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

Abstract

Provided is the use of a compound or a pharmaceutically acceptable salt thereof in the treatment of glucose metabolic diseases. The compound or pharmaceutically acceptable salt thereof can significantly lower the blood glucose level and improve the metabolic phenotype of diseases associated with the glucose metabolism, and can specifically reduce the food intake of mice and improve their blood glucose and glycated hemoglobin levels, glucose tolerance, and insulin sensitivity.

Description

The use of a compound or a pharmaceutically acceptable salt thereof in the treatment of metabolic disorders of glucose metabolism

[0001] This application claims priority to Chinese patent application 2024115501957, 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 glucose metabolism disorders. Background Technology

[0003] Glucose metabolism disorders encompass a variety of diseases, with diabetes being the most common type. Diabetes can be classified into several types: type 1 diabetes, type 2 diabetes, mixed diabetes, other specific types of diabetes, unclassified diabetes, and gestational diabetes. Besides these common types of diabetes, there are also some rare diseases associated with abnormal glucose metabolism. These rare diseases may present with clinical symptoms overlapping with common diseases, making them prone to misdiagnosis. For example, glycogen storage disease, autoimmune insulin receptor disease, and congenital hyperinsulinemia-hypoglycemia are all rare glucose metabolism disorders. These diseases not only affect a patient's physical health but can also significantly impact their quality of life. Therefore, early diagnosis and treatment of glucose metabolism disorders are crucial.

[0004] Type 1 diabetes, a type of glucose metabolism disorder, is primarily caused by the destruction of pancreatic β-cells due to an autoimmune response, leading to insufficient insulin secretion. Type 2 diabetes is usually associated with insulin resistance and relative insulin deficiency, and is often closely related to lifestyle factors such as obesity, lack of physical activity, and poor dietary habits. Long-term hyperglycemia can lead to various complications, including retinopathy, diabetic nephropathy, diabetic neuropathy, and cardiovascular disease. These complications significantly increase the disease burden and mortality risk in patients with diabetes. Diabetes management involves comprehensive lifestyle interventions, drug therapy, and blood glucose monitoring. Drug therapy includes oral hypoglycemic agents (such as metformin and sulfonylureas), injectable insulin, and recently developed sodium-glucose cotransporter 2 (SGLT2) inhibitors.

[0005] Tirzepatide (Mounjaro, brand name Mufengda, once a week), a diabetes treatment drug developed by Eli Lilly and Company, has been approved for marketing to improve glycemic control in adults with type 2 diabetes (T2DM). Summary of the Invention

[0006] To address the issue of frequent injections required for medications treating diabetes in existing technologies, this invention provides the application of a compound or a pharmaceutically acceptable salt thereof in the treatment of diabetes. Compared to known diabetes medications in the art, the compound or its pharmaceutically acceptable salt of this invention has a longer duration of action, which helps reduce the frequency of administration and improve patient adherence.

[0007] This invention provides, in one aspect, the use of compounds of the following formula or pharmaceutically acceptable salts thereof in the preparation of food or medicines for treating appetite-related diseases;

[0008] SEQ ID NO:1:YAibEGT FTSDY SIAibLD KK 1 AZ0K0 Z1FZ2E0W LZ3AGGPSSGA PPPS0;

[0009] SEQ ID NO:2:YAibEGT FTSDY SIAibLD KE0AQK0 AFVK 1 W LIAGG PSSGA PPPS0;

[0010] SEQ ID NO:3:YAibEGT FTSDY SIE0LD KK0AQK 1 AFVQW LIAGG PSSGA PPPS0;

[0011] SEQ ID NO:4:YAibEGT FTSDY SIE0LD K0IAQK 1 AFVQW LIAGG PSSGA PPPS0;

[0012] in,

[0013] The structure of Aib is

[0014] S0 is selected from Z0 is selected from glutamine (Q) and asparagine (N);

[0015] Z1 is selected from alanine (A) and glutamic acid (E);

[0016] Z2 is selected from valine (V) and isoleucine (I);

[0017] Z3 is selected from isoleucine (I) and leucine (L);

[0018] 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

[0019] K 1 This indicates that the amino group on the lysine side chain is linked to -X-X1-X2, and its structure is:

[0020] X is selected from

[0021] R1 and R2 are independently selected from H and CH3, respectively;

[0022] X1 is selected from

[0023] X2 is selected from

[0024] m, n, and p are independently selected from 2 and 3, respectively;

[0025] s is selected from 2 and 3;

[0026] q is selected from 15, 16, 17, 18 and 19.

