Use of compound or pharmaceutically acceptable salt thereof in treatment of lipid metabolic diseases

Abstract

Provided is the use of a compound or a pharmaceutically acceptable salt thereof in the treatment of lipid metabolic diseases. The compound or pharmaceutically acceptable salt thereof can significantly reduce body weight and improve the metabolic phenotype of diseases associated with lipid metabolism. The compound or pharmaceutically acceptable salt thereof is capable of reducing the expression of triglycerides, total cholesterol, and alkaline phosphatase, improving blood lipid level of the body, and reducing lipid accumulation in adipose tissue.

Description

Use of a compound or a pharmaceutically acceptable salt thereof in the treatment of lipid metabolism disorders

[0001] This application claims priority to Chinese patent application 2024115501779, filed on November 1, 2024. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of biomedical technology, and in particular to the use of a compound or a pharmaceutically acceptable salt thereof in the treatment of lipid metabolism disorders. Background Technology

[0003] In recent years, lipid metabolism has become a research hotspot, particularly its role in diseases such as cancer, diabetes, obesity, chronic kidney disease, neurodegenerative diseases, and liver disease. These studies not only focus on lipids themselves but also on the roles of fatty acids (FAs), especially polyunsaturated fatty acids (PUFAs).

[0004] Lipid metabolism disorders, also known as lipid metabolism disturbances, refer to abnormalities in the metabolism of lipids (such as cholesterol and triglycerides) in the body, caused by genetic factors, environmental factors, or both. These diseases can increase the risk of cardiovascular disease and are among the most important diseases affecting human health today.

[0005] In recent years, many innovative drugs have emerged in the research of lipid-lowering drugs. This research not only involves the fundamental theories of lipid metabolism but also includes new discoveries about drug targets, providing new insights into the treatment of atherosclerotic cardiovascular diseases.

[0006] Cardiovascular disease is one of the most common and serious diseases among modern adults, and abnormal lipid metabolism is an independent risk factor for cardiovascular disease. Current research focuses not only on lipoprotein components and lipid metabolism, but also on the cardiovascular protective effects of glycine. Furthermore, research also investigates the roles and molecular mechanisms of the PCSK9 / LDLR pathway, the small polypeptide EpK (mimicking the human apoE domain), polyunsaturated fatty acids, adiponectin, the LXR-ABCA1 pathway, and probucol in lipid metabolism.

[0007] Common lipid metabolism disorders include hypercholesterolemia: elevated levels of total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) in the blood; hypertriglyceridemia: elevated levels of triglycerides (TG) in the blood; mixed hyperlipidemia: the coexistence of high cholesterol and high triglycerides; low high-density lipoprotein cholesterol: decreased levels of high-density lipoprotein cholesterol (HDL-C) in the blood; and familial hypercholesterolemia: a hereditary disease characterized by abnormally elevated LDL-C levels.

[0008] Many lipid-lowering drugs, especially statins, can cause side effects such as muscle pain and abnormal liver function. These side effects limit their use for some patients and may affect patient adherence. Different patients respond differently to the same drug. Some patients may respond well to a particular drug, while others may respond poorly or experience adverse reactions. The ideal target for lipid level control remains controversial. Different guidelines may propose different treatment goals, which introduces some confusion into clinical practice. Lipid-lowering drugs may interact with other medications, affecting their efficacy or increasing the risk of side effects. Although some drugs can effectively lower lipid levels in the short term, their long-term efficacy and safety require further clinical data to verify.

[0009] In summary, existing drugs for treating lipid metabolism-related diseases have various problems, therefore, it is necessary to find a more suitable drug for treating lipid metabolism-related diseases. Summary of the Invention

[0010] To address the issue of high-frequency injections required for medications treating lipid metabolism disorders in existing technologies, this invention provides the application of a compound or a pharmaceutically acceptable salt thereof in the treatment of lipid metabolism disorders. Compared to known weight-loss drugs in the art, the compound or pharmaceutically acceptable salt of this invention has a longer duration of action, which helps reduce the frequency of medication and improve patient adherence.

[0011] In one aspect, this invention provides the use of compounds of the following formula or pharmaceutically acceptable salts thereof in the preparation of medicaments for lowering triglycerides;

[0012] SEQ ID NO:1:YAibEGT FTSDY SIAibLD KK 1 AZ0K0 Z1FZ2E0W LZ3AGG PSSGA PPPS0;

[0013] SEQ ID NO:2:YAibEGT FTSDY SIAibLD KE0AQK0 AFVK 1 W LIAGG PSSGA PPPS0;

[0014] SEQ ID NO:3:YAibEGT FTSDY SIE0LD KK0AQK 1 AFVQW LIAGG PSSGA PPPS0;

[0015] SEQ ID NO:4:YAibEGT FTSDY SIE0LD K0IAQK 1 AFVQW LIAGG PSSGA PPPS0;

[0016] in,

[0017] The structure of Aib is

[0018] S0 is selected from

[0019] Z0 is selected from glutamine (Q) and asparagine (N);

[0020] Z1 is selected from alanine (A) and glutamic acid (E);

[0021] Z2 is selected from valine (V) and isoleucine (I);

[0022] Z3 is selected from isoleucine (I) and leucine (L);

[0023] E0 and K0 indicate that the carboxyl group on the glutamic acid side chain and the amino group on the lysine side chain together form a lactam. In this case, the structure of K0Z1FZ2E0 is... The structure of E0AQK0 is The structure of E0LDKK0 is The structure of E0LDK0 is as follows

[0024] K 1 This indicates that the amino group on the lysine side chain is linked to -X-X1-X2, and its structure is:

[0025] X is selected from

[0026] R1 and R2 are independently selected from H and CH3, respectively;

[0027] X1 is selected from

[0028] X2 is selected from

[0029] m, n, and p are independently selected from 2 and 3, respectively;

[0030] s is selected from 2 and 3;

[0031] q is selected from 15, 16, 17, 18 and 19.

[0032] In some embodiments, the compound is selected from:

[0033] The compound used in the specific embodiments is WX-001, which is designated THDBHI20 in the embodiments.

[0034] In some implementations, the drug is administered once every 1 to 30 days, for example once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month.

[0035] The recommended starting dose for human clinical use was calculated based on the NOAEL (Novel Adaptive Efficiency Level) of toxicological studies. There are two methods for converting mouse-to-human dosing: one is based on surface area, with a conversion factor of 12.1; the other is based on body weight, with a conversion factor of approximately 9.1.

[0036] Based on a normal adult weighing 60kg, the human dose calculated by body surface area in a 28-day long-term rat toxicology experiment is 2.42mg; based on a 28-day long-term cynomolgus monkey toxicology clinical observation, the human dose calculated by body surface area is 0.73mg; using the most sensitive animal as an example, the estimated non-toxic dose for human clinical use is approximately 0.73mg; with a safety factor of approximately 10, the recommended starting dose for clinical use is approximately 0.05mg.

[0037] In some embodiments, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg, or 200 ng / kg.

[0038] Another aspect of the present invention provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating diseases related to triglycerides.

[0039] In some implementations, the triglyceride-related diseases are selected from at least one of the following: hyperlipidemia, atherosclerosis, coronary heart disease, and nephrotic syndrome.

[0040] In some implementations, the triglyceride-related disease or the patient is suitable for a dosing frequency of once every 1 to 30 days, such as once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month.

