WO2017133057A1 - 五味子木脂素类化合物的医药用途 - Google Patents

五味子木脂素类化合物的医药用途 Download PDF

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WO2017133057A1
WO2017133057A1 PCT/CN2016/076314 CN2016076314W WO2017133057A1 WO 2017133057 A1 WO2017133057 A1 WO 2017133057A1 CN 2016076314 W CN2016076314 W CN 2016076314W WO 2017133057 A1 WO2017133057 A1 WO 2017133057A1
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schisandra
schisandrin
chinensis
group
mice
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PCT/CN2016/076314
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English (en)
French (fr)
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黄诚
季光
顾明
范圣洁
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上海中医药大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin

Definitions

  • the invention relates to the field of medicine, in particular to a medical use of a schisandra lignan compound.
  • Nonalcoholic fatty liver disease is one of the most common liver diseases. As the disease progresses, nonalcoholic fatty liver may turn into cirrhosis and liver cancer; at the same time, it is also an independent cause of increased cardiovascular disease morbidity and mortality.
  • Farnesoid X receptor is a bile acid-activated nuclear receptor that regulates bile acid metabolism, lipid metabolism, glucose metabolism, liver metabolism, and intestinal bacteria by regulating the expression of a series of genes. Growth, etc., which play an important role in diseases such as cholestatic liver injury, inflammatory liver damage, liver fibrosis, fatty liver, dyslipidemia, and atherosclerosis. Studies have shown that bile acids can increase the rate of metabolism, and FXR activated by bile acids may affect body weight by affecting energy expenditure.
  • Insulin resistance refers to the decrease in the efficiency of insulin-promoting glucose uptake and utilization for various reasons, and the body's compensatory secretion of excess insulin produces hyperinsulinemia to maintain blood sugar stability. Insulin resistance is easy to cause metabolic syndrome and type 2 diabetes.
  • Schisandra is rich in volatile components, lignans and organic acids.
  • the lignans are: schisandrin, schisandrin A, schisandrin B, schisandra chinensis, pentoxide, and deoxy Schisandrin.
  • the object of the present invention is to provide a new use of Schisandra lignan compounds.
  • a first aspect of the present invention provides a schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof, for use in the preparation of an FXR transcription activator, wherein the schisandra lignan compound is selected From Schisandra A, Schisandrin B, Schisandra C, Biphenyldicarboxylate, Schizandrol A, Schisandrin B, Schisandrol, Schisandra Schisandra G, Heqing Schisandra, Isoflavone, Muzhi Ning, Anwu Lipoprotein, Schisandrin, schisandrin, schisandrone or pentatonic A1.
  • a second aspect of the present invention provides a schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof, for use in the preparation of a medicament for preventing and treating obesity, which is a schisandra lignan
  • the compound is selected from the group consisting of Schisandrin A, Schisandrin B, Schisandra C, Biphenyldicarboxylate, Schizandrol A, Schizandrol B, Schisandrin, Schisandra Schisandra G, Heqing Schisandra, and Isoflavones , pentacene, Schisandra ester, schisandrin, schisandrone or pentatonic A1.
  • a third aspect of the present invention provides a schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof, for use in the preparation of a medicament or a health care product for preventing and treating fatty liver, the schisandra chinensis
  • the compound is selected from the group consisting of Schisandrin A, Schisandrin B, Schisandra C, Biphenyldicarboxylate, Schizandrol A, Schizandrol B, Schisandrin, Schisandra Schisandra G, Heqing Schisandra, and Schisandra Schisandra Ning, berberine, Schisandrin, schisandrin, schisandrone or pentatonic A1.
  • a fourth aspect of the present invention provides a schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof for use in the preparation of a medicament for preventing or treating hyperglycemia, which is a schisandra
  • the compound is selected from the group consisting of Schisandrin A, Schisandrin B, Schisandra C, Biphenyldicarboxylate, Schizandrol A, Schizandrol B, Schisandrin, Schisandra Schisandra G, Heqing Schisandra, and Schisandra Schisandra Ning, berberine, Schisandrin, schisandrin, schisandrone or pentatonic A1.
  • a fifth aspect of the present invention provides a schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof, for use in the preparation of a medicament for preventing or treating hyperlipidemia, which is a schisandra
  • the lignans are selected from the group consisting of Schisandrin A, Schisandrin B, Schisandra C, Biphenyldiester, Schizandrol A, Schizandrol B, Schisandrin, Schisandra Schisandra G, Heqing Schisandra, and Schisandra Muzhining, pentaphylline, Schisandrin, schisandrin, schisandrone or pentatin A1.
  • a sixth aspect of the present invention provides a schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof, for use in the preparation of a medicament or a health care product for controlling insulin resistance, the schisandra chinensis
  • the compound is selected from the group consisting of Schisandrin A, Schisandrin B, Schisandra C, Biphenyldicarboxylate, Schizandrol A, Schizandrol B, Schisandrin, Schisandra Schisandra G, Heqing Schisandra, and Schisandra Muzhining, pentaphylline, Schisandrin, schisandrin, schisandrone or pentatin A1.
  • the Schisandra lignan compound is selected from the group consisting of Schisandrin A, Schisandrin B, Schisandra C, Schisandrin A, Schizandrol B, Schisandrin, Schisandra Schisandra G, Heqing Schisandra Or schisandra chinensis.
  • Figure 1 shows the effect of schisandra lignans such as schisandrin A, schisandrin B, bifendate, and pentapeptide on FXR transcriptional activity.
  • Figure 2 shows the concentration dependence of schisandra A, schisandrin B, Schisandrin, bifendate, and pentapeptide on FXR transcriptional activity.
  • Figure 3 shows the effects of schisandrin A, schisandrin B, bifendate, and pentapeptide on the body weight of obese C57BL/6 mice induced by high fat diet; in the figure: * indicates that compared with the control group, P ⁇ 0.05 .
  • Figure 4 shows the food intake of mice fed with schisandrin, schisandrin, bifendate, and pentoxide.
  • Figure 5 shows the effects of schisandrin A, schisandrin B, bifendate, and pentapeptide on visceral fat in obese mice.
  • Figure 6A-F shows the effects of schisandrin A, schisandrin B, bifendate, and pentapeptide on fat weight in obese mice.