[0027] In some embodiments, the compound is selected from:

[0028] The compound used in the specific embodiments is WX-001, which is designated THDBHI20 in the embodiments.

[0029] In some implementations, the appetite is related to glucose metabolism.

[0030] In some implementations, the appetite-related illness is caused by increased appetite.

[0031] In some implementations, the appetite-related disease is selected from hyperthyroidism.

[0032] In some implementations, the appetite-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, or once every seven days.

[0033] In some implementations, the drug can be used to suppress appetite.

[0034] For example, some hypoglycemic agents may increase heart rate, and caution may be needed when using them in patients with heart rate problems. Patients with severe gastrointestinal disorders, such as inflammatory bowel disease or gastroparesis, should also use these drugs with caution, as they may worsen gastrointestinal discomfort due to their ability to delay gastric emptying. Low-frequency dosing is particularly important for patients with gastrointestinal disorders or heart rate problems who also suffer from appetite-related disorders. The compound described in this application exhibits a more sustained and significant efficacy compared to existing similar products, such as Tirzepatide, under low-frequency dosing conditions. This means that the compound can maintain a stable therapeutic effect while reducing the frequency of dosing, providing patients with a more convenient and effective treatment option.

[0035] The reasons why high-frequency medication is not suitable may be due to the following:

[0036] Drug side effects and interactions: Long-term use of certain drugs may lead to side effects. For example, antibiotics may disrupt the gut microbiota and affect immunity; sedatives and hypnotics may affect cognitive function and cause dependence; antihistamines may affect the normal function of the immune system.

[0037] Damage to the immune system: Long-term use of certain medications, such as glucocorticoid anti-inflammatory drugs and antibacterial drugs, may damage the immune system and reduce the body's resistance to disease.

[0038] Drug dependence and resistance: Long-term use of certain drugs may lead to dependence on these drugs, and bacteria may develop resistance, reducing the effectiveness of the drugs.

[0039] Risks of polypharmacy: Because patients may have multiple diseases, they may need to use multiple medications at the same time, which increases the risk of adverse drug reactions, reduces quality of life, and may increase medical costs.

[0040] In some implementations, the appetite-related disease is resistant to or not sensitive to existing drugs; for example, Tirzepatide is not effective in improving the appetite-related disease when administered once a week.

[0041] For example, with a dosing frequency of once every seven days, the inhibition of food intake by this compound reached 89% within 24 hours after the first treatment in mice, compared to 80% for Tirzepatide. However, within the treatment cycle, the inhibition of food intake within 24 hours after the last (fourth) dose was 85% for this compound and only 70% for Tirzepatide.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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 suppressing appetite related to glucose metabolism.

[0046] 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, or once every seven days.

[0047] This invention uses db / db mice lacking the leptin receptor (LepR- / -) as a type 2 diabetes model. The effects of different treatment cycles on food intake accumulation and body weight were examined. It was found that this compound inhibits food intake accumulation in mice in a concentration-dependent manner. After treatment with this compound, food intake in mice was inhibited by 89%, a significantly higher inhibitory effect than that of semaglutide and tirzepatide. However, this compound had no significant effect on the body weight of db / db mice.

[0048] 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.

[0049] 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 insulin-related diseases.

[0050] In some implementations, the insulin-related disease is selected from at least one of the following: insulin resistance and insulin deficiency.

[0051] In some implementations, the insulin-related disease or the patient is suited to a dosing frequency of once every 1 to 30 days, such as once a day, once every two days, once every three days, or once every seven days.

[0052] Frequent insulin use may lead to side effects such as hypoglycemia, weight gain, and fat atrophy or hyperplasia at the injection site. Especially for patients with large fluctuations in blood sugar, frequent insulin use may increase the risk of hypoglycemia, affecting their quality of life and treatment adherence.

