CN114507179B - Para-benzene ring butanamide rosemary compound serving as hyaluronidase inhibitor and application of para-benzene ring butanamide rosemary compound in beauty products - Google Patents

Para-benzene ring butanamide rosemary compound serving as hyaluronidase inhibitor and application of para-benzene ring butanamide rosemary compound in beauty products Download PDF

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CN114507179B
CN114507179B CN202210130260.5A CN202210130260A CN114507179B CN 114507179 B CN114507179 B CN 114507179B CN 202210130260 A CN202210130260 A CN 202210130260A CN 114507179 B CN114507179 B CN 114507179B
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rosmarinic acid
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姜燕飞
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Beijing Qingyan Bozhi Health Management Co ltd
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Abstract

The invention discloses a p-benzene ring butanamide rosemary compound, a preparation method thereof and application thereof as a hyaluronidase inhibitor and in preparing anti-aging cosmetic products. Specifically, the invention discloses a series of preparation of rosmarinic acid derivatives. The in vitro activity test shows that the rosmarinic acid derivative has stronger hyaluronidase inhibition activity, IC 50 About 10-20 μ g/mL, the inhibitory activity is obviously higher than that of rosmarinic acid and IC 50 About 102. Mu.g/mL. The rosmarinic acid derivative has very low cytotoxicity, has obviously enhanced fat solubility compared with rosmarinic acid, is easier to be absorbed by skin tissues, and can be used as an anti-aging component for preparing a cosmetic product. The invention also discloses an application of the rosmarinic acid derivative as a cosmetic component in preparing an anti-skin-aging facial mask.

Description

Para-benzene ring butanamide rosemary compound serving as hyaluronidase inhibitor and application of para-benzene ring butanamide rosemary compound in beauty products
Technical Field
The invention relates to a p-benzene ring butanamide rosemary compound, a preparation method thereof, and application thereof as a hyaluronidase inhibitor and in the preparation of beauty products, belonging to the field of cosmetics.
Background
Hyaluronic acid belongs to the group of glycosaminoglycans, distributed mainly in the skin, brain and central nervous system. Hyaluronic acid is an essential structural element forming the human body, and can help some specific proteins to fix a desired position in the body, thereby playing a key role in tissue structure. In mammals, especially humans, the concentration of hyaluronic acid depends mainly on the ratio between its enzymatic synthesis by hyaluronidase enzyme and its enzymatic degradation by hyaluronidase enzyme. Hyaluronidase (EC3.2.1.35) is an important enzyme that degrades hyaluronic acid and can hydrolyze the 1,4 linkage between N-acetyl- β -D-glucosamine and D-glucuronic acid in hyaluronic acid. Hyaluronidase is effective in degrading hyaluronic acid, causing laxity of the subcutaneous tissue, and ultimately reacting to aging of the skin. Therefore, inhibiting the activity of hyaluronidase can effectively increase the concentration of hyaluronic acid in the tissue, and the final effect is to delay the relaxation and aging of the skin.
The natural product is an important source of hyaluronidase inhibitor, and rosmarinic acid is found to exhibit certain hyaluronidase inhibition activity. Rosemary is a herb used as both medicine and food, and Rosmarinic acid (shown in figure 1) is a pentacyclic triterpenoid existing in many plants, is a bioactive component existing in a plurality of plant extracts, and is commonly used as a cosmeceutical component of various skin care products. Rosmarinic acid is a polyphenol compound, is a natural antioxidant, has strong antioxidant activity, and has strong activity of eliminating free radicals in vivo and antioxidant effect. Rosmarinic acid has strong antiinflammatory activity, such as nephritis resisting, hepatitis resisting, and pneumonia resisting. Meanwhile, the rosmarinic acid also has antibacterial, antiviral and antidepressant activities. At present, rosmarinic acid has shown important application value in the fields of pharmacy, food, cosmetics and the like. Studies have also shown that the anti-skin-aging effect of rosmarinic acid may be attributed to its association with inhibition of several enzymes associated with skin wrinkle formation, such as hyaluronidase. Rosmarinic acid has weak hyaluronidase inhibition activity, and IC reported in literature 50 About 309 μ M. The rosmarinic acid is modified to improve the inhibition activity of the rosmarinic acid on hyaluronidase, and the obtained rosmarinic acid is easier to be absorbed by the skin and can be used as an active ingredient for resisting skin aging if the rosmarinic acid has higher lipid solubility.