  • A abdominal white fat content
  • B subcutaneous white fat content
  • C gonadal white fat content
  • D white blood fat content of the heart
  • E white fat content of the spleen
  • F white fat content of the kidney.
  • * indicates that P ⁇ 0.05 compared with the control group.
  • Figure 7A-E shows the effects of schisandrin A, schisandrin B, bifendate, and pentapeptide on the metabolic rate of obese C57BL/6 mice induced by high fat diet.
  • A carbon dioxide
  • B oxygen
  • C respiratory exchange rate
  • D number of movement steps
  • E body temperature.
  • * indicates that P ⁇ 0.05 compared with the control group.
  • Figure 8A-B shows the effects of schisandrin A, schisandrin B, bifendate, and pentasin on liver lipid content; A: triglyceride content; B: total cholesterol content.
  • * indicates that P ⁇ 0.05 compared with the control group.
  • Figure 9 shows the schisandra A, schisandrin B, biphenyl diester, and pentometin on obese mice The effect of abdominal blood glucose; in the figure: * indicates that compared with the control group, P ⁇ 0.05; ** indicates that compared with the control group, P ⁇ 0.01.
  • Figure 10 shows the improvement of glucose tolerance test in obese mice by schisandrin A, schisandrin B, bifendate, and pentapeptide.
  • * indicates that compared with the control group, P ⁇ 0.05; ** indicates P ⁇ 0.01 compared with the control group.
  • Figure 11 shows the improvement of insulin resistance test in obese mice by schisandrin A, schisandrin B, bifendate, and pentapeptide.
  • * indicates that P ⁇ 0.05 compared with the control group.
  • Figure 12 shows the improvement of blood lipids in obese mice by schisandrin A, schisandrin B, bifendate, and pentapeptide; A: Schisandrin A; B: Schisandrin B; C: biphenyl diester; : An pentoxide.
  • * indicates that P ⁇ 0.05 compared with the control group.
  • the present invention is based on the surprising discovery that Schisandra lignans can block the weight gain of C57BL/6 mice induced by high-fat diets, inhibit the increase of body fat cells, and improve fasting blood glucose and insulin resistance in mice. Abnormal blood lipids, etc.
  • FXR reporter gene analysis showed that Schisandra lignans can inhibit the transcriptional activity of the FXR gene. It is proved that Schisandra lignans not only have significant therapeutic activity against obesity, but also prevent, improve and/or treat various metabolic diseases such as fatty liver, hyperlipidemia, etc. by selectively inhibiting the transcriptional activity of FXR. The role.
  • the "schisandra lignan compound” includes, but is not limited to, the following compounds:
  • the Schisandra lignan compound is selected from the group consisting of Schisandra A, Schisandrin B, Schisandra C, Schizandrol A, Schizandrol B, Schisandrin, Schisandra Schisandra G, Heqing Schisandra, or different Nanzizizi Muzhi Ning.
  • the invention also provides corresponding all pharmaceutically acceptable salts, hydrates or prodrugs of the above compounds.
  • These salts may be formed by a positively charged moiety (eg, an amine group) of the compound and a negatively charged (eg, trifluoroacetic acid) having an opposite polarity; or by a negatively charged moiety (eg, a carboxyl group) of the compound Positive charges (eg, sodium, potassium, calcium, magnesium) are formed.
  • the compound may contain a non-aromatic double bond with one or more asymmetric centers. Thus these compounds may exist as racemic mixtures, as individual enantiomers, as individual diastereomers, as mixtures of diastereomers, as cis or trans isomers. All of these isomers are expected.
  • the "prodrug of Schisandra lignan compound” generally refers to a substance which, when administered by an appropriate method, can be converted into at least one of the above-mentioned Schisandra chinensis by metabolic or chemical reaction in a subject. a lipoprotein compound or a salt thereof.
  • the Schisandra lignan compound of the present invention can be obtained by a conventional method in the art such as alcohol extraction, chromatography, or the like. It can be obtained by extraction from plants such as Schisandra, and can also be purchased commercially or by using commercially available raw materials, and synthesized by a conventional compound synthesis method in the prior art.
  • the compounds of the present invention can be synthesized by one of ordinary skill in the art in accordance with known techniques. The synthesized compound can be further purified by column chromatography, high performance liquid chromatography or crystallization.
  • the Schisandra lignan compound of the present invention or a pharmaceutically acceptable salt, hydrate or prodrug thereof can effectively inhibit the transcriptional activity of the FXR gene, and thus the compound of the present invention or a pharmaceutically acceptable salt or hydrate thereof Or prodrugs can be used to prepare FXR gene transcriptional inhibitors or to prevent drugs or health products such as obesity, fatty liver, hyperglycemia, hyperlipidemia and insulin resistance.
  • the content of the Schisandra lignan compound of the present invention or a pharmaceutically acceptable salt, hydrate or prodrug thereof in the composition or pharmaceutical preparation is, for example, 0.0001 to 50% by weight; preferably 0.001 to 30% by weight; more preferably 0.01- 20wt%.
  • a therapeutically effective amount of the composition of the present invention is used in an amount between 0.001 and 500 mg/kg body weight per day, and any amount within the above range is an effective amount of the present invention.
  • the composition of the invention is used in an amount between 0.005 and 300 mg/kg body weight per day; more preferably, the composition of the invention is used in an amount between 0.01 and 100 mg/kg body weight per day.
  • the "therapeutically effective amount" can be used for single or combination therapy of the relevant disease. Those skilled in the art will appreciate that the amount administered at the time of actual administration may be higher or lower than the above dosage range.
  • the "therapeutically effective amount” and specific treatment regimen for a subject can be affected by a number of factors, including the pharmacodynamic activity of the compound or prodrug used, the age, weight, and general condition of the subject being administered. , gender, diet, time of administration, susceptibility to disease, progression of the disease, and judgment of the treating physician.
  • treatment refers to the administration of a schisandra lignan compound of the present invention to a body (containing obesity, symptoms of obesity, or having a precursor to obesity) to treat, alleviate, slow, alter, cure, affect, and improve A tumor, a symptom of a tumor, or a precursor to a tumor.
