WO2023151293A1 - P-phenylcyclobutanamide rosemary compound as hyaluronidase inhibitor and application thereof in beauty product - Google Patents

P-phenylcyclobutanamide rosemary compound as hyaluronidase inhibitor and application thereof in beauty product Download PDF

Info

Publication number
WO2023151293A1
WO2023151293A1 PCT/CN2022/123993 CN2022123993W WO2023151293A1 WO 2023151293 A1 WO2023151293 A1 WO 2023151293A1 CN 2022123993 W CN2022123993 W CN 2022123993W WO 2023151293 A1 WO2023151293 A1 WO 2023151293A1
Authority
WO
WIPO (PCT)
Prior art keywords
rosemary
compound
parts
rosmarinic acid
preparation
Prior art date
Application number
PCT/CN2022/123993
Other languages
French (fr)
Chinese (zh)
Inventor
姜燕飞
Original Assignee
北京青颜博识健康管理有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 北京青颜博识健康管理有限公司 filed Critical 北京青颜博识健康管理有限公司
Publication of WO2023151293A1 publication Critical patent/WO2023151293A1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • 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
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • 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
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • the invention relates to a p-phenylcyclobutanamide rosemary compound and a preparation method thereof, as well as its use as a hyaluronidase inhibitor and for making beauty 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.
  • Rosmarinic acid (Rosmarinic acid, Figure 1) is a pentacyclic triterpenoid compound that exists in many plants, and it is a biological compound that exists in many plant extracts. Active ingredients, commonly used as cosmeceutical ingredients in various skin care products. Rosmarinic acid is a polyphenolic compound, a natural antioxidant with strong antioxidant activity, and rosmarinic acid has a very strong activity of scavenging free radicals in the body and antioxidant effect.
  • Rosmarinic acid has strong anti-inflammatory activity, such as anti-nephritis, anti-hepatitis, anti-pneumonia, etc. At the same time, rosmarinic acid also has antibacterial, antiviral, and antidepressant activities. At present, rosmarinic acid has shown its important application value in the fields of pharmacy, food and cosmetics. Studies have also shown that the anti-aging effects of rosmarinic acid may be attributed to its inhibitory effect on several enzymes associated with skin wrinkle formation, such as hyaluronidase. The inhibitory activity of rosmarinic acid on hyaluronidase is weak, and the IC 50 reported in the literature is about 309 ⁇ M.
  • the modification of rosmarinic acid improves its inhibitory activity against hyaluronidase. At the same time, if the obtained rosmarinic acid has higher fat solubility, it is easier to be absorbed by the skin and can be used as an active ingredient for anti-aging skin .
  • rosmarinic acid has a weak inhibitory activity on hyaluronidase, with an IC 50 of about 309 ⁇ M.
  • rosmarinic acid is poorly fat-soluble, making it difficult to penetrate the skin.
  • rosmarinic acid was used as the core to optimize its structure, thereby enhancing the inhibitory activity of its derivatives against hyaluronidase.
  • the newly synthesized compound has enhanced fat solubility, which is more conducive to the application in cosmetics.
  • the main purpose of the present invention is to provide a class of p-benzenecyclobutanamide rosemary compounds and their preparation method and application.
  • the invention develops a class of p-phenylcyclobutanamide rosemary compounds, which have 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 p-benzenecyclobutanamide rosemary compound, the structure of which is shown in general formula (I):
  • Ring A is independently selected from phenyl, naphthyl, and 5-14 membered aromatic heterocyclic groups
  • phenyl, naphthyl or 5-14 membered aromatic heterocyclic groups are unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from deuterium, hydroxyl, mercapto, Amino, formylamino, methylsulfonyl, isopropylsulfonyl, mesylate, isopropylsulfonate, trifluoromethyloxy, C 1-8 alkyloxy, C 2-8 alkenyl Cyloxy group, C 2-8 alkynyloxy group, C 1-8 alkylamine group.
  • 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 p-phenylcyclobutanamide rosmarinoid compound involved in the present invention is a class of compounds with a new structure, and it has significantly enhanced hyaluronidase inhibitory activity and enhanced fat solubility compared with rosmarinic acid in vitro. Therefore, it can be used to prepare anti-aging cosmetics.
  • ring A is independently selected from phenyl, naphthyl, indolyl, pyridyl, quinolinyl, furyl, thienyl, isoxazolyl, benzoxazolyl, Imidazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzofuranyl, benzimidazolyl;
  • aromatic ring groups or aromatic heterocyclic groups are unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents, and the substituents are selected from deuterium, hydroxyl, amino, formylamino, methylsulfonyl, Isopropylsulfonyl, mesylate, isopropylsulfonate, trifluoromethyloxy, C 1-4 alkyloxy, C 2-4 alkenyloxy, C 2-4 alkyne Base oxy group, C 1-4 alkylamine group.
  • 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.
  • ring A is independently selected from phenyl, naphthyl, indolyl, pyridyl, quinolinyl;
  • aromatic ring groups or aromatic heterocyclic groups are unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents, and the substituents are selected from deuterium, hydroxyl, amino, formylamino, methylsulfonyl, Isopropylsulfonyl, mesylate, isopropylsulfonate, trifluoromethyloxy, C 1-4 alkyloxy, C 1-4 alkylamine.
  • 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 p-benzenecyclobutanamide rosemary compound is selected from the following compound structures:
  • the present invention provides a compound composition, which comprises the p-benzenecyclobutanamide rosemary compound described in the first aspect above, its stereoisomers, and its chemically acceptable One or more salts;
  • the compound composition also includes acceptable adjuvants in the field of cosmetics, such as carriers, diluents, excipients, fillers, binders, wetting agents, disintegrants, Emulsifiers, co-solvents, solubilizers, osmotic pressure regulators, surfactants, colorants, pH regulators, antioxidants, bacteriostats or buffers, etc.
  • the chemically acceptable salt of the p-benzenecyclobutanamide rosemary compound involved in the present invention is a salt formed by a p-benzenecyclobutanamide rosemary 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 p-benzenecyclobutanamide rosemary compounds:
  • Equal amounts of p-bromophencyclobutanide rosemary and various boric acid compounds, such as Cesium carbonate, tetrabutylammonium bromide, and potassium tetrachloropalladate are mixed in a methanol solvent and reacted at 37°C for 6 hours to obtain the product; wherein the limited range of ring A is consistent with the limited range of any one of the first aspects, Its reaction formula is as follows:
  • the preparation side of p-bromophencyclobutanamide rosemary is as follows:
  • the present invention provides a p-benzenecyclobutanamide rosemary compound as described in the first aspect, or the compound composition as described in the second aspect in the preparation of delaying the treatment of the skin by inhibiting the activity of hyaluronidase. Uses in aging cosmetics.
  • the present invention provides an anti-aging skin mask
  • the mask contains 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 87.48 parts of water, 4 parts of 1,3-propanediol, 1 part of glycerin, 0.15 parts of methylparaben, 0.15 parts of carbomer, 0.1 part of sodium hyaluronate, 0.2 parts of disodium EDTA, 1,2-hexane 0.4 part of diol, 0.2 part of panthenol;
  • Phase B 5 parts of water, 0.1 part 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 (daily use) essence 0.02 parts, PEG-40 hydrogenated castor oil 0.1 parts
  • Figure 1 Structural formula of rosmarinic acid.
  • test materials used in the following examples are commercially available products unless otherwise specified.
  • This preparation example prepares p-bromophencyclobutanamide rosemary, and the synthetic route is:
  • Embodiment 1 This embodiment prepares N-[3-(4-(pyridin-4-yl)phenyl)cyclobutyl]rosmarinamide, whose structural formula is as follows:
  • Example 2 This example prepares N-[3-(4-(2-fluoropyridin-3-yl)phenyl)cyclobutyl]rosmarinamide, whose structural formula is as follows:
  • Embodiment 3 This embodiment prepares N-[3-(4-(quinolin-4-yl)phenyl)cyclobutyl]rosmarinamide, whose structural formula is as follows:
  • Embodiment 4 The present embodiment prepares N-[3-(4-(naphthalene-2-yl)phenyl)cyclobutyl]rosmarinamide, and its structural formula is as follows:
  • Embodiment 5 This embodiment prepares N-[3-(4-(3-aminophenyl)phenyl)cyclobutyl]rosmarinamide, whose structural formula is as follows:
  • Embodiment 6 This embodiment prepares N-[3-(4-(2-methylsulfonylphenyl)phenyl)cyclobutyl]rosmarinamide, whose structural formula is as follows:
  • Example 7 This example prepares N-[3-(4-(3,5-dihydroxyphenyl)phenyl)cyclobutyl]rosmarinamide, whose structural formula is as follows:
  • Embodiment 8 This embodiment prepares N-[3-(4-(4-hydroxyphenyl)phenyl)cyclobutyl]rosmarinamide, whose structural formula is as follows:
  • Example 9 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.
  • in vitro hyaluronidase inhibitory activity screening showed significantly improved hyaluronidase inhibitory activity (IC 50 about 10-20 ⁇ g/mL).
  • compound W3 has an inhibitory activity IC 50 of 12.1 ⁇ g/mL for hyaluronidase, which is the most active inhibitor in this series.
  • 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 12 Compound W4 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 87.48 parts of water, 4 parts of 1,3-propanediol, 1 part of glycerin, 0.15 parts of methylparaben, 0.15 parts of carbomer, 0.1 part of sodium hyaluronate, 0.2 parts of disodium EDTA, 1,2-hexane 0.4 part of diol, 0.2 part of panthenol;
  • Phase B 5 parts of water, 0.1 part of triethanolamine;
  • Phase C 0.1 part of compound W4, 1 part of ethanol
  • Phase D (daily use) essence 0.02 parts, PEG-40 hydrogenated castor oil 0.1 parts
  • 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.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Disclosed in the present invention is a p-phenylcyclobutanamide rosemary compound and a preparation method therefor, and a use of the compound as a hyaluronidase inhibitor and an anti-aging beauty product. Specifically, disclosed in the present invention is preparation of a series of rosmarinic acid derivatives. In vitro activity tests show that such rosmarinic acid derivatives have strong hyaluronidase inhibitory activity, the IC50 of the rosmarinic acid derivatives is about 10-20 μg/mL, the inhibitory activity is obviously higher than that of a rosmarinic acid, and the IC50 of the rosmarinic acid is about 102 μg/mL. The rosmarinic acid derivatives have very low cytotoxicity, have remarkably enhanced fat solubility compared with rosmarinic acid, are more easily absorbed by skin tissues, and can be used as an anti-aging component for manufacturing a beauty product. Also disclosed in the present invention is an application of the rosmarinic acid derivatives as a beauty component to prepare an anti-aging skincare facial mask.

