WO2023151292A1 - 作为透明质酸酶抑制剂的3α-齐墩果酸衍生物及其在美容产品中的应用 - Google Patents

作为透明质酸酶抑制剂的3α-齐墩果酸衍生物及其在美容产品中的应用 Download PDF

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WO2023151292A1
WO2023151292A1 PCT/CN2022/123991 CN2022123991W WO2023151292A1 WO 2023151292 A1 WO2023151292 A1 WO 2023151292A1 CN 2022123991 W CN2022123991 W CN 2022123991W WO 2023151292 A1 WO2023151292 A1 WO 2023151292A1
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oleanolic acid
triazole
parts
compound
acid derivatives
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PCT/CN2022/123991
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English (en)
French (fr)
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姜燕飞
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北京青颜博识健康管理有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63—Steroids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/673—Vitamin B group
    • A61K8/675—Vitamin B3 or vitamin B3 active, e.g. nicotinamide, nicotinic acid, nicotinyl aldehyde
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/731—Cellulose; Quaternized cellulose derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
    • A61K2800/782—Enzyme inhibitors; Enzyme antagonists
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a 3 ⁇ -triazole-oleanolic acid derivative and a preparation method thereof, as well as its use as an inhibitor of hyaluronidase and for making cosmetic products, belonging to the field of cosmetics.
  • Hyaluronic acid belongs to glycosaminoglycans and is mainly distributed in the skin, brain and central nervous system.
  • Hyaluronic acid is an essential structural element in the formation of the human body.
  • Hyaluronic acid can help some specific proteins fix their desired positions in the body, thus playing a key role in tissue structure.
  • the concentration of hyaluronic acid is mainly determined by the ratio of its enzymatic synthesis by hyaluronan synthase and enzymatic degradation by hyaluronidase ongoing.
  • Hyaluronidase (EC 3.2.1.35) is an important enzyme that can degrade hyaluronic acid and can hydrolyze the 1 between N-acetyl- ⁇ -D-glucosamine and D-glucuronic acid in hyaluronic acid 4 connection keys.
  • Hyaluronidase can effectively degrade hyaluronic acid, causing relaxation of subcutaneous tissue, and the final reaction is skin aging. 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.
  • Natural products are an important source of hyaluronidase inhibitors.
  • oleanolic acid can effectively inhibit the activity of hyaluronidase (IC 50 is about 50 ⁇ g/mL).
  • Oleanolic acid Oleanolic Acid, OA
  • Oleanolic Acid, OA is a pentacyclic triterpenoid that exists in many plants ( Figure 1). It is a bioactive ingredient present in numerous plant extracts and is commonly used as a cosmeceutical ingredient in various skin care products.
  • Relevant biological studies have shown that oleanolic acid has anti-inflammatory, antioxidant and anti-aging activities, so the use of oleanolic acid can help improve the youthful state of the skin.
  • oleanolic acid has become a commonly used hepatoprotective drug in clinic. It has obvious protective effect on the acute liver damage caused by CCl4 in rats, can reduce the elevated ALT and AST, reduce inflammation, necrosis and interstitial inflammatory response, and prevent Fibrosis formation, promote the regeneration of liver cells, accelerate the recovery of necrotic tissue.
  • oleanolic acid has the effects of anti-inflammatory, cardiac strengthening, diuresis, increasing white blood cells, lowering blood sugar and promoting immune function.
  • Modifying the structure of oleanolic acid can further improve its inhibitory activity against hyaluronidase.
  • the main purpose of the present invention is to provide a class of 3 ⁇ -substituted oleanolic acid derivatives and their preparation methods and applications.
  • the present invention develops a class of oleanolic acid derivatives substituted by 3 ⁇ -triazole, which has significantly enhanced hyaluronidase inhibitory activity and can be used to develop anti-aging cosmetic products.
  • the present invention includes the following technical solutions:
  • the present invention provides a 3 ⁇ -triazole-oleanolic acid compound, the structure of which is shown in general formula (I):
  • R a , R b , R c , R d , Re are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, mercapto, amino, cyano, nitro, azido, formylamino, Methanesulfonyl, isopropylsulfonyl, mesylate, isopropylsulfonate, methoxy, trifluoromethyl, trifluoromethyloxy, C 1-8 alkyl, C 2-8 chain Alkenyl, C 2-8 alkynyl, phenyl, naphthyl.
