Use of Mazutide

Abstract

The present invention discloses the use of mazdutide. The use of the compound shown in formula (I) in the manufacture of a drug for lowering uric acid level in a patient, where formula (I) is as shown in the present invention. The mazdutide of the present invention has a significant effect of lowering uric acid level.

Description

[Technical field]

[0001] Priority and Related Applications This application claims priority to Chinese patent application No. 202110711050.0, entitled "Use of OXM3," filed on June 25, 2021, the entire contents of which, including any appendices, are incorporated herein by reference.

[0002] The present invention is in the field of medicine, more specifically, the present invention is in the field of uric acid reduction, the present invention relates to the use of mazdutide. [Background technology]

[0003] Hyperuricemia is a metabolic disease in which uric acid in the blood increases due to metabolic disorders of a substance called purine in the human body. The amount of uric acid produced and excreted in the body is roughly the same per day, with one-third of the amount produced coming from food and two-thirds being self-synthesized in the body, and one-third being excreted from the intestines and two-thirds being excreted from the kidneys. As long as there is a problem in any one of the above various pathways, an increase in uric acid will be caused.

[0004] There is a certain relationship between high uric acid levels and obesity and diabetes. Obesity is a state of metabolic disorder, which at the same time leads to hyperinsulinemia and insulin resistance in the body, resulting in an increase in the levels of fat cytokines circulating in the body, while type 2 diabetes is a disease dominated by impaired blood glucose metabolism, characterized by insulin resistance, chronic elevation of blood glucose levels due to progressive decline in pancreatic beta cell function. Both are related to insulin metabolism, and the metabolic action of insulin on glucose and fat is influenced by many fat cells, further strengthening insulin resistance, and finally leading to increased production of uric acid and increased reabsorption of uric acid by renal tubules, causing an increase in uric acid levels. In addition to obesity and diabetes, high uric acid can also cause other complications such as uremia, atherosclerosis, and hypertension. Too high uric acid levels can also cause other diseases such as hyperuricemia and gout. Hyperuricemia (in the Chinese Guidelines for the Diagnosis and Treatment of Hyperuricemia and Gout (2019), blood uric acid levels above 420 μmol / L on two separate days in both men and women are considered to be hyperuricemia) and gout are independent risk factors for diseases such as chronic kidney disease, hypertension, cardiovascular and cerebrovascular diseases, and diabetes, and are independent predictors of premature death (see Bardin T, Richette P. Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options [J]. BMC Med, 2017, 15(1):123).

[0005] GLP-1R / GCGR dual agonist Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted from the intestine that has multiple mechanisms for lowering blood glucose levels and reducing weight, including increasing glucose-dependent insulin secretion, inhibiting glucagon secretion, slowing gastric emptying, and suppressing central appetite.

[0006] Glucagon is a hormone secreted by pancreatic alpha cells and consists of a single chain polypeptide of 29 amino acids in length. Glucagon exerts its physiological effects by specifically binding to the glucagon receptor (GCGR) on the surface of target cells in the liver and kidney, and activating adenylate cyclase in the cells, thereby increasing the intracellular cAMP level. Glucagon is a hormone that promotes breakdown and metabolism, and short-term injection of glucagon can promote glycogenolysis and gluconeogenesis and increase blood glucose levels. However, studies have found that long-term activation of GCGR by glucagon injection can reduce appetite, stimulate the breakdown of fatty acids, and significantly increase energy expenditure in adipose tissue (see Campbell JE, Drucker DJ. Nature Reviews Endocrinology, 2015, 11(6):329-338).