Disclosure of Invention
Aiming at literature report that the inhibitory activity of rosmarinic acid on hyaluronidase is weak, IC 50 About 309 μ M. But do notRosmarinic acid has poor lipid solubility and is difficult to permeate into skin. The research takes rosmarinic acid as a parent nucleus and optimizes the structure of the rosmarinic acid, so that the inhibitory activity of the derivatives on hyaluronidase is enhanced. Meanwhile, the newly synthesized compound has enhanced fat solubility and is more beneficial to application in cosmetics. The invention mainly aims to provide a p-benzene ring butanamide rosemary compound, a preparation method and application thereof. The invention develops a p-phenylbutylamide rosemary compound, which has significantly enhanced hyaluronidase inhibition activity and can be used for developing beauty products for resisting skin aging.
In order to achieve the purpose, the invention comprises the following technical scheme:
in a first aspect, the invention provides a p-phenylbutylamide rosemary compound, wherein the structure is shown in the general formula (I):
Figure BDA0003502312730000021
ring A is independently selected from phenyl, naphthyl, 5-14 membered aromatic heterocyclic group;
wherein phenyl, naphthyl or 5-14 membered heteroaromatic group is unsubstituted or substituted with 1,2, 3,4 or 5 substituents each independently selected from deuterium, hydroxy, mercapto, amino, carboxamido, methanesulfonyl, isopropylsulfonyl, methanesulfonate, isopropylsulfonate, trifluoromethyloxy, C 1-8 Alkyloxy, C 2-8 Alkenyloxy radical, C 2-8 Alkynyl oxy, C 1-8 An alkylamino group.
C above 1-8 Means that the number of carbon atoms of the substituent is 1,2, 3,4, 5, 6, 7 or 8; c 2-8 The number of carbon atoms of the substituent is 2, 3,4, 5, 6, 7 or 8.
The p-benzocyclobutanamide rosemary compounds related by the invention are compounds with a brand new structure, and have obviously enhanced hyaluronidase inhibition activity and enhanced fat solubility compared with rosmarinic acid in vitro. Therefore, can be used for preparing cosmetics for resisting skin aging.
Preferably, in formula (I), ring A is independently selected from phenyl, naphthyl, indolyl, pyridyl, quinolyl, furyl, thienyl, isoxazolyl, benzoxazolyl, imidazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzofuryl, benzimidazolyl;
these aromatic or heteroaromatic groups are unsubstituted or substituted with 1,2, 3,4 or 5 substituents selected from deuterium, hydroxy, amino, carboxamido, methanesulfonyl, isopropylsulfonyl, methanesulfonate, isopropylsulfonate, trifluoromethyloxy, C 1-4 Alkyloxy, C 2-4 Alkenyloxy radical, C 2-4 Alkynyl oxy, C 1-4 An alkylamino group.
C above 1-4 Means that the number of carbon atoms of a substituent is 1,2, 3 or 4; c 2-4 The number of carbon atoms of the substituent is 2, 3 or 4.
Preferably, in formula (I), the A rings are independently selected from phenyl, naphthyl, indolyl, pyridyl, quinolyl;
these aromatic or heteroaromatic groups are unsubstituted or substituted with 1,2, 3,4 or 5 substituents selected from deuterium, hydroxy, amino, carboxamido, methanesulfonyl, isopropylsulfonyl, methanesulfonate, isopropylsulfonate, trifluoromethyloxy, C 1-4 Alkyloxy, C 1-4 An alkylamino group.
C above 1-4 Means that the number of carbon atoms of the substituent is 1,2, 3 or 4; c 2-4 The number of carbon atoms of the substituent is 2, 3 or 4.
Further preferably, the phenylbutylamide rosemary compound is selected from the following compound structures:
Figure BDA0003502312730000041
Figure BDA0003502312730000051
in a second aspect, the present invention provides a compound composition comprising one or more of the p-phenylbutylamide rosemary compounds, their stereoisomers, and their chemically acceptable salts, as described in the first aspect above; preferably, the compound composition further comprises cosmetically acceptable adjuvants such as carriers, diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, cosolvents, solubilizers, tonicity adjusting agents, surfactants, colorants, pH adjusting agents, antioxidants, bacteriostats, or buffers, and the like.
