WO2022194128A1 - 二苯烷类化合物及其制备方法、药物组合物和用途 - Google Patents

二苯烷类化合物及其制备方法、药物组合物和用途 Download PDF

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WO2022194128A1
WO2022194128A1 PCT/CN2022/080862 CN2022080862W WO2022194128A1 WO 2022194128 A1 WO2022194128 A1 WO 2022194128A1 CN 2022080862 W CN2022080862 W CN 2022080862W WO 2022194128 A1 WO2022194128 A1 WO 2022194128A1
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fluoro
unsubstituted
methoxy
substituted
metabolic syndrome
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French (fr)
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强桂芬
吉腾飞
杜冠华
马鹏
王子婧
许天姝
何萍
孙明霞
杨秀颖
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中国医学科学院药物研究所
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Definitions

  • the invention belongs to the technical field of medicine, and relates to a diphenylalkane compound and a preparation method, pharmaceutical composition and use thereof. Specifically, the compound 1-fluoro-3-methoxy-5-phenethylbenzene or a pharmaceutically acceptable salt thereof and a preparation method thereof, and a pharmaceutical composition containing a metabolite of the compound or a pharmaceutically acceptable salt thereof and its application in the preparation, prevention or treatment of metabolic syndrome and its complications.
  • Metabolic syndrome refers to the pathological state of metabolic disorder of protein, fat, carbohydrate and other substances in the human body. It has the following characteristics: 1 A combination of various metabolic disorders: including obesity, hyperglycemia, high blood pressure, dyslipidemia, high blood viscosity, high uric acid, fatty liver and hyperinsulinemia, these metabolic disorders are cardiovascular and cerebrovascular diseases. and the pathological basis of diabetes. 2Have a common pathological basis: At present, it is generally believed that the common cause is insulin resistance and hyperinsulinemia caused by obesity, especially central obesity.
  • 3It can cause an increase in various diseases: such as hypertension, coronary heart disease, stroke, and even some cancers, including breast, endometrial, and prostate cancers related to sex hormones, as well as pancreatic cancer, hepatobiliary cancer, and colon cancer of the digestive system. cancer etc. 4
  • prevention and treatment measures the prevention and treatment of one metabolic disorder is beneficial to the prevention and treatment of other metabolic disorders.
  • metabolic syndrome has become a worldwide public health problem.
  • the prevalence of metabolic syndrome in the world ranges from 10% to 84%, of which about 20% to 25% of adults suffer from metabolic syndrome.
  • National Health and Nutrition Examination Survey data estimate that in the United States, 35% of adults and 50% of the population over age 60 (30.3% men and 35.6% women) have been diagnosed with metabolic syndrome; of these, Mexican Americans Women have the highest incidence.
  • the prevalence of metabolic syndrome is about 41% in men and 38% in women.
  • Statistics from China show that the prevalence of metabolic syndrome among people aged 15 and over is 24.2%. Another study shows that the prevalence of Chinese people aged 60 and over is about 32.4%.
  • brown adipose tissue has a non-trembling thermogenic function, and its thermogenic function originates from its abundant mitochondria and specific high expression of mitochondrial inner membrane uncoupling protein 1 (UCP1).
  • UCP1 mitochondrial inner membrane uncoupling protein 1
  • the inner and outer intermembrane space of mitochondria leaks into the mitochondria, so that the mitochondrial electron transport chain generates electrochemical potential energy and dissipates it in the form of heat energy.
  • white fat can also appear characteristic of brown fat, a process called “white fat browning (Browning)". Brown fat activation and white fat browning can promote the body's energy consumption and improve glucose and lipid metabolism, which may be a new way to treat metabolic syndrome.
  • Metabolic syndrome is prone to many complications, such as cardiovascular and cerebrovascular diseases, cancer, liver cirrhosis, polycystic ovary syndrome, renal and pancreatic dysfunction.
  • cardiovascular and cerebrovascular diseases such as cardiovascular and cerebrovascular diseases, cancer, liver cirrhosis, polycystic ovary syndrome, renal and pancreatic dysfunction.
  • drugs for treatment there is currently no effective drug for treatment, so it is of great significance to find safe and effective anti-metabolic syndrome drugs with independent intellectual property rights in my country.
  • the technical problem solved by the present invention is to provide the diphenylalkane compound of the formula (I) or a pharmaceutically acceptable salt thereof:
  • X is selected from hydrogen, F, Cl, Br, I, unsubstituted C1-9 linear or branched alkyl, substituted or unsubstituted C3-8 cycloalkyl; the substitution position of X is selected from its benzene 1, 2, 3 or 4 digits on the ring;
  • n is an integer selected from 0, 1, 2, 3, 4, 5 or 6;
  • Y is selected from C, O, S, N or Si;
  • R is selected from hydrogen, substituted or unsubstituted C1-16 linear or branched alkyl, substituted or unsubstituted heterocyclic or non-heterocyclic C3-8 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted naphthyl, substituted or unsubstituted tetrahydronaphthyl, substituted or unsubstituted fluorenyl, substituted or unsubstituted unsubstituted imidazolyl, substituted or unsubstituted indolyl;
  • the substituents in the above-mentioned substitution or non-substitution are selected from F, Cl, Br, I, -NO 2 , -NH 2 , -SH, -SO 3 , carboxyl, C1-6 straight chain or branched chain alkyl amide group, C1-6 straight or branched chain alkyl ester group.
  • X is selected from hydrogen, F, Cl, Br, I, C1-4 linear or branched alkyl, or substituted or unsubstituted C3-8 cycloalkyl;
  • substitution position of X is selected from the 1, 2, 3 or 4 positions on its benzene ring;
  • n is an integer selected from 0, 1, 2, 3, 4, 5 or 6;
  • Y is selected from C, O, S, N or Si;
  • R is selected from hydrogen, methyl, ethyl, propyl, butyl, hexyl or cyclohexyl;
  • the above-mentioned substituted or unsubstituted substituents are selected from F, Cl, Br, I, -NO 2 , -NH 2 , -SH, -SO 3 , carboxyl, C1-3 straight chain or branched chain alkylamide group, C1-3 straight or branched chain alkyl ester group.
  • a preparation method of a diphenylalkane compound with a structure such as formula (I) or a pharmaceutically acceptable salt thereof is provided, that is, the corresponding aromatic aldehyde is used as the starting material, the Vichytine reaction is carried out, and then the compound is coupled with an iodo aromatic compound. Then, catalytic hydrogenation is carried out to obtain the compound of formula (I).
  • a diphenylalkane compound 1-fluoro-3-methoxy-5-phenethylbenzene and its pharmaceutically acceptable salts with novel chemical structure characteristics, its preparation method, pharmaceutical composition and use .
  • the present invention provides the following technical solutions:
  • the first aspect of the technical solution of the present invention is to provide a diphenylalkane compound 1-fluoro-3-methoxy-5-phenethylbenzene and a pharmaceutically acceptable salt thereof with novel chemical structural characteristics, Its structure is shown in formula (II):
  • the diphenylalkane compound of the invention has novel structure, the molecular formula is C 15 H 15 FO, and the names are 1-fluoro-3-methoxy-5-phenethylbenzene, 1-fluoro-3-methoxy-5-phenethylbenzene.
  • the second aspect of the technical solution of the present invention provides a chemical synthesis preparation method of the compound of the formula (II):
  • the third aspect of the technical solution of the present invention is to provide a new medicine that can be used for the preparation of prevention and/or treatment of metabolic syndrome. / or the application of drugs in the treatment of metabolic syndrome and its complications.
  • the metabolic syndrome refers to including but not limited to obesity, abnormal glucose metabolism, abnormal lipid metabolism, fatty liver, hypertension, hyperviscosity, hyperuricemia or gout.
  • the fourth aspect of the technical solution of the present invention is to provide a pharmaceutical composition, which contains a therapeutically effective dose of the diphenylalkane compound of formula (II) 1-fluoro-3-methoxy-5-phenethylbenzene and Its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective dose of the compound and a pharmacodynamically acceptable carrier.
  • a pharmaceutical composition comprising a pharmaceutically effective dose of the compound and a pharmacodynamically acceptable carrier.
  • it may be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants into a suitable administration form or dosage form for use as a medicament.
  • the compounds of the present invention may exist in isomeric forms, and the term “compounds of the present invention” generally includes isomers of the compounds.
  • the pharmaceutical composition of the present invention can be administered in unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum.
  • the route of administration of the pharmaceutical composition of the present invention may be injection administration.
  • Injections include intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection.
  • the dosage form for administration can be a liquid dosage form, a solid dosage form.
  • liquid dosage forms can be true solutions, colloids, particulate dosage forms, emulsion dosage forms, and suspension dosage forms.
  • Other dosage forms such as tablets, capsules, dropping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders and the like.
  • composition of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.
  • a wide variety of carriers well known in the art can be used.
  • carriers are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid Aluminum, etc.; wetting agents and binders, such as water, glycerin, polyethylene glycol, ethanol, propanol, starch syrup, dextrin, syrup, honey, glucose solution, acacia mucilage, gelatin pulp, sodium carboxymethyl cellulose , shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents, such as dry starch, alginate, agar powder, alginate, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitan Sugar alcohol fatty acid esters, sodium lauryl
  • carriers for formulating the dosage unit into a pill, a wide variety of carriers well known in the art can be used.