[0007] Endogenous oxyntomodulin (OXM) is a peptide hormone secreted by human intestinal L-cells after nutrient ingestion. OXM is a dual agonist of the glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR), and combines the appetite-suppressing and blood glucose-lowering effects of GLP-1R agonists with the GCGR-mediated energy expenditure-increasing effects (see Pocai A. Unraveling Oxyntomodulin, GLP1's enigmatic brother. J Endocrinol. 2012;15:335-346; Day JW, Ottaway N, Patterson JT, et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol. 2009;5:749-757.), potentially making it more effective than GLP-1R agonists in treating obesity and lowering blood glucose levels. Simultaneous intracellular injection of OXM significantly reduces body weight and appetite and increases energy expenditure. A study found that after gradual injection of OXM, GLP-1R knockout mice (GLP-1R- / -) lost weight, but the reduction was smaller than that in wild-type (WT) mice. This indicated that the weight-reducing effect of OXM requires simultaneous activation of both GLP1R and GCGR receptors (Kosinski JR, Huber J, Carrington PE, et al. The glucagon receptor is involved in mediating the body weight-lowering effects of oxyntomodulin. Obesity. 2012;20:1566~1571.). Preclinical data in rodents showed that GLP-1R / GCGR agonists are more effective at reducing weight than GLP-1R agonists.Similarly, Lao et al. reported that their GLP-1R / GCGR dual agonist showed a greater effect on weight loss in diet-induced obese rhesus monkeys (see Lao J, Hansen BC, DiMarchi R, et al. Effect of GLP1R / GCGR dual agonist in monkeys. Diabetes. 2013;62(suppl 1):A257; Ralf Elvert, Andreas W. Herling. Running on mixed fuel-dual agonistic approach of GLP-1 and GCG receptors leads to beneficial impact on body weight and blood glucose control:A comparative study between mice and non-human primate. Diabetes Obes Metab. 2018;20:1836-1851.). In animal studies after OXM treatment, activation of GCGR in the central nervous system may improve its whole-body glucose metabolism (see Mighiu PI, Yue JT, Filippi BM & Lam TK 2012 Hypothalamic glucagon signaling regulates glucose production. Diabetes 61(Suppl 1)A55. Nauck MA 2012 The design of the liraglutide clinical trial programme. Diabetes, Obesity and Metabolism 14(Suppl 2)4~12.). The hypoglycemic effect of OXM may be achieved mainly through weight loss, promotion of insulin secretion, and suppression of hepatic glucose production by activation of central nervous system GCGR.

[0008] These data suggest that OXM may be an anti-obesity and hypoglycemic drug with good drug tolerance. There are several uric acid lowering drugs currently on the market, such as xanthine oxidase inhibitors (XOIs) and uric acid excretion promoters, but there are no relevant studies on the effect of OXM on uric acid levels at present. Among them, allopurinol, febuxostat and benzbromarone are the first-choice drugs in China. In the United States, only allopurinol is used as the first-choice drug. However, current uric acid lowering drugs have problems in therapeutic efficacy and safety, such as the severe hypersensitivity reaction rate of allopurinol, the cardiovascular risk of febuxostat, the side effects of benzbromarone, and the low blood uric acid compliance rate. Therefore, the uric acid lowering drugs currently used to treat gout cannot meet clinical needs. Therefore, there is an urgent need for uric acid lowering preparations with strong safety and drug tolerance and obvious uric acid lowering effect to lower uric acid, especially in obese or diabetic patients. Summary of the Invention

[0009] In order to solve the problems existing in the prior art, such as the lack of a uric acid lowering preparation that has strong safety and drug tolerance and a clear uric acid lowering effect, the present invention provides the use of mazutide, which has a significant uric acid lowering effect.

[0010] The mazutide in this study is the OXM analogue mazutide. Mazutide is a long-acting synthetic peptide similar to mammalian oxyntomodulin (OXM) that utilizes a fatty acyl side chain to extend its duration of action and allow for once-weekly administration. When administered exogenously, OXM can improve glucose tolerance and induce weight loss (Pocai A. Action and therapeutic potential of oxyntomodulin. Mol Metab. 2013;3(3):241-251.). In humans, the hormone is thought to exert its biological effects through activation of the glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) (see Tan TM, Coadministration of glucagon-like peptide-1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia. Diabetes. 2013;62(4):1131-1138.). As an OXM analogue, the actions of mazutide are believed to be mediated by binding and activation of GLP-1R and GCGR.

[0011] The present invention provides the use of a compound of formula (I) (mazutide), or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for lowering uric acid levels in a patient. [ka]

[0012] The compound or a pharma- ceutically acceptable salt thereof is preferably the sole active ingredient or one of the active ingredients of the medicament.

[0013] Preferably, the drug further comprises hydroxymethylaminomethane and mannitol, more preferably sucrose or propylene glycol.

[0014] Furthermore, prior to use of the compound, the patient's serum uric acid level is preferably greater than 280 μmol / L.

[0015] Alternatively, the patient suffers from gout, hyperuricemia, uremia, atherosclerosis, hypertension, fatty liver, diabetes, obesity, or overweight with complications.

[0016] In certain cases, the patient not only has a serum uric acid level greater than 280 μmol / L, but also suffers from the above diseases at the same time.

[0017] In certain embodiments, the uric acid level is greater than 420 μmol / L.

[0018] The present invention further provides a method for lowering uric acid levels in a patient, comprising administering to the patient a compound of formula (I) or a drug as defined above.

[0019] The present invention further provides a method of treating gout comprising administering to a patient a compound of formula (I) or a drug as defined above.