  • 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 3 ⁇ -triazole-oleanolic acid compound involved in the present invention is a class of compounds with a new structure, and has significantly enhanced hyaluronidase inhibitory activity in vitro compared with oleanolic acid. Therefore, it can be used to prepare anti-aging cosmetics.
  • R a , R b , R c , R d , and Re are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, nitro, azido, methylsulfonyl, Mesylate, methoxy, trifluoromethyl, phenyl, naphthyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl.
  • 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.
  • the 3 ⁇ -triazole-oleanolic acid compound is selected from the following compound structures:
  • the present invention provides a compound composition, which comprises the 3 ⁇ -triazole-oleanolic acid compound, its stereoisomer, and its chemically acceptable compound as described in the first aspect. one or more salts;
  • the compound composition also includes cosmetically acceptable excipients, such as carriers, diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, cosolvents, solubilizers , Osmotic pressure regulator, surfactant, colorant, pH regulator, antioxidant, bacteriostat or buffer, etc.
  • cosmetically acceptable excipients such as carriers, diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, cosolvents, solubilizers , Osmotic pressure regulator, surfactant, colorant, pH regulator, antioxidant, bacteriostat or buffer, etc.
  • the chemically acceptable salt of the 3 ⁇ -triazole-oleanolic acid compound involved in the present invention is a salt formed by a 3 ⁇ -triazole-oleanolic acid 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.
  • the present invention provides a method for preparing 3 ⁇ -triazole-oleanolic acid compounds:
  • Will be substituted phenylacetylene, such as 3 ⁇ -azido-oleanolic acid is mixed with the catalyst CuI and reacted to obtain it; wherein the limited ranges of the substituents R a , R b , R c , R d , and R e are consistent with those defined in the first aspect;
  • the preparation method of 3 ⁇ -azido-oleanolic acid compounds is as follows:
  • the present invention provides a 3 ⁇ -triazole-oleanolic acid compound as described in the first aspect, or the compound composition as described in the second aspect is prepared by inhibiting the activity of hyaluronidase Use in cosmetics to delay skin aging.
  • the present invention provides an anti-aging skin mask, which includes the compound described in the first aspect or the compound composition described in the second aspect, and the formula and parts by weight of the mask are as follows:
  • Phase A 90.98 parts of water, 2 parts of glycerin, 0.3 parts of p-hydroxyacetophenone, 0.16 parts of carbomer, 0.05 parts of sodium hyaluronate, 0.05 parts of hydroxyethyl cellulose, 0.03 parts of disodium EDTA, dipotassium glycyrrhizinate 0.1 part, glycerol polyether-261 part, 0.4 part of 1,2-hexanediol, 0.5 part of nicotinamide;
  • Phase B 3 parts of water, 0.12 parts of triethanolamine
  • Phase C 0.1 part of the compound described in the first aspect or the compound composition described in the second aspect, 1 part of ethanol
  • Phase D 0.1 part of phenoxyethanol, 0.01 part of (daily) essence, 0.1 part of PEG-40 hydrogenated castor oil.
  • Figure 1 Structure of oleanolic acid and numbering of carbon atoms.
  • the structures of the compounds were determined by proton nuclear magnetic resonance spectroscopy ( 1 H NMR) or mass spectroscopy (MS). Proton NMR shifts ( ⁇ ) are given in parts per million (ppm).
  • the nuclear magnetic resonance spectrum is measured with a Mercury-400 type nuclear magnetic resonance instrument, deuterated chloroform (CDCl 3 ) is used as a solvent, and tetramethylsilane (TMS) or 3-(trimethylsilyl) deuterated sodium propionate (TSM) is used as an internal mark.
  • the electronic balance adopts the Japanese Yanaco LY-300 electronic balance.
  • This preparation example prepares 3 ⁇ -azido-oleanolic acid, and the synthetic route is:
  • Embodiment 1 This embodiment prepares 3 ⁇ -(4-phenyl-triazole)-oleanolic acid, its structural formula is as follows:
  • Example 7 Screening test for hyaluronidase inhibitory activity
  • 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.
  • 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.
  • 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 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 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 ⁇ L 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.