  • carriers are, for example, diluents and absorbents, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, polyvinylpyrrolidone, Gelucire, kaolin, talc, etc.; binders, such as acacia, tragacanth, Gelatin, ethanol, honey, liquid sugar, rice cereal or batter, etc.; disintegrants, such as agar powder, dry starch, alginate, sodium dodecyl sulfonate, methyl cellulose, ethyl cellulose, etc.
  • various carriers known in the art can be widely used.
  • carriers are, for example, polyethylene glycol, lecithin, cocoa butter, higher alcohols, enzymes of higher alcohols, gelatin, semisynthetic glycerolase and the like.
  • the active ingredient is mixed with the various carriers described above, and the mixture thus obtained is placed in hard gelatin capsules or soft capsules.
  • the active ingredients can also be made into microcapsules, suspended in an aqueous medium to form a suspension, or packed into hard capsules or made into injections.
  • the composition of the present invention can be made into injection preparations, such as solutions, suspensions, solutions, emulsions, lyophilized powder injections, such preparations may be aqueous or non-aqueous, and may contain one and/or Various pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants.
  • the diluent can be selected from water, ethanol, polyethylene glycol, 1,3-propylene glycol, ethoxylated isostearyl alcohol, polyoxygenated isostearyl alcohol, polyoxyethylene sorbitan fatty acid enzyme and the like.
  • an appropriate amount of sodium chloride, glucose or glycerol can be added to the injection preparation, and in addition, conventional cosolvents, buffers, pH adjusters and the like can be added. These excipients are commonly used in the art.
  • coloring agents can also be added to the pharmaceutical preparations if desired.
  • the dosage of the pharmaceutical composition of the present invention depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, the number of times of administration, etc. Therefore, the therapeutic dose of the present invention may vary widely.
  • the compounds of the present invention are employed in dosages well known to those skilled in the art. According to the actual effective amount of the drug contained in the final preparation of the pharmaceutical composition of the present invention, appropriate adjustments can be made to achieve the therapeutically effective amount to accomplish the purpose of treating metabolic syndrome of the present invention.
  • the daily dose of the compound of the present invention is 0.001 mg/kg body weight to 2000 mg/kg body weight, preferably 0.01 mg/kg body weight to 1000 mg/kg body weight, more preferably 0.1-500 mg/kg body weight, most preferably 1-100 mg/kg body weight.
  • the present invention shows that 1-fluoro-3-methoxy-5-phenethylbenzene has the effect of improving metabolic syndrome, and is applicable but not limited to obesity, abnormal glucose metabolism, abnormal lipid metabolism, fatty liver, hypertension, high viscosity Treatment of hyperuricemia, hyperuricemia, or gout.
  • the above dosages may be administered in a single dosage form or divided into several, eg, two, three or four dosage forms, subject to the clinical experience and dosing regimen of the administering physician.
  • the compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic drugs.
  • the fifth aspect of the technical solution of the present invention is to provide the diphenylalkane compound 1-fluoro-3-methoxy-5-phenethylbenzene of formula (II) described in the first aspect and a pharmaceutically acceptable salt thereof and the application of the pharmaceutical composition in the third aspect in the preparation of a medicine for preventing or treating metabolic syndrome and its complications.
  • the metabolic syndrome includes, but is not limited to, obesity, abnormal glucose metabolism, abnormal lipid metabolism, fatty liver, hypertension, hyperviscosity, hyperuric acid, or gout.
  • the obesity refers to that the body mass index (BMI) of a person is greater than or equal to 28kg/m 2 ;
  • the insulin resistance refers to the decrease in the efficiency of insulin promoting glucose uptake and utilization, and the body compensates for hyperinsulinemia;
  • the An abnormal glucose metabolism is a blood sugar level that is higher than normal.
  • the abnormal glucose metabolism includes insulin resistance or hyperinsulinemia, abnormal glucose tolerance, prediabetes, diabetes, diabetic complications, and diabetic complications include diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic liver disease, etc.;
  • the described Abnormal lipid metabolism refers to an increase in the concentration of at least one blood lipid index or abnormal deposition of fat in any tissue of the body;
  • the blood lipid index is selected from triglycerides, total cholesterol, low-density lipoprotein, high-density lipoprotein, and free fatty acids, including Hypertriglyceridemia, hypercholesterolemia, high and low density lipoproteinemia, low high density lipoproteinemia, high free fatty acidemia;
  • the fatty liver refers to the lesions with excessive fat accumulation in liver cells , including non-alcoholic fatty liver disease, non-alcoholic steatohepatitis; said hypertension refers to increased systemic arterial blood pressure, systolic blood pressure ⁇ 140 mm Hg, di
  • the present invention is a diphenylalkane compound 1-fluoro-3-methoxy-5-phenethylbenzene with novel structure;
  • the preparation method of the present invention is novel, the raw materials are easily obtained, the preparation process is simple, and the standardized production is easy;
  • the present invention can effectively prevent and treat metabolic syndrome, and can effectively activate uncoupling protein 1 (UCP1) in vitro. potential.
  • UCP1 uncoupling protein 1
  • Compound II the molecular formula is C 15 H 15 FO, named 1-fluoro-3-methoxy-5-phenethylbenzene, 1-fluoro-3-methoxy-5-phenethylbenzene.
  • Step 1 1) In 50 mL of anhydrous THF solution of methyl triphenylphosphonium iodide iodide 22.61 mmol, add 1.5 equivalents, 28.26 mmol of t-BuOK in portions, and continue stirring for 1 h under argon. Then 18.84 mmol of 3-fluoro-5-methoxybenzaldehyde were added and stirring was continued at 0°C overnight. After cooling, 30 mL of ether was added to precipitate insoluble salts. The mixture was collected by suction filtration, washed with diethyl ether, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography using cyclohexane as eluent. The product 1-vinyl-3-fluoro-5-methoxybenzene was obtained as a colorless oil with a yield of 80%.
  • Step 2 2) Into a dry 50 mL round-bottomed flask was charged 1.0 mmol of 1-vinyl-3-fluoro-5-methoxybenzene, 1.1 mmol of iodobenzene, 2.0 mmol of K 2 CO 3 and 0.01 mmol tris-(dibenzylideneacetone)dipalladium. Then 5.0 mL of ethanol was added and the mixture was heated to reflux under air atmosphere for 3 hours. After this time, the mixture was cooled to room temperature, filtered, washed with ether, and concentrated in vacuo. Finally, it was purified by column chromatography to obtain 1-fluoro-3-methoxy-5-styrylbenzene in about 50% yield.
  • Step 3 3
  • Step 3 3
  • the compound 1-fluoro-3-methoxy-5-styrylbenzene has the formula C 15 H 15 FO, HRESIMS m/z 231.11777 [M+H]+ (calcd for C 15 H 16 FO: m/z 231.11797) (figure 1).
  • mice 60 5-week-old C57BL/6J male mice, after 1 week of adaptive feeding, 10 were randomly selected as the normal control group, and the rest were used as the high-fat diet-induced metabolic syndrome group.
  • the normal control group was fed a standard mouse diet, and the high-fat diet-induced metabolic syndrome group was fed a high-fat diet (60% of calories from fat, Research Diets, USA).
  • the body weight of the mice was recorded once a week, and the food and water intake was recorded twice a week.
  • the mice in the high-fat diet-induced metabolic syndrome group were randomly divided into 5 groups with 10 mice in each group, namely: model control group and metformin hydrochloride positive control group.
  • mice The body weight of mice was recorded weekly.
  • mice gradually increased after feeding with high-fat diet. After 3 days of feeding, the weight of mice in the high-fat diet-induced metabolic syndrome group increased significantly compared with the normal control group (P ⁇ 0.001). After administration of 1-fluoro-3-methoxy-5-phenethylbenzene, each dose group could inhibit their body weight increase in a dose-dependent manner, and there was a statistical difference compared with the model control group after 3 days of administration; After 23 days of administration, the weight loss effect of the high-dose group was better than that of the metformin hydrochloride group; after 37 days of administration, the high-dose group could completely resist the weight gain induced by high-fat diet, and the actual weight value was lower than that of the normal control group; to 51 days of administration At the end of the experiment, the body weights of the drug treatment low, medium and high dose groups decreased by 7.70%, 13.33% and 21.73% respectively compared with the model control group (Table 1).
  • n 10, mean ⁇ SD, t-test was used for statistical analysis; * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001 (compared with model control group).
  • n 10, mean ⁇ SD, t-test was used for statistical analysis; ** P ⁇ 0.01, *** P ⁇ 0.001 (compared with model control group).
  • mice The food and water intake of mice were recorded twice a week.
  • n 10, mean ⁇ SD, t-test was used for statistical analysis. * P ⁇ 0.05, *** P ⁇ 0.001 (compared to model control group).
  • n 10, mean ⁇ SD, t-test was used for statistical analysis. * P ⁇ 0.05 (compared to model control group).
  • n 10, mean ⁇ SD, t-test was used for statistical analysis. * P ⁇ 0.05, *** P ⁇ 0.001 (vs. model control group).
  • mice 1-Fluoro-3-methoxy-5-phenethylbenzene was continuously administered to the end-stage, the mice were fasted from 8:00 in the morning, administered by gavage, and blood was collected from the tail tip at 12:00.
  • the fasting blood glucose level of mice with high-fat diet-induced metabolic syndrome was measured by the Fulishan blood glucose meter and the Fulishan blood glucose test paper, and recorded as the 0-min blood glucose value.
  • intraperitoneal injection of 20% glucose, 2 g/kg Blood was collected from the tip of the tail at 30 min, 60 min and 120 min, respectively, and the blood glucose level of the mice was determined by using the Auxiliary Glucose Meter and Auxiliary Blood Glucose Test Strips.
