WO2015169121A1 - Utilisation de dérivés de quercétine-o-glycoside dans le traitement de troubles du métabolisme lipidique - Google Patents

Utilisation de dérivés de quercétine-o-glycoside dans le traitement de troubles du métabolisme lipidique Download PDF

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WO2015169121A1
WO2015169121A1 PCT/CN2015/073814 CN2015073814W WO2015169121A1 WO 2015169121 A1 WO2015169121 A1 WO 2015169121A1 CN 2015073814 W CN2015073814 W CN 2015073814W WO 2015169121 A1 WO2015169121 A1 WO 2015169121A1
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quercetin
group
compound
lipid metabolism
liver
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PCT/CN2015/073814
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English (en)
Chinese (zh)
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尚靖
李妤
金�雨
吕金鹏
王路路
张志超
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南京睿鹰润泽生物医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/07—Benzo[b]pyran-4-ones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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  • the invention relates to the field of medicine, in particular to the application of a class of quercetin-O-glycoside derivatives in the treatment of disorders of lipid metabolism.
  • Lipid metabolism disorders refer to energy metabolism-related diseases characterized by abnormal lipid metabolism in the body, including fatty liver, obesity, atherosclerosis, and hyperlipoproteinemia.
  • the main feature of lipid metabolism disorders is the abnormality of lipids (lipids) and their metabolic products and amounts in the blood and other tissues and organs, which can show the accumulation of triglycerides and cholesterol, liver lobule inflammation and The increase in the content of alanine transaminase (ALT) and the change in the secretion of adipocytokines.
  • ALT alanine transaminase
  • the pathogenesis of lipid metabolism disorders is complicated and it is difficult to treat at present.
  • Quercetin-O-glycoside compounds are widely distributed in various fruits, vegetables and Chinese herbal medicines, and are abundant in saffron, saffron, chicory, and mango. In recent years, a large number of domestic and foreign literature reports have found that chicory has obvious effects of lowering blood sugar and blood lipids (Xinjiang Traditional Chinese Medicine, 2006, 24: 80-83).
  • the present invention uses quercetin as a raw material to synthesize a class of quercetin-O-glycoside derivatives, and its pharmacological and chemical studies show that the derivatives and pharmaceutical compositions of the present invention have potential application value in the treatment of lipid metabolism disorders .
  • R 1 represents a hydrogen atom, monosaccharide group, glucuronic acid or galacturonic acid
  • R 2 represents a hydrogen atom, a monosaccharide group, glucuronic acid or galacturonic acid
  • R 3 represents a hydrogen atom, a methyl group, a methanol group, an ethyl group, an ethanol group, an acetate group or a benzyl group;
  • R 4 represents a hydrogen atom, a methyl group, a methanol group, an ethyl group, an ethanol group, an acetate group or a benzyl group;
  • R 1 , R 2 , R 3 , and R 4 do not simultaneously represent a hydrogen atom.
  • the monosaccharide in the monosaccharide group is preferably glucose, galactose, rhamnose, xylose, arabinose or fructose.
  • the pharmaceutically acceptable salt, solvate or polymorph of the compound of the present invention has the same pharmacological activity as the compound of the present invention.
  • the present invention also discloses a pharmaceutical composition, which contains the compound (I) of the present invention or a pharmaceutically acceptable salt, solvate or polymorph thereof, and a pharmaceutically acceptable carrier.
  • the composition can be prepared into a variety of conventional preparations in the pharmaceutical field, such as tablets, granules, injections, dripping pills, capsules, aerosols, suppositories, plasters, etc., orally or intravenously, intramuscularly, subcutaneously or otherwise.
  • the composition can be administered in different doses.
  • the compounds of the present invention can also be used to treat other diseases related to lipid metabolism disorders.
  • the clinically used dose of the compound of the present invention is 0.01 mg to 1000 mg/day, and it can also deviate from this range according to the severity of the disease or the different dosage forms.
  • the compounds of the present invention can be prepared by the following methods:
  • Rat hepatocytes were cultured normally for 24 hours (6-well plate), and FFA was used to induce the establishment of a high-fat model of hepatocytes. After that, they were given different kinds of quercetin-O-glycoside derivatives (20 ⁇ M) and cultured for 24 hours. Remove the culture medium, wash twice with PBS, then add 100 ⁇ L of lysate to each well, scrape the cells, place on ice for 20min, centrifuge at 12000rpm/min for 10min, take the supernatant, operate according to the instructions of the TG and TC kits, and determine TG respectively , TC content.
  • Table 1 The effect of the quercetin-O-glycoside derivative of the present invention (20 ⁇ M) on the content of triglyceride (TG) in primary rat liver cells
  • Table 2 The effect of the quercetin-O-glycoside derivative of the present invention (20 ⁇ M) on the content of cholesterol (TC) in primary rat liver cells
  • quercetin-O-glycoside derivatives of the present invention can reduce the deposition of triglycerides (TG) and cholesterol (TC) in primary rat liver cells.
  • TG triglycerides
  • TC cholesterol
  • compound 2 quercetin-3-O- ⁇ -D-glucuronide
  • compound 4 quercetin-3-O- ⁇ -D-glucuronide
  • Quercetin-O-glycoside derivatives of the present invention (quercetin, quercetin-3-O- ⁇ -D-glucoside, quercetin-3-O- ⁇ -D-glucuronide) Pharmacodynamic Study on Rat Lipid Metabolism Disturbance Model Induced by High Fat Feed
  • the experimental groups are as follows: 1Normal group: normal feed + 0.5% CMC-Na; 2 High fat model group: high fat feed + 0.5% CMC-Na; 3 Simvastatin group (10 mg/kg): high fat feed + simvastatin 10mg/kg; 4 bezafibrate To Group (10mg/kg): high-fat diet + bezafibrate 10mg/kg; 5 Quercetin-3-O- ⁇ -D-glucoside group (25mg/kg): high-fat diet + quercetin-3 -O- ⁇ -D-glucoside 25mg/kg; 6Quercetin-3-O- ⁇ -D-glucuronide group (25mg/kg): high-fat feed + quercetin-3-O- ⁇ -D-Glucuronide 25mg/kg; 7Quercetin (25mg/kg): high-fat feed + quercetin 25mg/kg. While feeding the feed, the corresponding drugs were given by gavage every morning, and the
  • the rats were sacrificed, the liver was taken out, the miscellaneous tissues were removed, the blood was removed by rinsing with pre-cooled physiological saline, the filter paper was blotted dry, and it was immersed in 10% formaldehyde solution for fixation, dehydrated, immersed in wax, sliced, displayed, attached, baked slices Dye afterwards.
  • the acidic nucleus is stained blue by alkaline hematoxylin, and the alkaline cytoplasm is stained red by acidic eosin. As a result, the nucleus is blue and the cytoplasm is red.
  • liver index liver weight/body weight.
  • the blood was collected from the femoral artery and placed at room temperature for 2 hours, then centrifuged at 3500 r/min for 15 minutes. The upper clear transparent liquid was the collected serum, which was aliquoted and stored in a refrigerator at -70°C. Determine the content of TC, TG, LDL-C and HDL-C according to the method described in the kit instructions. Enzymatic endpoint method was used to determine the content of TC and TG, and chemical inhibition method was used to determine the content of LDL-C and HDL-C.
  • Preparation of protein sample Take the liver of each group of animals and extract the total protein in the tissue.
  • BCA protein quantification Take 1.2 mL of protein standard preparation solution and add it to a tube of protein standard (30 mg BSA), and make a 25 mg/mL protein standard solution after fully dissolving. Take an appropriate amount of 25mg/mL protein standard and dilute with PBS to the final concentration To It is 0.5mg/mL. According to the number of samples, prepare an appropriate amount of BCA working solution according to 50 volumes of BCA reagent A plus 1 volume of BCA reagent B (50:1), and mix thoroughly. Add 0,1,2,4,8,12,16,20 ⁇ l of standards to the standard wells of a 96-well plate, and add PBS to make up to 20 ⁇ l.
  • the protein sample is mixed with 5 ⁇ standard SDS-PAGE loading buffer to make the final concentration of SDS-PAGE loading buffer 1 ⁇ , and then boiled in a boiling water bath for 5 minutes, and the protein sample is stored at -20°C for later use.
  • ECL luminescent liquid A liquid + B liquid is mixed in equal volume (do not prepare under strong light). After 1 minute, fully contact the membrane protein face down with the mixed liquid, and after reacting for 5 minutes, transfer the film to another plastic wrap Top, remove the remaining liquid; gel image analysis: put the above-mentioned colored film into a gel imager, expose and analyze it with a fully automatic gel image analyzer.
  • Table 3 shows that the weight, liver index, cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) of the model group were significantly different from the normal group (p ⁇ 0.01). Simvastatin and bezafibrate can significantly reduce the content of TC, TG and LDL-C in the serum of rats, and increase the content of HDL-C, which is significantly different from the model group (p ⁇ 0.05 or p ⁇ 0.01).