  • the Schisandra lignan compound of the present invention or a pharmaceutically acceptable salt, hydrate or prodrug thereof or a composition thereof or a pharmaceutical preparation thereof can be administered orally, intravenously, intramuscularly, subcutaneously, intranasally, or intrarectally.
  • Solid carriers such as: starch, lactose, glycerol phosphate, microcrystalline cellulose, brown sugar and white clay, and liquid carriers such as sterile water, polyethylene glycol, nonionic surfactants and edible oils (such as corn oil, Peanut oil and sesame oil) are suitable for the characteristics of the active ingredient and the particular mode of administration required.
  • Adjuvants commonly used in the preparation of pharmaceutical compositions may also be advantageously included, such as flavoring agents, coloring agents, preservatives, and antioxidants such as vitamin E, vitamin C, BHT, and BHA.
  • the Schisandra lignan compounds of the present invention can also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds (as free base or pharmaceutically acceptable salts) may also be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, polyethylene glycol, and mixtures thereof in oils. These preparations contain preservatives to prevent the growth of microorganisms under normal conditions of storage and use.
  • the pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders (for the temporary preparation of sterile injectable solutions or dispersions). In all cases, these forms must be sterile and must be fluid to facilitate fluid discharge from the syringe. It must be stable under the conditions of manufacture and storage and must be preserved against the contamination and effects of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, an alcohol, a suitable mixture thereof, and a vegetable oil.
  • mice Eight-week-old C57/BJ6 mice weighed approximately 22-25 g/g.
  • the feeding condition is SPF grade, and the feeding temperature is 22-23 °C. 12 hours and nights alternate.
  • Animal feed was purchased from Research Diet (high fat D12492, low fat D12450B).
  • mice Eight-week-old mice were fed with a diet containing 60% (w/w) fat.
  • the treatment group mixed the drugs into the feed, and the mice were free to eat and drink. A total of 6 weeks of treatment. Mouse body weight and food intake were recorded every other day.
  • the pCMXGal-mFXR-LBD and MH100 ⁇ 4-TK-Luc plasmids were co-transfected into 293T cells with liposomes, and the specificity of FXR was used after 24 hours of culture.
  • GW4064 (10 ⁇ M) and Schisandrin A, Schisandrin B, Schisandrin, Pentasin and other schisandra lignans and prodrugs of Schisandrin (1, 3, 6, 12, 25
  • the cells were treated at a concentration of 50 ⁇ M). After 24 h of treatment, the cells were washed twice with PBS.
  • the pentatin A1 and the schisandra chinensis var. chinensis can significantly activate FXR transcriptional activity (see Figure 1 for details).
  • Schisandra A, Schisandrin B, Schisandra C, Biphenyl Diester, Pentasin to FXR Activation of transcriptional activity is concentration dependent (see Figure 2 for details).
  • mice were fed for 3 months with high-fat diet (Research Diet, D12492), obese mice were mixed with various drugs according to the mass fraction (dosage concentration 0.15wt%) for 6 weeks, every other day. Mouse body weight and food intake were recorded.
  • Figure 3 shows the effects of schisandrin A, schisandrin B, bifendate, and pentapeptide on the body weight of obese C57BL/6 mice induced by high fat diet; *: indicates that compared with the control group, P ⁇ 0.05 . It can be seen from Fig. 3 that the body weight of each group was significantly lower than that of the control group (P ⁇ 0.05), and Fig. 4 showed that the effect of blocking the weight gain of the mice in each group was not because the drug significantly changed the mice. Daily food intake, indicating that Schisandra A, Schisandra B, bifendate, and pentapeptide can reduce the body weight of obese mice, and have a weight loss effect.
  • Example 3 Effect of schisandrin A, schisandrin B, bifendate, and pentasaponin on the weight of adipose tissue in obese mice
  • mice were fed for 3 months with high-fat diet (Research Diet, D12492), obese mice were treated with the above-mentioned administration method (administered at a concentration of 0.15 wt%), administered continuously for 6 weeks, and then anesthetized.
  • the whole abdominal cavity and thoracic cavity of each group were observed to observe the fat cell bulk density of each group of mice, and the white fat of the mice were compared with the abdominal cavity, subcutaneous and gonads, heart, spleen and kidney around each group.
  • mice C57BJ/6 mice were fed with high-fat diet (Research Diet, D12492) for 3 months, and obese mice were treated by the above-mentioned administration method (administration concentration: 0.15 wt%), continuous administration for 4 weeks, continuous observation
  • the body temperature of the mice in each of the above groups was measured for 3 days, and the high-fat control mice and the schisandra-rich schisandrin B were further selected to observe the metabolic signs of the metabolic mice.
  • Figures 7A and 7B show that the carbon dioxide exhaled and oxygen consumption of the schisandrin-treated group were significantly higher than that of the high-fat control group.
  • Figure 7C shows that the respiratory exchange rate of the schisandrin treatment group was significantly higher than that of the day or night.
  • C57BJ/6 mice were fed with high-fat diet (Research Diet, D12492) for 3 months, and the obese mice were subjected to the above-mentioned continuous administration for 6 weeks.
  • the livers of the above groups were homogenized, extracted with chloroform, and chloroform was extracted. After the layer is dried, it is dissolved in isopropyl alcohol, and the content of triglyceride is measured. The detection result is shown in Fig. 8.
  • mice C57BJ/6 mice were fed with high-fat diet (Research Diet, D12492) for 3 months, and then administered with Schisandra A, Schisandrin B, Biphenyldicarboxylate, and Pentasin (administered at a concentration of 0.1% by weight)
  • the rats were continuously administered for 4 weeks, and fasting blood glucose was measured; the mice were administered at 9 am, and the mice were fasted overnight before measuring blood glucose.
  • Control mice were fed a low fat diet (Research Diet, D12450B).
  • Figure 9 shows the schisandra A, schisandrin B, biphenyl diester, and pentapeptide on fasting obese mice
  • the effect of blood glucose is that the fasting blood glucose of mice fed with high fat diet is significantly higher than that of low fat control mice.
  • fasting blood glucose was significantly decreased in mice fed with schisandrin A, schisandrin B, bifendate, and pentoxin for 6 weeks (P ⁇ 0.05).
  • mice C57BJ/6 mice were fed with high-fat diet (Research Diet, D12492) for 3 months, and subjected to the above-mentioned continuous administration for 6 weeks for glucose tolerance test; the mice were fasted overnight before blood glucose measurement. Control mice were fed a low fat diet (Research Diet, D12450B).