  • mice in the model control group Compared with the mice in the normal control group, the blood glucose level of the mice in the model control group increased significantly after intraperitoneal injection of glucose, indicating that the mice in the model control group had abnormal glucose tolerance.
  • the three dose groups of 1-fluoro-3-methoxy-5-phenethylbenzene showed different degrees of reducing blood sugar and improving glucose tolerance in mice with high-fat diet-induced metabolic syndrome. Dose-dependent; among them, the middle-dose and high-dose had the most obvious effect, with significant statistical difference (P ⁇ 0.01), and its biological activity in improving glucose tolerance was better than that of the positive drug metformin hydrochloride (P ⁇ 0.05) (Table 6, Table 6, Table 6, Table 6, Table 6). 7).
  • 1-fluoro-3-methoxy-5-phenethylbenzene can reduce hyperglycemia in mice with high-fat diet-induced metabolic syndrome, correct the impaired glucose tolerance, and improve the metabolic syndrome-induced hyperglycemia. Abnormal glucose metabolism.
  • n 10, mean ⁇ SD, t-test was used for statistical analysis. * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001 (compared to model control group).
  • n 10, mean ⁇ SD, t-test was used for statistical analysis. * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001 (compared to model control group).
  • mice 1-Fluoro-3-methoxy-5-phenethylbenzene was continuously administered to the end-stage, the mice were fasted from 8:00 in the morning, administered by gavage, and blood was collected from the tail tip at 12:00.
  • the fasting blood glucose level of mice with high-fat diet-induced metabolic syndrome was measured by the Fulishan blood glucose meter and the Fulishan blood glucose test paper, and recorded as the 0-min blood glucose value.
  • 0.5 U/kg insulin replacement human insulin injection (300 U: 3 ml), Eli Lilly, USA) freshly prepared with normal saline was injected intraperitoneally immediately.
  • Blood was collected from the tip of the tail at 30 min, 60 min and 90 min, respectively, and the blood glucose level of the mice was determined by using the Supplementary Glucose Meter and the Supplementary Glucose Test Strip.
  • n 10, mean ⁇ SD, t-test was used for statistical analysis. * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001 compared to the model control group.
  • n 10, mean ⁇ SD, t-test was used for statistical analysis. * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001 compared to the model control group.
  • mice were anesthetized, blood was collected and placed in a heparinized EP tube. Centrifuge at 5000 rpm for 10 minutes at 4°C. The supernatant was transferred to a new EP tube, 12 ⁇ L of plasma was diluted 5 times with normal saline to 60 ⁇ L, and triglyceride (triglyceride assay reagent) was detected in an automatic biochemical analyzer (TBA-40FR, Toshiba, Japan). kit, Beijing Zhongsheng Beikong Biotechnology Co., Ltd.) and total cholesterol (Total Cholesterol Determination Kit, Beijing Zhongsheng Beikong Biotechnology Co., Ltd.).
  • n 10, mean ⁇ SD, t-test was used for statistical analysis. * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001 (compared to model control group).
  • mice 72 6-week-old SD male rats, after adaptive feeding for 1 week, 12 were randomly selected as normal control group, and the rest were used as high-fat diet-induced metabolic syndrome group.
  • the normal control group was fed with standard rat chow, and the high-fat diet-induced metabolic syndrome group was fed with high-fat diet (60% calories from fat, Ruidi Biotechnology (Shenzhen) Co., Ltd.).
  • the body weight of the rats was recorded twice a week, and the food and water intake was recorded twice a week.
  • the rats in the high-fat diet-induced metabolic syndrome group were randomly divided into 5 groups, with 12 rats in each group.
  • Rat dose mouse dose/1.44.
  • model control group metformin hydrochloride positive control group (140 mg/kg), 1-fluoro-3-methoxy-5-phenethylbenzene drug treatment low-dose group (50 mg/kg), and drug treatment medium-dose group (100mg/kg), high-dose drug treatment group (200mg/kg).
  • high-fat feed model was established by intragastric administration (using 0.5% sodium carboxymethyl cellulose (0.5% CMC-Na) to prepare the drug), and the normal control group and the model control group were given 0.5% sodium carboxymethyl cellulose. 0.5mL/100g was administered once a day for 90 consecutive days. At the end of the experiment, glucose tolerance was measured.
  • 1-Fluoro-3-methoxy-5-phenethylbenzene was provided by Ji Tengfei's research group, Institute of Materia Medica, Chinese Academy of Medical Sciences.
  • n 12, mean ⁇ SD, t-test was used for statistical analysis; * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001 (compared with model control group).
  • n 12, mean ⁇ SD, t-test was used for statistical analysis; ** P ⁇ 0.01, *** P ⁇ 0.001 (compared with model control group).
  • n 12, mean ⁇ SD, t-test was used for statistical analysis. * P ⁇ 0.05 (compared to model control group).
  • n 12, mean ⁇ SD, t-test was used for statistical analysis. ** P ⁇ 0.01, *** P ⁇ 0.001 (compared to model control group).
  • 1-fluoro-3-methoxy-5-phenethylbenzene can reduce hyperglycemia in rats with metabolic syndrome induced by high-fat diet, correct the impaired glucose tolerance, and improve the metabolic syndrome induced by metabolic syndrome. Abnormal glucose metabolism.
  • n 12, mean ⁇ SD, t-test was used for statistical analysis. * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001 (compared to model control group).
  • n 12, mean ⁇ SD, t-test was used for statistical analysis. * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001 (compared to model control group).
  • mice 75 5-week-old C57BL/6J male mice, after adaptive feeding for 1 week, 10 were randomly selected as normal control group, and the rest were used as high-fat diet-induced metabolic syndrome group.
  • the normal control group was fed a standard mouse diet, and the high-fat diet-induced metabolic syndrome group was fed a high-fat diet (60% of calories from fat, Research Diets, USA).
  • mice with abnormal body weight in the metabolic syndrome mice fed with high-fat diet were excluded, and the remaining 50 mice were randomly divided into 5 groups with 10 mice in each group, namely: model control group, metformin hydrochloride positive control group ( 200mg/kg), 1-fluoro-3-methoxy-5-phenethylbenzene drug treatment low dose group (75mg/kg), drug treatment medium dose group (150mg/kg), drug treatment high dose group (300mg/kg) /kg), the high-fat feed model was established at the same time, and the oral administration was started (the drug was formulated with 0.5% sodium carboxymethyl cellulose (0.5% CMC-Na)), and the normal control group and the model control group were given 0.5% carboxymethyl cellulose.
  • model control group metformin hydrochloride positive control group ( 200mg/kg), 1-fluoro-3-methoxy-5-phenethylbenzene drug treatment low dose group (75mg/kg), drug treatment medium dose group (150mg/kg), drug treatment high dose group
  • mice The body weight of mice was recorded weekly.
  • mice After 30 days of high-fat diet feeding, the body weight of mice increased significantly, and there was a statistical difference compared with the normal control group (P ⁇ 0.001). After administration of 1-fluoro-3-methoxy-5-phenethylbenzene, each dose group could inhibit their body weight increase in a dose-dependent manner, and showed a decreasing trend compared with the model control group after administration for 5 days; After 55 days of administration, there was a statistical difference and it was better than the positive drug metformin group; by the end of the 55-day experiment, the weight loss of the drug treatment low, medium and high dose groups was 6.21%, 12.05% and 18.52% respectively compared with the model control group (Table 19) .
  • n 10, mean ⁇ SD, t-test was used for statistical analysis; * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001 (compared with model control group).
  • n 10, mean ⁇ SD, t-test was used for statistical analysis; * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001 (compared with model control group).
  • mice The food and water intake of mice were recorded twice a week.
  • n 10, mean ⁇ SD, t-test was used for statistical analysis. * P ⁇ 0.05, ** P ⁇ 0.01 (compared with model control group).
  • n 10, mean ⁇ SD, t-test was used for statistical analysis. * P ⁇ 0.05, *** P ⁇ 0.001 (vs. model control group).
  • Brown adipose tissue has a non-trembling thermogenic function, and its thermogenic function originates from its abundant mitochondria and specific high expression of mitochondrial inner membrane uncoupling protein 1 (UCP1), which promotes the transfer of protons from the inner and outer membrane spaces of mitochondria. It leaks into the mitochondria, so that the mitochondrial electron transport chain generates electrochemical potential energy and dissipates it in the form of heat energy.
  • UCP1 mitochondrial inner membrane uncoupling protein 1
  • the UCP1 promoter region was inserted into the stably transfected adipocyte line of Luciferase and tdTomato, and it was planted in 96-well plate for adipogenic induction and differentiation.
  • 10 ⁇ mol/L positive control drug ⁇ 3-adrenergic receptor was added to stimulate The cells were treated with CL316,243 (CAS:138908-40-4) and 1-fluoro-3-methoxy-5-phenethylbenzene, and the activity of Luciferase was detected by reporter gene method after 24 h, and the activity of 1-fluoro- Whether 3-methoxy-5-phenethylbenzene has a regulatory effect on UCP1 promoter activity.
  • n 4, mean ⁇ SD, t-test was used for statistical analysis. *P ⁇ 0.05 (compared to normal control group).