  • Example 10 Compound Q4 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:
  • Phase A 90.98 parts of water, 2 parts of glycerin, 0.3 parts of p-hydroxyacetophenone, 0.16 parts of carbomer, 0.05 parts of sodium hyaluronate, 0.05 parts of hydroxyethyl cellulose, 0.03 parts of disodium EDTA, dipotassium glycyrrhizinate 0.1 part, glycerol polyether-261 part, 0.4 part of 1,2-hexanediol, 0.5 part of nicotinamide;
  • Phase B 3 parts of water, 0.12 parts of triethanolamine
  • Phase C 0.1 part of compound Q4, 1 part of ethanol
  • Phase D 0.1 part of phenoxyethanol, 0.01 part of (daily) essence, 0.1 part of PEG-40 hydrogenated castor oil;
  • 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.

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Abstract

本发明涉及3α-三氮唑-齐墩果酸类衍生物及其制备方法，以及其作为透明质酸酶的抑制剂和用于制作抗衰老类美容产品的用途。具体而言，本发明公开了一系列3α-三氮唑-齐墩果酸衍生物，结构如通式(I)所述，及其制备方法。体外活性检测表明这类齐墩果酸衍生物具有较强的透明质酸酶抑制活性，IC 50约1-10μg/mL，抑制活性明显强于齐墩果酸，IC 50约56μg/mL。细胞增殖实验表明3α-三氮唑-齐墩果酸衍生物具有非常低的哺乳动物细胞毒性。3α-三氮唑-齐墩果酸衍生物具有较好的脂溶性，易被皮肤组织吸收，可作为抗衰老成分用于制作美容产品。本发明也公开了采用3α-三氮唑-齐墩果酸衍生物作为美容成分来制备一种抗皮肤衰老类面膜的用途。

Description

作为透明质酸酶抑制剂的3α-齐墩果酸衍生物及其在美容产品中的应用
相关申请的交叉引用
本申请要求2022年02月11日提交的中国申请号202210129217.7的权益。所述申请号202210129217.7据此全文以引用方式并入本文。
技术领域
本发明涉及一种3α-三氮唑-齐墩果酸衍生物及其制备方法，以及其作为透明质酸酶的抑制剂和用来制作美容产品的用途，属于化妆品领域。
背景技术
透明质酸属于糖胺聚糖，主要分布在皮肤、大脑和中枢神经系统中。透明质酸是形成人体一种必不可少的结构元素，透明质酸可以帮助一些特定蛋白质固定体内所需位置，从而在组织结构中发挥关键作用。在哺乳动物中，尤其是人类，透明质酸浓度主要取决于其酶促合成和酶促降解的比值，其中酶促合成是通过透明质酸合成酶进行的，酶促降解是通过透明质酸酶进行的。透明质酸酶(EC 3.2.1.35)是一种重要的酶，可降解透明质酸并可以水解透明质酸中N-乙酰-β-D-葡萄糖胺和D-葡萄糖醛酸之间的1,4连接键。透明质酸酶能够有效的降解透明质酸，造成皮下组织的松弛，最终反应为皮肤的衰老。所以，抑制透明质酸酶的活性能够有效提升组织中透明质酸的浓度，最终的效果就是，延缓皮肤的松弛与衰老。
天然产物是透明质酸酶抑制剂的重要来源，研究发现齐墩果酸能够有效的抑制透明质酸酶的活性(IC 50约50μg/mL)。齐墩果酸(Oleanolic Acid,OA)是一种在很多植物中存在的五环三萜类化合物(图1)。它是众多植物提取物中存在的生物活性成分，通常用作各种护肤产品的药妆成分。相关的生物学研究表明齐墩果酸具有抗炎、抗氧化和抗皮肤老化活性，所以齐墩果酸的 使用有助于改善皮肤的年轻状态。研究也表明，齐墩果酸的抗皮肤老化作用可能归因于其对几种与皮肤皱纹形成相关酶的抑制作用相关，如透明质酸酶。齐墩果酸已成为临床上常用的保肝药物，对CCl 4引起的大鼠急性肝损害有明显保护作用，可使升高的ALT和AST下降，炎症、坏死和间质炎症反应减轻，阻止纤维化形成，促进肝细胞的再生，加速坏死组织的恢复作用。另外，齐墩果酸具有消炎、强心、利尿、升高白细胞、降血糖和促进免疫功能等作用。