The chemically acceptable salt of the p-phenylbutylamide rosemary compound related by the invention is a salt formed by the p-phenylbutylamide rosemary compound and alkali selected from the following bases: 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 invention provides a preparation method of p-phenylbutylamide rosemary compounds:
mixing equivalent amount of para-bromobenzoyl butanamide rosemary with various boric acid compounds, such as
Figure BDA0003502312730000061
Cesium carbonate, tetrabutylammonium bromide and potassium tetrachloropalladate are mixed in a methanol solvent and react for 6 hours at 37 ℃ to obtain a product; wherein the defined range of ring A is in accordance with the range defined in any one of the first aspect, and the reaction formula is as follows:
Figure BDA0003502312730000062
preferably, rosemary is prepared by the following method:
mixing equivalent rosmarinic acid and p-bromobenzamide in anhydrous DMF in the presence of DCC and DMAP, heating the mixture to 50 ℃ for reacting for 6 hours to obtain an intermediate p-bromobenzamide rosemary, wherein the reaction formula is shown as follows:
Figure BDA0003502312730000063
in a fourth aspect, the invention provides a p-benzocyclobutanamide rosemary compound as described in the first aspect, or a compound composition as described in the second aspect, for preparing a cosmetic for delaying skin aging by inhibiting hyaluronidase activity.
In a fifth aspect, the invention provides an anti-skin aging facial mask, which contains the compound of the first aspect or the compound composition of the second aspect, and the formula and the parts by weight of the facial mask are as follows:
phase A: 87.48 parts of water, 4 parts of 1,3-propylene glycol, 1 part of glycerol, 0.15 part of methylparaben, 0.15 part of carbomer, 0.1 part of sodium hyaluronate, 0.2 part of EDTA disodium, 0.4 part of 1,2-hexanediol and 0.2 part of panthenol;
phase B: 5 parts of water and 0.1 part of triethanolamine;
and C phase: 0.1 part of the compound of the first aspect or the compound composition of the second aspect, and 1 part of ethanol
Phase D: 0.02 part of essence for daily use and 0.1 part of PEG-40 hydrogenated castor oil
Drawings
Fig. 1, structural formula of rosmarinic acid.
Detailed Description
The invention is further illustrated with reference to specific examples. It should be understood that the specific embodiments described herein are illustrative only and are not limiting upon the scope of the invention.
The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products which are not indicated by manufacturers and are available from normal sources.
The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples are all commercially available products unless otherwise specified.
Preparation example 1: rosemary is prepared by the following method:
the preparation example prepares the p-bromobenzene butyrylamide rosemary, and the synthetic route is as follows:
Figure BDA0003502312730000071
equal amounts of rosmarinic acid (720mg, 2mmol) and p-bromobenzamide (452mg, 2mmol) are mixed in anhydrous 10ml of DMF in the presence of DCC (453mg, 2.2mmol) and DMAP (36mg, 0.3mmol), and the reaction is heated to 50 ℃ to react for 6h, so as to obtain an intermediate p-bromobenzamide rosemary. Until complete consumption of starting material was monitored by TLC. The crude product was purified by column chromatography using petroleum ether/ethyl acetate as eluent to give the pure product 294mg (26%) of para-bromobenzobutanamide rosemary as a white solid. The product was characterized as follows: 1 HNMR(400MHz,acetone-d 6 ):δ.7.83-7.79(m,2H),7.63(d,J＝2.1Hz,1H),7.34(d,J＝1.8Hz,1H),7.26(dd,J＝7.8,1.8Hz,1H)，7.21(m,1H),6.99(d,J＝1.8Hz,1H),6.87(d,J＝1.8Hz,1H),6.75(d,J＝7.8Hz,1H),6.69(dd,J＝7.8,1.8Hz,1H),6.47(d,J＝15.6Hz,1H),6.31(m,1H),5.24(dd,J＝8.4,4.2Hz,1H),4.10(ms,1H),3.20(m,1H),3.14(dd,J＝14.4,4.2,Hz,1H),3.05(dd,J＝14.4,8.4Hz,1H),2.04-2.29(m,4H).HR-MS(ESI):[M+H]+ C28H27BrNO7 calcd for 569.4280, found 569.4256.