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Abstract

本发明属于医药技术领域，涉及二苯烷类化合物及其制备方法、药物组合物和用途，具体公开了一种如式(Ⅰ)二苯烷类化合物和1-氟-3-甲氧基-5-苯乙基苯(Ⅱ)和制备方法，及其在制备预防或治疗代谢综合征药物中的应用。该化合物具有明显的抗代谢综合征作用，可以单体或药用组合物形式在抗代谢综合征的临床治疗中应用。

Description

二苯烷类化合物及其制备方法、药物组合物和用途 技术领域
本发明属于医药技术领域，涉及二苯烷类化合物及其制备方法、药物组合物和用途。具体为化合物1-氟-3-甲氧基-5-苯乙基苯或其药学上可接受的盐及其制备方法，及含有该化合物代谢产物或其药学上可接受的盐的药物组合物及其在制备预防或治疗代谢综合征及其并发症中的应用。
背景技术
代谢综合征(metabolic syndrome,MetS)是指人体的蛋白质、脂肪、碳水化合物等物质发生代谢紊乱的病理状态，是一组复杂的代谢紊乱症候群，是导致糖尿病、心脑血管疾病的危险因素。其具有以下特点：①多种代谢紊乱集于一身：包括肥胖、高血糖、高血压、血脂异常、高血粘、高尿酸、脂肪肝和高胰岛素血症，这些代谢紊乱是心、脑血管病变以及糖尿病的病理基础。②有共同的病理基础：目前多认为共同原因为肥胖尤其是中心性肥胖所造成的胰岛素抵抗和高胰岛素血症。③可造成多种疾病增加：如高血压、冠心病、脑卒中、甚至某些癌症，包括与性激素有关的乳腺癌、子宫内膜癌、前列腺癌，以及消化系统的胰腺癌、肝胆癌、结肠癌等。④有共同的预防及治疗措施：防治住一种代谢紊乱，也就有利于其他代谢紊乱的防治。
随着发病率的逐年增加，代谢综合征已成为世界性的公共卫生问题。全世界的代谢综合征患病率在10％～84％之间，其中大约有20％～25％的成年人患有代谢综合征。美国国家健康和营养调查数据估计，在美国，35％的成年人和50％的60岁以上人口(30.3％的男性和35.6％的女性)，经诊断患有代谢综合征；其中，墨西哥裔美国妇女的发病率最高。依据国际糖尿病联合会的诊断标准，在欧洲，男性代谢综合征的患病率约为41％，女性约为38％。中国的统计数据显示，15岁及以上人群的代谢综合征患病率为24.2％。另有研究显示，中国60岁及以上人群的患病率约为32.4％。
新近研究表明，棕色脂肪组织具有非震颤性产热功能，其产热功能源于其富含大量线粒体且特异性高表达线粒体内膜解偶联蛋白1(uncoupling protein1,UCPl)，UCPl促进质子由线粒体内外膜间隙漏入线粒体内，从而使线粒体电子传递链产生电化学势能并以热能的形式散发。此外，在特定条件下，白色脂肪也可出现棕色脂肪的特征表现，这一过程称为“白色脂肪棕色化(Browning)”。棕色脂肪活化和白色脂肪棕色化可促进机体的能量消耗，改善糖脂代谢，可能是治疗代谢综合征的新途径。美国Scripps研究所的Kajimura教授认为，只要寻找到增加脂肪组织中UCP1的药物，将达到减少体内脂肪、抵抗肥胖及其代谢综合征的目的。然而，促进棕色脂肪活化和白色脂肪棕色化的药物研发始终未取得实质性进展。因此，我们通过构建UCP1启动子区域插入Luciferase和tdTomato的稳转棕色脂肪细胞株，优化UCP1诱导剂高通量筛选模型，并已申请了国家发明专利《抗代谢综合征药物靶点UCP1的基因工程 细胞株和高通量药物筛选模型的建立及应用》(申请号：201811248715.3)，试图寻找通过促产热效应发挥抗代谢综合征的新型UCP1诱导剂。
代谢综合征易引发诸多并发症，如心脑血管疾病、癌症、肝硬化、多囊卵巢综合征、肾脏和胰脏功能障碍。然而，目前尚无有效治疗药物，因此寻找具有我国自主知识产权的安全有效的抗代谢综合征药物具有非常重要的意义。
发明内容
本发明解决的技术问题在提供所述结构如式(Ⅰ)的二苯烷类化合物或其药学上可接受盐：
Figure PCTCN2022080862-appb-000001
其中，X选自氢，F，Cl，Br，I，非取代C1-9的直链或支链烷基基，取代或非取代的C3-8环烷基；X的取代位置选自其苯环上1、2、3或4位；
n选自0、1、2、3、4、5或6的整数；
Y选自C，O，S，N或Si；
R选自氢、取代或非取代的C1-16直链或支链烷基、取代或非取代的杂环或非杂环C3-8的环烷基、取代或非取代的苯基、取代或非取代的呋喃基、取代或非取代的噻吩基、取代或非取代的吡咯基、取代或非取代的萘基、取代或非取代的四氢萘基、取代或非取代的芴基、取代或非取代的咪唑基、取代或非取代的吲哚基；
上述所述的取代或非取代中的取代基选自F，Cl，Br，I，-NO 2，-NH 2，-SH，-SO 3，羧基，C1-6直链或支链烷基酰胺基，C1-6直链或支链烷酯基。
优选X选自氢，F，Cl，Br，I，C1-4的直链或支链烷基，或取代或非取代的C3-8环烷基；
X的取代位置选自其苯环上1、2、3或4位；
n选自0、1、2、3、4、5或6的整数；
Y选自C，O，S，N或Si；
R选自氢、甲基、乙基、丙基、丁基、己基或环己基；
上述所述的取代或非取代中的取代基选自F，Cl，Br，I，-NO 2，-NH 2，-SH，-SO 3，羧基，C1-3直链或支链烷基酰胺基，C1-3直链或支链烷酯基。同时提供了结构如式(Ⅰ)的二苯烷类化合物或其药学上可接受盐的制备方法，即通过相应的芳香醛为起始原料，通过维希悌反应，再与碘代芳香化合物偶联，进而进行催化氢化得到式(Ⅰ)化合物。并提供一种具有新的化学结构特征的二苯烷类化合物1‐氟‐3‐甲氧基‐5‐苯乙基苯及其药学上可接受的盐，其制备方法、药物组合物和用途。
为解决本发明的技术问题，本发明提供如下技术方案：
本发明技术方案的第一方面是提供了一种具有新的化学结构特征的二苯烷类化合物1-氟-3-甲氧基-5-苯乙基苯及其药学上可接受的盐，其结构如式(Ⅱ)所示：
Figure PCTCN2022080862-appb-000002
本发明二苯烷类化合物，结构新颖，分子式为C 15H 15FO，命名为1-fluoro-3-methoxy-5-phenethylbenzene，1-氟-3-甲氧基-5-苯乙基苯。
本发明技术方案的第二方面提供了所述式(Ⅱ)化合物的化学合成制备方法：
Figure PCTCN2022080862-appb-000003
(1)以3‐氟‐5‐甲氧基苯甲醛为原料，通过维希替反应生成1‐乙烯基‐3‐氟‐5‐甲氧基苯；
Figure PCTCN2022080862-appb-000004
(2)1-乙烯基-3-氟-5-甲氧基苯和碘甲烷反应得到中间体1-氟-3-甲氧基-5-苯乙烯基苯；
Figure PCTCN2022080862-appb-000005
↑此处虚线是否有别的意图
(3)1-氟-3-甲氧基-5-苯乙烯基苯通过催化氢化得到化合物1-氟-3-甲氧基-5-苯乙基苯，即为化合物Ⅱ；
Figure PCTCN2022080862-appb-000006
具体化学合成步骤如下：
1)向碘化甲基三苯基磷碘化物22.61mmol的50mL无水THF溶液中，分次添加1.5当量，28.26mmol t-BuOK，并在氩气下继续搅拌1h。然后加入18.84mmol 3-氟-5-甲氧基苯甲醛，并在0℃下继续搅拌过夜。冷却后，加入30mL乙醚以沉淀不溶性盐。通过抽滤收集混合物，用乙醚洗涤，并在减压下蒸发溶剂。粗产物通过硅胶色谱法纯化，使用环己烷作为洗脱剂。获得产物1-乙烯基-3-氟-5-甲氧基苯，为无色油状物，收率为80％。
2)在干燥的50mL圆底烧瓶中装入1.0mmol的1-乙烯基-3-氟-5-甲氧基苯，1.1mmol的碘苯，2.0mmol的K 2CO 3和0.01mmol的tris-(二亚苄基丙酮)二钯。然后加入5.0mL的乙醇， 并将混合物在空气气氛下加热至回流3小时。之后，将混合物冷却至室温，过滤，用乙醚洗涤，并真空浓缩。最后通过柱色谱法纯化得到1-氟-3-甲氧基-5-苯乙烯基苯，产率为约50％。
3)将约15g的1-氟-3-甲氧基-5-苯乙烯基苯在100mL的EtOH中搅拌，然后加入2g的10％Pd/C。将体系在氢气氛下搅拌4小时。过滤反应溶液，浓缩滤液，得到产物1-氟-3-甲氧基-5-苯乙苯，产率95％。
本发明技术方案的第三方面是提供一种新的可以用于制备预防和/或治疗代谢综合征的药物，即1-氟-3-甲氧基-5-苯乙基苯在制备预防和/或治疗代谢综合征及其并发症药物中的应用。所述的代谢综合征是指包括但不限于肥胖症、糖代谢异常、脂代谢异常、脂肪肝、高血压、高粘血症、高尿酸血症或痛风。
本发明技术方案的第四方面是提供了一种药物组合物，其含有治疗有效剂量的式(Ⅱ)的二苯烷类化合物1-氟-3-甲氧基-5-苯乙基苯及其药学上可接受的盐及药用载体。
本发明还涉及一种含有药物有效剂量所述的化合物和药效学上可接受的载体的药物组合物。用于此目的时，如果需要，可与一种或多种固体或液体药物赋形剂和/或辅剂结合，制成可作为入药使用的适当施用形式或剂量形式。
根据本发明，本发明化合物可以以异构体的形式存在，而且通常所述的“本发明化合物”包括该化合物的异构体。
本发明的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等。
本发明的药物组合物的给药途径可为注射给药。注射包括静脉注射、肌肉注射、皮下注射、皮内注射和穴位注射等。给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