[0053] In some implementations, the insulin-related disease is resistant to or has low sensitivity to existing drugs; for example, Tirzepatide, administered once weekly, is not effective in improving insulin-related diseases. To address this, some Tirzepatide implementations include a dose escalation period to maintain efficacy. However, the most frequently reported mild to moderate gastrointestinal adverse events during Tirzepatide treatment occur primarily during the dose escalation period.

[0054] 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.

[0055] 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 improving insulin sensitivity.

[0056] 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, or once every seven days.

[0057] 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.

[0058] 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 glycated hemoglobin.

[0059] In some implementations, the disease associated with glycated hemoglobin is selected from at least one of the following: hypertension, diabetic nephropathy, and hypothyroidism.

[0060] In some implementations, the disease associated with glycated hemoglobin 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, or once every seven days.

[0061] In some implementations, the glycated hemoglobin-related disease is resistant to or not sensitive to existing drugs. For example, Tirzepatide is not effective in improving glycated hemoglobin-related disease when administered once a week.

[0062] 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.

[0063] 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 glycated hemoglobin.

[0064] 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, or once every seven days.

[0065] 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.

[0066] Another aspect of the present invention provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of glycated hemoglobin inhibitors.

[0067] In some implementations, the hemoglobin inhibitor is used for non-therapeutic purposes.

[0068] 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.

[0069] Another aspect of the present invention provides the use of the said compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for lowering blood sugar.

[0070] 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, or once every seven days.

[0071] To investigate the effect of this compound on blood glucose control in mice, we measured fasting blood glucose and glycated hemoglobin (HbA1c) levels weekly. The results showed that this compound significantly reduced fasting blood glucose and HbA1c in db / db mice, and improved glucose tolerance and insulin sensitivity.

[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 said compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving glucose tolerance.

[0074] 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, or once every seven days.

[0075] 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.

[0076] Another aspect of the present invention provides the use of the said compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting alanine aminotransferase expression.

[0077] 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, or once every seven days.

[0078] 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.

[0079] Another aspect of the present invention provides the use of the said compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases related to alanine aminotransferase.

[0080] 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.

[0081] In some implementations, the alanine aminotransferase-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, or once every seven days.

[0082] 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.

[0083] Another aspect of the present invention provides the use of the said compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting the expression of aspartate aminotransferase.

[0084] 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, or once every seven days.

[0085] 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.

[0086] 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 treating diseases related to aspartate aminotransferase.

[0087] In some embodiments, the aspartate aminotransferase-related disease is selected from at least one of the following: steatohepatitis and drug-induced liver injury.

[0088] In some implementations, the disease associated with aspartate aminotransferase 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, or once every seven days.

[0089] 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.

[0090] 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:

[0091] 1) Diseases related to appetite;

[0092] 2) Insulin-related diseases;

[0093] 3) Diseases related to glycated hemoglobin;

[0094] 4) Diseases related to alanine aminotransferase;

[0095] 5) Diseases related to aspartate aminotransferase;

[0096] 6) Diseases related to triglycerides;

[0097] 7) Diseases related to total cholesterol

[0098] 8) Diseases related to high-density lipoprotein;

[0099] 9) Diseases related to low-density lipoprotein;

[0100] 10) Diseases related to alkaline phosphatase;

[0101] 11) Fatty liver; and,

[0102] 12) Diseases caused by leptin receptor deficiency.

[0103] 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;

[0104] 1) Suppresses appetite;

[0105] 2) Improves insulin sensitivity;

[0106] 3) Reduce glycated hemoglobin;

[0107] 4) Inhibits alanine aminotransferase expression;

[0108] 5) Inhibits the expression of aspartate aminotransferase;

[0109] 6) Lowers triglycerides;

[0110] 7) Lower total cholesterol;

[0111] 8) Lowering high-density lipoprotein;

[0112] 9) Lowering LDL cholesterol; and,

[0113] 10) Reduce alkaline phosphatase expression.

[0114] 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.