[0020] With regard to the dosage of the drug described above, the drug is administered once a week at a dose of 1.0 mg to 10 mg, preferably, the drug is administered once a week at a dose of about 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 4.0 mg, 4.5 mg, 5 mg, 6 mg, 7.5 mg, 9 mg or 10 mg; In one embodiment, the drug is administered about once a week in at least one escalating dose for a minimum of about 4 weeks, and after the escalating dose, in at least one maintenance dose about once a week for a minimum of about 4 weeks, wherein the escalating dose is selected from about 1.0 mg and about 2.0 mg, and wherein the maintenance dose is selected from about 3.0 mg; In one embodiment, the drug is administered about once a week in at least one escalating dose for a minimum of about 4 weeks, and after the escalating dose, in at least one maintenance dose about once a week for a minimum of about 4 weeks, wherein the escalating dose is selected from about 1.5 mg and about 3.0 mg, and wherein the maintenance dose is selected from about 4.5 mg; In one embodiment, the drug is administered about once a week with at least one escalating dose for a minimum of about 4 weeks, and after the escalating dose, with at least one maintenance dose about once a week for a minimum of about 4 weeks, where the escalating dose is selected from about 2.0 mg and about 4.0 mg, and where the maintenance dose is selected from about 6.0 mg.

[0021] According to another aspect of the present invention, there is provided a pharmaceutical composition for lowering uric acid levels in a patient, comprising a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier.

[0022] In preliminary studies, mazutide has been shown to have a good safety and tolerability profile in single and multiple ascending dose studies in healthy subjects, while at the same time having urate-lowering effects in obese and diabetic patients.

[0023] Single-dose study in healthy subjects (I8P-MC-OXAA): A single-center, double-blind, placebo-randomized controlled SAD study (escalating doses of 0.03 mg, 0.1 mg, 0.3 mg, 1.0 mg, 2.5 mg, and 5.0 mg) was completed to evaluate the safety, tolerability, and PK / PD of mazutide in primarily healthy subjects. Results showed that all subjects tolerated the dose escalation to 2.5 mg, but when escalating to 5 mg, all six subjects experienced gastrointestinal-related AEs (mainly nausea and vomiting), so 2.5 mg can be used as the maximum tolerated dose (MTD) for a single dose.

[0024] As used herein, "escalating dose" refers to a dose that is less than the maximum effective dose required by the patient.

[0025] As used herein, a "maintenance dose" refers to the dose that serves as the highest effective dose required by the patient.

[0026] As used herein, "pharmaceutically acceptable salts" are those familiar to those of skill in the art. In one embodiment, the pharmaceutically acceptable salts are trifluoroacetate salts.

[0027] As used herein, a "patient" refers to a mammal in need of treatment for a medical condition or illness. In one embodiment, a patient is a person suffering from a disease or condition that would benefit from treatment with mazutide.

[0028] As used herein, when in reference to a number, the term "about" can refer to, for example, ±5%, ±4%, ±3%, ±2%, ±1% or ±0.5%.

[0029] The amino acid references used herein, e.g., Ala (A), Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Trp (W), Met (M), Gly (G), Ser (S), Thr (T), Cys (C), Tyr (Y), Asn (N), Gln (Q), Asp (D), Glu (E), Lys (K), Arg (R), His (H), are familiar to those of skill in the art.

[0030] Preliminary results of a study in overweight or obese patients showed that mazutide can lower uric acid levels in these patients (see Figure 2 for details). Preliminary results of a study in type 2 diabetes patients showed that mazutide can also lower uric acid levels in this patient population (see Table 6 and Figure 3 for details).

[0031] The positive advances of the present invention are as follows: Mazutide has a significant uric acid lowering effect and can lower the uric acid level in the body of patients with hyperuricemia by 80 μmol / L or more. [Brief description of the drawings]

[0032] [Figure 1] A blueprint for a research trial. [Diagram 2] Change in uric acid from baseline after dosing in an overweight / obese population. [Diagram 3] Change in uric acid from baseline after administration in a diabetic population. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] The present invention will be further described below with reference to examples, but the present invention is not limited to the scope of these examples. In the following examples, the experimental methods not specified in the specific conditions are selected according to conventional methods and conditions or product specifications. EXAMPLES

[0034] Example 1 Study Drugs and Patients The structure of mazutide is shown in formula (I): [ka] The sequence is shown in SEQ ID NO:1, and the specific sequence is: His-Xaa-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Lys-Ala-Lys-Glu-Phe-Val-Glu-Trp-Leu-Leu-Glu-Gly-Gly-Pro-Ser-Ser-Gly, where Xaa is Aib (2-aminoisobutyric acid) and Lys at position 20 is ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO-(CH2) 18 It is chemically modified by attaching -CO2H to the ε-amino group of the Lys side chain, and the carboxy group of the C-terminal Gly is amidated to a C-terminal primary amide.