[0041] For certain patients, such as those without other cardiovascular risk factors and with only slightly elevated triglyceride levels, frequent medication may not be necessary. In such cases, over-reliance on medication may not provide significant benefits and could instead lead to unnecessary side effects and treatment costs.

[0042] In some implementations, the triglyceride-related disease is resistant to or not sensitive to existing drugs; for example, Tirzepatide is not effective in improving triglyceride-related disease when administered once a week.

[0043] In some embodiments, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg, or 200 ng / kg.

[0044] Another aspect of the present invention provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of triglyceride inhibitors.

[0045] In some implementations, the triglyceride inhibitor is used for non-therapeutic purposes.

[0046] In some embodiments, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg, or 200 ng / kg.

[0047] Another aspect of the present invention provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for lowering total cholesterol.

[0048] In some implementations, the drug is administered once every 1 to 30 days, for example once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month.

[0049] In some embodiments, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg, or 200 ng / kg.

[0050] Another aspect of the present invention provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating diseases related to total cholesterol.

[0051] In some implementations, the total cholesterol-related disease is selected from at least one of the following: hepatitis, atherosclerosis, and nephrotic syndrome.

[0052] In some implementations, the total cholesterol-related disease or its patients are suitable for a dosing frequency of once every 1 to 30 days, such as once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month.

[0053] For patients without significant cardiovascular disease risk and with only slightly elevated cholesterol levels, over-reliance on medication may not provide significant benefits and could instead cause unnecessary side effects and treatment costs. In some cases, such as when patients have other complications or adverse reactions to certain medications, frequent medication use may be inappropriate. For example, there are reports that long-term, high-dose use of statins may lead to elevated blood sugar levels.

[0054] In some implementations, the total cholesterol-related disease is resistant to or not sensitive to existing drugs; for example, Tirzepatide is not effective in improving total cholesterol-related disease when administered once a week.

[0055] In some embodiments, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg, or 200 ng / kg.

[0056] Another aspect of the present invention provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of total cholesterol inhibitors.

[0057] In some implementations, the total cholesterol inhibitor is used for non-therapeutic purposes.

[0058] In some embodiments, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg, or 200 ng / kg.

[0059] Another aspect of the present invention provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for lowering high-density lipoprotein.

[0060] In some implementations, the drug is administered once every 1 to 30 days, for example once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month.

[0061] In some embodiments, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg, or 200 ng / kg.

[0062] Another aspect of the present invention provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating diseases related to high-density lipoprotein.

[0063] In some embodiments, the disease associated with high-density lipoprotein is selected from at least one of the following: primary biliary cholangitis.

[0064] In some implementations, the disease associated with high-density lipoprotein or the patient is suitable for a dosing frequency of once every 1 to 30 days, such as once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month.

[0065] In some implementations, the high-density lipoprotein-related disease is resistant to or not sensitive to existing drugs. For example, Tirzepatide is not effective in improving high-density lipoprotein-related disease when administered once a week.

[0066] In some embodiments, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg, or 200 ng / kg.

[0067] Another aspect of the present invention provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of high-density lipoprotein inhibitors.

[0068] In some implementations, the high-density lipoprotein detection agent or inhibitor is used for non-diagnostic therapeutic purposes.

[0069] In some embodiments, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg, or 200 ng / kg.

[0070] Another aspect of the present invention provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for lowering low-density lipoprotein.

[0071] In some implementations, the drug is administered once every 1 to 30 days, for example once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month.

[0072] In some embodiments, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg, or 200 ng / kg.

[0073] Another aspect of the present invention provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating diseases related to low-density lipoprotein.

[0074] In some implementations, the diseases associated with low-density lipoprotein are selected from at least one of the following: atherosclerosis and coronary heart disease.

[0075] In some implementations, the disease associated with low-density lipoprotein or the patient is suitable for a dosing frequency of once every 1 to 30 days, such as once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month.

[0076] In some implementations, the LDL-related disease is resistant to or not sensitive to existing drugs; for example, Tirzepatide is not effective in improving LDL-related disease when administered once a week.

[0077] In some embodiments, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg, or 200 ng / kg.

[0078] Another aspect of the present invention provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of low-density lipoprotein inhibitors.

[0079] In some implementations, the low-density lipoprotein inhibitor is used for non-therapeutic purposes.

[0080] In some embodiments, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg, or 200 ng / kg.

[0081] Another aspect of the present invention provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for reducing alkaline phosphatase expression.

[0082] In some implementations, the drug is administered once every 1 to 30 days, for example once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month.

[0083] In some embodiments, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg, or 200 ng / kg.

[0084] In another aspect, the present invention provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for reducing liver fat.

[0085] In some implementations, the drug is administered once every 1-30 days, such as once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month. Patients with fatty liver need to pay special attention to medication use, especially since elevated alanine aminotransferase (ALT) levels may indicate liver damage. The following are some situations where high-frequency medication is not suitable for patients with alanine aminotransferase-related diseases:

[0086] Treatment of the underlying cause: For patients with fatty liver, the primary treatment is to control the underlying causes and risk factors, such as obesity, hyperlipidemia, and type 2 diabetes. For obese patients, a weight loss of 3% to 5% can effectively improve fatty liver.

[0087] Caution is advised when using medications: Patients with fatty liver should be very cautious when using lipid-lowering drugs, because to date no lipid-lowering drugs have a reducing effect on fat deposition in the liver, and some lipid-lowering drugs may have toxic effects on the liver.

[0088] Avoid hepatotoxic drugs: For patients with drug-induced liver injury (DILI), the suspected hepatotoxic drug should be discontinued immediately, as approximately 95% of patients will improve or recover on their own.

[0089] Comorbid chronic liver disease: The prevalence of fatty liver is low in patients with chronic hepatitis B virus (HBV) infection and chronic hepatitis B (CHB), but fatty liver is increasingly common in these patients and is mainly associated with metabolic dysfunction.

[0090] In some implementations, the fatty liver-related disease is resistant to or not sensitive to existing drugs. For example, Tirzepatide is not effective in improving the fatty liver-related disease when administered once a week.

[0091] In some embodiments, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg, or 200 ng / kg.

[0092] Another aspect of the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for treating or improving one or more of the following diseases:

[0093] 1) Diseases related to appetite;

[0094] 2) Insulin-related diseases;

[0095] 3) Diseases related to glycated hemoglobin;

[0096] 4) Diseases related to alanine aminotransferase;

[0097] 5) Diseases related to aspartate aminotransferase;

[0098] 6) Diseases related to triglycerides;

[0099] 7) Diseases related to total cholesterol

[0100] 8) Diseases related to high-density lipoprotein;

[0101] 9) Diseases related to low-density lipoprotein;

[0102] 10) Diseases related to alkaline phosphatase;

[0103] 11) Fatty liver; and,

[0104] 12) Diseases caused by leptin receptor deficiency.

[0105] Another aspect of the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the preparation of medicaments having two or more of the following functions;

[0106] 1) Suppresses appetite;

[0107] 2) Improves insulin sensitivity;

[0108] 3) Reduce glycated hemoglobin;

[0109] 4) Inhibits alanine aminotransferase;

[0110] 5) Inhibits aspartate aminotransferase;

[0111] 6) Lowers triglycerides;

[0112] 7) Lower total cholesterol;

[0113] 8) Lower high-density lipoprotein;

[0114] 9) Lowering LDL cholesterol; and

[0115] 10) Reduce alkaline phosphatase expression.

