CN114456225B - 3 alpha-oleanolic acid derivative serving as hyaluronidase inhibitor and application of derivative in cosmetic product - Google Patents
3 alpha-oleanolic acid derivative serving as hyaluronidase inhibitor and application of derivative in cosmetic product Download PDFInfo
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Abstract
The invention relates to a 3 alpha-triazole-oleanolic acid derivative, a preparation method thereof, and application of the derivative as a hyaluronidase inhibitor and in preparing anti-aging cosmetic products. Specifically, the invention discloses a series of 3 alpha-triazole-oleanolic acid derivatives with the structure shown in a general formula (I) and a preparation method thereof. The in vitro activity detection shows that the oleanolic acid derivatives have strong hyaluronidase inhibition activity and IC 50 About 1-10 mug/mL, the inhibiting activity is obviously stronger than that of oleanolic acid and IC 50 About 56. mu.g/mL. Cell proliferation experiments show that the 3 alpha-triazole-oleanolic acid derivative has very low mammalian cytotoxicity. The 3 alpha-triazole-oleanolic acid derivative has good lipid solubility, is easy to be absorbed by skin tissues, and can be used as an anti-aging component for preparing beauty products. The invention also discloses application of the 3 alpha-triazole-oleanolic acid derivative in preparing an anti-skin-aging facial mask by using the cosmetic component.
Description
Technical Field
The invention relates to a 3 alpha-triazole-oleanolic acid derivative, a preparation method thereof, and application thereof as a hyaluronidase inhibitor and in the preparation of cosmetic 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 required 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 (EC 3.2.1.35) 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 the hyaluronidase inhibitor, and researches show that the oleanolic acid can effectively inhibit the activity (IC) of the hyaluronidase 50 About 50. mu.g/mL). Oleanolic Acid (OA) is a pentacyclic triterpenoid found in many plants (fig. 1). It is a bioactive ingredient present in numerous plant extracts and is commonly used as a cosmeceutical ingredient in various skin care products. Related biological studies have shown that oleanolic acid has anti-inflammatory, antioxidant and anti-skin aging activities, so the use of oleanolic acid helps to improve the youthful state of the skin. Studies have also shown that the anti-skin aging effect of oleanolic acid may be attributed to its inhibitory effect on several enzymes associated with skin wrinkle formation, such as hyaluronidase. Oleanolic acid has become a commonly used liver-protecting drug in clinical treatment, for CCl 4 The induced rat acute liver injury has obvious protective effect, can reduce the elevation of ALT and AST, relieve inflammation, necrosis and interstitial inflammation reaction, prevent fibrosis formation, promote the regeneration of liver cells and accelerate the recovery of necrotic tissues. In addition, oleanolic acid has antiinflammatory, heart tonifying, diuretic, leukocyte increasing, blood glucose reducing, and immunity improving effects.
Modification of the oleanolic acid structure can further improve the hyaluronidase inhibition activity of the oleanolic acid structure. Hydroxyl and carboxylic acid of an oleanolic acid structure are modified and modified by various classical chemical modification strategies, and the tail end of a 3 beta-OH group is finally selected to be modified through determination and evaluation of hyaluronidase inhibition activity, so that a novel 3 alpha-substituted oleanolic acid derivative is obtained.
Disclosure of Invention
Aiming at weak hyaluronidase inhibition activity of oleanolic acid, the structure of oleanolic acid is optimized, so that the inhibition activity of the derivatives of oleanolic acid on hyaluronidase is enhanced. The invention mainly aims to provide a 3 alpha-substituted oleanolic acid derivative and a preparation method and application thereof. The invention develops a 3 alpha-triazole substituted oleanolic acid derivative, has remarkably 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 3 alpha-triazole-oleanolic acid compound, which has a structure shown in a general formula (I):
wherein R is a ，R b ，R c ，R d ，R e Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, mercapto, amino, cyano, nitro, azido, carboxamido, methylsulfonyl, isopropylsulfonyl, methylsulfonyl, isopropylsulfonate, methoxy, trifluoromethyl, trifluoromethyloxy, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, phenyl, naphthyl.
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 3 alpha-triazole-oleanolic acid compounds related by the invention are compounds with a brand new structure, and have hyaluronidase inhibition activity which is obviously enhanced compared with oleanolic acid in vitro. Therefore, can be used for preparing cosmetics for resisting skin aging.