[0035] 1.1 The physical and chemical characteristics of the study drugs are shown in Table 1. [Table 1]

[0036] 1.2 Study Drug Specification and Manufacturer The mazutide formulation is mazutide for injection, which consists of 2 mg mazutide, the inactive ingredients trishydroxymethylaminomethane, mannitol and sucrose. The vial contents were reconstituted with sterile water for injection to obtain a clear solution of mazutide. Alternatively, it consists of mazutide, the inactive ingredients trishydroxymethylaminomethane, mannitol and propylene glycol, and the manufacturing method is described in PCT / CN2022 / 089742. The placebo is a mazutide mimetic, which consists of the inactive ingredients trishydroxymethylaminomethane, mannitol and sucrose. The vial contents were reconstituted with sterile water for injection to obtain a clear solution of the inactive ingredients. In this study, the formulation specification is 2 mg / bottle, and the placebo specification is consistent with the formulation. Dulaglutide: specification 1.5 mg / tube, manufacturer: Vetter Pharma-Fertigung GmbH&Co.KG.

[0037] 1.3 Storage The formulation and placebo must be stored under refrigerated conditions (2°C to 8°C).

[0038] 1.4 Administration Method Both mazutide and placebo will be administered by subcutaneous injection once weekly. Each dose will be formulated and injected by a study nurse, who will refer to the drug use leaflet for details on preparation and use of the study medication.

[0039] 1.5 Selection Criteria 1. Obese or overweight subjects who meet all of the following criteria will be selected for this study: 1. Male or female, aged 18-75 years (inclusive). 2. Obese individuals with BMI ≥ 28.0kg / m2 or overweight individuals with BMI ≤ 24 < 28.0kg / m2, with at least one of the following: i. strong appetite, intolerable hunger before meals, and eating large amounts at each meal; ii. one or more of the following: prediabetes (impaired fasting glucose and / or impaired glucose tolerance), hypertension, dyslipidemia (see Appendix 4 for reference criteria), and fatty liver (within 6 months prior to screening); iii. pain in weight-bearing joints; iv. dyspnea or obstructive sleep apnea due to obesity. 3. At screening, have less than 5% weight change when controlled by simple diet and exercise for at least 12 weeks.