[0115] 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;

[0116] 1) Diseases related to appetite;

[0117] 2) Insulin-related diseases;

[0118] 3) Diseases related to glycated hemoglobin;

[0119] 4) Diseases related to alanine aminotransferase;

[0120] 5) Diseases related to aspartate aminotransferase;

[0121] 6) Diseases related to triglycerides;

[0122] 7) Diseases related to total cholesterol;

[0123] 8) Diseases related to high-density lipoprotein;

[0124] 9) Diseases related to low-density lipoprotein;

[0125] 10) Diseases related to alkaline phosphatase;

[0126] 11) Fatty liver; and

[0127] 12) Diseases caused by leptin receptor deficiency.

[0128] 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.

[0129] Another aspect of the present invention provides a method for treating or improving one or more of the following conditions, the method comprising administering to a subject in need an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof:

[0130] 1) Diseases related to appetite;

[0131] 2) Insulin-related diseases;

[0132] 3) Diseases related to glycated hemoglobin;

[0133] 4) Diseases related to alanine aminotransferase;

[0134] 5) Diseases related to aspartate aminotransferase;

[0135] 6) Diseases related to triglycerides;

[0136] 7) Diseases related to total cholesterol;

[0137] 8) Diseases related to high-density lipoprotein;

[0138] 9) Diseases related to low-density lipoprotein;

[0139] 10) Diseases related to alkaline phosphatase;

[0140] 11) Fatty liver; and

[0141] 12) Diseases caused by leptin receptor deficiency.

[0142] In some implementations, the disease related to appetite caused by glucose metabolism is selected from: hyperthyroidism.

[0143] In some implementations, the insulin-related disease is selected from at least one of the following: insulin resistance and insulin deficiency.

[0144] In some implementations, the disease associated with glycated hemoglobin is selected from at least one of the following: hypertension, diabetic nephropathy, and hypothyroidism.

[0145] 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.

[0146] In some embodiments, the aspartate aminotransferase-related disease is selected from at least one of the following: steatohepatitis and drug-induced liver injury.

[0147] In some implementations, the triglyceride-related diseases are selected from at least one of the following: hyperlipidemia, atherosclerosis, coronary heart disease, and nephrotic syndrome.

[0148] In some implementations, the total cholesterol-related disease is selected from at least one of the following: hepatitis, atherosclerosis, and nephrotic syndrome.

[0149] 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.

[0150] In some implementations, the diseases associated with low-density lipoprotein are selected from at least one of the following: atherosclerosis and coronary heart disease.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] In some implementations, the half-life of this liquid formulation observed after subcutaneous injection in mice is approximately 16 hours, and in cynomolgus monkeys it is approximately 5 days. The dosage is 15 nmol / kg. Administration frequency is once daily (Qd), twice weekly (Bw), or once weekly (Qw).

[0158] In one embodiment, the composition of the invention is administered in a therapeutically effective amount. In one embodiment, "therapeutically effective amount" is intended to comprise the amount of the individual agent or compound of the invention, or the agent or compound of the invention that effectively reduces appetite-related and improves insulin sensitivity.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] The reagents and raw materials used in this invention are all commercially available.

[0165] The positive and progressive effects of this invention are as follows:

[0166] This invention first uses db / db mice lacking the leptin receptor (LepR- / -) as a type 2 diabetes model. Under different treatment cycles, the changes in food intake accumulation and body weight were examined. It was found that this compound can inhibit food intake accumulation in mice in a concentration-dependent manner. After treatment with this compound, food intake in mice was inhibited by 89%. The inhibitory effect was significantly higher than that of semaglutide and tirzepatide. However, this compound had no significant effect on the body weight of db / db mice.

[0167] Secondly, to investigate the effect of this compound on blood glucose control in mice, we measured fasting blood glucose and glycated hemoglobin (HbA1c) levels weekly. The results showed that this compound significantly reduced fasting blood glucose and HbA1c in db / db mice, and improved glucose tolerance and insulin sensitivity.

[0168] Finally, this compound can significantly improve liver function transaminase levels, creatinine, and blood lipids in mouse serum.

[0169] Furthermore, some of the compounds disclosed herein exhibit stronger glycemic control efficacy compared to known diabetes drugs in the art. This could lead to better glycemic control in diabetic patients, reduced medical costs, and increased patient adherence. Attached Figure Description

[0170] Figure 1 shows the food intake of the db / db mouse model within 24 hours after the first administration.

[0171] Figure 2 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.