Example 1: this example prepares N- [3- (4- (pyridin-4-yl) phenyl) cyclobutyl ] rosemary amide, of the formula:
Figure BDA0003502312730000081
para-bromobenzamide rosemary (1136mg, 2mmol), para-4-pyridineboronic acid ester (410mg, 2mmol), cesium carbonate (764mg, 4mmol), tetrabutylammonium bromide (644mg, 2mmol), potassium tetrachloropalladate (16.3mg, 0.0 mmol)5 mmol) in 6mL of methanol solvent, reacted at 37 ℃ for 6h and checked by TLC, and the product was purified by column chromatography to give 169mg (15%) of compound as a white solid. The product was characterized as follows: 1 H NMR(400MHz,acetone-d 6 ):δ8.76(m,2H),8.00(m,2H),7.83-7.79(m,2H),7.63(d,J＝2.1Hz,1H),7.34(d,J＝1.8Hz,1H),7.26(dd,J＝7.8,1.8Hz,1H)，7.21(m,1H),6.99(d,J＝1.8Hz,1H),6.87(d,J＝1.8Hz,1H),6.75(d,J＝7.8Hz,1H),6.69(dd,J＝7.8,1.8Hz,1H),6.47(d,J＝15.6Hz,1H),6.31(m,1H),5.24(dd,J＝8.4,4.2Hz,1H),4.10(ms,1H),3.20(m,1H),3.14(dd,J＝14.4,4.2,Hz,1H),3.05(dd,J＝14.4,8.4Hz,1H),2.04-2.29(m,4H).HR-MS(ESI):[M+H]+ C33H31N2O7 calcd for 567.6180 found 567.6152.
Example 2: this example prepared N- [3- (4- (2-fluoropyridin-3-yl) phenyl) cyclobutyl ] rosemary amide, which has the following structural formula:
Figure BDA0003502312730000091
para-bromophenylbutylamide rosemary (1136mg, 2mmol), 2-fluoro-4-pyridineboronic acid (410mg, 2mmol), cesium carbonate (764mg, 4mmol), tetrabutylammonium bromide (644mg, 2mmol), potassium tetrachloropalladate (16.3mg, 0.05mmol) were mixed in 6mL of methanol solvent, reacted at 37 ℃ for 6h and checked by TLC, and the product was purified by column chromatography to give compound 151mg (13%) as a white solid. The product was characterized as follows: 1 H NMR(400MHz,acetone-d 6 ):δ8.54(m,1H),8.36(m,1H),7.56-7.66(m,2H),7.63(d,J＝2.1Hz,1H),7.38(m,2H),7.34(d,J＝1.8Hz,1H),7.26(dd,J＝7.8,1.8Hz,1H),6.99(d,J＝1.8Hz,1H),6.87(d,J＝1.8Hz,1H),6.75(d,J＝7.8Hz,1H),6.69(dd,J＝7.8,1.8Hz,1H),6.47(d,J＝15.6Hz,1H),6.31(m,1H),5.24(dd,J＝8.4,4.2Hz,1H),4.10(ms,1H),3.20(m,1H),3.14(dd,J＝14.4,4.2,Hz,1H),3.05(dd,J＝14.4,8.4Hz,1H),2.04-2.29(m,4H).HR-MS(ESI):[M+H]+ C33H30FN2O7 calcd for 585.6084, found 585.6072.
Example 3: this example prepares N- [3- (4- (quinolin-4-yl) phenyl) cyclobutyl ] rosemary amide, having the formula:
Figure BDA0003502312730000101
para-bromophenylbutylamide rosemary (1136mg, 2mmol), quinoline-4-boronic acid (344mg, 2mmol), cesium carbonate ((764mg, 4mmol), tetrabutylammonium bromide (644mg, 2mmol), potassium tetrachloropalladate (16.3mg, 0.05mmol), mixed in 6mL of methanolic solvent, reacted for 6h at 37 ℃ and checked by TLC, the product was purified by column chromatography to give compound 163mg (13%) as a white solid. 1 H NMR(400MHz,acetone-d 6 ):δ8.86(m,1H),8.12-8.05(m,2H),7.70-7.51(m,4H),7.38(m,2H),7.34(d,J＝1.8Hz,1H),7.26(dd,J＝7.8,1.8Hz,1H)，7.15(m,1H),6.99(d,J＝1.8Hz,1H),6.87(d,J＝1.8Hz,1H),6.75(d,J＝7.8Hz,1H),6.69(dd,J＝7.8,1.8Hz,1H),6.47(d,J＝15.6Hz,1H),6.31(m,1H),5.24(dd,J＝8.4,4.2Hz,1H),4.10(ms,1H),3.20(m,1H),3.14(dd,J＝14.4,4.2,Hz,1H),3.05(dd,J＝14.4,8.4Hz,1H),2.04-2.29(m,4H).HR-MS(ESI):[M+H]+ C37H33N2O7 calcd for 617.6780 found 617.6775.