  • mice were intraperitoneally injected with 1 g/kg body weight glucose, and the tail vein blood glucose values were measured at 0, 15, 30, 60, and 90 min.
  • Figure 10 shows the improvement of glucose tolerance test in obese mice by schisandrin A, schisandrin B, bifendate, and pentapeptide. It can be seen from Figure 10: Schisandra A, Schisandrin B, Biphenyl In the test of the obese mice fed with ester and pentoxide, the blood glucose at 30, 60 and 90 min was significantly decreased (P ⁇ 0.05), indicating Schisandrin A and Schisandra B. Inhibition of insulin resistance in obese mice induced by high fat diet can be achieved by bismuth, bifendate and pentoxide.
  • Example VIII Insulin tolerance test of schisandrin A, schisandrin B, bifendate, and pentasin in obese mice
  • mice C57BJ/6 mice were fed with high-fat diet (Research Diet, D12492) for 3 months, and subjected to the above-mentioned continuous administration for 6 weeks for insulin tolerance test; the mice were fasted overnight before blood glucose measurement. Control mice were fed a low fat diet (Research Diet, D12450B).
  • mice were rested for 3 days, and the insulin was injected at 10 U/kg body weight, and the tail vein blood glucose level was measured at 0, 15, 30, 60, 90, and 120 minutes, respectively.
  • FIG 11 shows the improvement of insulin resistance test in obese mice by schisandrin A, schisandrin B, bifendate, and pentapeptide.
  • * indicates that P ⁇ 0.05 compared with the control group. It can be seen from Fig. 11 that the obese mice fed with schisandrin A, schisandrin B, bifendate, and pentoxin were tested at 0, 15, 60, and 120 minutes in two hours after administration. The blood glucose showed a significant decrease (P ⁇ 0.05), indicating that schisandra A, schisandrin B, biphenyl diester, and pentane can increase the fat induced by high fat diet. Insulin sensitivity in mice significantly improved insulin resistance in obese mice induced by high fat diet.
  • Example IX Effect of schisandrin A, schisandrin B, bifendate, and pentapeptide on blood lipid levels in obese mice
  • C57BJ/6 mice were fed for 3 months via high-fat diet (Research Diet, D12492) and continuously administered for 6 weeks. Control mice were fed a low fat diet (Research Diet, D12450B).
  • mice After the mice were fasted for 12 hours, the hearts were bled, allowed to stand for 2 hours, centrifuged at 3000 rpm for 15 min, mouse serum was collected, and triglyceride, cholesterol, high-density lipoprotein and low-density lipoprotein levels were measured by an automatic biochemical analyzer.

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Abstract