[0172] Figures 3-5 show the trends of cumulative food consumption during treatment with this compound and comparative examples Semaglutide and Tirzepatide at dosing frequencies of once daily (Qd, Figure 3), twice weekly (Bw, Figure 4), or once weekly (Qw, Figure 5).

[0173] Figures 6-8 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 6), twice-weekly (Bw, Figure 7), or once-weekly (Qw, Figure 8) administration frequencies.

[0174] Figure 9 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.

[0175] Figure 10 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).

[0176] Figures 11-13 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 11), twice weekly (Bw, Figure 12), or once weekly (Qw, Figure 13).

[0177] Figure 14 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.

[0178] Figures 15-17 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 15), twice-weekly (Bw, Figure 16), or once-weekly (Qw, Figure 17).

[0179] Figure 18 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.

[0180] Figure 19 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)

[0181] Figure 20 shows the food intake of a mouse model induced by a high-fat diet within 24 hours after the first administration.

[0182] Figures 21-23 show the trend of percentage change in body weight during treatment with this compound and comparative examples Semaglutide and Tirzepatide at dosing frequencies of once daily (Qd, Figure 21), twice weekly (Bw, Figure 22), or once weekly (Qw, Figure 23).

[0183] Figure 24 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.

[0184] Figures 25-27 show the trends in food consumption during treatment with this compound and the comparative examples Semaglutide and Tirzepatide at dosing frequencies of once daily (Qd, Figure 25), twice weekly (Bw, Figure 26), or once weekly (Qw, Figure 27).

[0185] Figures 28-30 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 28), twice-weekly (Bw, Figure 29), or once-weekly (Qw, Figure 30) dosing frequencies.

[0186] Figure 31 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) doses for 28 days.

[0187] Figure 32 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).

[0188] Figures 33-35 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 33), twice weekly (Bw, Figure 34), or once weekly (Qw, Figure 35).

[0189] Figure 36 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.

[0190] Figures 37-39 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 37), twice-weekly (Bw, Figure 38), or once-weekly (Qw, Figure 39).

[0191] Figure 40 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.

[0192] Figure 41 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).

[0193] Figure 42 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).

[0194] Figure 43 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.

[0195] Figure 44 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.

[0196] Figure 45 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.

[0197] Figure 46 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. 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 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 ambient temperature for housing the mice was 22℃, and they had free access to standard normal feed and sterile water. The daily light / dark ratio was 12 hours:12 hours.

[0201] In Examples 3-4, 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).

[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] The comparative drugs, Semaglutide, were purchased from MedChemExpress (MCE), and Tirzepatide was synthesized by WuXi AppTec (batch number: ES18695-21-P1). All drugs were in powder form and were dissolved in 20mM trisodium citrate aqueous solution (pH 7.0±0.1) according to the required concentration before use. The trisodium citrate was purchased from Sinopharm Chemical Reagent Co., Ltd.

[0204] Example 1:

[0205] 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:

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

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

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

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

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

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

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

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

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

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

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

[0217] Group 12: db / db 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] The prepared injection solution was administered to mice via subcutaneous injection into 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] As shown in Figure 1, 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%).

[0227] As shown in Figure 2, the compound did not reduce the weight of mice in the db / db diabetes model after different treatment cycles.

[0228] Figures 3, 4, 5, 6, 7, and 8 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.

[0229] Figures 9 and 10 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.

[0230] Figures 11, 12, 13, 14, 15, 16, 17, and 18 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.

[0231] Example 2:

[0232] 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.

[0233] 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.

[0234] 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.

[0235] The study measured liver function (ALT, AST), kidney function (CREA, creatinine), and blood lipids (TG, CHO, HDL, LDL) in mouse serum.

[0236] Figure 19 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.