对于齐墩果酸结构进行修饰改造能够进一步提高其对透明质酸酶的抑制活性。我们采用各种经典的化学修饰策略对于齐墩果酸结构的羟基和羧酸进行修饰改造，经过透明质酸酶抑制活性的测定评价，最终选定对于3β-OH基团所在的末端进行改造，从而获得新的3α-取代的齐墩果酸衍生物。
发明内容
针对齐墩果酸具有偏弱的透明质酸酶抑制活性，对其结构进行优化，从而增强其衍生物对于透明质酸酶的抑制活性。本发明的主要目的在于提供一类3α-取代的齐墩果酸衍生物及其制备方法和应用。本发明开发了一类3α-三氮唑取代的齐墩果酸衍生物，且其具有显著增强的透明质酸酶抑制活性，可用于开发抗皮肤衰老的美容产品。
为了达到此目的，本发明包括以下技术方案：
第一方面，本发明提供一种3α-三氮唑-齐墩果酸类化合物，所述的结构如通式(I)所示：
Figure PCTCN2022123991-appb-000001
其中，R a，R b，R c，R d，R e各自独立选自氢、氘、氟、氯、溴、羟基、巯基、氨基、氰基、硝基、叠氮基、甲酰氨基、甲磺酰基、异丙磺酰基、甲磺酸酯基、异丙磺酸酯基、甲氧基、三氟甲基、三氟甲基氧基、C 1-8烷基、C 2-8链烯基、C 2-8链炔基、苯基、萘基。
上述C 1-8是指取代基的碳原子数为1个、2个、3个、4个、5个、6个、7个、8个；C 2-8是指取代基的碳原子数为2个、3个、4个、5个、6个、7个、8个。
本发明所涉及的3α-三氮唑-齐墩果酸类化合物是一类全新结构的化合物，且其体外具有较齐墩果酸明显增强的透明质酸酶抑制活性。因此可以用来制备抗皮肤衰老的化妆品。
优选地，通式(I)中，R a，R b，R c，R d，R e各自独立的选自氢、氘、氟、氯、溴、硝基、叠氮基、甲磺酰基、甲磺酸酯基、甲氧基、三氟甲基、苯基、萘基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基。
上述C 1-4是指取代基的碳原子数为1个、2个、3个、4个；C 2-4是指取代基的碳原子数为2个、3个、4个。
进一步优选地，所述3α-三氮唑-齐墩果酸类化合物选自如下所述的化合物结构：
Figure PCTCN2022123991-appb-000002
Figure PCTCN2022123991-appb-000003
第二方面，本发明提供一种化合物组合物，所述化合物组合物包含如第一方面所述的3α-三氮唑-齐墩果酸类化合物、其立体异构体、其化学上可接受的盐的一种或多种；
优选地，所述化合物组合物还包含化妆品领域可接受的辅料，例如载体、稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、乳化剂、助溶剂、增溶剂、渗透压调节剂、表面活性剂、着色剂、pH调节剂、抗氧剂、抑菌剂或缓冲剂等。
本发明所涉及的3α-三氮唑-齐墩果酸类化合物的化学上可接受的盐为 3α-三氮唑-齐墩果酸类化合物与选自如下的碱形成的盐：接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等；可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠。
第三方面，本发明提供3α-三氮唑-齐墩果酸类化合物的制备方法：
将取代的苯乙炔，如
Figure PCTCN2022123991-appb-000004
3α-叠氮-齐墩果酸，催化剂CuI混合，反应，即得；其中取代基团R a，R b，R c，R d，R e的限定范围与第一方面限定的范围一致；
其反应式如下所示：
Figure PCTCN2022123991-appb-000005
优选地，3α-叠氮-齐墩果酸类化合物的制备方如下所述：
(1)3β-齐墩果酸、甲基磺酰氯在吡啶溶剂中混合，低温反应，得到3β-甲基磺酸-齐墩果酸；