Preferably, in the formula (I), R a ，R b ，R c ，R d ，R e Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, nitro, azido, methylsulfonyl, methoxy, trifluoromethyl, phenyl, naphthyl, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl group.
C above 1-4 Means the number of carbon atoms of the substituent1, 2, 3, 4; c 2-4 The number of carbon atoms of the substituent is 2, 3 or 4.
Further preferably, the 3 alpha-triazole-oleanolic acid compound is selected from the following compound structures:
in a second aspect, the present invention provides a compound composition comprising one or more of the 3 α -triazole-oleanolic acid compounds of the first aspect, stereoisomers thereof, and chemically acceptable salts thereof;
preferably, the compound composition further comprises cosmetically acceptable adjuvants such as carriers, diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, cosolvents, solubilizers, osmotic pressure regulators, surfactants, colorants, pH regulators, antioxidants, bacteriostats, or buffers, and the like.
The chemically acceptable salt of the 3 alpha-triazole-oleanolic acid compound related by the invention is a salt formed by the 3 alpha-triazole-oleanolic acid compound and alkali selected from the following components: 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 a 3 alpha-triazole-oleanolic acid compound, which comprises the following steps:
substituted phenylacetylenes, e.g.
Mixing 3 alpha-azido-oleanolic acid and a catalyst CuI, and reacting to obtain the product; wherein the substituent group R a ，R b ，R c ，R d ，R e Is in accordance with the scope defined in the first aspect;
the reaction formula is shown as follows:
preferably, the 3 α -azido-oleanolic acid compound is prepared as follows:
(1) mixing 3 beta-oleanolic acid and methylsulfonyl chloride in pyridine solvent, and reacting at low temperature to obtain 3 beta-methanesulfonic acid-oleanolic acid;
(2) mixing 3 beta-methanesulfonic acid-oleanolic acid and sodium azide in DMF, reacting to obtain 3 alpha-azide-oleanolic acid,
the reaction formula is shown as follows:
in a fourth aspect, the present invention provides a use of the 3 α -triazole-oleanolic acid compounds of the first aspect, or the composition of the compounds of the second aspect, in 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 comprises 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: 90.98 parts of water, 2 parts of glycerol, 0.3 part of p-hydroxyacetophenone, 0.16 part of carbomer, 0.05 part of sodium hyaluronate, 0.05 part of hydroxyethyl cellulose, 0.03 part of EDTA disodium, 0.1 part of dipotassium glycyrrhizinate, 261 parts of glyceryl polyether, 0.4 part of 1, 2-hexanediol and 0.5 part of nicotinamide;
phase B: 3 parts of water and 0.12 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: 0.1 part of phenoxyethanol, 0.01 part of essence for daily use and 0.1 part of PEG-40 hydrogenated castor oil.
Drawings
FIG. 1: structure of oleanolic acid and numbering of carbon atom designation.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention. For all of the following examples or preparations, standard procedures and purification methods known to those skilled in the art may be used. Unless otherwise indicated, all temperatures are in degrees celsius (degrees celsius) and the structure of a compound is determined by nuclear magnetic resonance spectroscopy (NMR) and/or Mass Spectroscopy (MS).
For all the following examples or preparations, the structure of the compounds is determined by NMR 1 H NMR) or Mass Spectrometry (MS). Nuclear magnetic resonance hydrogen spectral shifts (δ) are given in units of parts per million (ppm). NMR spectra were measured using a Mercury-400 NMR spectrometer, deuterated chloroform (CDCl) 3 ) As solvent Tetramethylsilane (TMS) or sodium 3- (trimethylsilyl) deuteropropionate (TSM) was used as internal standard.
The electronic balance used was an electronic balance model Yanaco LY-300, Japan.
The column chromatography uses 200-300 mesh or 300-400 mesh silica gel as a carrier.
The anhydrous solvents were all processed by standard methods. Other reagents were commercially available analytical grade from Sigma-Aldrich Sigma Aldrich trade company, AffaeEnsa chemical company, Beijing Yinaoka technology company, and Shanghai ceramic Biochemical technology company, respectively.