Description

作为透明质酸酶抑制剂的对苯环丁酰胺迷迭香类化合物及其在美容产品中的应用P-phenylcyclobutanamide-rosmarinoids as hyaluronidase inhibitors and their use in cosmetic products
相关申请的交叉引用Cross References to Related Applications
本申请要求2022年02月11日提交的中国申请号202210130260.5的权益。所述申请号202210130260.5据此全文以引用方式并入本文。This application claims the benefit of Chinese application number 202210130260.5 filed on February 11, 2022. Said application number 202210130260.5 is hereby incorporated herein by reference in its entirety.
技术领域technical field
本发明涉及一种对苯环丁酰胺迷迭香类化合物及其制备方法，以及其作为透明质酸酶抑制剂和用来制作美容产品的用途，属于化妆品领域。The invention relates to a p-phenylcyclobutanamide rosemary compound and a preparation method thereof, as well as its use as a hyaluronidase inhibitor and for making beauty products, belonging to the field of cosmetics.
背景技术Background technique
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。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. In mammals, especially humans, 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-β-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.
天然产物是透明质酸酶抑制剂的重要来源，研究发现迷迭香酸展示出一定的透明质酸酶的抑制活性。迷迭香是一种药食兼用的草本植物，迷迭香酸(Rosmarinic acid，图1)是一种在很多植物中存在的五环三萜类化合物，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。 迷迭香酸是一种多酚类化合物，是一种天然抗氧化剂，具有较强的抗氧化活性，迷迭香酸具有极强的清除体内自由基的活性和抗氧化作用。迷迭香酸具有较强的抗炎活性，如抗肾炎、抗肝炎、抗肺炎等。同时迷迭香酸还具有抗菌、抗病毒、抗抑郁的活性。目前，迷迭香酸在制药、食品、化妆品等领域中已体现出其重要的应用价值。研究也表明，迷迭香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。迷迭香酸对于透明质酸酶的抑制活性较弱，文献报道的IC 50约309μM。对于迷迭香酸的修饰从而提高其对透明质酸酶的抑制活性，同时得到的迷迭香酸如果具有更高的脂溶性，更容易被皮肤吸收从而可以用来作为抗皮肤老化的活性成分。 Natural products are an important source of hyaluronidase inhibitors, and studies have found that rosmarinic acid exhibits certain hyaluronidase inhibitory activity. Rosemary is a kind of herbal plant with both medicine and food. Rosmarinic acid (Rosmarinic acid, Figure 1) is a pentacyclic triterpenoid compound that exists in many plants, and it is a biological compound that exists in many plant extracts. Active ingredients, commonly used as cosmeceutical ingredients in various skin care products. Rosmarinic acid is a polyphenolic compound, a natural antioxidant with strong antioxidant activity, and rosmarinic acid has a very strong activity of scavenging free radicals in the body and antioxidant effect. Rosmarinic acid has strong anti-inflammatory activity, such as anti-nephritis, anti-hepatitis, anti-pneumonia, etc. At the same time, rosmarinic acid also has antibacterial, antiviral, and antidepressant activities. At present, rosmarinic acid has shown its important application value in the fields of pharmacy, food and cosmetics. Studies have also shown that the anti-aging effects of rosmarinic acid may be attributed to its inhibitory effect on several enzymes associated with skin wrinkle formation, such as hyaluronidase. The inhibitory activity of rosmarinic acid on hyaluronidase is weak, and the IC 50 reported in the literature is about 309 μM. The modification of rosmarinic acid improves its inhibitory activity against hyaluronidase. At the same time, if the obtained rosmarinic acid has higher fat solubility, it is easier to be absorbed by the skin and can be used as an active ingredient for anti-aging skin .
发明内容Contents of the invention
针对文献报道迷迭香酸对于透明质酸酶的抑制活性较弱，IC 50约309μM。但是迷迭香酸的脂溶性较差，很难渗透皮肤。本研究以迷迭香酸为母核，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。同时新合成的化合物具有增强的脂溶性，更利于在化妆品中的应用。本发明的主要目的在于提供一类对苯环丁酰胺迷迭香类化合物及其制备方法和应用。本发明开发了一类对苯环丁酰胺迷迭香类化合物，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。 According to literature reports, rosmarinic acid has a weak inhibitory activity on hyaluronidase, with an IC 50 of about 309 μM. However, rosmarinic acid is poorly fat-soluble, making it difficult to penetrate the skin. In this study, rosmarinic acid was used as the core to optimize its structure, thereby enhancing the inhibitory activity of its derivatives against hyaluronidase. At the same time, the newly synthesized compound has enhanced fat solubility, which is more conducive to the application in cosmetics. The main purpose of the present invention is to provide a class of p-benzenecyclobutanamide rosemary compounds and their preparation method and application. The invention develops a class of p-phenylcyclobutanamide rosemary compounds, which have significantly enhanced hyaluronidase inhibitory activity, and can be used to develop anti-aging cosmetic products.
为了达到此目的，本发明包括以下技术方案：In order to achieve this purpose, the present invention includes the following technical solutions:
第一方面，本发明提供一种对苯环丁酰胺迷迭香类化合物，所述的结构如通式(I)所示：In a first aspect, the present invention provides a p-benzenecyclobutanamide rosemary compound, the structure of which is shown in general formula (I):
Figure PCTCN2022123993-appb-000001
Figure PCTCN2022123993-appb-000001
Figure PCTCN2022123993-appb-000002
Figure PCTCN2022123993-appb-000002
A环独立地选自苯基、萘基、5-14元芳杂环基；Ring A is independently selected from phenyl, naphthyl, and 5-14 membered aromatic heterocyclic groups;
其中苯基、萘基或5-14元芳杂环基为非取代或被1个、2个、3个、4个或者5个取代基取代，取代基各自独立选自氘、羟基、巯基、氨基、甲酰氨基、甲磺酰基、异丙磺酰基、甲磺酸酯基、异丙磺酸酯基、三氟甲基氧基、C 1-8烷基氧基、C 2-8链烯基氧基、C 2-8链炔基氧基、C 1-8烷基胺基。 Wherein the phenyl, naphthyl or 5-14 membered aromatic heterocyclic groups are unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from deuterium, hydroxyl, mercapto, Amino, formylamino, methylsulfonyl, isopropylsulfonyl, mesylate, isopropylsulfonate, trifluoromethyloxy, C 1-8 alkyloxy, C 2-8 alkenyl Cyloxy group, C 2-8 alkynyloxy group, C 1-8 alkylamine group.