(2)3β-甲基磺酸-齐墩果酸与叠氮钠在DMF中混合，反应得到3α-叠氮-齐墩果酸，
其反应式如下所示：
Figure PCTCN2022123991-appb-000006
第四方面，本发明提供一种如第一方面所述的3α-三氮唑-齐墩果酸类化 合物，或者如第二方面所述的化合物组合物在制备通过抑制透明质酸酶活性而延缓皮肤衰老的化妆品中的用途。
第五方面，本发明提供一种抗皮肤衰老类面膜，所述面膜包含第一方面所述的化合物或第二方面所述的化合物组合物，所述面膜的配方和重量份如下：
A相：水90.98份、甘油2份、对羟基苯乙酮0.3份、卡波姆0.16份、透明质酸钠0.05份、羟乙基纤维素0.05份、EDTA二钠0.03份、甘草酸二钾0.1份、甘油聚醚-261份、1，2-己二醇0.4份、烟酰胺0.5份；
B相：水3份、三乙醇胺0.12份；
C相：第一方面所述的化合物或第二方面所述的化合物组合物0.1份、乙醇1份
D相：苯氧乙醇0.1份、(日用)香精0.01份、PEG-40氢化蓖麻油0.1份。
附图说明
图1：齐墩果酸的结构及碳原子命名的编号。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本发明，不应视为对本发明的具体限制。对于以下全部实施例或制备例，可以使用本领域技术人员已知的标准操作和纯化方法。除非另有说明，所有温度以℃(摄氏度)表示，化合物的结构是通过核磁共振谱(NMR)和/或质谱(MS)来确定。
对于以下全部实施例或制备例，化合物的结构是通过核磁共振氢谱( 1H NMR)或质谱(MS)来确定的。核磁共振氢谱位移(δ)以百万分之一(ppm)的单位给出。核磁共振谱用Mercury-400型核磁共振仪测定，氘代氯仿(CDCl 3) 作溶剂，四甲基硅烷(TMS)或3-(三甲基硅基)氘代丙酸钠(TSM)为内标。
电子天平采用日本Yanaco LY-300型电子天平。
柱层析使用200～300目或300～400目硅胶为载体。
无水溶剂均通过标准方法处理。其它试剂均为市售分析纯分别购于Sigma-Aldrich西格玛奥德里奇(上海)贸易有限公司、阿法埃莎(中国)化学有限公司、北京伊诺凯科技有限公司、上海陶素生化科技有限公司。
制备例1：3α-叠氮-齐墩果酸
本制备例制备3α-叠氮-齐墩果酸，合成路线为：
Figure PCTCN2022123991-appb-000007
(1)将3β-齐墩果酸(912mg，2mmol)溶于8ml吡啶和1ml DCM的溶剂，将上述溶剂通过干冰/乙醇的冰浴冷却至-38℃，之后缓慢向反应液中逐滴滴加提前混合好的1ml干燥的含有甲磺酰氯(154μl,2mmol)的DCM。将反应混合物在-38℃搅拌1小时，然后在0℃再搅拌2小时。通过添加10ml H 2O淬灭反应。将反应产物通过旋蒸处理，之后通过柱色谱纯化，得到白色固体纯产物480.6mg(45％)，为3β-甲基磺酸-齐墩果酸。对产物进行如下表征： 1HNMR(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计算值535.3457,实测值535.3489。
(2)将3mmol 3β-甲基磺酸-齐墩果酸和6mmol叠氮钠混匀于30ml干 燥DMF中，加热至60℃并反应过夜。将反应混合物旋蒸去除DMF，之后采用DCM/甲醇从反应混合物中提取反应物。对于不溶物因为含有未反应的叠氮钠，需要用20％NaNO 2溶液中和至pH 6。然后将可溶性溶液与乙醇和甲苯再次共蒸发，将溶液置于高真空中以蒸发剩余的DMF过夜，粗产物通过柱色谱法纯化，得到化合物591mg(41％)，为固体3α-叠氮-齐墩果酸。对产物进行如下表征： 1H 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计算值482.3747,实测值482.3795。
实施例1：本实施例制备3α-(4-苯基-三氮唑)-齐墩果酸，其结构式如下：
Figure PCTCN2022123991-appb-000008