Preparation example 1: 3 alpha-azido-oleanolic acid
The preparation example prepares the 3 alpha-azido-oleanolic acid, and the synthetic route is as follows:
(1)3 beta-oleanolic acid (912mg, 2mmol) was dissolved in a solvent of 8ml pyridine and 1ml DCM, the above solvent was cooled to-38 ℃ by an ice bath of dry ice/ethanol, and then 1ml dry DCM containing methanesulfonyl chloride (154. mu.l, 2mmol) mixed in advance was slowly added dropwise to the reaction solution. The reaction mixture was stirred at-38 ℃ for 1 hour, then at 0 ℃ for a further 2 hours. By adding 10ml of H 2 And O, quenching the reaction. The reaction product was treated by rotary evaporation and then purified by column chromatography to give 480.6mg (45%) of pure product as 3 β -methylsulphonic acid-oleanolic acid as a white solid. The product was characterized as follows: 1 H NMR(400MHz,CDCl 3 ):δ5.19(t,J＝3.5Hz,1H),4.54(m,1H),3.16(s,3H),2.41–2.32(m,1H),2.20–2.13(m,1H),2.00–1.96(m,2H),1.84–1.76(m,2H),1.75–1.68(m,3H),1.61–1.53(m,6H),1.41–1.39(m,2H),1.34–1.28(m,4H),1.21–1.16(m,2H),1.02(s,3H),0.92(s,3H),0.91(s,3H),0.90(s,3H),0.87(s,3H),0.86(s,3H),0.84(s,3H).HR-MS(ESI):[M+H]+ C31H51O5S calculated 535.3457, found 535.3489.
(2) 3mmol 3. beta. -methylsulphonic acid-oleanolic acid and 6mmol sodium azide were mixed well in 30ml dry DMF, heated to 60 ℃ and reacted overnight. The reaction mixture was rotary evaporated to remove DMF, after which the reaction was extracted from the reaction mixture with DCM/methanol. For insoluble substances containing unreacted sodium azide, 20% NaNO is required 2 The solution was neutralized to pH 6. The soluble solution was then co-evaporated again with ethanol and toluene, the solution was placed under high vacuum to evaporate the remaining DMF overnight, and the crude product was purified by column chromatography to give 591mg (41%) of compound as solid 3 α -azido-oleanolic acid. The product was characterized as follows: 1 H NMR(400MHz,CDCl 3 ):δ5.19(t,J＝3.5Hz,1H),4.91(m,1H),2.43–2.34(m,1H),2.23–2.19(m,1H),2.00–1.92(m,2H),1.84–1.78(m,2H),1.75–1.68(m,3H),1.60–1.53(m,6H),1.41–1.37(m,2H),1.34–1.28(m,4H),1.21–1.16(m,2H),1.01(s,3H),0.92(s,3H),0.91(s,3H),0.89(s,3H),0.87(s,3H),0.86(s,3H),0.84(s,3H).HR-MS(ESI):[M+H]+ C30H48N3O2 calculated 482.3747, found 482.3795.
Example 1: preparation of 3 α - (4-phenyl-triazole) in this example) Oleanolic acid of the formula:
intermediate 3 α -azido-oleanolic acid (481mg, 1mmol), phenylacetylene (102mg,1mmol), and catalyst CuI (9.5mg, 5% mol) were mixed in 10ml ethanol and stirred at room temperature for half an hour to react. The product was purified by column chromatography to give compound 239mg (41%) as a white solid. The product was characterized as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.49-7.84(m,6H),5.19(t,J＝3.5Hz,1H),3.44(m,1H),2.43–2.34(m,1H),2.23–2.19(m,1H),2.00–1.96(m,2H),1.84–1.78(m,2H),1.75–1.68(m,3H),1.60–1.53(m,6H),1.41–1.39(m,2H),1.34–1.28(m,4H),1.21–1.16(m,2H),1.01(s,3H),0.92(s,3H),0.91(s,3H),0.90(s,3H),0.87(s,3H),0.86(s,3H),0.84(s,3H).HR-MS(ESI):[M+H]+ C38H54N3O2 calculated 584.4216, found 584.4255.