Example 4: this example prepares N- [3- (4- (naphthalen-2-yl) phenyl) cyclobutyl ] rosemary amide, of the formula:
Figure BDA0003502312730000111
para-bromobenzamide rosemary (1136mg, 2mmol), 2-naphthalene boronic acid (342mg, 2mmol), cesium carbonate (764mg, 4mmol), tetrabutylammonium bromide (644mg, 2mmol), potassium tetrachloropalladate (16.3mg, 0.05mmol) were mixed in 6mL of methanol solvent, reacted at 37 ℃ for 6h and checked by TLC, and the product was purified by column chromatography to give compound 92mg (15%) as a white solid. The product was characterized as follows: 1 H NMR(400MHz,acetone-d 6 ):δ8.06-8.00(m,3H),7.38-7.63(m,9H),7.26(dd,J＝7.8,1.8Hz,1H)，6.99(d,J＝1.8Hz,1H),6.87(d,J＝1.8Hz,1H),6.75(d,J＝7.8Hz,1H),6.69(dd,J＝7.8,1.8Hz,1H),6.47(d,J＝15.6Hz,1H),6.31(m,1H),5.24(dd,J＝8.4,4.2Hz,1H),4.10(ms,1H),3.20(m,1H),3.14(dd,J＝14.4,4.2,Hz,1H),3.05(dd,J＝14.4,8.4Hz,1H),2.04-2.29(m,4H).HR-MS(ESI):[M+H]+ C38H34NO7 calcd for 616.6900, found 616.6859.
Example 5: this example prepares N- [3- (4- (3-aminophenyl) phenyl) cyclobutyl ] rosemary amide, having the formula:
Figure BDA0003502312730000112
para-bromobenzamide rosemary (1136mg, 2mmol), 3-aminophenylboronic acid (monohydrate) (308mg, 2mmol), cesium carbonate (764mg, 4mmol), tetrabutylammonium bromide (644mg, 2mmol), potassium tetrachloropalladate (16.3mg, 0.05mmol) were mixed in 6mL of a methanol solvent, reacted at 37 ℃ for 6h and checked by TLC, and the product was purified by column chromatography to give 185mg (16%) of the compound as a white solid. The product was characterized as follows: 1 H NMR(400MHz,acetone-d 6 ):δ7.63(d,J＝2.1Hz,1H),7.51-7.34(m,5H),7.26(dd,J＝7.8,1.8Hz,1H)，7.21(m,1H),6.99-6.96(m,2H),6.89-6.87(m,2H),6.76-6.74(m,2H),6.69(dd,J＝7.8,1.8Hz,1H),6.47(d,J＝15.6Hz,1H),6.31(m,1H),5.24(dd,J＝8.4,4.2Hz,1H),4.10(ms,1H),3.20(m,1H),3.14(dd,J＝14.4,4.2,Hz,1H),3.05(dd,J＝14.4,8.4Hz,1H),2.04-2.29(m,4H).HR-MS(ESI):[M+H]+ C34H33N2O7 calcd for 581.6450, found 581.6426.