[0116] In some embodiments, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg, or 200 ng / kg.

[0117] Another aspect of the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating two or more of the following diseases;

[0118] 1) Diseases related to appetite;

[0119] 2) Insulin-related diseases;

[0120] 3) Diseases related to glycated hemoglobin;

[0121] 4) Diseases related to alanine aminotransferase;

[0122] 5) Diseases related to aspartate aminotransferase;

[0123] 6) Diseases related to triglycerides;

[0124] 7) Diseases related to total cholesterol;

[0125] 8) Diseases related to high-density lipoprotein;

[0126] 9) Diseases related to low-density lipoprotein;

[0127] 10) Diseases related to alkaline phosphatase;

[0128] 11) Fatty liver; and

[0129] 12) Diseases caused by leptin receptor deficiency.

[0130] In some embodiments, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg, or 200 ng / kg.

[0131] Another aspect of the present invention provides a method for treating or improving one or more of the following diseases, the method comprising administering an effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof to a subject in need;

[0132] 1) Diseases related to appetite;

[0133] 2) Insulin-related diseases;

[0134] 3) Diseases related to glycated hemoglobin;

[0135] 4) Diseases related to alanine aminotransferase;

[0136] 5) Diseases related to aspartate aminotransferase;

[0137] 6) Diseases related to triglycerides;

[0138] 7) Diseases related to total cholesterol

[0139] 8) Diseases related to high-density lipoprotein;

[0140] 9) Diseases related to low-density lipoprotein;

[0141] 10) Diseases related to alkaline phosphatase;

[0142] 11) Fatty liver; and,

[0143] 12) Diseases caused by leptin receptor deficiency.

[0144] In some implementations, the appetite-related disease is selected from hyperthyroidism.

[0145] In some implementations, the insulin-related disease is selected from at least one of the following: insulin resistance and insulin deficiency.

[0146] In some implementations, the disease associated with glycated hemoglobin is selected from at least one of the following: hypertension, diabetic nephropathy, and hypothyroidism.

[0147] In some embodiments, the alanine aminotransferase-related disease is selected from at least one of the following: viral hepatitis, alcoholic liver disease, fatty liver disease, and cirrhosis.

[0148] In some embodiments, the aspartate aminotransferase-related disease is selected from at least one of the following: steatohepatitis and drug-induced liver injury.

[0149] In some implementations, the triglyceride-related diseases are selected from at least one of the following: hyperlipidemia, atherosclerosis, coronary heart disease, and nephrotic syndrome.

[0150] In some implementations, the total cholesterol-related disease is selected from at least one of the following: hepatitis, atherosclerosis, and nephrotic syndrome.

[0151] In some implementations, the disease associated with high-density lipoprotein is selected from at least one of the following: chronic liver disease and primary biliary cholangitis.

[0152] In some implementations, the diseases associated with low-density lipoprotein are selected from at least one of the following: atherosclerosis and coronary heart disease.

[0153] In some implementations, the leptin receptor deficiency is leptin receptor knockout, such as in db / db mice.

[0154] As used in this article, “treatment” of a condition includes preventing or alleviating the condition, slowing the onset or progression of the condition, reducing the risk of developing the condition, preventing or delaying the development of symptoms associated with the condition, reducing or ending symptoms associated with the condition, producing complete or partial remission of the condition, curing the condition, or some combination thereof.

[0155] In some embodiments, the administration is carried out via a route selected from topical and / or subcutaneous administration (e.g., injection). The term "administration" means the delivery of one or more compounds or compositions to a subject, either non-enteric, transenteric, or topical. In one embodiment, the composition is administered topically. In another embodiment, the composition is administered systemically. Administration can be achieved to cells or tissue cultures or to a living organism (e.g., a human). Illustrative examples of non-enteric administration include, but are not limited to, intravenous, intramuscular, intra-articular, intrasheath, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. Illustrative examples of transenteric administration include, but are not limited to, oral, inhalation, intranasal, sublingual, and rectal administration. Illustrative examples of topical administration include, but are not limited to, percutaneous administration. In certain embodiments, the agent or composition is administered non-enterically, optionally by intravenous or oral administration to the subject.

[0156] In drug therapy, the "effective dose" refers to the dosage of a drug that produces the desired therapeutic effect. This dose is neither too low to produce a therapeutic effect, nor too high to cause adverse reactions or toxicity. The effective dose is the dose at which a drug achieves the optimal balance in the treatment of a disease, and is usually determined based on extensive clinical trials and scientific research.

[0157] The terms “subject,” “individual,” and “patient” are used interchangeably herein and refer to the animal to which treatment is provided, such as a human, comprising preventative treatment and suppression of disease states and secondary infections using a combination of drugs as described herein. As used herein, the term “subject” refers to both humans and non-human animals. The terms “non-human animal” and “non-human mammal” are used interchangeably herein and include all vertebrates, such as mammals like non-human primates (especially higher primates), sheep, dogs, rodents (e.g., mice or rats), guinea pigs, goats, pigs, cats, rabbits, cattle, horses, etc., and non-mammals like reptiles, amphibians, chickens, and turkeys.

[0158] In some implementations, the subject or individual is a human or non-human animal lacking the leptin receptor (LepR- / -), such as a db / db mouse.

[0159] In any of the methods according to the invention, and in one embodiment, the subject described herein is a human. In another embodiment, the subject is a non-human. In one embodiment, the subject is a vertebrate. In another embodiment, the subject is a mammal. In another embodiment, the subject is a primate, which in one embodiment is a non-human primate. In another embodiment, the subject is a rodent, which in one embodiment is a mouse and in another embodiment is a rat. In another embodiment, the subject is a canine, feline, bovine, equine, caprid, sheep, suidae, monkey, bear, fox, or wolf. In one embodiment, the subject is a chicken or a fish.

[0160] In one embodiment, the composition of the invention is administered in a therapeutically effective amount. In one embodiment, "therapeutically effective amount" is defined as the amount of a single agent or compound of the invention, or an agent or compound of the invention that effectively reduces appetite-related symptoms, improves insulin sensitivity, reduces triglycerides, total cholesterol, and improves fatty liver.

[0161] The present invention has found that the compounds of the present invention, or pharmaceutically acceptable salts thereof, exhibit good absorption and a long duration of action in treating the diseases of the present invention. Therefore, the amount of the compounds of the present invention, or pharmaceutically acceptable salts thereof, in a medicine for use in a subject can be at a very low dose or at a low frequency of administration (not limited thereto). Thus, the dose can be much lower than the dose or frequency of administration of weight-loss drugs known in the art (such as Tirzepatide). This results in the compounds of the present invention, or pharmaceutically acceptable salts thereof, having several beneficial effects, such as reduced potential side effects, reduced costs, reduced adverse reactions that may occur when used in combination with other drugs, and reduced drug dependence.

[0162] In some embodiments, the dosage (per kg body weight) is in the following ranges: 1, 3, 5, 10, 15, 30 nmol / kg. Preferably, it is 15 nmol / kg.

[0163] In some embodiments, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg, or 200 ng / kg.

[0164] In some implementations, the application may be administered once or repeatedly, with repeated application being preferred. Typically, application is dependent on need and may, for example, be provided on demand. In repeated applications, subsequent doses may be administered on the same and / or different days of the treatment schedule, wherein a single dose or more than a single dose may be administered on the same day. The application may be once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once every seven days, once every eight days, once every nine days, or once every ten days, and different frequencies may be combined. Application may last for one week or several weeks, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks, or more, or for one month or several months, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 months, or more.