Example 2: 3 alpha- (4- (3-methylphenyl) -triazole) -oleanolic acid
The intermediate 3 α -azido-oleanolic acid (481mg, 1mmol), 3-methylphenylacetylene (116mg,1mmol), and catalyst CuI (9.5mg, 5% mol) were mixed in 10ml of ethanol and reacted with stirring at room temperature for half an hour. The product was purified by column chromatography to give 191mg (31%) of compound as a white solid. The product was characterized as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.18-7.78(m,5H),5.19(t,J＝3.5Hz,1H),3.44(m,1H),2.46(s,3H),2.43–2.34(m,1H),2.23–2.19(m,1H),2.00–1.96(m,2H),1.84–1.78(m,2H),1.75–1.68(m,3H),1.60–1.53(m,6H),1.41–1.39(m,2H),1.34–1.28(m,4H),1.21–1.16(m,2H),1.01(s,3H),0.92(s,3H),0.91(s,3H),0.89(s,3H),0.87(s,3H),0.86(s,3H),0.84(s,3H).HR-MS(ESI):[M+H]+ C39H56N3O2 calculated 598.4373, found 598.4351.
Example 3: 3 alpha- (4- (4-fluorophenyl) -triazole) -oleanolic acid
Intermediate 3 α -azido-oleanolic acid (481mg, 1mmol), 4-fluorophenylacetylene (120mg,1mmol), and catalyst CuI (9.5mg, 5% mol) were mixed in 10ml ethanol and stirred at room temperature for half an hour to react. The product was purified by column chromatography to give compound 210mg (35%) as a white solid. The product was characterized as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.31-7.86(m,5H),5.19(t,J＝3.5Hz,1H),3.44(m,1H),2.43–2.34(m,1H),2.23–2.19(m,1H),2.00–1.96(m,2H),1.84–1.78(m,2H),1.75–1.68(m,3H),1.60–1.53(m,6H),1.41–1.39(m,2H),1.34–1.28(m,4H),1.21–1.16(m,2H),1.01(s,3H),0.92(s,3H),0.91(s,3H),0.89(s,3H),0.88(s,3H),0.87(s,3H),0.84(s,3H).HR-MS(ESI):[M+H]+ C38H53FN3O2 calculated 602.4122, found 602.4187.
Example 4: 3 alpha- (4- (4-phenyl) -triazole) -oleanolic acid
The intermediate 3 α -azido-oleanolic acid (481mg, 1mmol), 4-ethynylbiphenyl (178mg,1mmol) and catalyst CuI (9.5mg, 5% mol) were mixed in 10ml ethanol and stirred at room temperature for half an hour to react. The product was purified by column chromatography to give compound 329mg (50%) as a white solid. The product was characterized as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.59-8.21(m,10H),5.19(t,J＝3.5Hz,1H),3.44(m,1H),2.43–2.34(m,1H),2.23–2.19(m,1H),2.00–1.96(m,2H),1.84–1.78(m,2H),1.75–1.68(m,3H),1.60–1.53(m,6H),1.41–1.39(m,2H),1.34–1.28(m,4H),1.21–1.16(m,2H),1.01(s,3H),0.92(s,3H),0.88(s,3H),0.87(s,3H),0.84(s,3H).HR-MS(ESI):[M+H]+ C44H58N3O2 calculated 660.4529, found 660.4585.
Example 5: 3 alpha- (4- (3-fluoro-4-chlorophenyl) -triazole) -oleanolic acid
The intermediate 3 α -azido-oleanolic acid (481mg, 1mmol), 3 fluoro-4-chlorophenylacetylene (154mg,1mmol) and catalyst CuI (9.5mg, 5% mol) were mixed in 10ml ethanol and stirred at room temperature for half an hour to react. The product was purified by column chromatography to give 191mg (31%) of compound as a white solid. The product was characterized as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.46-7.75(m,4H),5.19(t,J＝3.5Hz,1H),3.44(m,1H),2.43–2.34(m,1H),2.23–2.19(m,1H),2.00–1.96(m,2H),1.84–1.78(m,2H),1.75–1.68(m,3H),1.60–1.53(m,6H),1.41–1.39(m,2H),1.34–1.28(m,4H),1.21–1.16(m,2H),1.01(s,3H),0.92(s,3H),0.91(s,3H),0.89(s,3H),0.88(s,3H),0.87(s,3H),0.84(s,3H).HR-MS(ESI):[M+H]+ C38H52ClFN3O2 calculated 636.3732, found 636.3741.
