Use of 6,7-dihydroxy-4-phenylcoumarin for the preparation of a medicament for weight loss

Abstract

The present application belongs to the technical field of medicine and disease treatment, and particularly relates to the use of 6,7-dihydroxy-4-phenyl coumarin in the preparation of weight loss drugs. The research results of the present application show that 6,7-dihydroxy-4-phenyl coumarin can reduce the body weight of high-fat diet-induced obese mice and reduce the blood lipids of high-fat diet-induced obese mice. Therefore, through systematic animal experiment research, it is found that 6,7-dihydroxy-4-phenyl coumarin has significant beneficial effects in regulating lipid metabolism and improving obesity-related metabolic disorders. As a natural small molecule compound, 6,7-dihydroxy-4-phenyl coumarin has good biological activity and safety, and has a broad application prospect in the preparation of drugs for weight loss.

Description

Technical Field

[0001] This invention belongs to the field of drug and disease treatment technology, specifically relating to the use of 6,7-dihydroxy-4-phenylcoumarin in the preparation of weight-loss drugs. Background Technology

[0002] Obesity is a chronic, complex disease defined as the excessive deposition of fat that can lead to health problems. Obesity increases the risk of type 2 diabetes and heart disease, affects bone health and the reproductive system, and increases the risk of certain cancers. Obesity also impacts quality of life, such as sleep and activity levels.

[0003] Obesity is primarily treated through weight loss. Current weight loss methods include a healthy diet, portion control, and exercise. Some patients may consider bariatric surgery or medication. Medications currently used for weight loss include orlistat capsules, lorcaserin, phenbutylbromide, topiramate extended-release capsules, naltrexone hydrochloride, bupropion hydrochloride compound extended-release tablets, and liralu injection.

[0004] While some medications are currently used in clinical practice for the long-term treatment of obesity, existing weight-loss drugs have low safety profiles and numerous adverse reactions. Specifically, orlistat, which inhibits gastrointestinal lipase leading to malabsorption of fat, has some efficacy but causes severe gastrointestinal discomfort, such as oily spots, steatorrhea, and fecal incontinence. Long-term use can also lead to fat-soluble vitamin deficiencies and even rare but serious liver damage. GLP-1 receptor agonists, as a new generation of weight-loss drugs, are more effective, but their adverse reactions are equally prominent: gastrointestinal reactions (nausea, vomiting, diarrhea) occur in 30% to 70% of patients and may lead to serious gastrointestinal motility disorders such as gastroparesis; furthermore, they may increase the incidence of gallstones, cholecystitis (4-9 times increased risk), and acute pancreatitis (9.09 times increased risk), and are contraindicated in high-risk populations due to animal studies showing a risk of medullary thyroid carcinoma. Centrally acting drugs, such as the naltrexone / bupropion combination, may not only raise blood pressure but also increase the risk of seizures and potentially induce depression and suicidal tendencies. The phentermine / topiramate combination carries the risk of drug abuse and dependence, and topiramate has a proven teratogenic effect. The common root of these safety concerns lies in the fact that existing drugs achieve weight loss through aggressive intervention in key metabolic nodes, but their insufficient target selectivity inevitably interferes with other physiological functions, leading to multi-systemic side effects. Summary of the Invention

[0005] To address the issues of low safety and numerous adverse reactions in existing weight-loss drugs, this invention provides a new strategy suitable for weight loss, specifically the use of 6,7-dihydroxy-4-phenylcoumarin in the preparation of weight-loss drugs.

[0006] To achieve the above objectives, the present invention adopts the following technical solution.

[0007] This invention provides the use of 6,7-dihydroxy-4-phenylcoumarin in the preparation of a weight-loss medicament. The structural formula of the 6,7-dihydroxy-4-phenylcoumarin is as follows:

[0008] .