  • simvastatin, quercetin-3-O- ⁇ -D-glucoside and quercetin-3-O- ⁇ -D-glucuronide can significantly improve the high-fat diet to a certain extent. Obesity and lipid metabolism disorders caused by feeding.
  • PPAR- ⁇ is the main target of bezafibrate to lower triglycerides.
  • the experimental results are shown in Fig. 3, compared with the blank control group, the expression of PPAR- ⁇ in the high-fat model group was down-regulated, indicating that high-fat diet feeding can cause disorder of triglyceride metabolism pathway in the liver and produce lipid accumulation.
  • the bezafibrate, quercetin-3-O- ⁇ -D-glucoside, and quercetin-3-O- ⁇ -D-glucuronide administration group showed significant expression of PPAR- ⁇ Activation; compared with the model group, the expression of PPAR- ⁇ in the quercetin administration group was not significantly activated. It is suggested that quercetin-3-O- ⁇ -D-glucoside and quercetin-3-O- ⁇ -D-glucuronide play a role in lowering triglycerides by acting on PPAR- ⁇ .
  • HMGR is the rate-limiting enzyme for liver cholesterol synthesis
  • ABCA1 is an important protein that mediates liver cholesterol efflux. It can be seen from Figure 4 that compared with the control group, quercetin-3-O- ⁇ -D-glucoside (2) and quercetin-3-O- ⁇ -D-glucuronide (4) are extremely Significantly up-regulate the increase in rat liver ABCA1 protein expression, and further significantly down-regulate the decrease in rat liver HMGR protein expression (P ⁇ 0.01), but quercetin (1) cannot significantly up-regulate the increase in rat liver ABCA1 protein expression .
  • quercetin-3-O- ⁇ -D-glucuronide (2) and quercetin-3-O- ⁇ -D-glucuronide (4) can directly regulate the synthesis of cholesterol in liver cells And efflux; Quercetin (1) cannot directly regulate the efflux of liver cell cholesterol.
  • Figure 1 shows the effects of quercetin-3-O- ⁇ -D-glucoside and quercetin-3-O- ⁇ -D-glucuronide on liver tissue structure in rats
  • Figure 2 shows the effects of quercetin-3-O- ⁇ -D-glucoside and quercetin-3-O- ⁇ -D-glucuronide on lipid deposition in the liver of rats
  • Figure 3 shows the effects of quercetin (1), quercetin-3-O- ⁇ -D-glucoside (2), and quercetin-3-O- ⁇ -D-glucuronide (4) on rats The expression of PPAR- ⁇ in the liver
  • Figure 4 shows the effects of quercetin (1), quercetin-3-O- ⁇ -D-glucuronide (2), and quercetin-3-O- ⁇ -D-glucuronide (4) on rats The influence of liver HMGR and ABCA1 protein expression
  • the first two steps were the same as in Example 1.
  • the obtained light yellow syrup (6.18g, 10mmol), bromomethanol (1.09g, 10mmol), potassium carbonate (1.38g, 10mmol) were dissolved in 50ml of tetrahydrofuran solution and heated.
  • the reaction was refluxed for 7 hours, and then purified by silica gel column chromatography to obtain a pale yellow solid.
  • the preparation process is the same as in Example 1.
  • the acetyl bromide- ⁇ -D-glucose used in the second step reaction is replaced with acetyl bromide- ⁇ -D-glucuronic acid methyl ester.
  • the reaction yield is 46.7%, mp245-248°C.
  • the preparation process is the same as in Example 2.
  • the acetyl bromide- ⁇ -D-glucose used in the second step reaction is replaced with acetyl bromide- ⁇ -D-glucuronic acid methyl ester.
  • the reaction yield is 50.2%, mp224-227°C.
  • the preparation process is the same as in Example 1.
  • the difference between the acidity of the 3 and 7 positions of the compound is used to control the reaction temperature between 10 °C and 15 °C, and the 7 position is successfully obtained.
  • the quercetin-7-O- ⁇ -D-glucoside (6), the product of the glycosylation reaction of the hydroxyl group, has a reaction yield of 34.7%, mp 202-206°C.
  • the preparation process is the same as that in Example 3.
  • the difference between the acidity of the 3-position and the 7-position hydroxyl group of the compound is used to control the reaction temperature between 14°C and 20°C.
  • the quercetin-7-O- ⁇ -D-glucuronide (7), the product of the glycosylation reaction of the hydroxyl group has a reaction yield of 46.2%, and mp213-215°C.
  • the preparation method is the same as that in Example 1.
  • the acetyl bromide- ⁇ -D-glucose is replaced with acetyl bromide- ⁇ -D-galactose to obtain quercetin-3-O- ⁇ -D-galactoside (8).
  • the rate is 49.1%, mp234 ⁇ 237°C.
  • the preparation method is the same as in Example 3.
  • the acetyl bromide- ⁇ -D-glucuronic acid methyl ester is replaced with acetyl bromide- ⁇ -D-galacturonic acid methyl ester to obtain quercetin-3-O- ⁇ -D -Galacturonic acid glycoside (9), the yield is 41.9%, mp 219 ⁇ 223°C.