Example 6: 3 alpha- (4- (4-mesylate phenyl) -triazole) -oleanolic acid
The intermediate 3 α -azido-oleanolic acid (481mg, 1mmol), 4-methanesulfonate phenylacetylene (196mg,1mmol), and catalyst CuI (9.5mg, 5% mol) were mixed in 10ml ethanol and stirred at room temperature for half an hour to react. The product was purified by column chromatography to give 189mg (28%) of compound as a white solid. The product was characterized as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.59-7.82(m,5H),5.19(t,J＝3.5Hz,1H),3.53(s,3H),3.44(m,1H),2.43–2.34(m,1H),2.23–2.19(m,1H),2.00–1.96(m,2H),1.84–1.78(m,2H),1.75–1.68(m,3H),1.60–1.53(m,6H),1.41–1.39(m,2H),1.34–1.28(m,4H),1.21–1.16(m,2H),1.01(s,3H),0.92(s,3H),0.91(s,3H),0.89(s,3H),0.88(s,3H),0.87(s,3H),0.84(s,3H).HR-MS(ESI):[M+H]+ C39H56N3O5S Calcd 678.3941, found 678.3986。
Example 7: hyaluronidase inhibitory Activity screening test
The experimental method comprises the following steps:hyaluronidase is derived from bovine testis, and hyaluronidase inhibitory activity screening references (Molecules, 2020; 25: 1923). 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 assay, bovine serum albumin was added to 20mM PBS, pH3.75 to a final concentration of 0.01%, which was the 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 1mL of a stop solution (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. The compound Vcpal (L-ascorbyl acid 6-hexadecanoate) is an activity screening control compound.
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 in vitro hyaluronidase inhibition activity shows that the 3 alpha-triazole oleanolic acid derivative has the obviously improved hyaluronidase inhibition activity. Wherein the inhibitory activity IC of compound Q5 on hyaluronidase 50 1.3. mu.g/mL, isThe most active inhibitors in the series. The inhibitory activity of the compound Q4 and Q5 is enhanced by more than 10 times compared with that of oleanolic acid. Other modified compounds also had more than 5-fold enhanced hyaluronidase inhibitory activity.
TABLE 1 inhibitory Activity of various Oleanolic acid derivatives on Hyaluronidase
Example 8: detection of skin permeability of compounds
The experimental method comprises the following steps:the present invention uses the software SwissADE (http:// www.swisadme.ch /) to make predictions of skin permeability. The specific operation was calculated according to the software application 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 are as follows:
the results are shown in Table 2, and the Logk of the oleanolic acid compound is calculated by adopting a computer simulation method p The more negative this constant is, the less likely it is that the compound is able to penetrate the skin. According to the results of the calculation, it can be seen that the other 5 oleanolic acid derivatives except the compound Q6 have better skin penetration effect than oleanolic acid OA, and thus are more suitable for being applied to the skin to inhibit skin aging. Compound Q4 had the best skin penetration effect.
Table 2: logk calculated for various compounds p
Example 9: thin and thinScreening 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. Test compounds were added to each well at different concentrations 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:
results are shown in table 3, and cell experiment tests show that 63 alpha-triazole-oleanolic acid derivatives have no obvious cytotoxicity at higher concentration. Therefore, the 63 alpha-triazole-oleanolic acid derivatives are suitable for preparing beauty products.
Table 3: cytotoxicity of various compounds on mammalian cells
Example 10: compound Q4 used as anti-skin aging component for preparing facial 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 international Nomenclature of Cosmetic materials.
Combined with the inhibitory activity of compound Q4 on hyaluronidase, the cytotoxicity of Q4, the skin permeability of Q4, it was selected as an anti-skin aging active ingredient for the preparation of cosmetic masks.
Phase A: 90.98 parts of water, 2 parts of glycerol, 0.3 part of p-hydroxyacetophenone, 0.16 part of carbomer, 0.05 part of sodium hyaluronate, 0.05 part of hydroxyethyl cellulose, 0.03 part of EDTA disodium, 0.1 part of dipotassium glycyrrhizinate, 261 parts of glyceryl polyether, 0.4 part of 1, 2-hexanediol and 0.5 part of nicotinamide;
phase B: 3 parts of water and 0.12 part of triethanolamine;
and C phase: 40.1 parts of compound Q and 1 part of ethanol
Phase D: 0.1 part of phenoxyethanol, 0.01 part of essence for daily use 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 1 g. Mixing the phase A components, homogenizing for 5 minutes (2000r/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 (8)
1. The 3 alpha-triazole-oleanolic acid compound is characterized by having a structure shown in a general formula (I):
wherein R is a ，R b ，R c ，R d ，R e Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, mercapto, amino, cyano, nitro, azido, carboxamido, methanesulfonyl, isopropylsulfonyl, methanesulfonate, isopropylsulfonate, methoxy, trifluoromethyl, trifluoromethyloxy, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, phenyl, naphthyl.