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。 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.
本发明所涉及的对苯环丁酰胺迷迭香类化合物是一类全新结构的化合物，且其体外具有较迷迭香酸明显增强的透明质酸酶抑制活性，以及增强的脂溶性。因此可以用来制备抗皮肤衰老的化妆品。The p-phenylcyclobutanamide rosmarinoid compound involved in the present invention is a class of compounds with a new structure, and it has significantly enhanced hyaluronidase inhibitory activity and enhanced fat solubility compared with rosmarinic acid in vitro. Therefore, it can be used to prepare anti-aging cosmetics.
优选地，通式(I)中，A环独立地选自苯基、萘基、吲哚基、吡啶基、喹啉基、呋喃基、噻吩基、异恶唑基、苯并恶唑基、咪唑基、三氮唑基、四氮唑基、嘧啶基、吡嗪基、哒嗪基、苯并噻唑基、苯并呋喃基，苯并咪唑基；Preferably, in general formula (I), ring A is independently selected from phenyl, naphthyl, indolyl, pyridyl, quinolinyl, furyl, thienyl, isoxazolyl, benzoxazolyl, Imidazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzofuranyl, benzimidazolyl;
这些芳香环基或芳杂环基为非取代或被1个、2个、3个、4个或者5个取代基取代，取代基选自氘、羟基、氨基、甲酰氨基、甲磺酰基、异丙磺酰基、甲磺酸酯基、异丙磺酸酯基、三氟甲基氧基、C 1-4烷基氧基、C 2-4链烯基氧基、C 2-4链炔基氧基、C 1-4烷基胺基。 These aromatic ring groups or aromatic heterocyclic groups are unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents, and the substituents are selected from deuterium, hydroxyl, amino, formylamino, methylsulfonyl, Isopropylsulfonyl, mesylate, isopropylsulfonate, trifluoromethyloxy, C 1-4 alkyloxy, C 2-4 alkenyloxy, C 2-4 alkyne Base oxy group, C 1-4 alkylamine group.
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。 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.
优选地，通式(I)中，A环独立地选自苯基、萘基、吲哚基、吡啶基、喹啉基；Preferably, in the general formula (I), ring A is independently selected from phenyl, naphthyl, indolyl, pyridyl, quinolinyl;
这些芳香环基或芳杂环基为非取代或被1个、2个、3个、4个或者5个取代基取代，取代基选自氘、羟基、氨基、甲酰氨基、甲磺酰基、异丙磺酰基、甲磺酸酯基、异丙磺酸酯基、三氟甲基氧基、C 1-4烷基氧基、C 1-4烷基胺基。 These aromatic ring groups or aromatic heterocyclic groups are unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents, and the substituents are selected from deuterium, hydroxyl, amino, formylamino, methylsulfonyl, Isopropylsulfonyl, mesylate, isopropylsulfonate, trifluoromethyloxy, C 1-4 alkyloxy, C 1-4 alkylamine.
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。 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.
进一步优选地，所述对苯环丁酰胺迷迭香类化合物选自如下所述的化合物结构：Further preferably, the p-benzenecyclobutanamide rosemary compound is selected from the following compound structures:
Figure PCTCN2022123993-appb-000003
Figure PCTCN2022123993-appb-000003
Figure PCTCN2022123993-appb-000004
Figure PCTCN2022123993-appb-000004
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上述第一个方面所述的对苯环丁酰胺迷迭香类化合物、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。In the second aspect, the present invention provides a compound composition, which comprises the p-benzenecyclobutanamide rosemary compound described in the first aspect above, its stereoisomers, and its chemically acceptable One or more salts; Preferably, the compound composition also includes acceptable adjuvants in the field of cosmetics, such as carriers, diluents, excipients, fillers, binders, wetting agents, disintegrants, Emulsifiers, co-solvents, solubilizers, osmotic pressure regulators, surfactants, colorants, pH regulators, antioxidants, bacteriostats or buffers, etc.
本发明所涉及的对苯环丁酰胺迷迭香类化合物的化学上可接受的盐为对苯环丁酰胺迷迭香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。The chemically acceptable salt of the p-benzenecyclobutanamide rosemary compound involved in the present invention is a salt formed by a p-benzenecyclobutanamide rosemary 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.
第三方面，本发明提供对苯环丁酰胺迷迭香类化合物的制备方法：In a third aspect, the present invention provides a method for preparing p-benzenecyclobutanamide rosemary compounds:
将等量的对溴苯环丁酰胺迷迭香与各种硼酸类化合物，如
Figure PCTCN2022123993-appb-000005
碳酸铯、四丁基溴化铵、四氯钯酸钾，混合于甲醇溶剂中，37℃反应6h，即得产物；其中A环的限定范围与第一方面中任一项限定的范围一致，其反应式如下所示： Equal amounts of p-bromophencyclobutanide rosemary and various boric acid compounds, such as
Figure PCTCN2022123993-appb-000005
Cesium carbonate, tetrabutylammonium bromide, and potassium tetrachloropalladate are mixed in a methanol solvent and reacted at 37°C for 6 hours to obtain the product; wherein the limited range of ring A is consistent with the limited range of any one of the first aspects, Its reaction formula is as follows:
Figure PCTCN2022123993-appb-000006
Figure PCTCN2022123993-appb-000006
优选地，对溴苯环丁酰胺迷迭香的制备方如下所述：Preferably, the preparation side of p-bromophencyclobutanamide rosemary is as follows:
等量的迷迭香酸与对溴苯环丁胺在DCC和DMAP存在下，在无水的DMF中混合，反应加热到50℃反应6h，获得中间体对溴苯环丁酰胺迷迭香，其反应式如下所示：An equal amount of rosmarinic acid and p-bromophencyclidine are mixed in anhydrous DMF in the presence of DCC and DMAP, and the reaction is heated to 50° C. for 6 h to obtain the intermediate p-bromophencyclidine rosemary, Its reaction formula is as follows:
Figure PCTCN2022123993-appb-000007
Figure PCTCN2022123993-appb-000007
第四方面，本发明提供一种如第一方面所述的对苯环丁酰胺迷迭香类化合 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。In the fourth aspect, the present invention provides a p-benzenecyclobutanamide rosemary compound as described in the first aspect, or the compound composition as described in the second aspect in the preparation of delaying the treatment of the skin by inhibiting the activity of hyaluronidase. Uses in aging cosmetics.
第五方面，本发明提供一种抗皮肤衰老类面膜，所述面膜含有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：In the fifth aspect, the present invention provides an anti-aging skin mask, the mask contains 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:
A相：水87.48份、1,3-丙二醇4份、甘油1份、羟苯甲酯0.15份、卡波姆0.15份、透明质酸钠0.1份、EDTA二钠0.2份、1，2-己二醇0.4份、泛醇0.2份；Phase A: 87.48 parts of water, 4 parts of 1,3-propanediol, 1 part of glycerin, 0.15 parts of methylparaben, 0.15 parts of carbomer, 0.1 part of sodium hyaluronate, 0.2 parts of disodium EDTA, 1,2-hexane 0.4 part of diol, 0.2 part of panthenol;
B相：水5份、三乙醇胺0.1份；Phase B: 5 parts of water, 0.1 part of triethanolamine;
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
D相：(日用)香精0.02份、PEG-40氢化蓖麻油0.1份Phase D: (daily use) essence 0.02 parts, PEG-40 hydrogenated castor oil 0.1 parts
附图说明Description of drawings
图1，迷迭香酸的结构式。Figure 1, Structural formula of rosmarinic acid.
具体实施方式Detailed ways
下面参照具体的实施例对本发明做进一步说明。应当理解，此处所描述的具体实施例仅用于解释本发明，并不用于限定本发明的范围。The present invention will be further described below with reference to specific embodiments. It should be understood that the specific embodiments described here are only used to explain the present invention, and are not intended to limit the scope of the present invention.
实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道购买得到的常规产品。If no specific technique or condition is indicated in the examples, it shall be carried out according to the technique or condition described in the literature in this field, or according to the product specification. The reagents or instruments used were not indicated by the manufacturer, and they were all conventional products that could be purchased through regular channels.
下面实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为市售产品。The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the following examples are commercially available products unless otherwise specified.
制备例1：对溴苯环丁酰胺迷迭香的制备方如下所述：Preparation Example 1: The preparation of p-bromophencyclobutanamide rosemary is as follows:
本制备例制备对溴苯环丁酰胺迷迭香，合成路线为：This preparation example prepares p-bromophencyclobutanamide rosemary, and the synthetic route is:
Figure PCTCN2022123993-appb-000008
Figure PCTCN2022123993-appb-000008
将等量的迷迭香酸(720mg,2mmol)与对溴苯环丁胺(452mg,2mmol)在DCC(453mg,2.2mmol)和DMAP(36mg,0.3mmol)存在下，在无水的10ml DMF中混合，反应加热到50℃反应6h，获得中间体对溴苯环丁酰胺迷迭香。直到通过TLC监测起始材料完全消耗。粗产物通过柱色谱纯化，使用石油醚/乙酸乙酯作为洗脱剂，得到对溴苯环丁酰胺迷迭香，白色固体纯产物294mg(26％)。对产物进行如下表征： 1H NMR(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计算值569.4280,实测值569.4256. The same amount of rosmarinic acid (720mg, 2mmol) and p-bromophencyclidine (452mg, 2mmol) in the presence of DCC (453mg, 2.2mmol) and DMAP (36mg, 0.3mmol), in anhydrous 10ml DMF Mixing in the medium, the reaction was heated to 50°C for 6h to obtain the intermediate p-bromophencyclobutanamide rosemary. Until complete consumption of starting material monitored by TLC. The crude product was purified by column chromatography using petroleum ether/ethyl acetate as eluent to give rosemary p-bromobenzenecyclobutanamide as a white solid pure product 294 mg (26%). The product was characterized as follows: 1 H NMR (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]+C28H27BrNO7Calculated value 569.4280, measured value 569.4256.
实施例1：本实施例制备N-[3-(4-(吡啶-4-基)苯基)环丁基]迷迭香酰胺，其结构式如下：Embodiment 1: This embodiment prepares N-[3-(4-(pyridin-4-yl)phenyl)cyclobutyl]rosmarinamide, whose structural formula is as follows:
Figure PCTCN2022123993-appb-000009
Figure PCTCN2022123993-appb-000009
对溴苯环丁酰胺迷迭香(1136mg,2mmol)、对4-吡啶硼酸酯(410mg,2mmol)、碳酸铯(764mg,4mmol)、四丁基溴化铵(644mg,2mmol)、四氯 钯酸钾(16.3mg,0.05mmol)，混合于6mL甲醇溶剂中，37℃反应6h,且用TLC进行检测，产物通过柱色谱法纯化，得到化合物169mg(15％)，为白色固体。对产物进行如下表征： 1H 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计算值567.6180,实测值567.6152. p-bromobenzenecyclobutanamide rosemary (1136mg, 2mmol), p-4-pyridine borate (410mg, 2mmol), cesium carbonate (764mg, 4mmol), tetrabutylammonium bromide (644mg, 2mmol), tetrachloro Potassium palladium (16.3 mg, 0.05 mmol) was mixed in 6 mL of methanol solvent, reacted at 37 ° C for 6 h, and detected by TLC. The product was purified by column chromatography to obtain 169 mg (15%) of the 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=2.1 Hz,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 calculated value 567.6180, measured value 567.6152.
实施例2：本实施例制备N-[3-(4-(2-氟吡啶-3-基)苯基)环丁基]迷迭香酰胺，其结构式如下：Example 2: This example prepares N-[3-(4-(2-fluoropyridin-3-yl)phenyl)cyclobutyl]rosmarinamide, whose structural formula is as follows:
Figure PCTCN2022123993-appb-000010
Figure PCTCN2022123993-appb-000010
对溴苯环丁酰胺迷迭香(1136mg,2mmol)、2-氟-4-吡啶硼酸(410mg,2mmol)、碳酸铯(764mg,4mmol)、四丁基溴化铵(644mg,2mmol)、四氯钯酸钾(16.3mg,0.05mmol)，混合于6mL甲醇溶剂中，37℃反应6h,且用TLC进行检测，产物通过柱色谱法纯化，得到化合物151mg(13％)，为白色固体。对产物进行如下表征： 1H 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计算值585.6084,实测值585.6072. p-bromobenzenecyclobutanamide rosemary (1136mg, 2mmol), 2-fluoro-4-pyridine boronic acid (410mg, 2mmol), cesium carbonate (764mg, 4mmol), tetrabutylammonium bromide (644mg, 2mmol), tetra Potassium chloropalladate (16.3 mg, 0.05 mmol) was mixed in 6 mL of methanol solvent, reacted at 37 ° C for 6 h, and detected by TLC. The product was purified by column chromatography to obtain 151 mg (13%) of the compound 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=2.1 Hz,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 calculated value 585.6084, measured value 585.6072.
实施例3：本实施例制备N-[3-(4-(喹啉-4-基)苯基)环丁基]迷迭香酰胺，其结构式如下：Embodiment 3: This embodiment prepares N-[3-(4-(quinolin-4-yl)phenyl)cyclobutyl]rosmarinamide, whose structural formula is as follows:
Figure PCTCN2022123993-appb-000011
Figure PCTCN2022123993-appb-000011
对溴苯环丁酰胺迷迭香(1136mg,2mmol)、喹啉-4-硼酸(344mg,2mmol)、碳酸铯((764mg,4mmol)、四丁基溴化铵(644mg,2mmol)、四氯钯酸钾(16.3mg,0.05mmol)，混合于6mL甲醇溶剂中，37℃反应6h,且用TLC进行检测，产物通过柱色谱法纯化，得到化合物163mg(13％)，为白色固体。对产物进行如下表征： 1H 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计算值617.6780,实测值617.6775. p-bromobenzenecyclobutanamide rosemary (1136mg, 2mmol), quinoline-4-boronic acid (344mg, 2mmol), cesium carbonate ((764mg, 4mmol), tetrabutylammonium bromide (644mg, 2mmol), tetrachloro Potassium palladium (16.3 mg, 0.05 mmol), mixed in 6 mL of methanol solvent, reacted at 37 ° C for 6 h, and detected by TLC, the product was purified by column chromatography to obtain 163 mg (13%) of the compound as a white solid. For the product Characterization was performed as follows: 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 calculated value 617.6780, measured value 617.6775.
实施例4：本实施例制备N-[3-(4-(萘-2-基)苯基)环丁基]迷迭香酰胺，其 结构式如下：Embodiment 4: The present embodiment prepares N-[3-(4-(naphthalene-2-yl)phenyl)cyclobutyl]rosmarinamide, and its structural formula is as follows:
Figure PCTCN2022123993-appb-000012
Figure PCTCN2022123993-appb-000012
对溴苯环丁酰胺迷迭香(1136mg,2mmol)、2-萘硼酸(342mg,2mmol)、碳酸铯(764mg,4mmol)、四丁基溴化铵(644mg,2mmol)、四氯钯酸钾(16.3mg,0.05mmol)，混合于6mL甲醇溶剂中，37℃反应6h,且用TLC进行检测，产物通过柱色谱法纯化，得到化合物92mg(15％)，为白色固体。对产物进行如下表征： 1H 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计算值616.6900,实测值616.6859. p-bromophenylcyclobutanamide rosemary (1136mg, 2mmol), 2-naphthylboronic acid (342mg, 2mmol), cesium carbonate (764mg, 4mmol), tetrabutylammonium bromide (644mg, 2mmol), potassium tetrachloropalladate (16.3 mg, 0.05 mmol), mixed in 6 mL of methanol solvent, reacted at 37 ° C for 6 h, and detected by TLC, the product was purified by column chromatography to obtain 92 mg (15%) of the compound 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]+ The calculated value of C38H34NO7 is 616.6900, and the measured value is 616.6859.
实施例5：本实施例制备N-[3-(4-(3-氨基苯基)苯基)环丁基]迷迭香酰胺，其结构式如下：Embodiment 5: This embodiment prepares N-[3-(4-(3-aminophenyl)phenyl)cyclobutyl]rosmarinamide, whose structural formula is as follows:
Figure PCTCN2022123993-appb-000013
Figure PCTCN2022123993-appb-000013
对溴苯环丁酰胺迷迭香(1136mg,2mmol)、3-氨基苯硼酸(一水)(308mg, 2mmol)、碳酸铯(764mg,4mmol)、四丁基溴化铵(644mg,2mmol)、四氯钯酸钾(16.3mg,0.05mmol)，混合于6mL甲醇溶剂中，37℃反应6h,且用TLC进行检测，产物通过柱色谱法纯化，得到化合物185mg(16％)，为白色固体。对产物进行如下表征： 1H 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计算值581.6450,实测值581.6426. p-Bromophenylcyclobutanamide rosemary (1136mg, 2mmol), 3-aminophenylboronic acid (monohydrate) (308mg, 2mmol), cesium carbonate (764mg, 4mmol), tetrabutylammonium bromide (644mg, 2mmol), Potassium tetrachloropalladate (16.3 mg, 0.05 mmol) was mixed in 6 mL of methanol solvent, reacted at 37 ° C for 6 h, and detected by TLC. The product was purified by column chromatography to obtain 185 mg (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, 1.8 Hz, 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] The calculated value of +C34H33N2O7 is 581.6450, and the measured value is 581.6426.
实施例6：本实施例制备N-[3-(4-(2-甲磺酰基苯基)苯基)环丁基]迷迭香酰胺，其结构式如下：Embodiment 6: This embodiment prepares N-[3-(4-(2-methylsulfonylphenyl)phenyl)cyclobutyl]rosmarinamide, whose structural formula is as follows:
Figure PCTCN2022123993-appb-000014
Figure PCTCN2022123993-appb-000014
对溴苯环丁酰胺迷迭香(1136mg,2mmol)、2-甲砜基苯硼酸(400mg,2mmol)、碳酸铯(764mg,4mmol)、四丁基溴化铵(644mg,2mmol)、四氯钯酸钾(16.3mg,0.05mmol)，混合于6mL甲醇溶剂中，37℃反应6h,且用TLC进行检测，产物通过柱色谱法纯化，得到化合物218mg(17％)，为白色固体。对产物进行如下表征： 1H 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计算值644.5170,实测值644.5159. p-bromobenzenecyclobutanamide rosemary (1136mg, 2mmol), 2-thiamphenicol phenylboronic acid (400mg, 2mmol), cesium carbonate (764mg, 4mmol), tetrabutylammonium bromide (644mg, 2mmol), tetrachloro Potassium palladium (16.3 mg, 0.05 mmol) was mixed in 6 mL of methanol solvent, reacted at 37 ° C for 6 h, and detected by TLC. The product was purified by column chromatography to obtain 218 mg (17%) of the 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 calculated value 644.5170, measured value 644.5159.
实施例7：本实施例制备N-[3-(4-(3,5-二羟基苯基)苯基)环丁基]迷迭香酰胺，其结构式如下：Example 7: This example prepares N-[3-(4-(3,5-dihydroxyphenyl)phenyl)cyclobutyl]rosmarinamide, whose structural formula is as follows:
Figure PCTCN2022123993-appb-000015
Figure PCTCN2022123993-appb-000015
对溴苯环丁酰胺迷迭香(1136mg,2mmol)、3,4-二羟基苯硼酸酯(472mg,2mmol)、碳酸铯(764mg,4mmol)、四丁基溴化铵(644mg,2mmol)、四氯钯酸钾(16.3mg,0.05mmol)，混合于6mL甲醇溶剂中，37℃反应6h,且用TLC进行检测，产物通过柱色谱法纯化，得到化合物131mg(11％)，为白色固体。对产物进行如下表征： 1H 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计算值598.6280,实测值598.6267. p-Bromobenzenecyclobutanamide rosemary (1136mg, 2mmol), 3,4-dihydroxyphenyl borate (472mg, 2mmol), cesium carbonate (764mg, 4mmol), tetrabutylammonium bromide (644mg, 2mmol) 1. Potassium tetrachloropalladate (16.3mg, 0.05mmol), mixed in 6mL of methanol solvent, reacted at 37°C for 6h, and detected by TLC, the product was purified by column chromatography to obtain 131mg (11%) 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(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 calculated value 598.6280, measured value 598.6267.
实施例8：本实施例制备N-[3-(4-(4-羟基苯基)苯基)环丁基]迷迭香酰胺，其结构式如下：Embodiment 8: This embodiment prepares N-[3-(4-(4-hydroxyphenyl)phenyl)cyclobutyl]rosmarinamide, whose structural formula is as follows:
Figure PCTCN2022123993-appb-000016