Example 6: this example prepares N- [3- (4- (2-methanesulfonylphenyl) phenyl) cyclobutyl ] rosemary amide, which has the following structural formula:
Figure BDA0003502312730000121
para-bromobenzamide rosemary (1136mg, 2mmol), 2-methylsulfonylphenylboronic acid (400mg, 2mmol), cesium carbonate (764mg, 4mmol), tetrabutylammonium bromide (644mg, 2mmol), potassium tetrachloropalladate (16.3mg, 0.05mmol) were mixed in 6mL of methanol solvent, reacted at 37 ℃ for 6h and checked by TLC, and the product was purified by column chromatography to give 218mg (17%) of compound as a white solid. The product was characterized as follows: 1 H NMR(400MHz,acetone-d 6 ):δ8.12(m,1H),7.97-7.78(m,3H),7.63(d,J＝2.1Hz,1H),7.51(m,1H),7.38-7.34(m,3H),7.26(dd,J＝7.8,1.8Hz,1H)，6.99(d,J＝1.8Hz,1H),6.87(d,J＝1.8Hz,1H),6.75(d,J＝7.8Hz,1H),6.69(dd,J＝7.8,1.8Hz,1H),6.47(d,J＝15.6Hz,1H),6.31(m,1H),5.24(dd,J＝8.4,4.2Hz,1H),4.10(m,1H),3.32(s,3H),3.20(m,1H),3.14(dd,J＝14.4,4.2,Hz,1H),3.05(dd,J＝14.4,8.4Hz,1H),2.04-2.29(m,4H).HR-MS(ESI):[M+H]+ C35H34NO9S calcd for 644.5170, found 644.5159.
Example 7: this example prepares N- [3- (4- (3,5-dihydroxyphenyl) phenyl) cyclobutyl ] rosemary amide, which has the formula:
Figure BDA0003502312730000131
para-bromophenylbutylamide rosemary (1136mg, 2mmol), 3,4-dihydroxybenzenesulfenate (472mg, 2mmol), cesium carbonate (764mg, 4mmol), tetrabutylammonium bromide (644mg, 2mmol), potassium tetrachloropalladate (16.3mg, 0.05mmol) were mixed in 6mL of methanol solvent, reacted at 37 ℃ for 6h and checked by TLC, and the product was purified by column chromatography to give 131mg (11%) of compound as a white solid. The product was characterized as follows: 1 H NMR(400MHz,acetone-d 6 ):δ7.63(d,J＝2.1Hz,1H),7.51(m,1H),7.38-7.34(m,3H),7.26(dd,J＝7.8,1.8Hz,1H)，6.99(d,J＝1.8Hz,1H),6.87(d,J＝1.8Hz,1H),6.75(d,J＝7.8Hz,1H),6.70-6.69(m,3H),6.47(d,J＝15.6Hz,1H),6.35-6.31(m,2H),5.24(dd,J＝8.4,4.2Hz,1H),4.10(ms,1H),3.20(m,1H),3.14(dd,J＝14.4,4.2,Hz,1H),3.05(dd,J＝14.4,8.4Hz,1H),2.04-2.29(m,4H).HR-MS(ESI):[M+H]+ C34H32NO9 calcd for 598.6280, found 598.6267.
Example 8: this example prepares N- [3- (4- (4-hydroxyphenyl) phenyl) cyclobutyl ] rosemary amide, which has the formula:
Figure BDA0003502312730000141
para-bromobenzoyl butanamide rosemary (1136mg, 2mmol), 4-hydroxybenzeneboronic acid ester (440mg, 2mmol), cesium carbonate (764mg, 4mmol), tetrabutylAmmonium bromide (644mg, 2mmol), potassium tetrachloropalladate (16.3mg, 0.05mmol), mixed in 6mL of methanol solvent, reacted at 37 ℃ for 6h and checked by TLC, and the product was purified by column chromatography to give 124mg (11%) of compound as a white solid. The product was characterized as follows: 1 H NMR(400MHz,acetone-d 6 ):δ7.63(d,J＝2.1Hz,1H),7.51(m,1H),7.42-7.34(m,5H),7.26(dd,J＝7.8,1.8Hz,1H)，6.99(d,J＝1.8Hz,1H),6.87-6.83(m,3H),6.75(d,J＝7.8Hz,1H),6.69(dd,J＝7.8,1.8Hz,1H),6.47(d,J＝15.6Hz,1H),6.31(m,1H),5.24(dd,J＝8.4,4.2Hz,1H),4.10(m,1H),3.20(m,1H),3.14(dd,J＝14.4,4.2,Hz,1H),3.05(dd,J＝14.4,8.4Hz,1H),2.04-2.29(m,4H).HR-MS(ESI):[M+H]+ C34H32NO7 calcd for 566.6300, found 566.6289.