本发明的组合物可以制成普通制剂、也可以是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将单位给药剂型制成片剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化纳、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等；湿润剂与粘合剂，如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素纳、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等；崩解剂，例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢纳与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等；崩解抑制剂，例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等；吸收促进剂，例如季铵盐、十二烷基硫酸钠等；润滑剂，例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成丸剂，可以广泛使用本领域公知的各种载体。关于载体的例子是， 例如稀释剂与吸收剂，如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等；粘合剂，如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等；崩解剂，如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。
为了将给药单元制成栓剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如聚乙二醇、卵磷脂、可可脂、高级醇、高级醇的酶、明胶、半合成甘油酶等。
为了将给药单元制成胶囊，将有效成分与上述的各种载体混合，并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分制成微囊剂，混悬于水性介质中形成混悬剂，亦可装入硬胶囊中或制成注射剂应用。
例如，将本发明的组合物制成注射用制剂，如溶液剂、混悬剂、溶液剂、乳剂、冻干粉针剂，这种制剂可以是含水或非水的，可含一种和/或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂或分散剂。如稀释剂可选自水、乙醇、聚乙二醇、1，3一丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酶等。另外，为了制备等渗注射液，可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油，此外，还可以添加常规的助溶剂、缓冲剂、pH调节剂等。这些辅料是本领域常用的。
此外如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
本发明药用组合物的给药剂量取决于许多因素，例如所要预防或治疗疾病的性质和严重程度，患者或动物的性别、年龄、体重、性格及个体反应，给药途径、给药次数等，因此本发明的治疗剂量可以有大范围的变化。一般来讲，本发明化合物使用剂量是本领域技术人员公知的。可以根据本发明药用组合物中最后的制剂中所含有的实际有效药物数量，加以适当的调整，以达到其治疗有效量的要求，完成本发明的治疗代谢综合征的目的。
本发明化合物的日剂量为0.001mg/kg体重～2000mg/kg体重，优选0.01mg/kg体重～1000mg/kg体重，更优选0.1-500mg/kg体重，最优选1-100mg/kg体重。本发明显示1-氟-3-甲氧基-5-苯乙基苯具有改善代谢综合征的作用，适用但不限于肥胖症、糖代谢异常、脂代谢异常、脂肪肝、高血压、高粘血症、高尿酸或痛风的治疗。上述剂量可以单一剂量形式或分成几个，例如二、三或四个剂量形式给药，这受限于给药医生的临床经验以及给药方案。本发明的化合物或组合物可单独服用，或与其它治疗药物或对症药物合并使用。
本发明技术方案的第五方面是提供了第一方面所述式(Ⅱ)的二苯烷类化合物1-氟-3-甲氧基-5-苯乙基苯及其药学上可接受的盐和第三方面所述药物组合物在制备预防或治疗代谢综合征及其并发症药物中的应用。所述代谢综合征包括但不限于肥胖症、糖代谢异常、脂代谢异常、脂肪肝、高血压、高粘血症、高尿酸或痛风。所述的肥胖症是指人的身体质量指数BMI大于或等于28kg/m 2；所述的胰岛素抵抗是指胰岛素促进葡萄糖摄取和利用的效率下降，机体代偿性出现高胰岛素血症；所述的糖代谢异常是血糖值高于正常值。所述的糖代谢异常包括胰岛素抵抗或高胰岛素血症、糖耐量异常、糖尿病前期、糖尿病、糖尿病并发症，糖尿病并 发症包括糖尿病肾病、糖尿病神经病变、糖尿病视网膜病变、糖尿病肝病等；所述的脂代谢异常是指至少一种血脂指标浓度增高或者脂肪在机体任何组织的异常沉积；所述的血脂指标选自甘油三酯、总胆固醇、低密度脂蛋白、高密度脂蛋白、游离脂肪酸，包括高甘油三酯血症、高胆固醇血症、高低密度脂蛋白血症、低高密度脂蛋白血症、高游离脂肪酸血症；所述的脂肪肝是指肝细胞内脂肪堆积过多的病变，包括非酒精性脂肪性肝病、非酒精性脂肪性肝炎；所述的高血压是指体循环动脉血压增高，收缩压≥140毫米汞柱，舒张压≥90毫米汞柱；所述的高粘血症是一种或几种血液粘滞因子升高，引发的血液过度粘稠与血流缓慢，表现为血液流变学参数异常；所述的血液流变学参数选自全血粘度、血浆粘度、红细胞压积、全血还原粘度、红细胞聚集指数、红细胞变形指数、红细胞刚性指数、血沉方程K值；所述的高尿酸血症是指血液中尿酸水平异常升高，超过正常上限；所述的痛风是指血中尿酸含量过高，即高尿酸血症而导致尿酸盐结晶沉积在关节内。所述的代谢综合征引发的并发症包括心脑血管疾病、癌症、肝硬化、多囊卵巢综合征、肾脏和胰脏功能障碍。
有益技术效果
本发明通过药理学研究发现：
1-氟-3-甲氧基-5-苯乙基苯具有深入研究与开发的价值。有关该化合物的结构、制备方法及其药理活性研究迄今未见报道。具体而言，其有益技术效果如下：
(1)本发明为二苯烷类化合物1-氟-3-甲氧基-5-苯乙基苯，结构新颖；
(2)本发明制备方法新颖，原料易得，制备工艺简单，易于规范化生产；
(3)本发明能有效防治代谢综合征，在体外能有效激活解偶联蛋白1(UCP1)，作为UCP1诱导剂，有进一步开发成通过促产热效应发挥抗代谢综合征及其并发症药物的潜力。
附图说明
图1化合物1-氟-3-甲氧基-5-苯乙基苯的质谱
图2化合物1-氟-3-甲氧基-5-苯乙基苯的 1H NMR图谱
图3化合物1-氟-3-甲氧基-5-苯乙基苯的 13C NMR图谱
具体实施方式
以下实施例对本发明作进一步的说明，但本发明并不限于这些实施例。
一、1-氟-3-甲氧基-5-苯乙基苯的化学(化合物Ⅱ)
Figure PCTCN2022080862-appb-000007
化合物Ⅱ：分子式为C 15H 15FO，命名为1-fluoro-3-methoxy-5-phenethylbenzene，1-氟-3-甲氧基-5-苯乙基苯。
实施例1：1-氟-3-甲氧基-5-苯乙基苯的化学合成
Figure PCTCN2022080862-appb-000008
步骤一，1)向碘化甲基三苯基磷碘化物22.61mmol的50mL无水THF溶液中，分次添加1.5当量，28.26mmo t-BuOK，并在氩气下继续搅拌1h。然后加入18.84mmol 3-氟-5-甲氧基苯甲醛，并在0℃下继续搅拌过夜。冷却后，加入30mL乙醚以沉淀不溶性盐。通过抽滤收集混合物，用乙醚洗涤，并在减压下蒸发溶剂。粗产物通过硅胶色谱法纯化，使用环己烷作为洗脱剂。获得产物1-乙烯基-3-氟-5-甲氧基苯，为无色油状物，收率为80％。
步骤二，2)在干燥的50mL圆底烧瓶中装入1.0mmol的1-乙烯基-3-氟-5-甲氧基苯，1.1mmol的碘苯，2.0mmol的K 2CO 3和0.01mmol的tris-(二亚苄基丙酮)二钯。然后加入5.0mL的乙醇，并将混合物在空气气氛下加热至回流3小时。之后，将混合物冷却至室温，过滤，用乙醚洗涤，并真空浓缩。最后通过柱色谱法纯化得到1-氟-3-甲氧基-5-苯乙烯基苯，产率约为50％。
步骤三，3)将约15g的1-氟-3-甲氧基-5-苯乙烯基苯在100mL的EtOH中搅拌，然后加入2g的10％Pd/C。将体系在氢气氛下搅拌4小时。过滤反应溶液，浓缩滤液，分离得到淡黄色油状液体化合物1-氟-3-甲氧基-5-苯乙苯，产率95％。化合物1-氟-3-甲氧基-5-苯乙基苯的分子式为C 15H 15FO，HRESIMS m/z 231.11777[M+H]+(calcd forC 15H 16FO：m/z 231.11797)(图1)。化合物1-氟-3-甲氧基-5-苯乙基苯的H NMR(400Hz,CDCl 3)δ7.32(m,J＝16.00Hz,2H),7.20(m,3H),6.50(m,3H),3.78(s,3H),2.91(s,4H)(图2)。化合物1-氟-3-甲氧基-5-苯乙基苯的 13C NMR(101MHz,CDCl 3)δ164.83,162.40,160.83,144.85,141.31,128.46,126.10,110.08,107.71,99.26,76.73,55.47,37.90,37.88,37.47(图3)。
二、小鼠口服1-氟-3-甲氧基-5-苯乙基苯的药理学研究