Figure PCTCN2022123993-appb-000016
对溴苯环丁酰胺迷迭香(1136mg,2mmol)、4-羟基苯硼酸酯(440mg,2mmol)、碳酸铯(764mg,4mmol)、四丁基溴化铵(644mg,2mmol)、四氯钯酸钾(16.3mg,0.05mmol)，混合于6mL甲醇溶剂中，37℃反应6h,且用TLC进行检测，产物通过柱色谱法纯化，得到化合物124mg(11％)，为白色固体。对产物进行如下表征： 1H 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计算值566.6300,实测值566.6289. p-bromobenzenecyclobutanamide rosemary (1136mg, 2mmol), 4-hydroxyphenyl borate (440mg, 2mmol), cesium carbonate (764mg, 4mmol), tetrabutylammonium bromide (644mg, 2mmol), tetrachloro Potassium palladium (16.3 mg, 0.05 mmol) was mixed in 6 mL of methanol solvent, reacted at 37 ° C for 6 h, and detected by TLC. The product was purified by column chromatography to obtain 124 mg (11%) 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(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 calculated value 566.6300, measured value 566.6289.
实施例9：透明质酸酶抑制活性筛选试验Example 9: Screening test for hyaluronidase inhibitory activity
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，pH3.75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。Vcpal用作本测定的阳性对照化合物。 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. Vcpal was used as a positive control compound for this assay.
通过下面公式计算样品对透明质酸酶的抑制活性：Calculate the inhibitory activity of the sample to hyaluronidase by the following formula:
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％Inhibitory activity (%)=[1–(OD hyaluronic acid–OD sample)/(OD hyaluronic acid–OD hyaluronidase)]×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。 The IC 50 was calculated by the inhibitory activity of different concentrations, and the software GraphPad Prism 8.0 was used for calculation.
结果如下：体外透明质酸酶抑制活性筛选显示具有明显提高的透明质酸酶抑制活性(IC 50约10-20μg/mL)。其中化合物W3对于透明质酸酶的抑制活性IC 50为12.1μg/mL，是这一系列中活性最强的抑制剂。 The results are as follows : in vitro hyaluronidase inhibitory activity screening showed significantly improved hyaluronidase inhibitory activity (IC 50 about 10-20 μg/mL). Among them, compound W3 has an inhibitory activity IC 50 of 12.1 μg/mL for hyaluronidase, which is the most active inhibitor in this series.
表1，各种化合物对透明质酸酶的抑制活性Table 1. Inhibitory activity of various compounds on hyaluronidase
Figure PCTCN2022123993-appb-000017
Figure PCTCN2022123993-appb-000017
实施例10：化合物皮肤渗透性的检测Example 10: Detection of Compound Skin Penetration
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。 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.
结果如下：The result is as follows:
结果如表2，我们采用计算机模拟的方法对对苯环丁酰胺迷迭香类计算了其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，所有修饰的对苯环丁酰胺迷迭香类衍生物均有比迷迭香酸RA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W3、W4、W8具有最好的皮肤渗透效果。 The results are shown in Table 2. We calculated the Log K p of p-phenylcyclobutanamide rosemary by computer simulation method. The larger the negative number obtained by this constant, the less likely the compound can penetrate the skin. According to the calculated results, it can be seen that all modified p-phenylcyclobutanamide rosmarinoid derivatives have better skin penetration effects than rosmarinic acid RA, so they are more suitable for skin application to inhibit skin aging. Compounds W3, W4, W8 had the best skin penetration.
表2：各种化合物计算获得的Log K p Table 2: Calculated Log K p for various compounds
Figure PCTCN2022123993-appb-000018
Figure PCTCN2022123993-appb-000018
实施例11：细胞毒性的筛选Example 11: Screening for Cytotoxicity
实验方法：experimental method:
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。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.
结果如下：The result is as follows:
结果如表3，细胞实验检测发现，8个对苯环丁酰胺迷迭香类衍生物物没有明显的细胞毒性。因此，这8个对苯环丁酰胺迷迭香类衍生物适合用于制备美容产品。The results are shown in Table 3. The cell test found that the 8 p-phenylcyclobutanamide rosemary derivatives had no obvious cytotoxicity. Therefore, these 8 p-benzenecyclobutanamide rosemary derivatives are suitable for the preparation of cosmetic products.
表3：各种化合物对于哺乳动物细胞的细胞毒性Table 3: Cytotoxicity of various compounds on mammalian cells
Figure PCTCN2022123993-appb-000019
Figure PCTCN2022123993-appb-000019
实施例12：化合物W4作为抗皮肤衰老成分制备美容面膜Example 12: Compound W4 is used as an anti-aging ingredient to prepare a beauty mask
一种抗皮肤衰老面膜，其配方和重量份数如下：An anti-aging skin mask, its formula and parts by weight are as follows:
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。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.
结合化合物W4对于透明质酸酶的抑制活性，W4的细胞毒性，W4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。Combining the inhibitory activity of compound W4 for hyaluronidase, the cytotoxicity of W4, and the skin permeability of W4, it was selected as an anti-aging active ingredient for the preparation of a cosmetic mask.
A相：水87.48份、1,3-丙二醇4份、甘油1份、羟苯甲酯0.15份、卡波姆0.15份、透明质酸钠0.1份、EDTA二钠0.2份、1，2-己二醇0.4份、泛醇0.2份；Phase A: 87.48 parts of water, 4 parts of 1,3-propanediol, 1 part of glycerin, 0.15 parts of methylparaben, 0.15 parts of carbomer, 0.1 part of sodium hyaluronate, 0.2 parts of disodium EDTA, 1,2-hexane 0.4 part of diol, 0.2 part of panthenol;
B相：水5份、三乙醇胺0.1份；Phase B: 5 parts of water, 0.1 part of triethanolamine;
C相：化合物W4 0.1份、乙醇1份Phase C: 0.1 part of compound W4, 1 part of ethanol
D相：(日用)香精0.02份、PEG-40氢化蓖麻油0.1份Phase D: (daily use) essence 0.02 parts, PEG-40 hydrogenated castor oil 0.1 parts
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。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.
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。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 (9)