[0165] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0166] The reagents and raw materials used in this invention are all commercially available.

[0167] The positive and progressive effects of this invention are as follows:

[0168] This invention first investigated the therapeutic effects of the compounds of this invention or their pharmaceutically acceptable salts on obesity. The compounds of this invention or their pharmaceutically acceptable salts can reduce food intake and body weight in obese mice, improve blood lipids, glucose tolerance, and insulin sensitivity, and reduce lipid accumulation in adipose tissue and liver.

[0169] Furthermore, the compounds of the present invention, or pharmaceutically acceptable salts thereof, exhibit stronger weight-loss efficacy compared to known weight-loss drugs in the art. The drugs have a longer duration of action and, at the same dosage, are more effective in suppressing appetite, improving insulin levels, lowering total cholesterol, and improving fatty liver disease. Attached Figure Description

[0170] Figure 1 shows the food intake of a mouse model induced by a high-fat diet within 24 hours after the first administration.

[0171] Figures 2-4 show the trend of percentage change in body weight during treatment with this compound and comparative examples Semaglutide and Tirzepatide at a dosing frequency of once daily (Qd, Figure 2), twice weekly (Bw, Figure 3), or once weekly (Qw, Figure 4).

[0172] Figure 5 shows the percentage change in body weight after 28 days of treatment with this compound and comparative examples Semaglutide and Tirzepatide at once-daily (Qd), twice-weekly (Bw), or once-weekly (Qw) dosing frequencies.

[0173] Figures 6-8 show the trends in food consumption during treatment with this compound and the comparative examples Semaglutide and Tirzepatide at once-daily (Qd, Figure 6), twice-weekly (Bw, Figure 7), or once-weekly (Qw, Figure 8) dosing frequencies.

[0174] Figures 9-11 show the trends in daily food intake in mice during treatment with this compound and comparative examples Semaglutide and Tirzepatide at once-daily (Qd, Figure 9), twice-weekly (Bw, Figure 10), or once-weekly (Qw, Figure 11) dosing frequencies.

[0175] Figure 12 shows the blood glucose statistics of mice after fasting for 16 hours after treatment with this compound and comparative examples Semaglutide and Tirzepatide at once-daily (Qd), twice-weekly (Bw), or once-weekly (Qw) frequencies for 28 days.

[0176] Figure 13 shows the statistical graph of glycated hemoglobin absorbance (OD value) after 28 days of treatment with this compound and comparative examples Semaglutide and Tirzepatide at a dosing frequency of once a day (Qd), twice a week (Bw), or once a week (Qw).

[0177] Figures 14-16 show the trends in glucose tolerance in mice after treatment with this compound and comparative examples Semaglutide and Tirzepatide for 28 days at a frequency of once daily (Qd, Figure 14), twice weekly (Bw, Figure 15), or once weekly (Qw, Figure 16).

[0178] Figure 17 shows the area under the curve of glucose tolerance in mice after treatment with this compound and comparative examples Semaglutide and Tirzepatide at once-daily (Qd), twice-weekly (Bw), or once-weekly (Qw) frequencies for 28 days.

[0179] Figures 18-20 show the trends in insulin sensitivity in mice after treatment with this compound and comparative examples Semaglutide and Tirzepatide for 28 days at a frequency of once daily (Qd, Figure 18), twice weekly (Bw, Figure 19), or once weekly (Qw, Figure 20).

[0180] Figure 21 shows the area under the curve of insulin sensitivity in mice after treatment with this compound and comparative examples Semaglutide and Tirzepatide at once-daily (Qd), twice-weekly (Bw), or once-weekly (Qw) frequencies for 28 days.

[0181] Figure 22 shows the statistical distribution of serum lipid levels in mice after treatment with this compound and comparative examples Semaglutide and Tirzepatide at once-daily (Qd), twice-weekly (Bw), or once-weekly (Qw) doses. (Two-way ANOVA; *p<0.05; **p<0.01 vs ND excipients; n=6-8. #p<0.05; ##p<0.01 vs HFD excipients; n=6-8)

[0182] Figure 23 shows the triglyceride content in mouse liver tissue after treatment with this compound and comparative examples Semaglutide and Tirzepatide for 28 days at a frequency of once a day (Qd), twice a week (Bw), or once a week (Qw).

[0183] Figure 24 shows the gross images (top) and relative weight (bottom) of mouse liver tissue after treatment with this compound and comparative examples Semaglutide and Tirzepatide at once-daily (Qd), twice-weekly (Bw), or once-weekly (Qw) dosing frequencies.

[0184] Figure 25 shows the gross images (top) and relative weight (bottom) of brown adipose tissue in mice after treatment with this compound and comparative examples Semaglutide and Tirzepatide at once-daily (Qd), twice-weekly (Bw), or once-weekly (Qw) dosing frequencies.

[0185] Figure 26 shows the gross image (top) and relative weight (bottom) of subcutaneous white adipose tissue in mice after treatment with this compound and comparative examples Semaglutide and Tirzepatide at once-daily (Qd), twice-weekly (Bw), or once-weekly (Qw) dosing frequencies.

[0186] Figure 27 shows the gross image (top) and relative weight (bottom) of white adipose tissue in mice after treatment with this compound and comparative examples Semaglutide and Tirzepatide at once-daily (Qd), twice-weekly (Bw), or once-weekly (Qw) dosing frequencies.

[0187] Figure 28 shows the food intake of the db / db mouse model within 24 hours after the first administration.

[0188] Figure 29 shows the percentage change in body weight after 28 days of treatment with this compound and comparative examples Semaglutide and Tirzepatide at once-daily (Qd), twice-weekly (Bw), or once-weekly (Qw) dosing frequencies.

[0189] Figures 30-32 show the trends in cumulative food consumption during treatment with this compound and comparative examples Semaglutide and Tirzepatide at dosing frequencies of once daily (Qd, Figure 30), twice weekly (Bw, Figure 31), or once weekly (Qw, Figure 32).

[0190] Figures 33-35 show the trends in daily food intake in mice during treatment with this compound and the comparative examples Semaglutide and Tirzepatide at once-daily (Qd, Figure 33), twice-weekly (Bw, Figure 34), or once-weekly (Qw, Figure 35) administration frequencies.

[0191] Figure 36 shows the blood glucose statistics of mice after fasting for 16 hours after treatment with this compound and comparative examples Semaglutide and Tirzepatide at once-daily (Qd), twice-weekly (Bw), or once-weekly (Qw) frequencies for 28 days.

[0192] Figure 37 shows a statistical graph of glycated hemoglobin absorbance (OD value) after 28 days of treatment with this compound and comparative examples Semaglutide and Tirzepatide at a dosing frequency of once a day (Qd), twice a week (Bw), or once a week (Qw).

[0193] Figures 38-40 show the trends in glucose tolerance in mice after treatment with this compound and comparative examples Semaglutide and Tirzepatide for 28 days at a frequency of once daily (Qd, Figure 38), twice weekly (Bw, Figure 39), or once weekly (Qw, Figure 40).

[0194] Figure 41 shows the area under the curve of glucose tolerance in mice after treatment with this compound and comparative examples Semaglutide and Tirzepatide at once-daily (Qd), twice-weekly (Bw), or once-weekly (Qw) frequencies for 28 days.