Example 9: hyaluronidase inhibitory Activity screening assay
The experimental method comprises the following steps:hyaluronidase was derived from Niu Gaowan, hyaluronidase inhibitory activity screening reference (Molecules, 2020. Notably, under low negative ion conditions, long-chain hyaluronic acid and hyaluronidase readily form an inactive complex, which can hinder the catalytic activity of hyaluronidase and interfere with hyaluronidase inhibition activity screening assays. Therefore, it should be avoided to add too much positively charged protein to interfere with the negative ion concentration in the buffer system when testing, which will restore hyaluronidase activity. For the specific test, bovine serum albumin was added to 20mMPBS at pH3.75 to a final concentration of 0.01%, which was a prepared reaction buffer. mu.L of the sample (concentration range 1-400. Mu.g/mL) was mixed with 95. Mu.L of the reaction solution containing hyaluronidase (7.5U/mL) and incubated at 37 ℃ for 10 minutes. Then, 100. Mu.L of hyaluronic acid was added to the above reaction solution, and incubation was continued at 37 ℃ for 45 minutes. After the degradation reaction, hyaluronic acid which was not degraded was removed by precipitation after mixing for 10 minutes by adding a stop solution containing 1mL (containing 0.1% BSA,24mM sodium acetate and 79mM acetic acid, pH = 3.75). The absorbance at a wavelength of 600nm was measured using a PE microplate reader. Each sample was tested in at least triplicate. Vcpal was used as a positive control compound for this assay.
The inhibitory activity of the sample on hyaluronidase was calculated by the following formula:
inhibitory activity (%) = [1- (OD hyaluronic acid-OD sample)/(OD hyaluronic acid-OD hyaluronidase) ] × 100%
Calculation of IC by inhibitory Activity at different concentrations 50 The calculation was performed using the software GraphPad Prism 8.0.
The results are as follows: the screening of the hyaluronidase inhibition activity in vitro shows that the hyaluronidase inhibition activity (IC) is obviously improved 50 About 10-20. Mu.g/mL). Wherein the inhibitory activity IC of the compound W3 on hyaluronidase 50 12.1. Mu.g/mL, is the most active inhibitor in this series.
TABLE 1 inhibitory Activity of various Compounds on Hyaluronidase
Figure BDA0003502312730000151
Example 10: detection of skin Permeability of Compounds
The experimental method comprises the following steps: book (I)The invention uses software SwissATEM (http:// www.swisadme.ch /) to make the prediction of skin permeability. The specific operation is calculated according to the software using instructions. The formula of the compound or SMILES is copied into a software window and calculated to obtain a constant, logK, related to skin permeability as follows p 。
The results were as follows:
the results are shown in Table 2, and the LogK of rosemary was calculated by using a computer simulation method for p-phenylbutylamide p The more negative this constant is, the less likely it is that the compound is able to penetrate the skin. According to the calculation results, all the modified paraphranilide rosemary derivatives have better skin penetration effect than rosmarinic acid RA, and are more suitable for being applied to skin to inhibit skin aging. The compounds W3, W4, W8 had the best skin penetration effect.
Table 2: logk calculated for various compounds p
Figure BDA0003502312730000161
Example 11: screening for cytotoxicity
The experimental method comprises the following steps:
the cytotoxicity of the compound is detected by adopting a CCK-8 kit. Specifically, hepG2 cells, MCF-7 cells and A549 cells were inoculated into 96-well plates at a cell density of about 5000 cells/200. Mu.L of culture medium per well, and the cells were cultured overnight. Different concentrations of test compound were added to each well and incubation was continued for 48 hours. Adding 10 mu L of CCK-8 reagent into each hole, uniformly mixing, continuously culturing for 1-4 hours, observing the obvious change of the color of the culture solution, detecting by using an enzyme-labeling instrument, and determining the light absorption value of 450 nm. Paclitaxel was used as a positive control.
The results are as follows:
the results are shown in table 3, and the cell experiment tests show that 8 compounds have no obvious cytotoxicity to the benzene ring butanamide rosemary derivatives. Therefore, the 8 p-benzene ring butanamide rosemary derivatives are suitable for preparing cosmetic products.