number

[0040] 1.6 Exclusion criteria 1. Obese or overweight subjects who meet any one of the following criteria will be excluded from this study: 1. The investigator suspects that the subject is an allergic or potentially allergic patient to the study drug or ingredient. 2. Use of any one of the following medications or treatments prior to screening: 1) Previous use of GLP-1 receptor (GLP-1R) agonists or GLP-1R / GCGR agonists. 2) Use of medications that affect weight within 3 months prior to screening, including systemic steroid hormone therapy (intravenous, oral, or intra-articular), metformin, SGLT2 inhibitors, thiazolidinediones (TZDs), tricyclic antidepressants, psychiatric medications, or sedatives (imipramine, amitriptyline, mirtazapine, paroxetine, phenelzine, chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid, valproic acid derivatives, lithium salts, etc.). 3) Use of herbal medicine or health food that affects weight within 3 months prior to screening. 4) had used or was currently using weight-loss medications within 3 months prior to screening, including sibutramine hydrochloride, orlistat, phentermine, phenylpropanolamine, chlorbenzindole, phentermine, bupropion, lorcaserin, phentermine / topiramate mixture, and naltrexone / bupropion mixture; 5) Participated in another clinical trial (received treatment with a study drug) within 3 months prior to screening. 3. Have a history or evidence of any one of the following conditions prior to screening: 1) Patients were diagnosed with diabetes according to the WHO 1999 criteria. 2) At screening, fasting venous glucose level is ≥ 7.0mmol / L, or venous glucose level is ≥ 11.1mmol / L 2 hours after glucose loading in a 75g oral glucose tolerance test (OGTT) (for subjects with fasting glucose level of 6.1mmol / L-7.0mmol / L at screening, venous glucose level must be collected 2 hours after OGTT glucose loading for confirmation). 3) Patients with retinopathy in the past or at the time of screening. 4) Obesity due to secondary diseases or drugs, including obesity due to elevated cortisol hormone (e.g., Cushing's syndrome), obesity due to damage to the pituitary gland and hypothalamus, and obesity due to reduction / cessation of weight-loss medication. 5) Having previously undergone weight loss surgery or acupuncture or other weight loss treatments within the year prior to screening. 6) Have a history of depression or a history of serious mental illness such as schizophrenia or bipolar disorder. 7) Still stable uncontrolled hypertension at screening after at least 4 weeks of antihypertensive drug treatment, defined as systolic blood pressure >140mmHg and / or diastolic blood pressure >100mmHg. 8) Systolic blood pressure <90mmHg and / or diastolic blood pressure <50mmHg at screening. 9) History of malignant tumors at the time of screening (excluding cured basal cell carcinoma of the skin and intraepithelial neoplasia of the cervix). 10) Have any heart-related disease (angina pectoris, myocardial infarction, cardiomyopathy, acute or chronic heart failure, etc.) at the time of screening. 11) Had hemorrhagic or ischemic stroke or transient ischemia within 6 months prior to screening. 12) At the time of screening, the patient has a personal history of thyroid C-cell carcinoma, or a personal or related family history of MEN (multiple endocrine neoplasia) 2A or 2B syndrome. 13) History of acute or chronic pancreatitis, cholecystitis, or pancreatic injury at the time of screening. 14) At the time of screening, the patient had any chronic gastrointestinal or systemic disease that may affect gastrointestinal motility, or had used any medication that may alter gastrointestinal motility, appetite, or absorption within 3 months prior to screening. 15) There is a limb deformity or amputation, and height, weight, and other indicators cannot be accurately determined. 16) Subjects who have had major or medium-sized surgery, severe trauma, or severe infection within one month prior to screening and who are deemed by the investigator to be ineligible to participate in this study. 17) History of suicidal tendencies or behavior. 18) Surgery is scheduled during the study period, but outpatient surgeries that the investigators determine will not affect the safety of the subjects or the study outcomes will be excluded. 19) Subjects who test positive for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen (HBsAg), hepatitis C (HCV) antibody, or syphilis antibody at the time of screening. 20) History of alcohol abuse within 1 month prior to screening, including an average weekly alcohol intake of more than 21 units for men and 14 units for women, or an unwillingness to abstain from alcohol consumption 24 hours prior to dosing and throughout the study period (1 unit = 360 mL of beer, or 150 mL of red wine, or 45 mL of distilled spirits / white liquor). 21) A positive urine screen for drug or narcotic abuse. 4. Any one of the laboratory test indicators meets the following criteria (at screening, if there is a clear reason for recheck, it can be done within one week, and the investigator should record the reason for recheck): 1) Serum calcitonin ≥ 15ng / L at screening. 2) At screening, glutamate aminotransferase ≥ 2.0 x ULN and / or aspartate aminotransferase ≥ 2.0 x ULN and / or total bilirubin ≥ 1.0 x ULN and / or alkaline phosphatase ≥ 2.0 x ULN. 3) At screening, eGFR < 60mL / min / 1.73m2, estimated by the CKD-EPI formula (see Table 2 below): eGFR = a x [(serum creatinine (μmol / L) / b)] x (0.993) Age: [Table 2] 4) Thyroid function (FT3, FT4 or TSH) is abnormal at screening. 5) Fasting triglycerides ≥ 5.64 mmol / L (500 mg / dl) at screening. 6) Blood amylase or lipase >2.0×ULN at screening. 7) At screening, the international normalized ratio (INR) of prothrombin time exceeded the upper limit of the normal range. 5. At screening, a 12-lead electrocardiogram showed a heart rate <50 beats / min or >90 beats / min. 6. At screening, clinically abnormal 12-lead electrocardiograms (ECGs): without a pacemaker, second or third degree atrioventricular block, long QT syndrome or QTcF>450ms (QTc Fridericia formula: QTcF=QT / (RR^0.33)), PR interval <120ms or PR interval >220ms, QRS>120ms, left or right bundle branch block, preexcitation syndrome or serious arrhythmias requiring treatment. 7. Pregnant or lactating women, men or women of childbearing potential who do not wish to use contraception throughout the study period. 8. Within 3 months prior to screening, blood donation and / or blood loss ≥ 400 mL, or bone marrow donation, or hemoglobinopathy, hemolytic anemia, sickle cell anemia, or hemoglobin < 110 g / L (male) or < 100 g / L (female). 9. The investigator believes that the subject has any other factor that may affect the efficacy or safety evaluation of this study and is therefore not suitable for participation in this study.