实验小鼠：60只5周龄C57BL/6J雄性小鼠，适应性喂养1周后，从中随机抽取10只作 为正常对照组，其余作为高脂饲料诱导代谢综合征组。正常对照组喂饲标准小鼠饲料，高脂饲料诱导代谢综合征组喂饲高脂饲料(60％热量来自脂肪,美国Research Diets公司)。每周记录小鼠体重1次，记录摄食摄水量2次，同时高脂饲料诱导代谢综合征组小鼠随机分为5组，每组10只，分别为：模型对照组、盐酸二甲双胍阳性对照组(200mg/kg)、1-氟-3-甲氧基-5-苯乙基苯药物治疗低剂量组(30mg/kg)、药物治疗中剂量组(100mg/kg)、药物治疗高剂量组(300mg/kg)，高脂饲料造模同时开始灌胃给药(采用0.5％羧甲基纤维素钠(0.5％CMC-Na)配制药物)，正常对照组及模型对照组给予0.5％羧甲基纤维素钠，按照0.1mL/10g每天给药1次，连续给药51天。实验终末期，测定葡萄糖耐量与胰岛素耐量，检测血脂水平，磁共振检测脂水比与脂肪分布。1-氟-3-甲氧基-5-苯乙基苯由中国医学科学院药物研究所吉腾飞课题组提供。
实验例2、1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征小鼠体重的影响
实验方法：每周记录小鼠体重。
实验结果：高脂饲料喂养后小鼠体重逐渐增加，喂养3天后，高脂饲料诱导代谢综合征组小鼠体重明显增加，与正常对照组相比具有统计学差异(P<0.001)。1-氟-3-甲氧基-5-苯乙基苯各剂量组给药后均可剂量依赖性地抑制其体重增长，给药3天与模型对照组比较即具有统计学差异；至给药23天，高剂量组的减重效果优于盐酸二甲双胍组；给药37天，高剂量组可完全抵抗高脂饮食诱发的体重增长，实际体重数值低于正常对照组；至给药51天实验结束，药物治疗低、中、高三剂量组较模型对照组体重降低分别为7.70％、13.33％和21.73％(表1)。至给药终点，模型对照组体重增长率66.91％，盐酸二甲双胍阳性对照组为44.73％，药物治疗低、中、高三剂量组则分别为53.65％、44.52％和30.43％(表2)。可见，1-氟-3-甲氧基-5-苯乙基苯可剂量依赖性抑制高脂饮食诱发的体重增长，具有明显的抗肥胖作用。
表1 1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征小鼠体重的影响
Figure PCTCN2022080862-appb-000009
Figure PCTCN2022080862-appb-000010
注：n＝10，mean±SD，采用t检验进行统计学分析； *P<0.05, **P<0.01， ***P<0.001(与模型对照组相比)。
表2 1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征小鼠体重增长率的影响
Figure PCTCN2022080862-appb-000011
注：n＝10，mean±SD，采用t检验进行统计学分析； **P<0.01， ***P<0.001(与模型对照组相比)。
实验例3、1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征小鼠摄食摄水量的影响
实验方法：每周记录两次小鼠摄食摄水量。
实验结果：平均计算给药期间摄食摄水量发现，与正常对照组小鼠进食普通饲料相比，模型对照组小鼠进食高脂饲料的24小时摄食摄水量均有降低，且具有统计学差异，考虑与饲料含油脂量过多，小鼠进食量减少继而导致进水量相应减少有关。阳性对照药盐酸二甲双胍组的24小时摄食摄水量均较模型对照组明显减少，与盐酸二甲双胍组相似，1-氟-3-甲氧基-5-苯乙基苯高剂量组摄食摄水量也出现减少，考虑与体重降低，机体所需食物与水均随之减少有关(表3，表4)。
表3 1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征小鼠24小时摄食量的影响
Figure PCTCN2022080862-appb-000012
注：n＝10，mean±SD，采用t检验进行统计学分析。 *P<0.05, ***P<0.001(与模型对照组相比)。
表4 1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征小鼠24小时摄水量的影响
Figure PCTCN2022080862-appb-000013
注：n＝10，mean±SD，采用t检验进行统计学分析。 *P<0.05(与模型对照组相比)。
实验例4、1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征小鼠脂水比的影响
实验方法：实验终末期，采用核磁共振方法检测小鼠脂水比，脂水比越高，表明小鼠脂肪含量高，代谢综合征越严重。脂水比降低，表明小鼠脂肪含量降低，代谢综合征状况有所改善。
实验结果：与正常对照组相比，模型对照组脂水比出现明显升高(P<0.001)。与模型对照组相比，1-氟-3-甲氧基-5-苯乙基苯低、中、高三剂量连续给药51天后均能明显降低高脂饲料诱导代谢综合征小鼠的脂水比，其中，中剂量与高剂量具有统计学差异(分别为P<0.05,P<0.001)(表5)。结果表明，1-氟-3-甲氧基-5-苯乙基苯可降低体内脂肪含量，改善代谢综合征。
表5 1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征小鼠脂水比的影响
Figure PCTCN2022080862-appb-000014
注：n＝10，mean±SD，采用t检验进行统计学分析。 *P<0.05， ***P<0.001(与模型对照组相比)。
实验例5、1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征小鼠糖代谢的影响
实验方法：1-氟-3-甲氧基-5-苯乙基苯连续给药至终末期，小鼠自上午8:00开始禁食，灌胃给药，12:00尾尖取血，采用辅理善血糖仪和辅理善血糖试纸测定高脂饲料诱导代谢综合征小鼠禁食血糖值，记录为0min血糖值。随后立即腹腔注射20％葡萄糖，2g/kg。分别于30min、60min、120min尾尖取血，采用辅理善血糖仪和辅理善血糖试纸测定小鼠血糖值。通过AUC＝0.25×空腹血糖+0.5×30min血糖+0.75×60min血糖+0.5×120min血糖公式计算曲线下面积，比较造模及给药对葡萄糖耐量的影响。
实验结果：与正常对照组小鼠相比，模型对照组小鼠腹腔注射葡萄糖后血糖水平升高更为明显，说明模型对照组小鼠出现糖耐量异常。连续给药51天后，1-氟-3-甲氧基-5-苯乙基苯三个剂量组均显示出不同程度降低高脂饲料诱导代谢综合征小鼠血糖，改善葡萄糖耐量的作用，具有剂量依赖性；其中，中剂量与高剂量作用最明显，均具有显著统计学差异(P<0.01)，其改善糖耐量的生物活性优于阳性药盐酸二甲双胍(P<0.05)(表6，表7)。综上，1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征小鼠的高血糖具有降低作用，纠正受损的葡萄糖耐量，从而改善代谢综合征引发的糖代谢异常。
表6 1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征小鼠葡萄糖耐量的影响
Figure PCTCN2022080862-appb-000015
注：n＝10，mean±SD，采用t检验进行统计学分析。 *P<0.05， **P<0.01， ***P<0.001(与模型对照组相比)。
表7 1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征小鼠葡萄糖耐量曲线下面积的影响
Figure PCTCN2022080862-appb-000016
注：n＝10，mean±SD，采用t检验进行统计学分析。 *P<0.05， **P<0.01， ***P<0.001(与模型对照组相比)。
实验例6、1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征小鼠胰岛素抵抗的影响
实验方法：1-氟-3-甲氧基-5-苯乙基苯连续给药至终末期，小鼠自上午8:00开始禁食，灌胃给药，12:00尾尖取血，采用辅理善血糖仪和辅理善血糖试纸测定高脂饲料诱导代谢综合征小鼠禁食血糖值，记录为0min血糖值。随后立即腹腔注射用生理盐水新鲜配制的0.5U/kg胰岛素(重组人胰岛素注射液(300U:3ml)，美国礼来公司)。分别于30min、60min、90min尾尖取血，采用辅理善血糖仪和辅理善血糖试纸测定小鼠血糖值。通过AUC＝0.125×空腹血糖+0.375×30min血糖+0.5×60min血糖+0.25×90min血糖公式计算曲线下面积，比较造模及给药对胰岛素耐量的影响。
实验结果：与正常对照组相比，模型对照组小鼠胰岛素耐量曲线下面积明显增加(P<0.05)，出现明显的胰岛素抵抗。连续给药51天后，1-氟-3-甲氧基-5-苯乙基苯三剂量组均显示不同程度降低高脂饲料诱导代谢综合征小鼠血糖的作用，其中，中剂量与高剂量对胰岛素耐量具有明显统计学差异的改善作用(分别为P<0.05，P<0.001)，其作用优于阳性药盐酸二甲双胍，证实1-氟-3-甲氧基-5-苯乙基苯具有改善代谢综合征引发胰岛素抵抗的作用(表8，表9)。
表8 1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征小鼠胰岛素耐量的影响
Figure PCTCN2022080862-appb-000017
注：n＝10，mean±SD，采用t检验进行统计学分析。与模型对照组相比， *P<0.05， **P<0.01， ***P<0.001。
表9 1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征小鼠胰岛素耐量曲线下面积的影响