[0009] While existing drugs are used in the long-term treatment of obesity, their safety profiles are not high and they have numerous adverse reactions. For example, orlistat can easily cause severe gastrointestinal discomfort and fat-soluble vitamin deficiencies; GLP-1 receptor agonists pose significant risks of gastrointestinal intolerance, biliary tract disease, and pancreatitis; and centrally acting drugs face problems such as cardiovascular toxicity, neuropsychiatric side effects, and potential addiction. The fundamental reason for this is that existing drugs achieve weight loss by aggressively intervening in key metabolic nodes, resulting in insufficient target selectivity and inevitably interfering with other physiological functions, with unknown long-term risks. In contrast, the 6,7-dihydroxy-4-phenylcoumarin provided in this invention, as a naturally derived phenolic hydroxycoumarin derivative, achieves weight loss through a multi-target synergistic mechanism by mildly regulating lipid metabolism and inhibiting abnormal adipose tissue proliferation and insulin resistance induced by a high-fat diet. This effectively combats weight gain, fat accumulation, and metabolic disorders caused by a high-fat diet while avoiding the systemic toxicity caused by excessive inhibition of digestion and absorption, strong hormone receptor agonism, or central intervention in appetite in existing weight-loss drugs. This significantly improves drug safety and provides a safer and more reliable new option for the treatment of obesity.

[0010] The 6,7-dihydroxy-4-phenylcoumarin provided by this invention, verified in a high-fat diet-induced obese mouse model, exhibits both "highly effective fat reduction" and "systemic protection," overcoming the shortcomings of existing weight-loss drugs with poor safety and numerous side effects. Therefore, 6,7-dihydroxy-4-phenylcoumarin achieves highly effective weight loss without adverse reactions through multiple mechanisms including "lipid regulation, liver protection, intestinal protection, and non-central nervous system regulation," thus breaking through the bottleneck of existing weight-loss drugs where "efficacy and safety" cannot be simultaneously achieved. This provides a novel anti-obesity candidate molecule for long-term oral administration with negligible side effects for clinical use.

[0011] Preferably, the drug is a solution.

[0012] Preferably, the drug is an intraperitoneal injection formulation or an oral administration formulation.

[0013] Preferably, the drug uses 6,7-dihydroxy-4-phenylcoumarin as the active ingredient and is supplemented with pharmaceutically acceptable excipients.

[0014] Preferably, the excipients are selected from any one or more of solvents, cosolvents, and dispersants.

[0015] Preferably, the solvent includes water and physiological saline.

[0016] Preferably, the concentration of 6,7-dihydroxy-4-phenylcoumarin in the drug is 0.08 mg / mL to 2 mg / mL.

[0017] Preferably, the dosage of the drug is 0.4 mg / kg to 10 mg / kg.

[0018] Preferably, the drug is used to inhibit weight gain and adipose tissue hyperplasia caused by a high-fat diet.

[0019] Compared with the prior art, the present invention has the following beneficial effects: The purpose of this invention is to provide the use of 6,7-dihydroxy-4-phenylcoumarin in the preparation of weight-loss drugs. The 6,7-dihydroxy-4-phenylcoumarin provided by this invention, verified in a high-fat diet-induced obese mouse model, exhibits both "highly effective fat reduction" and "systemic protection," overcoming the shortcomings of existing weight-loss drugs such as poor safety and numerous side effects. Therefore, 6,7-dihydroxy-4-phenylcoumarin achieves highly effective weight loss without adverse reactions through multiple mechanisms including "lipid regulation, liver protection, intestinal protection, and non-central nervous system regulation," thus breaking through the bottleneck of existing weight-loss drugs where "efficacy and safety" cannot be simultaneously achieved, providing a novel anti-obesity candidate molecule for long-term oral administration with negligible side effects for clinical use. Attached Figure Description

[0020] Figure 1 This is the structural formula of 6,7-dihydroxy-4-phenylcoumarin in this invention.