[0195] Figures 42-44 show the trends in insulin sensitivity in mice after treatment with this compound and comparative examples Semaglutide and Tirzepatide for 28 days at once-daily (Qd, Figure 42), twice-weekly (Bw, Figure 43), or once-weekly (Qw, Figure 44).

[0196] Figure 45 shows the area under the curve of insulin sensitivity in mice after treatment with this compound and comparative examples Semaglutide and Tirzepatide at once-daily (Qd), twice-weekly (Bw), or once-weekly (Qw) frequencies for 28 days.

[0197] Figure 46 shows the statistical distribution of serum lipid levels in mice after treatment with this compound and comparative examples Semaglutide and Tirzepatide at once-daily (Qd), twice-weekly (Bw), or once-weekly (Qw) doses. (Two-way ANOVA; *p<0.05; **p<0.01 vs dbdb WT excipient; n=6-8. #p<0.05; ##p<0.01 vs dbdb excipient; n=6-8). Detailed Implementation

[0198] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0199] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto:

[0200] In Examples 1-2, the mice used were 6-week-old wild-type C57BL / 6 mice purchased from Hunan Silex Company. The ambient temperature for housing the mice was 22℃. The mice had free access to standard normal feed or high-fat feed and sterile water. The daily light / dark cycle was 12 hours:12 hours (7:00 AM to 7:00 PM).

[0201] In Examples 3-4, the mice used were 6-week-old leptin receptor knockout mice (db / db) and their wild-type isotype (WT) mice, purchased from Jiangsu Jicui Pharmaceutical Co., Ltd. The baseline weight of the mice ranged from approximately 50-55g. The mice were housed at an ambient temperature of 22℃ and had free access to standard feed and sterile water. The daily light / dark ratio was 12 hours:12 hours.

[0202] The compound used in the examples was provided by Tonghua Dongbao Pharmaceutical Co., Ltd., and is described below as WX-001, which is designated as THDBHI20 in the examples.

[0203] Semaglutide was purchased from MedChemExpress (MCE), and Tirzepatide was synthesized by WuXi AppTec (batch number: ES18695-21-P1). All of the above reagents are in powder form. When using, prepare a 20mM trisodium citrate aqueous solution (pH 7.0±0.1) according to the required concentration, and prepare immediately before use. Trisodium citrate was purchased from Sinopharm Chemical Reagent Co., Ltd.

[0204] Example 1:

[0205] A diet-induced obesity mouse model was established by feeding mice a high-fat diet (60% kcal) for 20 weeks. The high-fat diet was purchased from Research Diets, Inc., USA. The average weight of the fed mice was approximately 50 g. Mice fed a normal diet (ND) were randomly divided into two groups. Mice fed a high-fat diet (HFD) were randomly divided into 10 groups, with the specific group arrangements and numbers as follows:

[0206] Group 1: ND mice + Vehicle (n=8), twice a week (Bw); (Extramorphic group)

[0207] Group 2: ND mice + this compound (THDBHI20) (n=8, Bw);

[0208] Group 3: HFD mice + Vehicle (n=8, Bw); (Body shaping group)

[0209] Group 4: HFD mice + this compound once a day (n=8, Qd);

[0210] Group 5: HFD mice + this compound twice a week (n=8, Bw);

[0211] Group 6: HFD mice + this compound once a week (n=8, Qw);

[0212] Group 7: HFD mice + Semaglutide once a day (n=8, Qd);

[0213] Group 8: HFD mice + Semaglutide twice a week (n=8, Bw);

[0214] Group 9: HFD mice + Semaglutide once a week (n=8, Qw);

[0215] Group 10: HFD mice + Tirzepatide once a day (n=8, Qd);

[0216] Group 11: HFD mice + Tirzepatide (tirzepatide) twice a week (n=8, Bw);

[0217] Group 12: HFD mice + Tirzepatide once a week (n=8, Qw).

[0218] This invention sets up three different dosing frequency gradients for the first time: once a day (Qd), twice a week (Bw), and once a week (Qw) to investigate the maintenance of the efficacy of the compound at different dosing intervals, and to compare whether the compound has significantly superior efficacy compared with the comparative examples Semaglutide and Tirzepatide at the same dosing interval.

[0219] The specific dosing regimen is shown in Table 1 below:

[0220] Table 1 Dosing Regimen

[0221] Mice were treated subcutaneously via the triangular region of their backs for four consecutive weeks. The injection volume was 10 μL / g. Administration time: 9:30-11:00 AM.

[0222] Before treatment, the weight of the mice was recorded, including mice on a normal diet and mice on a high-fat diet. Mice with significantly different weights were excluded. Blood was collected from the tail vein, and the initial 6-hour fasting blood glucose level was recorded. Blood glucose test strips were purchased from Sinocare Biosensors Co., Ltd. After treatment, the weight and food consumption of the mice were recorded daily. Fasting 6-hour blood glucose was recorded weekly. After four weeks of treatment, fasting blood glucose, glycated hemoglobin, and glucose tolerance were measured in the mice.

[0223] For the detection of glycated hemoglobin absorbance, whole blood from mice was collected, centrifuged, and the lower red blood cell pellet was collected. The pellet was washed 2-3 times with physiological saline, and then diluted with 1.5 times the volume of distilled water. Following the method of the Nanjing Jiancheng reagent kit (A056-1-1), the pellet was heated in an acidic environment to partially dehydrate the hexose, generating 5-hydroxymethylfurfural (5-HMF). 5-HMF reacts with TBA to produce a yellow color, and then quantification was performed colorimetrically at 443 nm.

[0224] In the glucose tolerance test, mice were pre-stimulated to reduce excitability and fasted for 16 hours beforehand. A 20% glucose solution was injected intraperitoneally at a volume of 10 μL / g. Blood glucose levels were recorded at 0, 15, 30, 60, 90, and 120 minutes. After all measurements were completed, the mice were returned to the arsenal and given water and food. D-glucose powder was purchased from Aladdin.

[0225] As shown in Figure 1, after 24 hours of treatment, this compound suppressed food intake by 89%, demonstrating a more significant appetite-suppressing effect compared to Tirzepatide (79.9%) and Semaglutide (78.35%). The results regarding daily food intake in mice showed a decrease in sensitivity to the inhibitory effect of this compound compared to the other two comparative drugs. Specifically, within 24 hours of the first administration, this compound suppressed food intake by 89%. With continuous administration in the Qd group, the inhibitory effect gradually decreased, reaching 31% on day 28, indicating reduced sensitivity in mice. In the Tirzepatide comparative group, the initial treatment reduced food intake by 80%, decreasing to 18.9% on day 28, indicating reduced sensitivity in mice. In the Qw group, after the final administration, the inhibitory effect of this compound on food intake in mice was 77%. In the Tirzepatide control group, the inhibition of food intake decreased by 70% after the last dose. These data indicate that continuous administration reduces the sensitivity of mice to this compound, but compared to the control group, this compound maintains a relatively high level of sensitivity.

[0226] As shown in Figures 2, 3, and 4, after treatment with this compound, the body weight decreased by 39% in the Qd group, 34% in the Bw group, and 28% in the Qw group. In comparison, the Tirzepatide group showed a 36% reduction in body weight in the Qd group, a 26% reduction in the Bw group, and a 15% reduction in the Qw group. At the same treatment frequency, the weight-loss effect of this compound was significantly higher than that of Tirzepatide, especially with the Qw dosing frequency.