将中间体3α-叠氮-齐墩果酸(481mg，1mmol)，苯乙炔(102mg,1mmol)，与催化剂CuI(9.5mg,5％mol)混合于10ml乙醇中，室温下搅拌半个小时反应。产物通过柱色谱法纯化，得到化合物239mg(41％)，为白色固体。对产物进行如下表征： 1H 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计算值584.4216,实 测值584.4255。
实施例2：3α-(4-(3-甲基苯基)-三氮唑)-齐墩果酸
Figure PCTCN2022123991-appb-000009
将中间体3α-叠氮-齐墩果酸(481mg，1mmol)，3-甲基苯乙炔(116mg,1mmol)，与催化剂CuI(9.5mg,5％mol)混合于10ml乙醇中，室温下搅拌反应半个小时。产物通过柱色谱法纯化，得到化合物191mg(31％)，为白色固体。对产物进行如下表征： 1H 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计算值598.4373,实测值598.4351。
实施例3：3α-(4-(4-氟苯基)-三氮唑)-齐墩果酸
Figure PCTCN2022123991-appb-000010
将中间体3α-叠氮-齐墩果酸(481mg，1mmol)，4-氟苯乙炔(120mg,1mmol)，与催化剂CuI(9.5mg,5％mol)混合于10ml乙醇中，室温下搅拌半个小时反应。产物通过柱色谱法纯化，得到化合物210mg(35％)，为白色固体。对产物进行如下表征： 1H 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计算值602.4122,实测值602.4187。
实施例4：3α-(4-(4-苯基苯基)-三氮唑)-齐墩果酸
Figure PCTCN2022123991-appb-000011
将中间体3α-叠氮-齐墩果酸(481mg，1mmol)，4-乙炔联苯(178mg,1mmol)，与催化剂CuI(9.5mg,5％mol)混合于10ml乙醇中，室温下搅拌半个小时反应。产物通过柱色谱法纯化，得到化合物329mg(50％)，为白色固体。对产物进行如下表征： 1H 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计算值660.4529,实测值660.4585。
实施例5：3α-(4-(3氟-4氯苯基)-三氮唑)-齐墩果酸
Figure PCTCN2022123991-appb-000012
将中间体3α-叠氮-齐墩果酸(481mg，1mmol)，3氟-4氯苯乙炔(154mg, 1mmol)，与催化剂CuI(9.5mg,5％mol)混合于10ml乙醇中，室温下搅拌半个小时反应。产物通过柱色谱法纯化，得到化合物191mg(31％)，为白色固体。对产物进行如下表征： 1H 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计算值636.3732,实测值636.3741。
实施例6：3α-(4-(4-甲磺酸酯苯基)-三氮唑)-齐墩果酸
Figure PCTCN2022123991-appb-000013
将中间体3α-叠氮-齐墩果酸(481mg，1mmol)，4-甲磺酸酯苯乙炔(196mg,1mmol)，与催化剂CuI(9.5mg,5％mol)混合于10ml乙醇中，室温下搅拌半个小时反应。产物通过柱色谱法纯化，得到化合物189mg(28％)，为白色固体。对产物进行如下表征： 1H 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计算值678.3941,实测值678.3986。
实施例7：透明质酸酶抑制活性筛选试验
实验方法：透明质酸酶来源于牛睾丸，透明质酸酶抑制活性筛选参考文 献(Molecules,2020；25:1923)。值得注意的是，在低负离子条件下，长链透明质酸和透明质酸酶容易形成无活性的复合物，这会阻碍透明质酸酶的催化活性并干扰透明质酸酶抑制活性筛选试验。所以，在试验时应该避免添加过多的带正电荷的蛋白质从而干扰到缓冲液体系中的负离子浓度，这将恢复透明质酸酶的活性。具体试验时，在20mM PBS，pH 3.75中加入牛血清白蛋白至终浓度为0.01％，此为制备好的反应缓冲液。将5μL的样品(浓度范围为1-400μg/mL)与95μL含有透明质酸酶(7.5U/mL)反应液混匀，在37℃下孵育10分钟。然后将100μL透明质酸加入到上述反应液中，在37℃下继续孵育45分钟。降解反应后，通过加入含有1mL的终止液(含有0.1％BSA，24mM乙酸钠和79mM乙酸，pH＝3.75)，混匀10分钟后，没有降解的透明质酸通过沉淀进行去除。使用PE酶标仪检测600nm波长处的吸光值。每个样品至少重复进行测试三次。化合物Vcpal(L-ascorbic acid 6-hexadecanoate)是活性筛选对照化合物。