[0041] 2. Diabetic subjects who meet any one of the following criteria will be excluded from this study: 1. Type 1 diabetes, specific diabetes or gestational diabetes. 2. Ketoacidosis or lactic acidosis occurred within 6 months prior to screening. 3. A history of severe hypoglycemic episodes within 6 months prior to screening, defined as neurohypoglycemic episodes and needing supportive care from others to recover, or complete lack of awareness of hypoglycemia or poor awareness of hypoglycemic symptoms. Investigators will consider patients to be excluded from the study if they are unable to understand and consent to hypoglycemic symptoms and appropriate treatment. 4. Acute myocardial infarction, unstable angina, coronary artery bypass graft, percutaneous coronary intervention (excluding diagnostic angiography), transient ischemic attack (TIA), cerebrovascular accident, acute or chronic heart failure occurred within 6 months prior to screening. 5. At the time of screening, the investigator is aware of any abnormal 12-lead electrocardiogram that may increase the subject's risk or cause confounding of electrocardiogram data analysis (QT) (e.g., QTcF>450ms, PR interval <120ms or PR interval >220ms, second and third degree atrioventricular block, ventricular conduction delay i.e. QRS>120ms, right bundle branch block, left bundle branch block, preexcitation syndrome), or medications that affect the cardiac QT interval (antiarrhythmics class IA and class III, cisapride, macrolide antibiotics, and psychotropic medications (phenothiazines (methodazine, chlorpromazine, misopridazine), butyrophenones (fluoroperidol, haloperidol), and loperamide). 6. Have been diagnosed with long QT syndrome in the past. 7. Uncontrolled blood pressure at screening: systolic blood pressure >140mmHg or <90mmHg, diastolic blood pressure >90mmHg or <50mmHg. 8. Heart rate <50 bpm or >90 bpm at screening. 9. Active or untreated malignancy or in remission of clinical malignancy within 5 years prior to screening (patients without recurrence after surgery for basal and squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, and papillary thyroid carcinoma are excluded). 10. History of acute or chronic pancreatitis, or serum lipase / amylase >2x upper limit of normal at screening, or fasting triglycerides >5.65mmol / L (500mg / dl). If the patient is on lipid-modifying therapy, the drug dose must be stable for 30 days before screening. 11. Clinically significant liver disease, acute or chronic hepatitis at screening, or aminotransferases (ALT and AST) and alkaline phosphatase (ALP) >2x upper limit of normal and total bilirubin >upper limit of normal at screening. 12. Calcitonin ≥ 15ng / L at screening. 13. At screening, total glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2, estimated by the modified MDRD equation: eGFR = 175 × [(blood creatinine (μmol / L) / 88.4)] - 1.234 × [age (years)] - 0.179 × 0.79 (female) or × 1 (male). 14. Has a psychiatric disorder in the past or at the time of screening that the investigator considers to be inappropriate for participation in this study. 15. Have been diagnosed with gastroparesis or any form of bariatric surgery, or have a clinically suspected gastric emptying disorder. 16. Known history of regular substance abuse. 17. HIV virus infection and / or HIV antibody positive or syphilis antibody positive at screening. 18. History of hepatitis B and / or positive hepatitis B surface antigen or positive hepatitis C (HCV) antibody test at screening. 19. Have had Gilbert syndrome in the past. 20. INR above upper limit of normal at screening. 21. History of thyroid medullary C-cell carcinoma, personal history of MEN (multiple endocrine neoplasia) 2A or 2B syndrome, or relevant family history. 22. In the past, the patient had been clearly diagnosed with autonomic neuropathy, which was manifested by urinary retention, resting tachycardia, orthostatic hypotension, and diabetic diarrhea. 23. Significant percentage change (>5%) in body weight within 3 months prior to screening. 24. Within 3 months prior to screening, blood donation ≥ 400 mL or excessive blood loss, or bone marrow transplantation, or hemoglobinopathy, hemolytic anemia, sickle cell anemia, or hemoglobin < 110 g / L (male) or < 100 g / L (female). 25. Hyperthyroidism or hypothyroidism as evidenced by clinical evaluation and / or abnormal TSH levels that the investigator believes to be at increased patient risk. 26. Use of hypoglycemic drugs other than metformin within 2 months prior to screening. 27. Have used weight loss medications in the 3 months prior to screening, or plan to use them during the study period, including liraglutide, orlistat, sibutramine hydrochloride, phenylpropanolamine, chlorpheniramine indole, phentermine, lorcaserin hydrochloride, phentermine, phentermine / topiramate, amphetamine ketone, and naltrexone / bupropion. 28. Long-term use of glucocorticoids (cumulative or continuous use >2 weeks) within the year prior to screening, or use of glucocorticoids (excluding topical, intraocular, intranasal, intra-articular, or inhaled administration) within the 4 weeks prior to screening. 29. At the time of screening, you are using any central nervous system stimulants (e.g., methylphenidate hydrochloride), excluding caffeine-containing beverages. 30. Known to be allergic to the test drug or ingredients. 31. Participated in any drug or device clinical trial within 3 months prior to screening (defined as entering the randomized dosing phase). 32. Unless surgically sterilized or menstruating, female subjects of childbearing potential will not inform their sexual partners of their participation in a clinical study and will not use effective contraception for the duration of the study. Male subjects will not inform their female partners of their participation in a clinical study and will not use effective contraception for the duration of the study. 33. Subject is pregnant or breastfeeding, or plans to become pregnant or breastfeed during the study period. 34. The investigator will consider any significant clinical and laboratory abnormalities that may interfere with the interpretation of the treatment effect and safety data of this study. 35. The investigator considers that the subject may have other factors, such as a psychiatric disorder, that may affect the subject's suitability for this study, the efficacy of treatment, or the safety assessment. 36. Average weekly alcohol intake >21 units for men and >14 units for women, or no intention to abstain from alcohol consumption 24 hours prior to dosing and throughout the study period (1 unit = 360 mL beer, or 150 mL red wine, or 45 mL distilled liquor / white liquor).