[0227] Changes in mouse body weight under different dosing cycles. This compound was found to inhibit body weight in obese mice in a frequency-dependent manner.

[0228] Figures 2-4 and 5 show that this compound reduced the weight of mice in a high-fat diet-induced obesity model to varying degrees after different treatment cycles. Under the same treatment cycle, the weight-loss effect of this compound was more significant than that of the other two drugs, especially at the Qw dosing frequency.

[0229] Figures 6, 7, 8, 9, 10, and 11 show that this compound exhibits a more significant inhibitory effect at Qd and Qw dosing cycles. The inhibitory effect of this compound on food intake in mice shows a decrease in sensitivity. This is reflected in the Qd dosing frequency, with the inhibitory effect being stronger in the early stages than in the later stages. This decrease in sensitivity is also observed in other drugs, and the decrease in drug sensitivity of this compound is slower than that of the other two drugs. During the dosing cycle, the accumulation of food intake in mice was inhibited in a dosing frequency-dependent manner. The inhibitory effect of this compound on food intake at Qd and Qw dosing frequencies was significantly higher than that of the control group, Tirzepatide.

[0230] Figures 12 and 13 show that under different treatment cycles, this compound improved fasting blood glucose and glycated hemoglobin in HFD mice. The effect of once a week on improving blood glucose and glycated blood glucose in HFD mice was more significant.

[0231] Figures 14, 15, 16, and 17 show that the compound had a similar effect on improving glucose tolerance in HFD mice under different treatment cycles, with no frequency-dependent gradient, while the Tirzepatide group showed a significant frequency-dependent gradient. Insulin sensitivity in mice was assessed after four weeks of treatment and one week of rest. Mice were fasted for 6 hours prior to testing. 0.75U of insulin was administered intraperitoneally at a volume of 10 μl / g. Blood glucose concentrations were recorded at 0, 15, 30, 60, 90, and 120 minutes. After all measurements were completed, the mice were returned to their original environment and given water and food. Insulin was purchased from Novo Nordisk.

[0232] Figures 18, 19, 21 and 22 show that the compound's effect on improving insulin sensitivity in HFD mice under different treatment cycles is cycle-dependent, and its effect is more significant than that of other drugs under the same dosing cycle.

[0233] Example 2:

[0234] After completing the above experiments, the mice were euthanized and samples were taken for analysis. The experimental mice were handled, and one eyeball was removed using curved forceps to collect blood. Three types of adipose tissue and the liver were collected from the mice for later use. The mouse blood samples were incubated at room temperature for 2 hours, centrifuged at 3000 rpm for 5 minutes, and the supernatant was used to analyze the levels of triglycerides and total cholesterol in the serum.

[0235] Adipose tissue and liver tissue samples requiring staining were dissected, weighed, and appropriate-sized tissue blocks were placed in at least 10 times their volume of 4% paraformaldehyde tissue fixative. After paraffin embedding and hematoxylin-eosin staining, the three types of adipose tissue were stained with hematoxylin and eosin (HE). Liver tissue was frozen sectioned and stained with Oil Red O.

[0236] Approximately 80 mg of subcutaneous adipose tissue and liver were weighed, ultrasonically ground, and dissolved in anhydrous ethanol. The triglyceride content in the tissue was then measured using a triglyceride detection kit from Nanjing Jiancheng Company.

[0237] The study measured liver function (ALT, alanine aminotransferase, AST, aspartate aminotransferase) and blood lipids (TG, total cholesterol, HDL, and LDL) in mouse serum.

[0238] Figure 22 shows that this compound can improve liver function, creatinine, triglycerides, and total cholesterol in obese mice; the treatment with the three drugs has a certain improving effect on liver function indicators in obese mice; under the same treatment cycle, this compound shows a significant advantage in terms of Qd dosing frequency; regarding blood lipids, this compound has a good effect in reducing serum triglycerides, but its inhibitory effect on cholesterol is not significant. All three drugs have a significant effect on improving low-density lipoprotein.

[0239] Serum triglyceride (TG), total cholesterol (CHO), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels are indicators of the body's lipid metabolism status. This compound significantly inhibited blood lipid levels in obese mice. Compared with the comparative drug Tirzepatide, this compound significantly inhibited TG and CHO at a once-weekly dosing frequency. At a once-weekly dosing frequency, this compound, semaglutide, and Tirzepatide had no significant effect on LDL levels. The difference in LDL-improving effects between this compound and Tirzepatide was not significant.

[0240] A high-fat diet leads to fatty liver in mice, damaging hepatocytes and increasing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. This compound inhibited ALT levels at three different dosing frequencies. At a once-weekly dosing frequency, its inhibitory effect on ALT was significantly superior to semaglutide and tirzepatide. The inhibitory effects of this compound and tirzepatide on AST were similar. This compound effectively reduced ALP (alkaline phosphatase) levels. Furthermore, this compound and tirzepatide significantly improved liver function indicators compared to semaglutide. Figure 23 shows that this compound had a superior inhibitory effect on hepatic lipid accumulation (TG) compared to other drugs.

[0241] Figures 24, 25, 26, and 27 show that this compound significantly reduced the weight of the three types of adipose tissue and the liver, and was superior to other drugs at the same dosing frequency, especially in the once-weekly group. Treatment with this compound significantly inhibited lipid deposition in the liver of mice, and significantly reduced the weight of the three types of adipose tissue.

[0242] Example 3:

[0243] WT mice were randomly divided into two groups. db / db mice were randomly divided into 10 groups, with the specific group assignments and numbers as follows:

[0244] Group 1: WT mice + Vehicle (n=8), twice a week (Bw);

[0245] Group 2: WT mice + this compound (THDBHI20) (n=8, Bw);

[0246] Group 3: db / db mice + Vehicle (n=8, Bw);

[0247] Group 4: db / db mice + this compound once a day (n=8, Qd);

[0248] Group 5: db / db mice + this compound twice a week (n=8, Bw);

[0249] Group 6: db / db mice + this compound once a week (n=8, Qw);

[0250] Group 7: db / db mice + Semaglutide once a day (n=8, Qd);

[0251] Group 8: db / db mice + Semaglutide twice a week (n=8, Bw);

[0252] Group 9: db / db mice + Semaglutide once a week (n=8, Qw);

[0253] Group 10: db / db mice + Tirzepatide once a day (n=8, Qd);

[0254] Group 11: db / db mice + Tirzepatide twice a week (n=8, Bw);

[0255] Group 12: db / db mice + Tirzepatide once a week (n=8, Qw).

[0256] Three different dosing frequency gradients were set up: once a day (Qd), twice a week (Bw), and once a week (Qw) to investigate the maintenance of the compound's efficacy at different dosing intervals, and to compare whether the compound had significantly superior efficacy compared to the comparative examples Semaglutide and Tirzepatide at the same dosing interval.

[0257] The dosing schedule was carried out in accordance with the dosing schedule in Table 1 of Example 1.

[0258] The prepared injection solution was administered subcutaneously to mice via the triangular region of their backs for four consecutive weeks. The injection volume was 10 μl / g, and the concentration was 15 nmol / kg. Administration time: 9:30 AM – 11:00 AM.

[0259] Before administration, the initial weight and food intake of the mice were recorded. Mice with significantly different weights were excluded. Blood was collected from the tail vein, and the initial 8-hour fasting blood glucose level was recorded. Blood glucose test strips were purchased from Sinocare Biosensors Co., Ltd. After administration, the weight and food consumption of the mice were recorded daily. Fasting 8-hour blood glucose levels were recorded weekly.