本发明涉及医药领域，特别是涉及五味子木脂素类化合物，或其药学上可接受的盐、水合物或前药在制备FXR转录激活剂、防治肥胖等中的应用，所述五味子木脂素类化合物选自五味子甲素、五味子乙素、五味子丙素、联苯双酯、五味子醇甲、五味子醇乙、五味子酚、滇藏五味子素G、鹤庆五味子癸素、异南五味子木脂宁、安五脂素、五味子酯戊、五味子烯、五味子酮或五脂素A1。

Description

五味子木脂素类化合物的医药用途 技术领域
本发明涉及医药领域，特别是涉及一种五味子木脂素类化合物的医药用途。
背景技术
研究表明，肥胖、高脂血症和II型糖尿病均为伴随终生的慢性疾病，患者需要及时用药，以免病情恶化。非酒精性脂肪肝是最常见的肝脏疾病之一。随着病情的发展，非酒精性脂肪肝可能转变为肝硬化、肝癌；同时，其也是患者心血管疾病发病率和死亡率增加的独立致病因素。
法尼醇X受体(farnesoid X receptor，FXR)是一种胆汁酸激活的核受体，其通过调控一系列基因的表达，影响胆汁酸代谢、脂代谢、糖代谢、肝脏代谢、肠道细菌的生长等，其在胆汁淤积性肝损伤、炎症性肝损伤、肝纤维化、脂肪肝、血脂代谢紊乱和动脉粥样硬化等病症中发挥重要作用。有研究证实，胆汁酸可以增加代谢速率，被胆汁酸激活的FXR可能通过对能量消耗产生影响来影响体重。最近的研究发现，激活肠道FXR可以促进肠道FGF15表达改变胆汁酸组成成分，诱导白色脂肪棕色化，增加能量消耗而减肥(Nature Medicine,21:159-165,2015)。因此，通过激活FXR可能成为减肥的新疗法。近期的研究还发现，FXR除了能改善胆汁酸的代谢平衡，还能调控肝脏脂质代谢，有望成为治疗脂肪肝的药物靶点。
胰岛素抵抗是指各种原因使胰岛素促进葡萄糖摄取和利用的效率下降，机体代偿性的分泌过多胰岛素产生高胰岛素血症，以维持血糖的稳定。胰岛素抵抗易导致代谢综合征和2型糖尿病。
五味子富含挥发性成分、木脂素类成分和有机酸类成分。其中，木脂素类成分有：五味子素、五味子甲素、五味子乙素、五味子丙素、安五脂素、去氧五味子素等。
发明内容
本发明的目的旨在提供五味子木脂素类化合物的新用途。
本发明的第一方面提供了一种五味子木脂素类化合物，或其药学上可接受的盐、水合物或前药在制备FXR转录激活剂中的应用，所述五味子木脂素类化合物选自五味子甲素、五味子乙素、五味子丙素、联苯双酯、五味子醇甲、五味子醇乙、五味子酚、滇藏五味子素G、鹤庆五味子癸素、异南五味子木脂宁、安五脂素、五味子酯戊、五味子烯、五味子酮或五脂素A1。
本发明的第二方面提供了一种五味子木脂素类化合物，或其药学上可接受的盐、水合物或前药在制备防治肥胖的药物或保健品中的应用，所述五味子木脂素类化合物选自五味子甲素、五味子乙素、五味子丙素、联苯双酯、五味子醇甲、五味子醇乙、五味子酚、滇藏五味子素G、鹤庆五味子癸素、异南五味子木脂宁、安五脂素、五味子酯戊、五味子烯、五味子酮或五脂素A1。
本发明的第三方面提供了一种五味子木脂素类化合物，或其药学上可接受的盐、水合物或前药在制备防治脂肪肝的药物或保健品中的应用，所述五味子木脂素类化合物选自五味子甲素、五味子乙素、五味子丙素、联苯双酯、五味子醇甲、五味子醇乙、五味子酚、滇藏五味子素G、鹤庆五味子癸素、异南五味子木脂宁、安五脂素、五味子酯戊、五味子烯、五味子酮或五脂素A1。
本发明的第四方面提供了一种五味子木脂素类化合物，或其药学上可接受的盐、水合物或前药在制备防治高血糖的药物或保健品中的应用，所述五味子木脂素类化合物选自五味子甲素、五味子乙素、五味子丙素、联苯双酯、五味子醇甲、五味子醇乙、五味子酚、滇藏五味子素G、鹤庆五味子癸素、异南五味子木脂宁、安五脂素、五味子酯戊、五味子烯、五味子酮或五脂素A1。
本发明的第五方面提供了一种五味子木脂素类化合物，或其药学上可接受的盐、水合物或前药在制备防治高脂血症的药物或保健品中的应用，所述五味子木脂素类化合物选自五味子甲素、五味子乙素、五味子丙素、联苯双酯、五味子醇甲、五味子醇乙、五味子酚、滇藏五味子素G、鹤庆五味子癸素、异南五味子木脂宁、安五脂素、五味子酯戊、五味子烯、五味子酮或五脂素A1。
本发明的第六方面提供了一种五味子木脂素类化合物，或其药学上可接受的盐、水合物或前药在制备防治胰岛素抵抗的药物或保健品中的应用，所述五味子木脂素类化合物选自五味子甲素、五味子乙素、五味子丙素、联苯双酯、五味子醇甲、五味子醇乙、五味子酚、滇藏五味子素G、鹤庆五味子癸素、异南五味子 木脂宁、安五脂素、五味子酯戊、五味子烯、五味子酮或五脂素A1。
在一优选例中，所述五味子木脂素类化合物选自五味子甲素、五味子乙素、五味子丙素、五味子醇甲、五味子醇乙、五味子酚、滇藏五味子素G、鹤庆五味子癸素或异南五味子木脂宁。
本发明各个方面的细节将在随后的章节中得以详尽描述。通过下文以及权利要求的描述，本发明的特点、目的和优势将更为明显。
附图说明：
图1体现了五味子甲素、五味子乙素、联苯双酯、安五脂素等五味子木脂素类化合物对FXR转录活性的影响。
图2体现了五味子甲素、五味子乙素、五味子丙素、联苯双酯、安五脂素等化合物对FXR转录活性的浓度依赖性。
图3体现了五味子甲素、五味子乙素、联苯双酯、安五脂素对高脂饲料诱导的肥胖C57BL/6小鼠的体重影响；图中：*表示与对照组比较，P<0.05。
图4体现了五味子甲素、五味子乙素、联苯双酯、安五脂素喂养小鼠摄食量。
图5体现了五味子甲素、五味子乙素、联苯双酯、安五脂素对肥胖小鼠内脏脂肪的影响。
图6A—F现了五味子甲素、五味子乙素、联苯双酯、安五脂素对肥胖小鼠各部位脂肪重量的影响。A：腹腔白脂肪含量；B：皮下白脂肪含量；C：性腺旁白脂肪含量；D：心脏旁白脂肪含量；E：脾脏旁白脂肪含量；F：肾旁白脂肪含量。图中：*表示与对照组比较，P<0.05。
图7A—E体现了五味子甲素、五味子乙素、联苯双酯、安五脂素对高脂饲料诱导的肥胖C57BL/6小鼠的代谢率影响。A：二氧化碳；B：氧气；C：呼吸交换率；D：运动步数；E：体温。图中：*表示与对照组比较，P<0.05。
图8A—B体现了五味子甲素、五味子乙素、联苯双酯、安五脂素对肝脏脂质含量的影响；A：甘油三酯含量；B：总胆固醇含量。图中：*表示与对照组比较，P<0.05。