通过下面公式计算样品对透明质酸酶的抑制活性：
抑制活性(％)＝[1–(OD透明质酸–OD样品)/(OD透明质酸–OD透明质酸酶)]×100％
通过不同浓度的抑制活性计算IC 50，采用软件GraphPad Prism 8.0进行计算。
结果如下：体外透明质酸酶抑制活性筛选显示3α-三氮唑齐墩果酸衍生物具有明显提高的透明质酸酶抑制活性。其中化合物Q5对于透明质酸酶的抑制活性IC 50为1.3μg/mL，是这一系列中活性最强的抑制剂。化合物Q4,Q5的抑制活性较之齐墩果酸的抑制活性增强10倍以上。其他修饰的化合物也有5倍以上增强的透明质酸酶抑制活性。
表1，各种齐墩果酸衍生物对透明质酸酶的抑制活性
  透明质酸酶抑制IC 50
  μg/mL
Q1 11.2
Q2 8.3
Q3 7.3
Q4 2.4
Q5 1.3
Q6 9.8
OA 56
Vcpal 3.0
实施例8：化合物皮肤渗透性的检测
实验方法：本发明采用软件SwissADME(http：//www.swisadme.ch/)来进行皮肤渗透率的预测。具体操作遵照软件使用说明书进行计算。如下，将化合物的结构式或者SMILES复制到软件窗口，经过计算获得与皮肤渗透率相关的常数，Log K p。
结果如下：
结果如表2，我们采用计算机模拟的方法对齐墩果酸类化合物计算了其Log K p，这一常数所得到的负数越大，代表化合物能够透过皮肤的可能性越小。根据计算的结果可以看到，除了化合物Q6，其余5个齐墩果酸类衍生物均有比齐墩果酸OA更好皮肤渗透效果，因此更适合用于皮肤涂抹抑制皮肤衰老。化合物Q4具有最好的皮肤渗透效果。
表2：各种化合物计算获得的LogK p
Figure PCTCN2022123991-appb-000014
Figure PCTCN2022123991-appb-000015
实施例9：细胞毒性的筛选
实验方法：
采用CCK-8试剂盒进行了化合物细胞毒性的检测。具体操作为，分别接种HepG2细胞、MCF-7细胞、A549细胞，到96孔板中，每孔约5000细胞/200μL培养液，细胞过夜培养。向每孔中加入不同浓度的待测化合物，继续培养48小时。向每孔中加入10μL的CCK-8试剂，混匀后继续培养1-4小时，观察培养液颜色发生明显变化，采用酶标仪进行检测，测定450nm吸光值。紫杉醇为阳性对照物。
结果如下：
结果如表3，细胞实验检测发现，6个3α-三氮唑-齐墩果酸衍生物在较高浓度下没有明显的细胞毒性。因此，这6个3α-三氮唑-齐墩果酸衍生物适合用于制备美容产品。
表3：各种化合物对于哺乳动物细胞的细胞毒性
Figure PCTCN2022123991-appb-000016
Figure PCTCN2022123991-appb-000017
实施例10：化合物Q4作为抗皮肤衰老成分制备美容面膜
一种抗皮肤衰老面膜，其配方和重量份数如下：
文中出现的化妆品成分名称均为INCI(International Nomenclature of Cosmetic Ingredients)，即国际化妆品原料命名所规定的名称。
结合化合物Q4对于透明质酸酶的抑制活性，Q4的细胞毒性，Q4的皮肤渗透性，其选为抗皮肤衰老活性成分用于制备化妆品面膜。
A相：水90.98份、甘油2份、对羟基苯乙酮0.3份、卡波姆0.16份、透明质酸钠0.05份、羟乙基纤维素0.05份、EDTA二钠0.03份、甘草酸二钾0.1份、甘油聚醚-261份、1，2-己二醇0.4份、烟酰胺0.5份；
B相：水3份、三乙醇胺0.12份；
C相：化合物Q40.1份、乙醇1份
D相：苯氧乙醇0.1份、(日用)香精0.01份、PEG-40氢化蓖麻油0.1份；