[0260] Four weeks after treatment, fasting blood glucose and glucose tolerance in mice were measured. Specific procedures: All mice were pre-stimulated 5-7 days in advance (by repeatedly lifting and lowering the mice by their tails, stroking their tails, and handling them three times) to acclimatize them to the experimental procedure and reduce their excitement on the day of the experiment. The mice were fasted at 5:30 PM the day before the experiment, and new cages and feed racks were used. Normal water intake was ensured during the fasting period. The experiment began at 9:00 AM the next day (16 hours of fasting). Recording forms, timers, blood glucose reagents, and all necessary experimental equipment were prepared. On the day of the experiment, a 20% glucose injection solution was prepared using physiological saline. The weight of each mouse was recorded. A small circular incision was made at the tail of each mouse, and the tail was stroked several times to allow blood to flow to the tail tip. Blood was immediately collected using blood glucose test strips, and the initial blood glucose value was read using a blood glucose meter. (This is the baseline blood glucose value at t=0). Record and calculate the required amount of glucose solution (10 μL / g) for each mouse, and pre-draw the corresponding amount of glucose solution using a 1 ml syringe. Place the experimental mice individually in their cages and allow them to acclimatize for 5–10 minutes. Once everything is ready, inject glucose intraperitoneally, and record the injection time for each mouse. Blood samples are collected again from the tail incision site at 15, 30, 60, 90, and 120 minutes after injection. Measure and record the blood glucose concentration. After all measurements are completed, return the mice to their original environment and provide water and food. D-glucose powder was purchased from Aladdin.

[0261] After one week of continuous drug administration and rest, insulin sensitivity in mice was assessed. Specific procedures: All mice were pre-stimulated 5-7 days in advance to acclimatize to all experimental procedures and reduce excitability during the experiment. On the day of the experiment, mice were fasted starting at 8:00 AM, and new cages and feed racks were used. Normal water intake was ensured during the fasting period. The experiment began at 2:00 PM (fasting for 4-6 hours). Recording forms, timers, blood glucose reagents, and all necessary experimental equipment were prepared. Insulin solution was prepared (0.75U, 10ml physiological saline + 7.5μL Humulin; after complete dissolution, it was filtered and sterilized using a 0.22μm filter). On the day of the experiment, the weight of each mouse was recorded, and the required amount of insulin solution per mouse was calculated (the injection volume of insulin solution is 10μL / g). The corresponding amount of insulin solution was pre-drawn using a 1ml syringe. The experimental mice were placed individually in their cages for 5-10 minutes to acclimatize. Make a small circular incision at the tail of each mouse with scissors. Stroking the tail several times allows blood to flow towards the tip. Immediately collect the blood with a blood glucose test strip and read the initial blood glucose level using a blood glucose meter (this is the baseline blood glucose level at t=0). Once everything is ready, inject insulin solution intraperitoneally and record the injection time for each mouse. Collect blood again from the tail incision at 15, 30, 60, 90, and 120 minutes after injection. Measure and record the blood glucose concentration. After all measurements are completed, return the mice to their original location and provide water and food. Insulin was purchased from Novo Nordisk.

[0262] In the glucose tolerance test, mice were pre-stimulated to reduce excitability and fasted for 16 hours beforehand. A 20% glucose solution was injected intraperitoneally at a volume of 10 μl / g. Blood glucose levels were recorded at 0, 15, 30, 60, 90, and 120 minutes. After all measurements were completed, the mice were returned to the arsenal and given water and food. D-glucose powder was purchased from Aladdin.

[0263] As shown in Figure 28, after 24 hours of treatment, this compound was able to suppress food intake by 89%, which is a more significant appetite suppressant compared to Tirzepatide (79.9%) and Semaglutide (78.35%).

[0264] As shown in Figure 29, the compound did not reduce the weight of mice in the db / db diabetes model after different treatment cycles.

[0265] Figures 30, 31, 32, 33, 34, and 35 show that this compound significantly inhibits food intake in mice under Qd, Bw, and Qw dosing cycles. The inhibitory effect of this compound on food intake in mice exhibits decreased sensitivity. This is reflected in the Qd dosing frequency, with the inhibitory effect being stronger in the early stages than in the later stages. Such decreased sensitivity is also observed in other drugs, and the decrease in drug sensitivity of this compound is slower than that of the other two drugs.

[0266] Figures 36 and 37 show that, under different treatment cycles, this compound improved fasting blood glucose and glycated hemoglobin in db / db mice. At frequencies of twice a week and once a week, the improvement effect on blood glucose and glycated blood glucose in db / db mice was more significant than that of the other two comparative drugs.

[0267] Figures 38, 39, 40, 41, 42, 43, 44, and 45 show that the compound had a similar effect on improving glucose tolerance in db / db mice under different treatment cycles. However, the compound's effect on improving insulin sensitivity in db / db mice under different treatment cycles showed a certain cycle dependence, and its effect was more significant than that of other drugs under the same dosing cycle.

[0268] Example 4:

[0269] After completing the above experiments, the mice were euthanized and samples were taken for analysis. The experimental mice were handled, and one eyeball was removed using curved forceps to collect blood. Liver tissue was also collected for later use. The mouse blood samples were incubated at room temperature for 2 hours, then centrifuged at 3000 rpm for 5 minutes. The supernatant was used to analyze the levels of triglycerides and total cholesterol in the serum. The lower red blood cell precipitate was used to detect the level of glycated hemoglobin.

[0270] Approximately 80 mg of subcutaneous adipose tissue and liver were weighed, ultrasonically ground, and dissolved in anhydrous ethanol. The triglyceride content in the tissue was then measured using a triglyceride detection kit from Nanjing Jiancheng Company.

[0271] For the detection of glycated hemoglobin absorbance, whole blood from mice was collected, centrifuged, and the lower red blood cell pellet was collected. The pellet was washed 2-3 times with physiological saline, and then diluted with 1.5 times the volume of distilled water. Following the method of the Nanjing Jiancheng reagent kit (A056-1-1), the pellet was heated in an acidic environment to partially dehydrate the hexose, generating 5-hydroxymethylfurfural (5-HMF). 5-HMF reacts with TBA to produce a yellow color, and then quantification was performed colorimetrically at 443 nm.

[0272] The study measured liver function (ALT, AST), kidney function (CREA, creatinine), and blood lipids (TG, CHO, HDL, LDL) in mouse serum.

[0273] Figure 46 shows that this compound can improve liver function, creatinine, and total cholesterol in db / db and WT mice; treatment with the three drugs has a certain improving effect on liver function in db / db mice; under the same cycle treatment, this compound shows a significant advantage in Qd / Qw treatment; regarding blood lipids, this compound has a good effect in reducing serum triglycerides, but its inhibitory effect on cholesterol is not obvious. All three drugs have a significant effect on improving low-density lipoprotein.