图9体现了五味子甲素、五味子乙素、联苯双酯、安五脂素对肥胖小鼠空 腹血糖的影响；图中：*表示与对照组比较，P<0.05；**表示与对照组比较，P<0.01。
图10体现了五味子甲素、五味子乙素、联苯双酯、安五脂素对肥胖小鼠葡萄糖耐受试验的改善作用；图中：*表示与对照组比较，P<0.05；**表示与对照组比较，P<0.01。
图11体现了五味子甲素、五味子乙素、联苯双酯、安五脂素对肥胖小鼠胰岛素耐受试验的改善作用；图中：*表示与对照组比较，P<0.05。
图12体现了五味子甲素、五味子乙素、联苯双酯、安五脂素对肥胖小鼠血脂的改善作用；A：五味子甲素；B：五味子乙素；C：联苯双酯；D：安五脂素。图中：*表示与对照组比较，P<0.05。
具体实施方式
本发明的问世是基于这样一个意外发现：五味子木脂素类化合物可阻断高脂餐诱导的C57BL/6小鼠体重增加，抑制体脂肪细胞的体积增加，改善小鼠空腹血糖、胰岛素抵抗和血脂异常等。另外，FXR报告基因分析结果显示：五味子木脂素类化合物能够抑制FXR基因的转录活性。证明五味子木脂素类化合物不仅对肥胖具有显著治疗活性，还可同时通过选择性地抑制FXR的转录活性起到预防、改善和/或治疗多种代谢性疾病如脂肪肝、高脂血症等的作用。
如本发明所用，所述的“五味子木脂素类化合物”包括但不限于如下化合物：
Figure PCTCN2016076314-appb-000001
Figure PCTCN2016076314-appb-000002
Figure PCTCN2016076314-appb-000003
较优选地，所述五味子木脂素类化合物选自五味子甲素、五味子乙素、五味子丙素、五味子醇甲、五味子醇乙、五味子酚、滇藏五味子素G、鹤庆五味子癸素或异南五味子木脂宁。
本发明还提供了上述化合物的相应的所有药学上可以接受的盐、水合物或前药。这些盐可以由化合物中带正电荷的部分(例如，胺基)与具有相反电性的带负电荷(例如，三氟醋酸)形成；或者由化合物中带负电荷的部分(例如，羧基)与正电荷(例如，钠、钾、钙、镁)形成。化合物可以含有一个非芳香性的双键，具有一个或多个不对称中心。所以这些化合物可以作为外消旋的混合物、单独的对映异构体、单独的非对映异构体、非对映异构体混合物、顺式或反式异构体存在。所有这些异构体都是可预期的。所述的“五味子木脂素类化合物的前药”通常分别指一种物质，当用适当的方法施用后，可在受试者体内进行代谢或化学反应而分别转变成至少一种上述五味子木脂素类化合物或其盐。
本发明的五味子木脂素类化合物可通过本领域的常规方法如醇提、层析等从 五味子等植物中提取获得，亦可通过商业途径购买或者利用市售原料，通过现有技术中传统的化合物合成方法合成获得。本领域的普通技术人员根据现有公知技术可以合成本发明的化合物。合成的化合物可以进一步通过柱色谱法、高效液相色谱法或结晶等方式进一步纯化。
合成化学改造、保护官能团方法学(保护或去保护)对合成应用化合物是很有帮助的，并且是现有技术中的公知的技术，如R.Larock,Comprehensive Organic Transformations,VCH Publishers(1989)；T.W.Greene and P.G.M.Wuts,Protective Groups in Organic Synthesis,3rd Ed.,John Wiley and Sons(1999)；L.Fieser and M.Fieser,Fieser and Fieser’s Reagents for Organic Synthesis,John Wiley and Sons(1994)；and L.Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis,John Wiley and Sons(1995)中都有公开。
本发明的五味子木脂素类化合物或其药学上可接受的盐、水合物或前药可以有效地抑制抑制FXR基因的转录活性，故而本发明的化合物或其药学上可接受的盐、水合物或前药可用于制备FXR基因转录抑制剂或者防治肥胖、脂肪肝、高血糖、高血脂和胰岛素抵抗等药物或保健品。
本发明的五味子木脂素类化合物或其药学上可接受的盐、水合物或前药在组合物或药物制剂中的含量例如0.0001-50wt％；较佳的0.001-30wt％；更加的0.01-20wt％。
治疗有效量的本发明的组合物的用量介于0.001-500mg/kg体重/天之间，任何介于上述范围之内的用量皆为本发明的有效量。优选的，本发明的组合物的用量介于0.005-300mg/kg体重/天之间；更优选的，本发明的组合物的用量介于0.01-100mg/kg体重/天之间。所述的“治疗有效量”可用于相关疾病的单一用药或联合用药治疗。本领域的专业人员能够理解，在实际给药时的用量可高于或低于上述剂量范围。针对某一对象(如哺乳动物—人)的“治疗有效量”和具体治疗方案可受诸多因素的影响，包括所用化合物或其前药的药效活性、给药对象的年龄、体重、一般情况、性别、饮食、给药时间、疾病易感性、疾病进程以及治疗医师的判断等。所述“治疗”指的是给予机体(含有肥胖、具有肥胖的症状、或者具有肥胖的前兆)本发明的五味子木脂素类化合物，以治疗、减轻、减缓、改变、治愈、影响、改善其肿瘤、肿瘤的症状或肿瘤的前兆。
本发明的五味子木脂素类化合物或其药学上可接受的盐、水合物或前药或其组合物或其药物制剂可以通过口服、静脉内、肌肉内、皮下、鼻腔内、直肠内等途径给药。固体载体如：淀粉、乳糖、磷酸二醇、微晶纤维素、黑糖和白陶土，而液态载体如：无菌水、聚乙二醇、非离子型表面活性剂和食用油(如玉米油、花生油和芝麻油)，只要适合活性成分的特性和所需要的特定给药方式。在制备药物组合物中通常使用的佐剂也可有利地被包括，如，调味剂、色素、防腐剂和抗氧化剂如维生素E、维生素C、BHT和BHA。
本发明的五味子木脂素类化合物也可胃肠外或腹腔内给药。也可在适当混合有表面活性剂(如羟丙基纤维素)的水中制备这些活性化合物(作为游离碱或药学上可接受的盐)的溶液或悬浮液。还可在甘油、聚乙二醇及其在油中的混合物中制备分散液。在常规储存和使用条件下，这些制剂中含有防腐剂以防止微生物的生长。