[0021] Figure 2 This is a graph showing the weight loss results of 6,7-dihydroxy-4-phenylcoumarin in this invention; wherein: Figure 2 Figure A in the diagram is a schematic diagram of the construction of a mouse obesity model and the administration regimen of 6,7-dihydroxy-4-phenylcoumarin; Figure 2 Figure B shows the weight loss in obese mice during 6,7-dihydroxy-4-phenylcoumarin administration, where # indicates the difference between the NOR-M and model groups. P <0.05, ## indicates that compared to the NOR-M and model groups, P <0.01, ### indicates that compared to the NOR-M and model groups, P <0.001, * indicates that NOR-H is compared with the model group. P <0.05, ** indicates that NOR-H is compared to the model group. P <0.01, *** indicates that NOR-H is lower than the model group. P<0.001, & indicates that NOR-L is compared with the model group. P <0.05, && indicates that NOR-L is compared with the model group. P <0.01, &&& indicates that NOR-L is compared with the model group, P <0.001; Figure 2 Figure C in the figure shows the change in body weight in obese mice during administration of 6,7-dihydroxy-4-phenylcoumarin; where # indicates the difference between the NOR-M and model groups. P <0.05, ## indicates that compared to the NOR-M and model groups, P <0.01, ### indicates that compared to the NOR-M and model groups, P <0.001, * indicates that NOR-H is compared with the model group. P <0.05, ** indicates that NOR-H is compared to the model group. P <0.01, *** indicates that NOR-H is lower than the model group. P <0.001, & indicates that NOR-L is compared with the model group. P <0.05, && indicates that NOR-L is compared with the model group. P <0.01, &&& indicates that NOR-L is compared with the model group, P <0.001; Figure 3 The changes in blood glucose, cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) in mice after intervention with 6,7-dihydroxy-4-phenylcoumarin in this invention are shown below; wherein: Figure 3 Figure A shows the changes in blood glucose in mice after intervention with 6,7-dihydroxy-4-phenylcoumarin; Figure 3 Figure B in the figure shows the changes in total cholesterol in mice after intervention with 6,7-dihydroxy-4-phenylcoumarin; Figure 3 Figure C in the figure shows the changes in triglycerides in mice after intervention with 6,7-dihydroxy-4-phenylcoumarin; Figure 3 Figure D shows the changes in high-density lipoprotein in mice after intervention with 6,7-dihydroxy-4-phenylcoumarin; Figure 3 Figure E in the figure shows the changes in low-density lipoprotein in mice after intervention with 6,7-dihydroxy-4-phenylcoumarin; In the above figure, * indicates that each group is compared with the model group. P <0.05, ** indicates that each group is compared to the model group. P <0.01, *** indicates that compared to the model group, each group has a lower value. P <0.001. Detailed Implementation

[0022] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments, but this should not be construed as limiting the invention. Unless otherwise specified, the technical means used in the following embodiments are conventional means well known to those skilled in the art, and the materials, reagents, etc. used in the following embodiments are commercially available unless otherwise specified.

[0023] The experimental animals used in the following examples are as follows: C57BL / 6 mice were purchased from Jiangsu Huachuang Xinno Pharmaceutical Technology Co., Ltd., and were raised under strict hygiene and good ventilation conditions, with free access to food and water.

[0024] The conditions for raising the animals are as follows: no specific pathogens, a temperature of 23.5℃±2.5℃, a humidity of 55%±5%, and a day-night light cycle of 12 hours of light and 12 hours of darkness.

[0025] Among them, the English name for specific pathogen-free animals is Specific Pathogen Free Animals, SPF.

[0026] All animal experiments in this invention were approved by the Animal Welfare Committee of Xi'an People's Hospital. Xi'an People's Hospital is also known as Xi'an Fourth Hospital.

[0027] Example 1 I. Methods 1. Establishment of experimental animals and models Establishment of a mouse obesity model: Before the experiment, C57BL / 6 mice were housed separately in plastic cages in the experimental environment, with free access to food and water for 7 days to allow them to acclimatize. After acclimatization, they were randomly divided into two groups: a blank control group of 6 mice, which continued to be fed a basal diet; and a high-fat model group of 24 mice, which were fed a high-fat diet. The basal diet, referring to the maintenance diet for rats and mice, was purchased from Wuhan Wanqian Jiaxing Biotechnology Co., Ltd. The high-fat diet was purchased from Nantong Trofi Feed Technology Co., Ltd., and contained the following components by weight percentage:

[0028] It contains 42% fat, 14% protein, 44% carbohydrates and 0.2% cholesterol.