[0274] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. The use of compounds of the following formula or pharmaceutically acceptable salts thereof in the preparation of medicaments having functions selected from: 1) Lowering triglycerides; 2) To treat or prevent diseases related to triglycerides; 3) Lower total cholesterol; 4) To treat or prevent diseases related to total cholesterol; 5) Lowering high-density lipoprotein; 6) To treat or prevent diseases associated with high-density lipoprotein; 7) Lower LDL cholesterol; 8) To treat or prevent diseases associated with low-density lipoprotein; 9) Reduce alkaline phosphatase expression; and, 10) Reduce liver fat; The compound or a pharmaceutically acceptable salt thereof is as follows: SEQ ID NO:1: YAibEGT FTSDY SIAibLD KK 1 AZ0K0 Z1FZ2E0W LZ3AGGPSSGAPPPS0; SEQ ID NO:2:YAibEGT FTSDY SIAibLD KE0AQK0 AFVK 1 W LIAGGPSSGA PPPS0; SEQ ID NO:3:YAibEGT FTSDY SIE0LD KK0AQK 1 AFVQW LIAGGPSSGA PPPS0; SEQ ID NO:4:YAibEGT FTSDY SIE0LD K0IAQK 1 AFVQW LIAGGPSSGA PPPS0 in, The structure of Aib is S0 is selected from Z0 is selected from glutamine (Q) and asparagine (N); Z1 is selected from alanine (A) and glutamic acid (E); Z2 is selected from valine (V) and isoleucine (I); Z3 is selected from isoleucine (I) and leucine (L); E0 and K0 indicate that the carboxyl group on the glutamic acid side chain and the amino group on the lysine side chain together form a lactam. In this case, the structure of K0Z1FZ2E0 is... The structure of E0AQK0 is The structure of E0LDKK0 is The structure of E0LDK0 is as follows: K 1 This indicates that the amino group on the lysine side chain is linked to -X-X1-X2, and its structure is: X is selected from R1 and R2 are independently selected from H and CH3, respectively; X1 is selected from X2 is selected from m, n, and p are independently selected from 2 and 3, respectively; s is selected from 2 and 3; q is selected from 15, 16, 17, 18, and 19; Preferably, the compound is selected from: More preferably, the drug is administered once every 1-30 days, for example once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month; and / or, The dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg or 200 ng / kg.

2. The application as described in claim 1, characterized in that, 1) The triglyceride-related diseases mentioned are selected from at least one of the following: hyperlipidemia, atherosclerosis, coronary heart disease, and nephrotic syndrome; 2) The diseases associated with total cholesterol are selected from at least one of the following: atherosclerosis and nephrotic syndrome; 3) The diseases associated with high-density lipoprotein are selected from: primary biliary cholangitis; or, 4) The diseases associated with low-density lipoprotein are selected from at least one of the following: atherosclerosis and coronary heart disease.

3. The application as described in claim 1 or 2, characterized in that, 1) The triglyceride-related diseases or patients therein are suitable for a dosing frequency of once every 1 to 30 days, such as once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month; 2) For the aforementioned diseases related to total cholesterol or for patients who are suitable for a dosing frequency of once every 1 to 30 days, such as once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month; or, 3) For patients with the aforementioned high-density lipoprotein-related diseases, a dosing frequency of once every 1 to 30 days is appropriate, such as once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month.

4. The use of the compound as defined in claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a total cholesterol inhibitor, a high-density lipoprotein inhibitor, or a low-density lipoprotein inhibitor; Preferably, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg or 200 ng / kg.

5. The use of the compound as defined in claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament having two or more of the following functions; 1) Suppresses appetite; 2) Improves insulin sensitivity; 3) Reduce glycated hemoglobin; 4) Inhibits alanine aminotransferase; 5) Inhibits aspartate aminotransferase; 6) Lowers triglycerides; 7) Lower total cholesterol; 8) Lower high-density lipoprotein; 9) Lowering LDL cholesterol; and, 10) Reduce alkaline phosphatase expression; Preferably, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg or 200 ng / kg.

6. The use of the compound as defined in claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating two or more of the following diseases; 1) Diseases related to appetite; 2) Insulin-related diseases; 3) Diseases related to glycated hemoglobin; 4) Diseases related to alanine aminotransferase; 5) Diseases related to aspartate aminotransferase; 6) Diseases related to triglycerides; 7) Diseases related to total cholesterol; 8) Diseases related to high-density lipoprotein; 9) Diseases related to low-density lipoprotein; 10) Diseases related to alkaline phosphatase; 11) Fatty liver; and, 12) Diseases caused by leptin receptor deficiency; Preferably, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg or 200 ng / kg.

7. A method for treating or improving two or more of the following diseases, comprising administering to a subject in need an effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof; said diseases being selected from: 1) Diseases related to appetite; 2) Insulin-related diseases; 3) Diseases related to glycated hemoglobin; 4) Diseases related to alanine aminotransferase; 5) Diseases related to aspartate aminotransferase; 6) Diseases related to triglycerides; 7) Diseases related to total cholesterol; 8) Diseases related to high-density lipoprotein; 9) Diseases related to low-density lipoprotein; 10) Diseases related to alkaline phosphatase; 11) Fatty liver; and, 12) Diseases caused by leptin receptor deficiency; Preferably, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg / kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng / kg, 1 ng / kg, 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, 100 ng / kg, 110 ng / kg, 120 ng / kg, 130 ng / kg, 140 ng / kg, 150 ng / kg, 160 ng / kg, 170 ng / kg, 180 ng / kg, 190 ng / kg or 200 ng / kg.

8. The method as described in claim 7, characterized in that, The method satisfies one or more of the following: 1) The diseases related to appetite mentioned are selected from: hyperthyroidism; 2) The insulin-related diseases are selected from at least one of the following: insulin resistance and insulin deficiency; 3) The diseases associated with glycated hemoglobin are selected from at least one of the following: hypertension, diabetic nephropathy, and hypothyroidism; 4) The diseases associated with alanine aminotransferase are selected from at least one of the following: viral hepatitis, alcoholic liver disease, fatty liver disease, and cirrhosis; 5) The diseases associated with aspartate aminotransferase are selected from at least one of the following: fatty liver disease and drug-induced liver injury; 6) The triglyceride-related diseases mentioned are selected from at least one of the following: hyperlipidemia, atherosclerosis, coronary heart disease, and nephrotic syndrome; 7) The diseases associated with total cholesterol are selected from at least one of the following: hepatitis, atherosclerosis, and nephrotic syndrome; 8) The diseases associated with high-density lipoprotein are selected from at least one of the following: chronic liver disease and primary biliary cholangitis; 9) The diseases associated with low-density lipoprotein are selected from at least one of the following: atherosclerosis and coronary heart disease; and, 10) The leptin receptor deficiency is leptin receptor knockout.

9. The method as described in claim 7 or 8, characterized in that, The method satisfies one or more of the following: 1) The application is performed via a route selected from topical and / or subcutaneous application; 2) The dosage is 1-30 nmol / kg, for example 1, 3, 5, 10, 15, 30 nmol / kg, preferably 15 nmol / kg; 3) The application can be a single application or repeated application, preferably repeated application; 4) The application is performed once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once every seven days, once every eight days, once every nine days, or once every ten days; and, 5) The application lasts from one week to several months.

10. The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, used to treat or improve two or more of the following conditions: 1) Diseases related to appetite; 2) Insulin-related diseases; 3) Diseases related to glycated hemoglobin; 4) Diseases related to alanine aminotransferase; 5) Diseases related to aspartate aminotransferase; 6) Diseases related to triglycerides; 7) Diseases related to total cholesterol; 8) Diseases related to high-density lipoprotein; 9) Diseases related to low-density lipoprotein; 10) Diseases related to alkaline phosphatase; 11) Fatty liver; and, 12) Diseases caused by leptin receptor deficiency.

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