[0237] Example 3:

[0238] 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:

[0239] Group 1: ND mice + Vehicle (n=8), twice a week (Bw); (Body shaping group)

[0240] Group 2: ND mice + this compound (THDBHI20) (n=8, Bw);

[0241] Group 3: HFD mice + Vehicle (n=8, Bw); (Body shaping group)

[0242] Group 4: HFD mice + this compound once a day (n=8, Qd);

[0243] Group 5: HFD mice + this compound twice a week (n=8, Bw);

[0244] Group 6: HFD mice + this compound once a week (n=8, Qw);

[0245] Group 7: HFD mice + Semaglutide once a day (n=8, Qd);

[0246] Group 8: HFD mice + Semaglutide twice a week (n=8, Bw);

[0247] Group 9: HFD mice + Semaglutide once a week (n=8, Qw);

[0248] Group 10: HFD mice + Tirzepatide once a day (n=8, Qd);

[0249] Group 11: HFD mice + Tirzepatide (tirzepatide) twice a week (n=8, Bw);

[0250] Group 12: HFD mice + Tirzepatide once a week (n=8, Qw).

[0251] 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.

[0252] The dosing schedule was carried out in accordance with the dosing schedule in Table 1 of Example 1.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] As shown in Figure 20, 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.

[0258] As shown in Figures 21, 22, and 23, 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.

[0259] 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.

[0260] Figures 21-23 and 24 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.

[0261] Figures 25, 26, 27, 28, 29, and 30 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 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.

[0262] Figures 31 and 32 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.

[0263] Figures 33, 34, 35, and 36 show that the compound had a similar effect on improving glucose tolerance in HFD mice under different treatment cycles, without a frequency-dependent gradient, while the Tirzepatide group showed a significant frequency-dependent effect. 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.

[0264] Figures 37, 38, 39 and 40 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 treatment cycle.

[0265] Example 4:

[0266] 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.

[0267] 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.

[0268] 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.

[0269] The study measured liver function (ALT, alanine aminotransferase, AST, aspartate aminotransferase) and blood lipids (TG, total cholesterol, HDL, and LDL) in mouse serum.

[0270] Figure 41 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.

[0271] 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.

[0272] 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 42 shows that this compound had a superior inhibitory effect on hepatic lipid accumulation (TG) compared to other drugs.

[0273] Figures 43, 44, 45, and 46 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.

[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) To treat or prevent diseases related to appetite; 2) Suppresses appetite related to glucose metabolism; 3) Treatment of insulin-related diseases; 4) Improves insulin sensitivity; 5) Treatment of diseases related to glycated hemoglobin; 6) Lower glycated hemoglobin; 7) Improves glucose tolerance; 8) Lowers blood sugar; 9) Inhibits alanine aminotransferase expression; 10) Treatment of diseases related to alanine aminotransferase; 11) Inhibit the expression of aspartate aminotransferase; and, 12) Treatment of diseases related to aspartate aminotransferase; The compound or a pharmaceutically acceptable salt thereof is as follows: SEQ ID NO:1: YAibEGT FTSDY SIAibLD KK 1 AZ0K0 Z1FZ2E0W LZ3AGGPSSGA PPPS0; 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: Preferably, the drug is administered once every 1-30 days, for example once a day, once every two days, once every three days, or once every seven days; and / or, The dosage of the compound or its pharmaceutically acceptable salt is within 0.2 mg / kg, and the dosage of the compound or its pharmaceutically acceptable salt 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, The appetite is related to glucose metabolism; and / or the appetite-related disease is caused by increased appetite.

3. The application as described in claim 1, characterized in that, 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; or, 5) The diseases associated with aspartate aminotransferase are selected from at least one of the following: fatty liver disease and drug-induced liver injury.

4. The application as described in claim 1 or 3, characterized in that, 1) For the aforementioned appetite-related diseases or patients, 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, or once every seven days; 2) The insulin-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 or once every seven days; 3) For the diseases or patients associated with glycated hemoglobin, 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, or once every seven days; 4) For the aforementioned alanine aminotransferase-related diseases or patients, 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, or once every seven days; or, 5) For the diseases or patients associated with aspartate aminotransferase, 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, or once every seven days.

5. The use of the compound as defined in claim 1 or a pharmaceutically acceptable salt thereof in the preparation of glycated hemoglobin inhibitors; Preferably, the hemoglobin inhibitor is used for non-therapeutic purposes; 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.

6. A method for treating or improving a disease 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 disease 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; or, 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. The method as described in claim 6, 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.

8. The method as described in claim 6 or 7, 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.

9. The compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, for the treatment or improvement 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; or, 12) Diseases caused by leptin receptor deficiency.

10. The use of the compound as defined in claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a food for treating appetite-related diseases.

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