[0029] Meanwhile, mice in the high-fat model group were given a high-sugar drinking water. High-sugar drinking water refers to a carbohydrate intake of 42 g / L; the carbohydrates were a mixture of sucrose and fructose in a mass ratio of 45:55.

[0030] The model was established for 4 months. Body weight was measured weekly. Successful modeling was defined as the body weight of mice in the high-fat model group exceeding that of rats in the blank control group by at least 20%. The schematic diagram of the rat obesity model construction and the 6,7-dihydroxy-4-phenylcoumarin administration regimen is shown below. Figure 2 As shown in Figure A.

[0031] Six mice were randomly assigned to each group, as follows: Model group, high-dose model group, medium-dose model group, and low-dose model group.

[0032] The specific treatment methods for each of the above experimental groups are as follows: Model group: high-fat diet + high-sugar drinking water + intraperitoneal injection of physiological saline.

[0033] The high-dose treatment group in the model consisted of a high-fat diet, high-sugar drinking water, and intraperitoneal injection of 6,7-dihydroxy-4-phenylcoumarin at 10 mg / kg·d. The English name for the high-dose treatment group in the model is NOR-H.

[0034] The model's medium-dose administration group consisted of a high-fat diet, high-sugar drinking water, and intraperitoneal injection of 6,7-dihydroxy-4-phenylcoumarin at 2 mg / kg·d. The English name for this model's medium-dose administration group is NOR-M.

[0035] The low-dose treatment group in the model consisted of a high-fat diet, high-sugar drinking water, and intraperitoneal injection of 6,7-dihydroxy-4-phenylcoumarin at 0.4 mg / kg·d. The English name for the low-dose treatment group in the model is NOR-L.

[0036] 6,7-Dihydroxy-4-phenylcoumarin was purchased from Taoshu Biotechnology Co., Ltd. The structural formula of 6,7-dihydroxy-4-phenylcoumarin is shown below. Figure 1 .

[0037] 2. Administration method After grouping the mice, the blank control group continued to be fed a basal diet daily with free access to food, while the other experimental groups were given a high-fat diet daily and simultaneously began receiving the drug. Mice in the low-dose model group received an intraperitoneal injection of a low dose of 6,7-dihydroxy-4-phenylcoumarin at a dose of 0.4 mg / kg·d; mice in the medium-dose model group received an intraperitoneal injection of a medium dose of 6,7-dihydroxy-4-phenylcoumarin at a dose of 2 mg / kg·d; and mice in the high-dose model group received an intraperitoneal injection of a high dose of 6,7-dihydroxy-4-phenylcoumarin at a dose of 10 mg / kg·d. Mice in the model groups received an equal volume of physiological saline intraperitoneally.

[0038] Mice in each group were injected continuously for 3 weeks. Food intake was measured daily, and body weight was measured every three days. Body weight and weight gain were observed and recorded for each group.

[0039] 3. Experimental Data Detection and Processing Detection Indicators After anesthetizing mice in each group with isoflurane, blood was collected from the orbital vein. After standing at room temperature, the blood was centrifuged at 3000 rpm for 10 minutes. The serum was then collected and stored at -20°C for analysis. After blood processing, serum total cholesterol, total triglycerides, high-density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol (LDL) were determined using an enzyme colorimetric assay kit. The abbreviations for total cholesterol (TC), total triglycerides (TG), high-density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol (LDL) are as follows:

[0040] II. Results 1. Results of the weight loss experiment The experimental data on body weight of mice in each group after 3 weeks of administration of 6,7-dihydroxy-4-phenylcoumarin are as follows: Figure 2 Image B in the middle~ Figure 2 As shown in Figure C.