适用于注射的药物形式包括：无菌水溶液或分散液和无菌粉(用于临时制备无菌注射液或分散液)。在所有情况中，这些形式必须是无菌的且必须是流体以易于注射器排出流体。在制造和储存条件下必须是稳定的，且必须能防止微生物如细菌和真菌的污染和影响。载体可以是溶剂或分散介质，其中含有如水、醇、它们的适当混合物和植物油。
下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载的内容相似或均等的方法及材料皆可应用于本发明方法中。本文所述的较佳实施方法与材料仅作示范之用。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本专利说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
实验设计与材料
1.药物和动物
8周龄C57/BJ6小鼠，体重约22-25克/只。饲养条件为SPF级，饲养温度22-23℃。12小时昼夜交替。动物饲料购自Research Diet(高脂D12492，低脂D12450B)。
以下实施例以五味子甲素、五味子乙素、五味子丙素、联苯双酯、安五脂素以及其他五味子木脂素类化合物作为活性药物，其化学结构式如“具体实施方式”章节所示。
2.实验仪器
血糖仪及试纸购自Roche(全力康)。
小鼠代谢笼系统(TSE，德国)
小鼠直肠体温测量仪(Physitema美国)
3.动物与分组
8周龄小鼠用含60％(w/w)脂肪的饲料喂养，治疗组将药物混入饲料，小鼠自由进食、饮水。共治疗6周。隔日记录小鼠体重和摄食量。
实施例一.五味子木脂素类化合物和联苯双酯激活FXR转录活性测试
293T细胞长至50％～80％的密度时，将pCMXGal-mFXR-LBD、MH100×4-TK-Luc质粒与脂质体共转染于293T细胞中，培养24小时后使用FXR的特异性配体GW4064(10μM)和五味子甲素、五味子乙素、五味子丙素、安五脂素等五味子木脂素类化合物及五味子丙素的前药联苯双酯(1、3、6、12、25、50μM)的浓度处理细胞。处理24h后，用PBS洗细胞两次。每孔加入65μL的裂解液，摇床振荡15min，1000rpm离心5min，取上清裂解液10μL，加LAR Ⅱ液20μL，混匀，测荧光，2秒延迟，读10秒。Renilla荧光值作为内参，相同实验重复三次，每次实验三个复孔，统计数据。
经报告基因检测，五味子甲素、五味子乙素、五味子丙素、五味子醇乙、五味子酚、五味子醇甲、五味子酯戊、五味子烯、五味子酮、鹤庆五味子癸素、滇藏五味子素G、五脂素A1、异南五味子木脂宁等均能显著激活FXR转录活性(详见图1所示)。五味子甲素、五味子乙素、五味子丙素、联苯双酯、安五脂素对FXR 转录活性的激活具有浓度依赖性(详见图2所示)。
实施例二.五味子甲素、五味子乙素、联苯双酯、安五脂素对肥胖小鼠体重的影响
C57BJ/6小鼠经高脂饲料(Research Diet，D12492)饲养3个月后，肥胖小鼠经各种药物按质量分数混入饲料(给药浓度为0.15wt％)，连续给药6周，隔日记录小鼠体重和摄食量。
图3体现了五味子甲素、五味子乙素、联苯双酯、安五脂素对高脂饲料诱导的肥胖C57BL/6小鼠的体重影响；图中*：表示与对照组比较，P<0.05。由图3可见：各组给药组相对于对照组的体重呈现明显降低(P<0.05)，同时图4表明各组药物的阻断小鼠体重增长的效果并不是因为药物明显改变小鼠的每日摄食量，表明五味子甲素、五味子乙素、联苯双酯、安五脂素可减轻肥胖小鼠的体重，具有减肥作用。
实施例三.五味子甲素、五味子乙素、联苯双酯、安五脂素对肥胖小鼠脂肪组织重量的影响
C57BJ/6小鼠经高脂饲料(Research Diet，D12492)饲养3个月后，肥胖小鼠经上述给药方式治疗(给药浓度为0.15wt％)，连续给药6周，然后经麻醉，打开各组小鼠整个腹腔和胸腔观测拍照各组小鼠的脂肪细胞堆积密度，并称重比较各组小鼠腹腔、皮下及性腺、心脏、脾脏、肾脏周围白色脂肪。观测和称重如图5和6所示，由图5可见：经五味子甲素、五味子乙素、联苯双酯、安五脂素治疗的肥胖小鼠的脂肪细胞堆积密度呈现明显降低，图6表明各组药物均可不同程度的明显降低肥胖小鼠腹腔、皮下、性腺旁、心脏旁、脾脏旁和肾旁等生理部位的脂肪组织重量，进一步说明各组药物具有减肥作用。
实施例四.五味子甲素、五味子乙素、联苯双酯、安五脂素对肥胖小鼠代谢率的改善作用
C57BJ/6小鼠经高脂饲料(Research Diet，D12492)饲养3个月后，肥胖小鼠经上述给药方式治疗(给药浓度为0.15wt％)，连续给药4周后，连续观察测 量上述各组给药组小鼠3天的体温，并进一步选取高脂对照小鼠和五味子富含成分五味子乙素进行代谢笼小鼠体征观察来评价药物对肥胖小鼠代谢率改善的效果。图7A和7B表明五味子乙素治疗组的二氧化碳呼出量和氧气消耗量都明显高于高脂对照组，图7C表明无论在白天还是夜晚五味子乙素治疗组的呼吸交换率也都显著高于高脂对照组，而图7D表明给予五味子乙素并没有明显增加小鼠的日运动量。图7E表明对于各组给药小鼠直肠体温的测试显示五味子甲素、五味子乙素和安五脂素的体温较高脂对照组都显著升高。这些数据说明五味子甲素、五味子乙素、联苯双酯、安五脂素可以明显改善肥胖小鼠的代谢率，并提示各组药物减肥的疗效可能主要是通过升高体温，增加体内糖脂的能量消耗，而非明显增加小鼠的运动量。
实施例五.五味子甲素、五味子乙素、联苯双酯、安五脂素对肥胖小鼠脂肪肝的改善作用
C57BJ/6小鼠经高脂饲料(Research Diet，D12492)饲养3个月后，肥胖小鼠经上述连续给药6周，对上述各组小鼠的肝脏进行匀浆，氯仿抽提，将氯仿层干燥后用异丙醇溶解，测其中的甘油三酯含量；检测结果如图8所示，经五味子甲素、五味子乙素、联苯双酯、安五脂素治疗后，五味子甲素、五味子乙素能使肥胖小鼠肝脏中的甘油三酯(图8A)和总胆固醇(图8B)含量显著降低(P<0.05)。
综上实验结果可见：五味子甲素、五味子乙素、联苯双酯、安五脂素可显著改善肥胖小鼠的脂肪肝程度。
实施例六.五味子甲素、五味子乙素、联苯双酯、安五脂素对肥胖小鼠的空腹血糖试验
C57BJ/6小鼠经高脂饲料(Research Diet，D12492)饲养3个月后，经灌胃五味子甲素、五味子乙素、联苯双酯、安五脂素(给药浓度为0.1wt％)，连续给药4周，测空腹血糖；小鼠在上午9时给药，测血糖前小鼠禁食过夜。对照小鼠喂食低脂饲料(Research Diet，D12450B)。