[0042] Example 2 Overall Study Design 1. Obesity or overweight The study was planned to enroll 36 overweight or obese patients with less than 5% weight change controlled by diet and exercise for at least 12 weeks. The double-blind treatment period of the study was divided into three cohorts, Cohort 1 (n=12), Cohort 2 (n=12), and Cohort 3 (n=12), respectively, and subjects in each cohort were randomized in a 2:1 ratio to either the mazutide treatment group (n=8) or the placebo group (n=4). The description of the subcutaneous injection dosing schedule of mazutide or placebo in Cohort 1, Cohort 2, and Cohort 3, respectively, was as follows (shown in Figure 1): Cohort 1: Subject's starting dose was 1.0 mg, administered once a week, and after 4 consecutive weeks of administration, if the subject tolerated the drug well*, the dose was increased to 2.0 mg, administered once a week, and after 4 consecutive weeks of administration, the subject's drug tolerance was again monitored, and if the drug was tolerated well*, the dose continued to be increased to 3.0 mg, administered once a week, and administered for 4 consecutive weeks. (Increasing at an ascending rate of 1 mg every 4 weeks to the target dose). Cohort 2: Subject's starting dose was 1.5 mg, administered once a week, and after 4 consecutive weeks of administration, if the subject tolerated the drug well*, the dose was increased to 3.0 mg, administered once a week, and after 4 consecutive weeks of administration, the subject's drug tolerance was observed again, and if the drug was tolerated well*, the dose continued to be increased to 4.5 mg, administered once a week, administered for 4 consecutive weeks (increasing at an ascending rate of 1.5 mg every 4 weeks until the target dose). In cohort 2, if a subject is unable to tolerate the drug at 3.0 mg or 4.5 mg, the dose should be adjusted according to the criteria shown in Table 3. [Table 3] remarks: *If a subject in Cohort 2 is unable to tolerate 3 mg during the escalation process, they should be tapered to 2.25 mg after 1 week off in Cohort 2 (backup 1), with subsequent dose escalation occurring in Cohort 2 (backup 1). #If a subject in cohort 2 is unable to tolerate 4.5 mg during the uptick, they will need to be reduced to 3.75 mg after one week off medication in cohort 2 (backup2) and maintained at that dose until the end of the study. &Dosing for subjects in Cohort 3 will begin after subjects in Cohort 2 have completed a 4-week drug tolerance test at 1.5 mg; if subjects in Cohort 2 cannot tolerate 1.5 mg, there is no need to consider higher doses of 2.0 mg or more for subjects in Cohort 3. Cohort 3: The subjects will be started after the subjects in Cohort 2 have completed 4 weeks of treatment with 1.5 mg with good drug tolerance, and if the subjects in Cohort 2 cannot tolerate 1.5 mg, there is no need to consider a higher dose of 2.0 mg or more for the subjects in Cohort 3. The starting dose for the subjects in this cohort will be 2.0 mg, administered once a week, and if the subjects are well-tolerated* after 4 consecutive weeks of administration, the dose will be increased to 4.0 mg, administered once a week, and after 4 consecutive weeks of administration, the subjects will be re-observed for drug tolerance, and if the subjects are well-tolerated*, the dose will continue to be increased to 6.0 mg, administered once a week, and administered for 4 consecutive weeks. (Increasing at an increasing rate of 2 mg every 4 weeks until the target dose).