  1. 一种对苯环丁酰胺迷迭香类化合物，其特征在于，具有通式(I)所示的结构：A p-benzenecyclobutanamide rosemary compound, is characterized in that, has the structure shown in general formula (I):
    Figure PCTCN2022123993-appb-100001
    Figure PCTCN2022123993-appb-100001
    A环独立地选自苯基、萘基、5-14元芳杂环基；Ring A is independently selected from phenyl, naphthyl, and 5-14 membered aromatic heterocyclic groups;
    其中苯基、萘基或5-14元芳杂环基为非取代或被1个、2个、3个、4个或者5个取代基取代，取代基各自独立选自氘、羟基、巯基、氨基、甲酰氨基、甲磺酰基、异丙磺酰基、甲磺酸酯基、异丙磺酸酯基、三氟甲基氧基、C 1-8烷基氧基、C 2-8链烯基氧基、C 2-8链炔基氧基、C 1-8烷基胺基。 Wherein the phenyl, naphthyl or 5-14 membered aromatic heterocyclic groups are unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from deuterium, hydroxyl, mercapto, Amino, formylamino, methylsulfonyl, isopropylsulfonyl, mesylate, isopropylsulfonate, trifluoromethyloxy, C 1-8 alkyloxy, C 2-8 alkenyl Cyloxy group, C 2-8 alkynyloxy group, C 1-8 alkylamine group.
  2. 根据权利要求1所述的对苯环丁酰胺迷迭香类化合物，其特征在于，通式(I)中，p-Benzene cyclobutanamide rosemary compound according to claim 1, characterized in that, in the general formula (I),
    A环独立地选自苯基、萘基、吲哚基、吡啶基、喹啉基、呋喃基、噻吩基、异恶唑基、苯并恶唑基、咪唑基、三氮唑基、四氮唑基、嘧啶基、吡嗪基、哒嗪基、苯并噻唑基、苯并呋喃基，苯并咪唑基；Ring A is independently selected from phenyl, naphthyl, indolyl, pyridyl, quinolinyl, furyl, thienyl, isoxazolyl, benzoxazolyl, imidazolyl, triazolyl, tetrazole Azolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzofuryl, benzimidazolyl;
    这些芳香环基或芳杂环基为非取代或被1个、2个、3个、4个或者5个取代基取代，取代基选自氘、羟基、氨基、甲酰氨基、甲磺酰基、异丙磺酰基、甲磺酸酯基、异丙磺酸酯基、三氟甲基氧基、C 1-4烷基氧基、C 2-4链烯基氧基、C 2-4链炔基氧基、C 1-4烷基胺基。 These aromatic ring groups or aromatic heterocyclic groups are unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents, and the substituents are selected from deuterium, hydroxyl, amino, formylamino, methylsulfonyl, Isopropylsulfonyl, mesylate, isopropylsulfonate, trifluoromethyloxy, C 1-4 alkyloxy, C 2-4 alkenyloxy, C 2-4 alkyne Base oxy group, C 1-4 alkylamine group.
  3. 根据权利要求1或权利要求2所述的对苯环丁酰胺迷迭香类化合物，其特征在于，通式(I)中，The p-benzenecyclobutanamide rosemary compound according to claim 1 or claim 2, characterized in that, in the general formula (I),
    A环独立地选自苯基、萘基、吲哚基、吡啶基、喹啉基；Ring A is independently selected from phenyl, naphthyl, indolyl, pyridyl, quinolinyl;
    这些芳香环基或芳杂环基为非取代或被1个、2个、3个、4个或者5个取代基取代，取代基选自氘、羟基、氨基、甲酰氨基、甲磺酰基、异丙磺酰基、甲磺酸酯基、异丙磺酸酯基、三氟甲基氧基、C 1-4烷基氧基、C 1-4烷基胺基。 These aromatic ring groups or aromatic heterocyclic groups are unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents, and the substituents are selected from deuterium, hydroxyl, amino, formylamino, methylsulfonyl, Isopropylsulfonyl, mesylate, isopropylsulfonate, trifluoromethyloxy, C 1-4 alkyloxy, C 1-4 alkylamine.
  4. 根据权利要求1或权利要求2或权利要求3所述的对苯环丁酰胺迷迭香类化合物，其特征在于，所述的化合物选自以下结构：The p-benzenecyclobutanamide rosemary compound according to claim 1 or claim 2 or claim 3, wherein said compound is selected from the following structures:
    Figure PCTCN2022123993-appb-100002
    Figure PCTCN2022123993-appb-100002
  5. 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1-4中任一项所述的对苯环丁酰胺迷迭香类化合物、其立体异构体、其化学上可接受的盐的一种或多种；A compound composition, characterized in that: the compound composition comprises the p-benzenecyclobutanamide rosemary compound described in any one of claims 1-4, its stereoisomers, and its chemically acceptable one or more salts;
    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。Preferably, the compound composition further comprises cosmetically acceptable excipients.
  6. 权利要求1-4中任一项所述的对苯环丁酰胺迷迭香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：The preparation method of the p-benzenecyclobutanamide rosemary compound described in any one of claims 1-4, is characterized in that, described preparation method comprises the following steps:
    将等量的对溴苯环丁酰胺迷迭香与各种硼酸类化合物，如
    Figure PCTCN2022123993-appb-100003
    Cs 2CO 3、TBAB、K 2PdCl 4，混合于甲醇溶剂中，37℃反应6h，即得产物；其中A环的限定范围与权利要求1-4中任一项限定的范围一致，其反应式如下所示：     Equal amounts of p-bromophencyclobutanide rosemary and various boric acid compounds, such as
    Figure PCTCN2022123993-appb-100003
    Cs 2 CO 3 , TBAB, K 2 PdCl 4 , mixed in methanol solvent, and reacted at 37°C for 6 hours to obtain the product; wherein the limited range of ring A is consistent with that defined by any one of claims 1-4, and the reaction The formula is as follows:
    Figure PCTCN2022123993-appb-100004
    Figure PCTCN2022123993-appb-100004
  7. 根据权利要求6所述的对苯环丁酰胺迷迭香类化合物的制备方法，其特征在于，对溴苯环丁酰胺迷迭香的制备方如下所述：The preparation method of p-phenylcyclobutanamide rosemary compound according to claim 6, is characterized in that, the preparation side of p-bromobenzenecyclobutanamide rosemary is as follows:
    等量的迷迭香酸与对溴苯环丁胺在DCC和DMAP存在下，在无水的DMF中混合，反应加热到50℃反应6h，获得中间体对溴苯环丁酰胺迷迭香，其反应式如下所示：An equal amount of rosmarinic acid and p-bromophencyclidine are mixed in anhydrous DMF in the presence of DCC and DMAP, and the reaction is heated to 50° C. for 6 h to obtain the intermediate p-bromophencyclidine rosemary, Its reaction formula is as follows:
    Figure PCTCN2022123993-appb-100005
    Figure PCTCN2022123993-appb-100005
  8. 权利要求1-4中任一项所述的对苯环丁酰胺迷迭香类化合物或者权利要求5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。Use of the p-phenylcyclobutanamide rosemary compound described in any one of claims 1-4 or the compound composition described in claim 5 in the preparation of cosmetics that delay skin aging by inhibiting hyaluronidase activity .
  9. 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1-4中任一项所述的化合物或者权利要求5所述的化合物组合物，所述面膜的配方和重量份如下：An anti-skin aging facial mask, characterized in that: the facial mask comprises the compound according to any one of claims 1-4 or the compound composition according to claim 5, and the formula and parts by weight of the facial mask are as follows:
    A相：水87.48份、1,3-丙二醇4份、甘油1份、羟苯甲酯0.15份、卡波姆0.15份、透明质酸钠0.1份、EDTA二钠0.2份、1，2-己二醇0.4份、泛醇0.2份；Phase A: 87.48 parts of water, 4 parts of 1,3-propanediol, 1 part of glycerin, 0.15 parts of methylparaben, 0.15 parts of carbomer, 0.1 part of sodium hyaluronate, 0.2 parts of disodium EDTA, 1,2-hexane 0.4 part of diol, 0.2 part of panthenol;
    B相：水5份、三乙醇胺0.1份；Phase B: 5 parts of water, 0.1 part of triethanolamine;
    C相：权利要求1-4中任一项所述的化合物或者权利要求5所述的化合物组合物0.1份、乙醇1份Phase C: 0.1 part of the compound described in any one of claims 1-4 or the compound composition described in claim 5, 1 part of ethanol
    D相：(日用)香精0.02份、PEG-40氢化蓖麻油0.1份。Phase D: (daily use) essence 0.02 part, PEG-40 hydrogenated castor oil 0.1 part.
PCT/CN2022/123993 2022-02-11 2022-10-09 P-phenylcyclobutanamide rosemary compound as hyaluronidase inhibitor and application thereof in beauty product WO2023151293A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210130260.5 2022-02-11
CN202210130260.5A CN114507179B (en) 2022-02-11 2022-02-11 Para-benzene ring butanamide rosemary compound serving as hyaluronidase inhibitor and application of para-benzene ring butanamide rosemary compound in beauty products