[0041] The results showed that 6,7-dihydroxy-4-phenylcoumarin could significantly reduce the weight of obese mice at all doses.

[0042] As shown above, 6,7-dihydroxy-4-phenylcoumarin can significantly reduce the weight of obese mice.

[0043] 2. Results of lipid-lowering experiment Three weeks after administration of 6,7-dihydroxy-4-phenylcoumarin, the experimental results of blood glucose and blood biochemical parameters in each group of mice are as follows: Figure 3 Figure A in the middle~ Figure 3 As shown in Figure E.

[0044] The results showed that 6,7-dihydroxy-4-phenylcoumarin significantly reduced blood glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol in obese mice at concentrations of 10 mg / kg and 2 mg / kg. At 0.4 mg / kg, it also significantly reduced triglycerides, total cholesterol, and high-density lipoprotein cholesterol in obese mice.

[0045] These results indicate that 6,7-dihydroxy-4-phenylcoumarin can significantly reduce blood lipids in obese mice.

[0046] The experimental results above show that 6,7-dihydroxy-4-phenylcoumarin has a significant weight-loss effect and can reduce triglycerides, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol in hyperlipidemic mice.

[0047] The 6,7-dihydroxy-4-phenylcoumarin provided by this invention, verified in a high-fat diet-induced obese mouse model, exhibits both "highly effective weight loss" and "systemic protection," overcoming the shortcomings of existing weight-loss drugs with poor safety and numerous side effects. Specifically, its effects are manifested in the following aspects: Therefore, 6,7-dihydroxy-4-phenylcoumarin achieves highly effective weight loss without adverse reactions through multiple mechanisms including "lipid regulation, liver protection, intestinal protection, and non-central nervous system regulation." This breaks through the bottleneck of existing weight-loss drugs where "efficacy and safety" cannot be simultaneously achieved, providing a novel anti-obesity candidate molecule for long-term oral administration with negligible side effects.

[0048] It should be noted that when numerical ranges are involved in this invention, it should be understood that the two endpoints of each numerical range and any value between the two endpoints can be selected. To avoid redundancy, this invention describes preferred embodiments.

[0049] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments, all of which fall within the scope of the invention.

Claims

The use of 1,6,7-dihydroxy-4-phenylcoumarin in the preparation of weight-loss drugs, characterized in that, The structural formula of the 6,7-dihydroxy-4-phenylcoumarin is as follows: 。 2. The use of 6,7-dihydroxy-4-phenylcoumarin according to claim 1 in the preparation of a weight-loss drug, characterized in that, The drug is a solution.

3. The use of 6,7-dihydroxy-4-phenylcoumarin according to claim 2 in the preparation of a weight-loss drug, characterized in that, The drug is an intraperitoneal injection preparation or an oral administration preparation.

4. The use of 6,7-dihydroxy-4-phenylcoumarin according to claim 3 in the preparation of a weight-loss drug, characterized in that, The drug uses 6,7-dihydroxy-4-phenylcoumarin as its active ingredient, supplemented with pharmaceutically acceptable excipients.

5. The use of 6,7-dihydroxy-4-phenylcoumarin according to claim 4 in the preparation of a weight-loss drug, characterized in that, The excipients are selected from any one or more of solvents, cosolvents, and dispersants.

6. The use of 6,7-dihydroxy-4-phenylcoumarin according to claim 5 in the preparation of a weight-loss drug, characterized in that, The solvents include water and physiological saline.

7. The use of 6,7-dihydroxy-4-phenylcoumarin according to claim 6 in the preparation of a weight-loss drug, characterized in that, The concentration of 6,7-dihydroxy-4-phenylcoumarin in the drug is 0.08 mg / mL to 2 mg / mL.

8. The use of 6,7-dihydroxy-4-phenylcoumarin according to claim 1 in the preparation of a weight-loss drug, characterized in that, The drug is used to inhibit weight gain and adipose tissue hyperplasia caused by a high-fat diet.

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