Table 3: cytotoxicity of various compounds on mammalian cells
Figure BDA0003502312730000171
Example 12: compound W4 used as anti-skin aging component for preparing beauty mask
The formula and the parts by weight of the anti-skin-aging mask are as follows:
the names of Cosmetic Ingredients appearing herein are each INCI (International Nomenclature of Cosmetic Ingredients), a name prescribed by the International Nomenclature of Cosmetic materials.
In combination with the inhibitory activity of the compound W4 on hyaluronidase, the cytotoxicity of W4, the skin permeability of W4, it was selected as an anti-skin aging active ingredient for the preparation of cosmetic masks.
Phase A: 87.48 parts of water, 4 parts of 1,3-propylene glycol, 1 part of glycerol, 0.15 part of methylparaben, 0.15 part of carbomer, 0.1 part of sodium hyaluronate, 0.2 part of EDTA disodium, 0.4 part of 1,2-hexanediol and 0.2 part of panthenol;
phase B: 5 parts of water and 0.1 part of triethanolamine;
and C phase: 0.1 part of compound W and 1 part of ethanol
Phase D: 0.02 part of (daily) essence and 0.1 part of PEG-40 hydrogenated castor oil
The preparation method comprises the following steps: the respective components were weighed according to the above formulation, wherein each part by mass was 1g. Mixing the phase A components, homogenizing for 5 minutes (2000 r/min), stirring and heating to 80 ℃, keeping the temperature constant at 80 ℃, and continuing stirring for 5 minutes; cooling to 45 deg.C, adding phase B under stirring, and stirring for 5 min; adding phase C and phase D, stirring, cooling to 25 deg.C, and packaging.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.

Claims (6)

1. A p-benzene ring butanamide rosemary compound is characterized by having a structure shown in a general formula (I):
Figure 976116DEST_PATH_IMAGE002
general formula (I)
Ring A is independently selected from pyridin-4-yl, 2-F-pyridin-3-yl, quinolin-4-yl, naphthalen-2-yl, 3-aminophenyl, 2-methanesulfonylphenyl, 3,5-dihydroxyphenyl, or 4-hydroxyphenyl.
2. A composition characterized by: the composition comprises the p-phenylbutylamide rosemary compound or the chemically acceptable salt thereof according to claim 1, and further comprises an auxiliary material acceptable in the field of cosmetics.
3. The method for preparing p-phenylbutylamide rosemary compounds according to claim 1, wherein said method comprises the following steps:
mixing equivalent amount of para-bromobenzenesulfonamide rosemary with
Figure 486732DEST_PATH_IMAGE004
、Cs 2 CO 3 、TBAB、K 2 PdCl 4 Mixed in methanol solvent, 37 o C, reacting for 6 hours to obtain a product; wherein the A ring is defined in accordance with claim 1, and has the following formula:
Figure 890DEST_PATH_IMAGE006
。
4. the method for preparing p-phenylbutylamides rosemary compounds according to claim 3, wherein the p-bromobenzoylamide rosemary is prepared as follows:
mixing equal amount of rosmarinic acid and p-bromobenzylamine in the presence of DCC and DMAP in anhydrous DMF, and heating to 50% oC Reacting for 6h to obtain an intermediate p-bromobenzene butyrylamide rosemary, wherein the reaction formula is shown as follows:
Figure 192837DEST_PATH_IMAGE008
。
5. use of a paraphenylbutyrylamide rosemary compound according to claim 1 or a composition according to claim 2 for the preparation of a cosmetic for delaying skin aging by inhibiting hyaluronidase activity.
6. An anti-skin aging facial mask is characterized in that: the facial mask comprises the compound of claim 1 or the composition of claim 2, and the formula and the parts by weight of the facial mask are as follows:
phase A: 87.48 parts of water, 4 parts of 1,3-propylene glycol, 1 part of glycerol, 0.15 part of methylparaben, 0.15 part of carbomer, 0.1 part of sodium hyaluronate, 0.2 part of EDTA disodium, 0.4 part of 1,2-hexanediol and 0.2 part of panthenol;
phase B: 5 parts of water and 0.1 part of triethanolamine;
and C phase: 0.1 part of the compound of claim 1 or the composition of claim 2, 1 part of ethanol;
phase D: 0.02 part of essence for daily use and 0.1 part of PEG-40 hydrogenated castor oil.
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