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Abstract

La présente invention concerne le domaine de la synthèse pharmaceutique et de la pharmacologie et concerne en particulier un procédé de préparation d'une classe de dérivés de quercétine-O-glycoside et leur utilisation dans le traitement de troubles du métabolisme lipidique. Les dérivés, tels que les composés de formule I, comprennent des sels des composés de formule I et des isomères optiques et des racémates des composés de formule I. Le problème technique à résoudre par la présente invention concerne la conception et la synthèse d'une classe de dérivés de quercétine-O-glycoside, et des études d'activité pharmacologique in vitro et in vivo ont montré que les dérivés de quercétine-O-glycoside peuvent jouer un rôle d'abaissement des lipides, dans des expérimentations à la fois in vivo et in vitro. En outre, la présente invention concerne également une composition pharmaceutique pour le traitement de troubles du métabolisme lipidique.
PCT/CN2015/073814 2014-05-05 2015-03-06 Utilisation de dérivés de quercétine-o-glycoside dans le traitement de troubles du métabolisme lipidique WO2015169121A1 (fr)

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Cited By (4)

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US10639294B2 (en) * 2018-10-02 2020-05-05 Janssen Pharmaceutica Nv Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide metabolite
CN111925405A (zh) * 2020-08-20 2020-11-13 湖南省人民医院 一种甲基异茜草素a环糖基化衍生物及其制备方法和应用
JP2022511400A (ja) * 2018-10-02 2022-01-31 ヤンセン ファーマシューティカ エヌ．ベー． ヒドロキシエチルケルセチングルクロニドを含む医薬組成物
US11304968B2 (en) 2018-11-16 2022-04-19 Janssen Pharmaceutica Nv Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide

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CN106031732A (zh) * 2015-03-12 2016-10-19 南京瑞菁医药科技有限责任公司 槲皮素糖苷类化合物在治疗肝纤维化中的用途
CN104788518A (zh) * 2015-05-04 2015-07-22 中国药科大学 槲皮素-3-O-β-D-葡萄糖苷的制备方法及其脂质调节方面的用途
CN106243173B (zh) * 2016-07-14 2020-10-30 塔里木大学 从南疆骏枣中提取及分离纯化降血脂活性化合物槲皮素-3-O-β-D-半乳糖苷的方法
CN111961097B (zh) * 2020-08-12 2023-01-24 青岛海合生物科技有限公司 一种辣椒素类衍生物及其制备方法和在制备心血管疾病的药物中的应用

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CN1978452A (zh) * 2005-12-01 2007-06-13 新疆医科大学 罗布麻甲素制备新工艺
CN1817876A (zh) * 2006-03-20 2006-08-16 中国农业科学院作物科学研究所 用芦丁制备槲皮素及异槲皮苷的方法
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10639294B2 (en) * 2018-10-02 2020-05-05 Janssen Pharmaceutica Nv Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide metabolite
JP2022511400A (ja) * 2018-10-02 2022-01-31 ヤンセン ファーマシューティカ エヌ．ベー． ヒドロキシエチルケルセチングルクロニドを含む医薬組成物
US11304968B2 (en) 2018-11-16 2022-04-19 Janssen Pharmaceutica Nv Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide
CN111925405A (zh) * 2020-08-20 2020-11-13 湖南省人民医院 一种甲基异茜草素a环糖基化衍生物及其制备方法和应用

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