图9体现了五味子甲素、五味子乙素、联苯双酯、安五脂素对肥胖小鼠空腹 血糖的影响，由图9可见：经高脂饲料饲养的小鼠空腹血糖显著高于低脂对照小鼠。但经五味子甲素、五味子乙素、联苯双酯、安五脂素喂食6周后的小鼠空腹血糖显著降低(P<0.05)。
实施例七.五味子甲素、五味子乙素、联苯双酯、安五脂素对肥胖小鼠的葡萄糖耐受试验
C57BJ/6小鼠经高脂饲料(Research Diet，D12492)饲养3个月后，经上述连续给药6周，进行葡萄糖耐受试验；测血糖前小鼠禁食过夜。对照小鼠喂食低脂饲料(Research Diet，D12450B)。
测小鼠葡萄糖耐受试验：小鼠腹腔注射1g/kg体重葡萄糖，0、15、30、60、90min时测小鼠尾静脉血糖值。
图10体现了五味子甲素、五味子乙素、联苯双酯、安五脂素对肥胖小鼠葡萄糖耐受试验的改善作用，由图10可见：经五味子甲素、五味子乙素、联苯双酯、安五脂素喂食后的肥胖小鼠在给药后两小时进行的测试中，小鼠在30、60和90min时的血糖呈现明显下降(P<0.05)，表明五味子甲素、五味子乙素、联苯双酯、安五脂素可改善经高脂饲料诱导的肥胖小鼠的胰岛素抵抗。
实施例八.五味子甲素、五味子乙素、联苯双酯、安五脂素对肥胖小鼠的胰岛素耐受试验
C57BJ/6小鼠经高脂饲料(Research Diet，D12492)饲养3个月后，经上述连续给药6周，进行胰岛素耐受试验；测血糖前小鼠禁食过夜。对照小鼠喂食低脂饲料(Research Diet，D12450B)。
测小鼠胰岛素糖耐受试验：小鼠休息3天，注射胰岛素10U/kg体重，分别于0、15、30、60、90、120min时测小鼠尾静脉血糖值。
图11体现了五味子甲素、五味子乙素、联苯双酯、安五脂素对肥胖小鼠胰岛素耐受试验的改善作用；图中：*表示与对照组比较，P<0.05。由图11可见：经五味子甲素、五味子乙素、联苯双酯、安五脂素喂食后的肥胖小鼠在给药后两小时进行的测试中，小鼠在0、15、60和120min时的血糖呈现明显下降(P<0.05)，表明五味子甲素、五味子乙素、联苯双酯、安五脂素可增加高脂饲料诱导的肥胖 小鼠的胰岛素敏感性，可显著改善经高脂饲料诱导的肥胖小鼠的胰岛素抵抗。
实施例九.五味子甲素、五味子乙素、联苯双酯、安五脂素对肥胖小鼠的血脂水平影响
C57BJ/6小鼠经高脂饲料(Research Diet，D12492)饲养3个月后，经上述连续给药6周。对照小鼠喂食低脂饲料(Research Diet，D12450B)。
在小鼠禁食12小时后心脏采血，静置2小时，3000rpm离心15min，收集小鼠血清，全自动生化仪测甘油三酯、胆固醇、高密度脂蛋白和低密度脂蛋白水平。
测试结果见图12所示。由图12可见：高脂组小鼠的总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL-c)和低密度脂蛋白(LDL-c)水平均高于低脂对照小鼠。而经五味子甲素、五味子乙素、联苯双酯、安五脂素喂食6周后的给药组小鼠的甘油三酯、总胆固醇和低密度脂蛋白有一定的降低。表明：五味子甲素、五味子乙素、联苯双酯、安五脂素可显著降低肥胖小鼠的血清总胆固醇、高密度脂蛋白和低密度脂蛋白。
本发明所涉及的多个方面已做如上阐述。然而，应理解的是，在不偏离本发明精神之前提下，本领域专业人员可对其进行等同改变和修饰，所述改变和修饰同样落入本申请所附权利要求的覆盖范围。

Claims (7)

  1. 五味子木脂素类化合物，或其药学上可接受的盐、水合物或前药在制备FXR转录激活剂中的应用，所述五味子木脂素类化合物选自五味子甲素、五味子乙素、五味子丙素、联苯双酯、五味子醇甲、五味子醇乙、五味子酚、滇藏五味子素G、鹤庆五味子癸素、异南五味子木脂宁、安五脂素、五味子酯戊、五味子烯、五味子酮或五脂素A1。
  2. 五味子木脂素类化合物，或其药学上可接受的盐、水合物或前药在制备防治肥胖的药物或保健品中的应用，所述五味子木脂素类化合物选自五味子甲素、五味子乙素、五味子丙素、联苯双酯、五味子醇甲、五味子醇乙、五味子酚、滇藏五味子素G、鹤庆五味子癸素、异南五味子木脂宁、安五脂素、五味子酯戊、五味子烯、五味子酮或五脂素A1。
  3. 五味子木脂素类化合物，或其药学上可接受的盐、水合物或前药在制备防治脂肪肝的药物或保健品中的应用，所述五味子木脂素类化合物选自五味子甲素、五味子乙素、五味子丙素、联苯双酯、五味子醇甲、五味子醇乙、五味子酚、滇藏五味子素G、鹤庆五味子癸素、异南五味子木脂宁、安五脂素、五味子酯戊、五味子烯、五味子酮或五脂素A1。
  4. 五味子木脂素类化合物，或其药学上可接受的盐、水合物或前药在制备防治高血糖的药物或保健品中的应用，所述五味子木脂素类化合物选自五味子甲素、五味子乙素、五味子丙素、联苯双酯、五味子醇甲、五味子醇乙、五味子酚、滇藏五味子素G、鹤庆五味子癸素、异南五味子木脂宁、安五脂素、五味子酯戊、五味子烯、五味子酮或五脂素A1。
  5. 五味子木脂素类化合物，或其药学上可接受的盐、水合物或前药在制备防治高脂血症的药物或保健品中的应用，所述五味子木脂素类化合物选自五味子甲素、五味子乙素、五味子丙素、联苯双酯、五味子醇甲、五味子醇乙、五味子酚、滇藏五味子素G、鹤庆五味子癸素、异南五味子木脂宁、安五脂素、五味子酯戊、五味子烯、五味子酮或五脂素A1。
  6. 五味子木脂素类化合物，或其药学上可接受的盐、水合物或前药在制备防治胰岛素抵抗的药物或保健品中的应用，所述五味子木脂素类化合物选自五味子甲素、五味子乙素、五味子丙素、联苯双酯、五味子醇甲、五味子醇乙、五味子酚、滇藏五味子素G、鹤庆五味子癸素、异南五味子木脂宁、安五脂素、五味 子酯戊、五味子烯、五味子酮或五脂素A1。
  7. 权利要求1～6任一权利要求所述的应用，其特征在于，所述五味子木脂素类化合物选自五味子甲素、五味子乙素、五味子丙素、五味子醇甲、五味子醇乙、五味子酚、滇藏五味子素G、鹤庆五味子癸素或异南五味子木脂宁。
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