(OD hyaluronic acid–OD hyaluronidase)]×100%

The IC ₅₀ was calculated by the inhibitory activity of different concentrations, and the software GraphPad Prism 8.0 was used for calculation.

The results are as follows : In vitro hyaluronidase inhibitory activity screening showed that the synthesized 1,3-disubstituted indole derivatives had strong hyaluronidase inhibitory activity. Among them, compound Q5 has an inhibitory activity IC ₅₀ of 2.1 μg/mL for hyaluronidase, which is the most active inhibitor in this series. The inhibitory activity of compounds Q4 and Q5 was more than 10 times stronger than that of oleanolic acid.

Table 1. Inhibitory activity of various compounds on hyaluronidase

Example 8: Detection of Compound Skin Penetration

Experimental method: the present invention uses the software SwissADME (http://www.swisadme.ch/) to predict the skin permeability. The specific operation is calculated according to the software instruction manual. As follows, copy the structural formula or SMILES of the compound to the software window, and obtain the constant related to skin permeability, Log K _p , through calculation.

The result is as follows:

The results are shown in Table 2. We used computer simulation to calculate the Log K _p of the above-mentioned compounds. The larger the negative number of this constant, the less likely it is that the compound can penetrate the skin. According to the calculation results, it can be seen that the eight 1,3-disubstituted indole derivatives have good fat solubility, that is, skin penetration effect, so they are more suitable for skin application to inhibit skin aging. Compound B8 had the best skin penetration, and the other compounds had similar skin penetration.

Table 2: Calculated Log K _p for various compounds

Example 9: Screening for Cytotoxicity

experimental method:

The CCK-8 kit was used to detect the cytotoxicity of the compounds. The specific operation is to inoculate HepG2 cells, MCF-7 cells, and A549 cells into 96-well plates respectively, with about 5000 cells/200 μL culture solution per well, and culture the cells overnight. Various concentrations of test compounds were added to each well, and culture was continued for 48 hours. Add 10 μL of CCK-8 reagent to each well, mix well and continue to incubate for 1-4 hours. Observe that the color of the culture solution changes significantly. Use a microplate reader to detect and measure the absorbance at 450 nm. Paclitaxel was used as a positive control.

The result is as follows:

The results are shown in Table 3. It was found in cell experiments that none of the eight 1,3-disubstituted indole derivatives had obvious cytotoxicity. Therefore, these eight 1,3-disubstituted indole derivatives are suitable for the preparation of cosmetic products.

Table 3: Cytotoxicity of various compounds on mammalian cells

Example 10: Compound B5 is used as an anti-aging ingredient to prepare a beauty mask

An anti-aging skin mask, its formula and parts by weight are as follows:

The names of cosmetic ingredients appearing in this article are INCI (International Nomenclature of Cosmetic Ingredients), which is the name stipulated by the International Nomenclature of Cosmetic Ingredients.

Combined with the inhibitory activity of compound B5 on hyaluronidase, the cytotoxicity of B5, and the skin permeability of B5, it is selected as an anti-aging active ingredient for the preparation of a cosmetic mask.

Phase B: 3 parts of water, 0.12 parts of triethanolamine;

Phase C: 0.1 part of compound B5, 1 part of ethanol, 0.1 part of phenoxyethanol

Phase D: (daily use) essence 0.01 part, PEG-40 hydrogenated castor oil 0.1 part

The preparation method comprises the following steps: according to the above formula, weighing each component, wherein each part by mass is 1g. Mix the components of phase A, homogenize for 5 minutes (2000r/min), stir and heat to 80°C, keep the temperature constant at 80°C, and continue stirring for 5 minutes; cool down to 45°C, add phase B while stirring, and continue stirring for 5 minutes; Add Phase C and Phase D, continue to stir and mix, cool to 25°C, and fill.

Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention also intends to include these modifications and variations.

Claims

A 1,3-disubstituted indole compound, characterized in that it has a structure shown in general formula (I):

Wherein, R a , R b , R c , R d , Re are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, methoxy, trifluoromethyloxy, formylamino, methyl Sulfonyl, isopropylsulfonyl, mesylate, isopropylsulfonate, trifluoromethyl, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl.
The 1,3-disubstituted indole compound according to claim 1, characterized in that, in general formula (I), R a , R b , R c , R d , R e are each independently selected from hydrogen, Deuterium, fluorine, chlorine, bromine, trifluoromethyl, C 1-4 alkyl, C 2-4 alkenyl.
The 1,3-disubstituted indole compound according to claim 1 or claim 2, wherein the compound is selected from the following structures:
A compound composition, characterized in that, the compound composition comprises the 1,3-disubstituted indole compound described in any one of claims 1-3, its stereoisomer, its chemically acceptable one or more salts;

Preferably, the compound composition further comprises cosmetically acceptable excipients.
The preparation method of the 1,3-disubstituted indole compound described in any one of claims 1-3, characterized in that the preparation method comprises the following steps:

Mix an equal amount of 3-((1,1'-biphenyl)-4-thio)-indole, AlMe 3 for 1 hour, add various isocyanates, such as
After reacting for 16h, it is obtained; wherein the substituents R a , R b , R c , R d , and R e are defined in the same range as any one of claims 1-3;

Its reaction formula is as follows:
The preparation method of 1,3-disubstituted indole compounds according to claim 5, characterized in that, the preparation of 3-((1,1'-biphenyl)-4-thio)-indole compounds party as follows:

Mix indole, thiol, and TBHP in a cyanide solvent, then add I2 as a catalyst, and continue the reaction at room temperature to obtain the intermediate 3-((1,1'-biphenyl)-4-thio)-indole ,

Its reaction formula is as follows:
The 1,3-disubstituted indole compound indole described in any one of claims 1-3 or the compound composition described in claim 4 are used in the preparation of cosmetics that delay skin aging by inhibiting hyaluronidase activity the use of.
An anti-skin aging facial mask, characterized in that: the facial mask comprises the compound according to any one of claims 1-3 or the compound composition according to claim 4, and the formula and parts by weight of the facial mask are as follows:

Phase A: 92.68 parts of water, 2 parts of 1,2-butanediol, 0.1 part of methylparaben, 0.16 part of carbomer, 0.05 part of hydroxyethyl cellulose, 0.03 part of disodium EDTA, 0.05 part of sodium hyaluronate , 0.4 parts of 1,2-hexanediol, 0.1 parts of panthenol;

Phase B: 3 parts of water, 0.12 parts of triethanolamine;

Phase C: 0.1 part of the compound described in any one of claims 1-3 or the compound composition described in claim 4, 1 part of ethanol, 0.1 part of phenoxyethanol

Phase D: (daily use) essence 0.01 part, PEG-40 hydrogenated castor oil 0.1 part.