Figure PCTCN2022080862-appb-000018
注：n＝10，mean±SD，采用t检验进行统计学分析。与模型对照组相比， *P<0.05， **P<0.01， ***P<0.001。
实验例7、1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征小鼠脂代谢的影响
实验方法：实验终末期，麻醉小鼠后，取血置于肝素化EP管中。4℃，5000rpm离心10分钟。将上清液转移至新的EP管中，取12μL血浆用生理盐水稀释5倍至60μL，于全自动生化分析仪(TBA-40FR，东芝，日本)中检测甘油三酯(甘油三酯测定试剂盒，北京中生北控生物科技股份有限公司)与总胆固醇(总胆固醇测定试剂盒，北京中生北控生物科技股份有限公司)的浓度。
实验结果：与正常对照组相比，模型对照组小鼠血浆甘油三酯浓度有所升高，具有统计学差异(P<0.001)；与模型对照组相比，连续给药51天后，1-氟-3-甲氧基-5-苯乙基苯显示出剂量依赖性降低高脂饲料诱导代谢综合征小鼠血浆甘油三酯的作用，其中高剂量组具有统计学差异(P<0.05)(表10)。与正常对照组相比，模型对照组小鼠总胆固醇明显升高(P<0.01)；各剂量组给药51天均有剂量依赖性降低总胆固醇的趋势，且高剂量给药组出现统计学差异(P<0.05)(表10)。综上，1-氟-3-甲氧基-5-苯乙基苯给药51天对于代谢综合征引发的高脂血症具有降低作用。
表10 1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征小鼠血脂的影响
Figure PCTCN2022080862-appb-000019
注：n＝10，mean±SD，采用t检验进行统计学分析。 *P<0.05， **P<0.01， ***P<0.001(与模型对照组相比)。
三、大鼠口服1-氟-3-甲氧基-5-苯乙基苯的药理学研究
实验大鼠：72只6周龄的SD雄性大鼠，适应性喂养1周后，从中随机抽取12只作为正常对照组，其余作为高脂饲料诱导代谢综合征组。正常对照组喂饲标准大鼠饲料，高脂饲料诱导代谢综合征组喂饲高脂饲料(60％热量来自脂肪,睿迪生物科技(深圳)有限公司)。每周记录大鼠体重2次，记录摄食摄水量2次，同时高脂饲料诱导代谢综合征组大鼠随机分为5组，每组12只，参考徐叔云教授主编的《药理实验方法学》，大鼠给药剂量＝小鼠给药剂量/1.44。分别为：模型对照组、盐酸二甲双胍阳性对照组(140mg/kg)、1-氟-3-甲氧基-5-苯乙基苯药物治疗低剂量组(50mg/kg)、药物治疗中剂量组(100mg/kg)、药物治疗高剂量组(200mg/kg)。高脂饲料造模同时开始灌胃给药(采用0.5％羧甲基纤维素钠(0.5％CMC-Na)配制药物)，正常对照组及模型对照组给予0.5％羧甲基纤维素钠，按照0.5mL/100g每天给药1次，连续给药90天。实验终末期，测定葡萄糖耐量。1-氟-3-甲氧基-5-苯乙基苯由中国医学科学院药物研究所吉腾飞课题组提供。
实验例8、1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征大鼠体重的影响
实验方法：每周记录大鼠体重。
实验结果：高脂饲料喂养后大鼠体重逐渐增加，喂养2天后，高脂饲料诱导代谢综合征组大鼠体重明显增加，与正常对照组相比具有统计学差异(P<0.05)。1-氟-3-甲氧基-5-苯乙基苯各剂量组给药后均可剂量依赖性地抑制其体重增长，高剂量给药2天与模型对照组比较即具有统计学差异，且优于盐酸二甲双胍组；至给药90天实验结束，药物治疗低、中、高三剂量组较模型对照组体重降低分别为15.44％、16.82％和22.48％，高剂量组体重与正常对照组几乎一致(表11)。至给药终点，模型对照组体重增长率330.24％，盐酸二甲双胍阳性对照组为262.57％，药物治疗低、中、高三剂量组则分别为267.58％、259.90％和235.10％(表12)。可见，1-氟-3-甲氧基-5-苯乙基苯可剂量依赖性抑制高脂饮食诱发的体重增长，具有明显的抗肥胖作用。
表11 1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征大鼠体重的影响
Figure PCTCN2022080862-appb-000020
注：n＝12，mean±SD，采用t检验进行统计学分析； *P<0.05, **P<0.01， ***P<0.001(与模型对照组相比)。
表12 1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征大鼠体重增长率的影响
Figure PCTCN2022080862-appb-000021
注：n＝12，mean±SD，采用t检验进行统计学分析； **P<0.01， ***P<0.001(与模型对照组相比)。
实验例9、1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征大鼠摄食摄水量的影响
实验方法：每周记录两次大鼠摄食摄水量。
实验结果：平均计算给药期间摄食摄水量发现，与正常对照组小鼠进食普通饲料相比，模型对照组小鼠进食高脂饲料的24小时摄食摄水量均有降低，且具有统计学差异，考虑与饲料含油脂量过多，大鼠进食量减少继而导致进水量相应减少有关。阳性对照药盐酸二甲双胍组的24小时摄食量均较模型对照组无变化，但24小时摄水量明显增加，与盐酸二甲双胍组相似， 1-氟-3-甲氧基-5-苯乙基苯高剂量组摄食量也无明显变化，但摄水量出现增加(表13，表14)。
表13 1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征大鼠24小时摄食量的影响
Figure PCTCN2022080862-appb-000022
注：n＝12，mean±SD，采用t检验进行统计学分析。 *P<0.05(与模型对照组相比)。
表14 1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征大鼠24小时摄水量的影响
Figure PCTCN2022080862-appb-000023
注：n＝12，mean±SD，采用t检验进行统计学分析。 **P<0.01， ***P<0.001(与模型对照组相比)。
实验例10、1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征大鼠糖代谢的影响
实验方法：1-氟-3-甲氧基-5-苯乙基苯连续给药至终末期，大鼠自上午8:00开始禁食，灌胃给药，12:00尾尖取血，采用辅理善血糖仪和辅理善血糖试纸测定高脂饲料诱导代谢综合征大鼠禁食血糖值，记录为0min血糖值。随后立即腹腔注射40％葡萄糖，2g/kg，0.5ml/100g。分别于30min、60min、120min尾尖取血，采用辅理善血糖仪和辅理善血糖试纸测定大鼠血糖值。通过AUC＝0.25×空腹血糖+0.5×30min血糖+0.75×60min血糖+0.5×120min血糖公式计算曲线下面积，比较造模及给药对葡萄糖耐量的影响。
实验结果：与正常对照组大鼠相比，模型对照组大鼠腹腔注射葡萄糖后血糖水平升高更为明显，说明模型对照组大鼠出现糖耐量异常。连续给药90天后，1-氟-3-甲氧基-5-苯乙基苯三个剂量组均显示出不同程度降低高脂饲料诱导代谢综合征大鼠血糖，改善葡萄糖耐量的作用；与模型对照组相比，三个剂量组降低曲线下面积均具有显著统计学差异(P<0.01，P<0.001)，且低、中剂量与阳性药盐酸二甲双胍相当，高剂量优于阳性药盐酸二甲双胍(表15，表16)。综上，1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征大鼠的高血糖具有降低作用，纠正受损的葡萄糖耐量，从而改善代谢综合征引发的糖代谢异常。
表15 1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征大鼠葡萄糖耐量的影响
Figure PCTCN2022080862-appb-000024
Figure PCTCN2022080862-appb-000025
注：n＝12，mean±SD，采用t检验进行统计学分析。 *P<0.05， **P<0.01， ***P<0.001(与模型对照组相比)。
表16 1-氟-3-甲氧基-5-苯乙基苯对高脂饲料诱导代谢综合征大鼠葡萄糖耐量曲线下面积的影响
Figure PCTCN2022080862-appb-000026
注：n＝12，mean±SD，采用t检验进行统计学分析。 *P<0.05， **P<0.01， ***P<0.001(与模型对照组相比)。
四、小鼠治疗性给药1-氟-3-甲氧基-5-苯乙基苯的药理学研究
实验小鼠：75只5周龄C57BL/6J雄性小鼠，适应性喂养1周后，从中随机抽取10只作为正常对照组，其余作为高脂饲料诱导代谢综合征组。正常对照组喂饲标准小鼠饲料，高脂饲料诱导代谢综合征组喂饲高脂饲料(60％热量来自脂肪,美国Research Diets公司)。喂养30天后，剔除高脂饲料喂养的代谢综合征小鼠中体重异常的小鼠，余下50只，随机分为5组，每组10只，分别为：模型对照组、盐酸二甲双胍阳性对照组(200mg/kg)、1-氟-3-甲氧基-5-苯乙基苯药物治疗低剂量组(75mg/kg)、药物治疗中剂量组(150mg/kg)、药物治疗高剂量组(300mg/kg)，高脂饲料造模同时开始灌胃给药(采用0.5％羧甲基纤维素钠(0.5％CMC-Na)配制药物)，正常对照组及模型对照组给予0.5％羧甲基纤维素钠，按照0.1mL/10g每天给药1次，每周记录小鼠体重2次，记录摄食摄水量2次，连续给药55天。1-氟-3-甲氧基-5-苯乙基苯由中国医学科学院药物研究所吉腾飞课题组提供。