Publications (1)

Publication Number Publication Date
WO2023151293A1 true WO2023151293A1 (en) 2023-08-17

Family

ID=81551336

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/123993 WO2023151293A1 (en) 2022-02-11 2022-10-09 P-phenylcyclobutanamide rosemary compound as hyaluronidase inhibitor and application thereof in beauty product

Country Status (2)

Country Link
CN (1) CN114507179B (en)
WO (1) WO2023151293A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114507179B (en) * 2022-02-11 2022-10-04 北京青颜博识健康管理有限公司 Para-benzene ring butanamide rosemary compound serving as hyaluronidase inhibitor and application of para-benzene ring butanamide rosemary compound in beauty products

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101039683A (en) * 2004-08-13 2007-09-19 血管技术国际有限公司 Compositions and methods using hyaluronic acid and hyaluronidase inhibitors
CN101854944A (en) * 2007-09-17 2010-10-06 梁启铭 Compositions and method with treatment inflammation of Plectlanthus amboinicus (Lour) Spreng extract and inflammation relevant disease
CN114507179A (en) * 2022-02-11 2022-05-17 北京青颜博识健康管理有限公司 Para-benzene ring butanamide rosemary compound serving as hyaluronidase inhibitor and application of para-benzene ring butanamide rosemary compound in beauty products

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113980098B (en) * 2021-12-27 2022-03-29 浙江湃肽生物有限公司深圳分公司 Nonapeptide-1 derivative and synthesis method and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101039683A (en) * 2004-08-13 2007-09-19 血管技术国际有限公司 Compositions and methods using hyaluronic acid and hyaluronidase inhibitors
CN101854944A (en) * 2007-09-17 2010-10-06 梁启铭 Compositions and method with treatment inflammation of Plectlanthus amboinicus (Lour) Spreng extract and inflammation relevant disease
CN114507179A (en) * 2022-02-11 2022-05-17 北京青颜博识健康管理有限公司 Para-benzene ring butanamide rosemary compound serving as hyaluronidase inhibitor and application of para-benzene ring butanamide rosemary compound in beauty products

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AYOOB IRAM, LONE SHABIR H., MASOOD-UR-RAHMAN, ZARGAR OVAIS A., BASHIR ROHINA, SHAKEEL-U-REHMAN, KHUROO MOHD A., BHAT KHURSHEED A.: "New Semi-Synthetic Rosmarinic Acid-Based Amide Derivatives as Effective Antioxidants", CHEMISTRYSELECT, WILEY - V C H VERLAG GMBH & CO. KGAA, DE, vol. 2, no. 31, 31 October 2017 (2017-10-31), DE , pages 10153 - 10156, XP093084859, ISSN: 2365-6549, DOI: 10.1002/slct.201701812 *
CARDULLO NUNZIO, CATINELLA GIORGIA, FLORESTA GIUSEPPE, MUCCILLI VERA, ROSSELLI SERGIO, RESCIFINA ANTONIO, BRUNO MAURIZIO, TRINGALI: "Synthesis of Rosmarinic Acid Amides as Antioxidative and Hypoglycemic Agents", JOURNAL OF NATURAL PRODUCTS, AMERICAN CHEMICAL SOCIETY, US, vol. 82, no. 3, 22 March 2019 (2019-03-22), US , pages 573 - 582, XP093084860, ISSN: 0163-3864, DOI: 10.1021/acs.jnatprod.8b01002 *
KANG JIE; TANG YANBO; LIU QUAN; GUO NAN; ZHANG JIAN; XIAO ZHIYAN; CHEN RUOYUN; SHEN ZHUFANG: "Isolation, modification, and aldose reductase inhibitory activity of rosmarinic acid derivatives from the roots ofSalvia grandifolia", FITOTERAPIA, IDB HOLDING, MILAN., IT, vol. 112, 24 May 2016 (2016-05-24), IT , pages 197 - 204, XP029632330, ISSN: 0367-326X, DOI: 10.1016/j.fitote.2016.05.011 *

Also Published As

Publication number Publication date
CN114507179A (en) 2022-05-17
CN114507179B (en) 2022-10-04

Similar Documents

Publication Publication Date Title
Von Angerer et al. 2-Phenylindoles. Relationship between structure, estrogen receptor affinity, and mammary tumor inhibiting activity in the rat
CN108473432B (en) Process for bleaching keratin materials using thiopyridone compounds
CN110028491A (en) Fibroblast growth factor receptor inhibitor
CN105592888A (en) Kdm1a inhibitors for the treatment of disease
Chen et al. Sorafenib derivatives induce apoptosis through inhibition of STAT3 independent of Raf
WO2023151293A1 (en) P-phenylcyclobutanamide rosemary compound as hyaluronidase inhibitor and application thereof in beauty product
Cui et al. Effect of curcumin derivatives on hen egg white lysozyme amyloid fibrillation and their interaction study by spectroscopic methods
US9414998B2 (en) Preventing or ameliorating agent for pigmentation
BRPI0815048B1 (en) PHENOXY-PIRROLIDINE DERIVATIVES, THEIR USES AND PHARMACEUTICAL COMPOSITIONS
Guo et al. Discovery of new benzensulfonamide derivatives as tripedal STAT3 inhibitors
Lee et al. Synthetic tyrosyl gallate derivatives as potent melanin formation inhibitors
WO2023151291A1 (en) 1,3-disubstituted indole derivative as hyaluronidase inhibitor and use thereof in cosmetic product
WO2023151292A1 (en) 3α-OLEANOLIC ACID DERIVATIVES AS HYALURONIDASE INHIBITORS AND USES THEREOF IN COSMETIC PRODUCTS
JP2021534215A (en) Aromatic molecules for use in the treatment of pathological symptoms
Dei et al. Design and synthesis of aminoester heterodimers containing flavone or chromone moieties as modulators of P-glycoprotein-based multidrug resistance (MDR)
EP1351919B1 (en) Retinol derivatives and process for preparing same
Wang et al. Discovery of 4-methoxy-N-(1-naphthyl) benzenesulfonamide derivatives as small molecule dual-target inhibitors of tubulin and signal transducer and activator of transcription 3 (STAT3) based on ABT-751
CN105949180B (en) Treat compound and its application of central nervous system degenerative disease
NZ748656A (en) Amide derivatives of polycaffeoylquinic acids, process for producing same and uses thereof
Matsukawa et al. Isolation and characterization of novel endogenous digitalis-like factors in the ovary of the giant toad, Bufo m arinus
JP2016214085A (en) Hair growth inhibitor evaluation or selection method
Gao et al. Design, synthesis and antitumor evaluation of novel 1H-indole-2-carboxylic acid derivatives targeting 14-3-3η protein
JP5886121B2 (en) Melanin production inhibitor
WO2022063325A1 (en) Crystal form of pyridinylphenyl compound and preparation method therefor
JP5510799B2 (en) Tyrosinase inhibitor

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22925651

Country of ref document: EP

Kind code of ref document: A1