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WO-2026092666-A1 - USE OF COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF IN TREATMENT OF GLUCOSE METABOLIC DISEASES

WO2026092666A1WO 2026092666 A1WO2026092666 A1WO 2026092666A1WO-2026092666-A1

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.

Inventors

  • QIU, Yan
  • ZHANG, FENG
  • DU, ZHIQIANG
  • Chang, Xiaohui

Assignees

  • 通化东宝药业股份有限公司

Dates

Publication Date
20260507
Application Date
20251031
Priority Date
20241101

Claims (10)

  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 AZ 0 K 0 Z 1 FZ 2 E 0 W LZ 3 AGGPSSGA PPPS 0 ; SEQ ID NO:2: YAibEGT FTSDY SIAibLD KE 0 AQK 0 AFVK 1 W LIAGGPSSGA PPPS 0 ; SEQ ID NO:3：YAibEGT FTSDY SIE 0 LD KK 0 AQK 1 AFVQW LIAGGPSSGA PPPS 0 ; SEQ ID NO:4：YAibEGT FTSDY SIE 0 LD K 0 IAQK 1 AFVQW LIAGGPSSGA PPPS 0 ; in, The structure of Aib is S 0 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 E 0 AQK 0 is The structure of E 0 LDKK 0 is The structure of E 0 LDK 0 is as follows K1 indicates that the amino group on the lysine side chain is linked to -XX1 - X2 , and its structure is: X is selected from R1 and R2 are independently selected from H and CH3 , respectively; X 1 is selected from X 2 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 is 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 mentioned 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 is 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 the following conditions includes administering to a subject in need an effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof; said condition is 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, wherein 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 is used to treat or improve 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 food for treating appetite-related diseases.

Description

The use of a compound or a pharmaceutically acceptable salt thereof in the treatment of glucose metabolism disorders 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 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 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. 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. 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 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. 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; SEQ ID NO:1：YAibEGT FTSDY SIAibLD KK 1 AZ 0 K 0 Z 1 FZ 2 E 0 W LZ 3 AGGPSSGA PPPS 0 ; SEQ ID NO:2: YAibEGT FTSDY SIAibLD KE 0 AQK 0 AFVK 1 W LIAGG PSSGA PPPS 0 ; SEQ ID NO:3：YAibEGT FTSDY SIE 0 LD KK 0 AQK 1 AFVQW LIAGG PSSGA PPPS 0 ; SEQ ID NO:4: YAibEGT FTSDY SIE 0 LD K 0 IAQK 1 AFVQW LIAGG PSSGA PPPS 0 ; in, The structure of Aib is S 0 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 E 0 AQK 0 is The structure of E 0 LDKK 0 is The structure of E 0 LDK 0 is as follows K1 indicates that the amino group on the lysine side chain is linked to -XX1 - X2 , and its structure is: X is selected from R1 and R2 are independently selected from H and CH3 , respectively; X 1 is selected from X 2 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. In some embodiments, the compound is selected from: The compound used in the specific embodiments is WX-001, which is designated THDBHI20 in the embodiments. In some implementations, the appetite is related to glucose metabolism. In some implementations, the appetite-related illness is caused by increased appetite. In some implementations, the appetite-related disease is selected from hyperthyroidism.