制备方法，包括以下步骤：按照上述配方，称量各个组分，其中每个质量份为1g。将A相组分混合，均质5分钟(2000r/min)后搅拌加热至80℃，保持温度恒定80℃，继续搅拌5分钟；降温至45℃后边搅拌边加入B相，继续搅拌5分钟；加入C相和D相，继续搅拌混匀，冷却至25℃，灌装。
显然，本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。

Claims (8)

  1. 一种3α-三氮唑-齐墩果酸类化合物，其特征在于，具有通式(I)所示的结构：
    Figure PCTCN2022123991-appb-100001
    其中，R a，R b，R c，R d，R e各自独立选自氢、氘、氟、氯、溴、羟基、巯基、氨基、氰基、硝基、叠氮基、甲酰氨基、甲磺酰基、异丙磺酰基、甲磺酸酯基、异丙磺酸酯基、甲氧基、三氟甲基、三氟甲基氧基、C 1-8烷基、C 2-8链烯基、C 2-8链炔基、苯基、萘基。
  2. 根据权利要求1所述的3α-三氮唑-齐墩果酸类化合物，其特征在于，通式(I)中，R a，R b，R c，R d，R e各自独立的选自氢、氘、氟、氯、溴、硝基、叠氮基、甲磺酰基、甲磺酸酯基、甲氧基、三氟甲基、苯基、萘基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基。
  3. 根据权利要求1或权利要求2所述的3α-三氮唑-齐墩果酸类化合物，其特征在于，所述的化合物选自以下结构：
    Figure PCTCN2022123991-appb-100002
  4. 一种化合物组合物，其特征在于，所述化合物组合物包含权利要求1-3中任一项所述的3α-三氮唑-齐墩果酸类化合物、其立体异构体、其化学上可接受的盐的一种或多种；
    优选地，所述化合物组合物还包含化妆品领域可接受的辅料。
  5. 权利要求1-3中任一项所述的3α-三氮唑-齐墩果酸类化合物的制备方法，其特征在于，所述制备方法包括以下步骤：
    将各种取代的苯乙炔，结构式为
    Figure PCTCN2022123991-appb-100003
    3α-叠氮-齐墩果酸、催化剂CuI，混合反应，即得；其中取代基团R a，R b，R c，R d，R e的限定范围与权利要求1-3中任一项限定的范围一致；
    其反应式如下所示：
    Figure PCTCN2022123991-appb-100004
  6. 根据权利要求5所述的3α-三氮唑-齐墩果酸类化合物的制备方法，其特征在于，3α-叠氮-齐墩果酸类化合物的制备方如下所述：
    (1)3β-齐墩果酸、甲基磺酰氯在吡啶溶剂中混合，低温反应，得到3β-甲基磺酸-齐墩果酸；
    (2)3β-甲基磺酸-齐墩果酸与叠氮钠在DMF中混合，反应得到3α-叠氮-齐墩果酸，
    其反应式如下所示：
    Figure PCTCN2022123991-appb-100005
  7. 权利要求1-3中任一项所述的3α-三氮唑-齐墩果酸类化合物或者权利要求4所述的化合物组合物在制备通过抑制透明质酸酶活性而延缓皮肤衰老的化妆品中的用途。
  8. 一种抗皮肤衰老类面膜，其特征在于：所述面膜包含权利要求1-3中任一项所述的化合物或者权利要求4所述的化合物组合物，所述面膜的配方和重量份如下：
    A相：水90.98份、甘油2份、对羟基苯乙酮0.3份、卡波姆0.16份、透明质酸钠0.05份、羟乙基纤维素0.05份、EDTA二钠0.03份、甘草酸二钾0.1份、甘油聚醚-261份、1，2-己二醇0.4份、烟酰胺0.5份；
    B相：水3份、三乙醇胺0.12份；
    C相：权利要求1-3中任一项所述的化合物或者权利要求4所述的化合物 组合物0.1份、乙醇1份
    D相：苯氧乙醇0.1份、(日用)香精0.01份、PEG-40氢化蓖麻油0.1份。
PCT/CN2022/123991 2022-02-11 2022-10-09 作为透明质酸酶抑制剂的3α-齐墩果酸衍生物及其在美容产品中的应用 WO2023151292A1 (zh)

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