2. Root of herbaceous plantThe 3 alpha-triazole-oleanolic acid compound of claim 1, wherein in the general formula (I), R is a ，R b ，R c ，R d ，R e Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, nitro, azido, methylsulfonyl, methoxy, trifluoromethyl, phenyl, naphthyl, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl group.
3. The 3 alpha-triazole-oleanolic acid compound of claim 1 or claim 2, wherein the compound is selected from the following structures:
4. a compound composition, characterized in that the compound composition comprises the 3 α -triazole-oleanolic acid compound according to any one of claims 1 to 3, or a chemically acceptable salt thereof; the compound composition also comprises auxiliary materials acceptable in the field of cosmetics.
5. The preparation method of the 3 alpha-triazole-oleanolic acid compounds as claimed in any one of claims 1 to 3, wherein the preparation method comprises the following steps:
various substituted phenylacetylenes with the structural formula
Mixing 3 alpha-azido-oleanolic acid and a catalyst CuI for reaction to obtain the product; wherein the substituent group R a ，R b ，R c ，R d ，R e Is in accordance with the scope defined in any one of claims 1 to 3;
the reaction formula is shown as follows:
6. the preparation method of the 3 alpha-triazole-oleanolic acid compounds according to claim 5, wherein the preparation method of the 3 alpha-azide-oleanolic acid compounds is as follows:
(1) mixing 3 beta-oleanolic acid and methylsulfonyl chloride in pyridine solvent, and reacting at low temperature to obtain 3 beta-methanesulfonic acid-oleanolic acid;
(2) mixing 3 beta-methanesulfonic acid-oleanolic acid and sodium azide in DMF, reacting to obtain 3 alpha-azide-oleanolic acid,
the reaction formula is shown as follows:
7. use of the 3 α -triazole-oleanolic acid compounds of any one of claims 1 to 3 or the compound composition of claim 4 in the preparation of cosmetics for delaying skin aging by inhibiting hyaluronidase activity.
8. An anti-skin aging facial mask is characterized in that: the facial mask comprises the compound of any one of claims 1-3 or the compound composition of claim 4, and the formula and the parts by weight of the facial mask are as follows:
phase A: 90.98 parts of water, 2 parts of glycerol, 0.3 part of p-hydroxyacetophenone, 0.16 part of carbomer, 0.05 part of sodium hyaluronate, 0.05 part of hydroxyethyl cellulose, 0.03 part of EDTA disodium, 0.1 part of dipotassium glycyrrhizinate, 261 parts of glycerol polyether, 0.4 part of 1, 2-hexanediol and 0.5 part of nicotinamide;
phase B: 3 parts of water and 0.12 part of triethanolamine;
and C phase: 0.1 part of the compound of any one of claims 1 to 3 or the compound composition of claim 4, 1 part of ethanol;
phase D: 0.1 part of phenoxyethanol, 0.01 part of daily essence and 0.1 part of PEG-40 hydrogenated castor oil.
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| PCT/CN2022/123991 WO2023151292A1 (en) | 2022-02-11 | 2022-10-09 | 3α-OLEANOLIC ACID DERIVATIVES AS HYALURONIDASE INHIBITORS AND USES THEREOF IN COSMETIC PRODUCTS |
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| CN106967146A (en) * | 2017-05-16 | 2017-07-21 | 烟台大学 | Oleanolic acid terazole derivatives and its production and use |
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| CN114456225B (en) * | 2022-02-11 | 2022-09-09 | 北京青颜博识健康管理有限公司 | 3 alpha-oleanolic acid derivative serving as hyaluronidase inhibitor and application of derivative in cosmetic product |
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| CN106366151A (en) * | 2016-08-25 | 2017-02-01 | 沈阳药科大学 | Oleanolic acid-3-one derivative having antitumor effects, preparation method, and application thereof |
| CN106967146A (en) * | 2017-05-16 | 2017-07-21 | 烟台大学 | Oleanolic acid terazole derivatives and its production and use |
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| Title |
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| Friedelane triterpenoids: transformations toward A-ring modifications including 2-homoderivatives;Jayanta Das,et al.;《New J. Chem.》;20180306;第42卷;第6673-6688页 * |
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