实验例11、1-氟-3-甲氧基-5-苯乙基苯治疗性给药对高脂饲料诱导代谢综合征小鼠体重的影响
实验方法：每周记录小鼠体重。
实验结果：高脂饲料喂养30天后小鼠体重显著增加，与正常对照组相比具有统计学差异(P<0.001)。1-氟-3-甲氧基-5-苯乙基苯各剂量组给药后均可剂量依赖性地抑制其体重增长，给药5天与模型对照组比较出现降低趋势；至给药20天出现统计学差异且优于阳性药二甲双胍组；至给药55天实验结束，药物治疗低、中、高三剂量组较模型对照组体重降低分别为6.21％、12.05％和18.52％(表19)。与造模30天给药前相比，模型对照组体重增长率30.66％，盐酸二甲双胍阳性对照组为12.22％，药物治疗低、中、高三剂量组则分别为23.25％、15.59％ 和7.77％(表20)。可见，1-氟-3-甲氧基-5-苯乙基苯可剂量依赖性治疗高脂饮食诱发的体重增长，具有明显的抗肥胖作用。
表17 1-氟-3-甲氧基-5-苯乙基苯治疗性给药对高脂饲料诱导代谢综合征小鼠体重的影响
Figure PCTCN2022080862-appb-000027
注：n＝10，mean±SD，采用t检验进行统计学分析； *P<0.05, **P<0.01， ***P<0.001(与模型对照组相比)。
表18 1-氟-3-甲氧基-5-苯乙基苯治疗性给药对高脂饲料诱导代谢综合征小鼠体重增长率的影响
Figure PCTCN2022080862-appb-000028
注：n＝10，mean±SD，采用t检验进行统计学分析； *P<0.05， **P<0.01， ***P<0.001(与模型对照组相比)。
实验例12、1-氟-3-甲氧基-5-苯乙基苯治疗性给药对高脂饲料诱导代谢综合征小鼠摄食摄水量的影响
实验方法：每周记录两次小鼠摄食摄水量。
实验结果：平均计算给药期间摄食摄水量发现，与正常对照组小鼠进食普通饲料相比，模型对照组小鼠进食高脂饲料的24小时摄食摄水量均有降低，且具有统计学差异，考虑与饲料含油脂量过多，小鼠进食量减少继而导致进水量相应减少有关。阳性对照药盐酸二甲双胍组的24小时摄食量均较模型对照组明显减少，与盐酸二甲双胍组相似，1-氟-3-甲氧基-5-苯乙基苯低、高剂量组摄食量出现减少，考虑与体重降低，机体所需食物随之减少有关。与模型对照组相比，各给药组对24小时摄水量均无明显影响(表21，表22)。
表19 1-氟-3-甲氧基-5-苯乙基苯治疗性给药对高脂饲料诱导代谢综合征小鼠24小时摄食量的影响
Figure PCTCN2022080862-appb-000029
注：n＝10，mean±SD，采用t检验进行统计学分析。 *P<0.05, **P<0.01(与模型对照组相比)。
表20 1-氟-3-甲氧基-5-苯乙基苯治疗性给药对高脂饲料诱导代谢综合征小鼠24小时摄水量的影响
Figure PCTCN2022080862-appb-000030
注：n＝10，mean±SD，采用t检验进行统计学分析。 *P<0.05， ***P<0.001(与模型对照组相比)。
五、体外药理学实验
实验例13、1-氟-3-甲氧基-5-苯乙基苯对解偶联蛋白1(uncoupling protein 1,UCP1)的诱导作用
棕色脂肪组织具有非震颤性产热功能，其产热功能源于其富含大量线粒体且特异性高表达线粒体内膜解偶联蛋白1(uncoupling protein1,UCPl)，UCPl促进质子由线粒体内外膜间隙漏入线粒体内，从而使线粒体电子传递链产生电化学势能并以热能的形式散发。因此，我们在本发明人申请的专利《抗代谢综合征药物靶点UCP1的基因工程细胞株和高通量药物筛选模型的建立及应用》(申请号：201811248715.3)的基础上，检测了1-氟-3-甲氧基-5-苯乙基苯对于脂肪细胞UCP1启动子活性的调节作用。
实验方法：将UCP1启动子区域插入Luciferase和tdTomato的稳转脂肪细胞株种于96孔板中，进行成脂诱导分化，Day 6分别加入10μmol/L的阳性对照药β3-肾上腺素能受体激动剂CL316,243(CAS:138908-40-4)与1-氟-3-甲氧基-5-苯乙基苯处理细胞，于24h后采用报告基因方法检测Luciferase的活性，观察1-氟-3-甲氧基-5-苯乙基苯是否对UCP1启动子活性具有 调节作用。
实验结果：阳性对照药CL316,243可增加脂肪细胞UCP1的启动子活性(P<0.05)，与之相似，1-氟-3-甲氧基-5-苯乙基苯也可明显增强UCP1启动子活性(P<0.05)(表11)。综上，1-氟-3-甲氧基-5-苯乙基苯的抗代谢综合征的作用可能与诱导UCP1有关，为UCP1诱导剂。
表21 1-氟-3-甲氧基-5-苯乙基苯对解偶联蛋白1(uncoupling protein1,UCPl)的诱导作用
Figure PCTCN2022080862-appb-000031
注：n＝4，mean±SD，采用t检验进行统计学分析。*P<0.05(与正常对照组相比)。

Claims (11)

  1. 式(Ⅰ)所示的二苯烷类化合物或其药学上可接受的盐：
    Figure PCTCN2022080862-appb-100001
    其中，X选自氢，F，Cl，Br，I，非取代C1-9的直链或支链烷基，取代或非取代的C3-8环烷基；X的取代位置选自其苯环上1、2、3或4位；
    n选自0、1、2、3、4、5或6的整数；
    Y选自C，O，S，N或Si；
    R选自氢、取代或非取代的C1-16直链或支链烷基、取代或非取代的杂环或非杂环C3-8的环烷基、取代或非取代的苯基、取代或非取代的呋喃基、取代或非取代的噻吩基、取代或非取代的吡咯基、取代或非取代的萘基、取代或非取代的四氢萘基、取代或非取代的芴基、取代或非取代的咪唑基、取代或非取代的吲哚基；
    上述所述的取代或非取代中的取代基选自F，Cl，Br，I，-NO 2，-NH 2，-SH，-SO 3，羧基，C1-6直链或支链烷基酰胺基，C1-6直链或支链烷酯基。
  2. 根据权利要求1的二苯烷类化合物或其药学上可接受的盐，其特征在于，
    X选自氢，F，Cl，Br，I，C1-4的直链或支链烷基，或取代或非取代的C3-8环烷基；
    X的取代位置选自其苯环上1、2、3或4位；
    n选自0、1、2、3、4、5或6的整数；
    Y选自C，O，S，N或Si；
    R选自氢、甲基、乙基、丙基、丁基、己基或环己基；
    上述所述的取代或非取代中的取代基选自F，Cl，Br，I，-NO 2，-NH 2，-SH，-SO 3，羧基，C1-3直链或支链烷基酰胺基，C1-3直链或支链烷酯基。
  3. 根据权利要求1或2任一项的二苯烷类化合物或其药学上可接受的盐，其特征在于，所述的化合物选自：
    Figure PCTCN2022080862-appb-100002
  4. 制备权利要求3所述的化合物Ⅱ的方法，其特征在于，包括以下步骤：
    Figure PCTCN2022080862-appb-100003
    (1)以3‐氟‐5‐甲氧基苯甲醛为原料，通过维希替反应生成1‐乙烯基‐3‐氟‐5‐甲氧基苯；
    Figure PCTCN2022080862-appb-100004
    Figure PCTCN2022080862-appb-100005
    (2)1-乙烯基-3-氟-5-甲氧基苯和碘甲烷反应得到中间体1-氟-3-甲氧基-5-苯乙烯基苯；
    Figure PCTCN2022080862-appb-100006
    (3)1-氟-3-甲氧基-5-苯乙烯基苯通过催化氢化得到化合物1-氟-3-甲氧基-5-苯乙基苯，即为化合物Ⅱ；
    Figure PCTCN2022080862-appb-100007
  5. 一种药物组合物，其特征在于，所述的药物组合物由有效剂量的权利要求1-3任一项所述的二苯烷类化合物或其药学上可接受的盐和药学上可接受的载体或辅料组成。
  6. 权利要求1-3任一项所述的二苯烷类化合物或其药学上可接受的盐在制备治疗和/或预防代谢综合征及其并发症药物中的应用。
  7. 根据权利要求6的应用，其特征在于，所述的代谢综合征选自肥胖症、糖代谢异常、脂代谢异常、脂肪肝、高血压、高粘血症、高尿酸血症或痛风。
  8. 根据权利要求7的应用，其特征在于，所述的糖代谢异常包括胰岛素抵抗或高胰岛素血症、糖耐量异常、糖尿病前期、糖尿病、糖尿病并发症；所述的糖尿病并发症包括糖尿病肾病、糖尿病神经病变、糖尿病视网膜病变、糖尿病肝病。
  9. 根据权利要求7的应用，其特征在于，所述的脂代谢异常包括高甘油三酯血症、高胆固醇血症、高低密度脂蛋白血症、低高密度脂蛋白血症、高游离脂肪酸血症。
  10. 根据权利要求7的应用，其特征在于，所述的脂肪肝包括非酒精性脂肪性肝病、非酒精性脂肪性肝炎。
  11. 根据权利要求6的应用，其特征在于，所述的代谢综合征并发症包括心脑血管疾病、 癌症、肝硬化、多囊卵巢综合征、肾脏和胰脏功能障碍。
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CN101528709A (zh) * 2006-10-19 2009-09-09 弗·哈夫曼-拉罗切有限公司 对痕量胺相关受体有亲和性的氨基甲基-2-咪唑类
CN101917980A (zh) * 2007-11-01 2010-12-15 奥克塞拉有限公司 用于治疗眼科疾病和紊乱的胺衍生化合物
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