[0043] 2. Diabetes The study was planned to enroll 42 patients with type 2 diabetes who had not yet achieved standard control of glycated hemoglobin after at least 2 months of lifestyle intervention or stable-dose metformin (≥1000 mg / day or maximum tolerated dose). The study was divided into three cohorts, Cohort 1 (n=14), Cohort 2 (n=14), and Cohort 3 (n=14), and each cohort was randomized in a ratio of 8:4:2 to mazutide (n=8), placebo (n=4), and Dulaglutide 1.5 mg (n=2). The dosing regimens of the active comparator Dulaglutide in Cohort 1, Cohort 2, and Cohort 3 were all 1.5 mg QW, administered for 12 consecutive weeks, and the dosing schedules of mazutide and placebo were described as follows: Cohort 1: The subject's starting dose was 1.0 mg, administered once a week, and after 4 consecutive weeks of administration, if the subject tolerated the drug well, the dose was increased to 2.0 mg, administered once a week, and after 4 consecutive weeks of administration, the subject's drug tolerance was observed again, and if the drug was tolerated well, the dose was increased to 3.0 mg, administered once a week, and administered for 4 consecutive weeks (increasing at an upward rate of 1 mg every 4 weeks to the target dose). Cohort 2: The subject's starting dose is 1.5mg, administered once a week. After 4 weeks of continuous administration, if the subject's drug tolerance is good, increase it to 3.0mg, administered once a week. After 4 weeks of continuous administration, drug tolerance is observed again. If the subject's drug tolerance to 3.0mg is low and the drug tolerance criteria is reached, the subject needs to be considered for the next dose in cohort 2 (backup 1). If the drug tolerance is good, continue to increase it to 4.5mg, administered once a week. After 4 weeks of continuous administration, if the subject's drug tolerance to 4.5mg is low and the drug tolerance criteria is reached, the subject needs to be considered for the next dose in cohort 2 (backup 2). (Increase at an increasing rate of 1.5mg every 4 weeks until the target dose). Cohort 2 (backup 1): If the subject could not tolerate the 3.0 mg dose, the medication was stopped for 1 week and reduced to 2.25 mg. After 2 weeks of continuous administration, the subject's drug tolerance was observed again. If the drug tolerance was good, the dose was increased to 3.0 mg and continued for 4 weeks. Cohort 2 (backup 2): If a subject was unable to tolerate the 4.5 mg dose, the dose was stopped for 1 week and then reduced to 3.75 mg, which was administered continuously for 2 weeks until the end of the study. Cohort 3: subjects will be started after cohort 2 subjects have completed a 4-week drug tolerance test at 1.5 mg. If cohort 2 subjects cannot tolerate 1.5 mg, there is no need to consider a higher dose of 2.0 mg or more for cohort 3 subjects. The starting dose for subjects in this cohort will be 2.0 mg, administered once a week. After 4 consecutive weeks of administration, if the subject's drug tolerance is good, the dose will be increased to 4.0 mg, administered once a week. After 4 consecutive weeks of administration, the subject's drug tolerance will be observed again. If the drug tolerance is good, the dose will continue to be increased to 6.0 mg, administered once a week, administered for 4 consecutive weeks. (Increasing at an increasing rate of 2 mg every 4 weeks until the target dose).

[0044] Example 3 Safety Study Evaluation Obese or overweight patients: As of March 15, 2021, a total of 36 cases had been enrolled, and 36 cases were included in the analysis. The study showed that patients generally had good safety and tolerability, with no SAEs, no AEs related to dose discontinuation, no hypoglycemic events, no severe adverse events or acute pancreatitis, no subjects discontinued or withdrew from the study due to adverse events, no injection site reactions, and only two subjects in cohort 1 developed mild urticaria. Gastrointestinal adverse reactions were the most common adverse reaction (15 / 24 cases, 62.5%), among which the highest incidences were decreased appetite (29.2%), diarrhea (25%), and nausea (16.7%). The incidence rate of gastrointestinal reactions was higher than that of placebo, which was consistent with the mechanism of action of the drug. In addition, the mean heart rate increased in the mazutide study group compared to the placebo group, but no serious cardiac-related adverse events were observed. Diabetic patients: As of April 26, 2021, a total of 42 cases had been enrolled, and 42 cases were included in the analysis. The subjects in this study had an overall good safety and drug tolerability, with no adverse events leading to discontinuation due to dose escalation, and no cases of acute pancreatitis, severe hypoglycemia, allergic reactions, or injection site adverse reactions.

[0045] Example 4. Uric acid lowering effect of mazutide determined by clinical safety studies 1. Obese subjects: As of March 15, 2021, a total of 36 cases were enrolled and 36 cases were included in the analysis. Table 4 shows the uric acid levels of each group before administration, i.e., baseline values. [Table 4] Figure 2 shows the average change in each group after administration compared to the baseline before administration. Figure 2 shows that the uric acid levels of cohorts 1, 2, and 3 all clearly decreased after administration, and were clearly superior to the placebo group.

[0046] 2. Diabetic subjects: As of April 26, 2021, a total of 42 cases were enrolled and 36 cases were included in the analysis. Table 5 shows the uric acid levels of each group before administration, i.e., baseline values. [Table 5] Table 6 shows the average change in each group on the 85th day after administration compared to the baseline before administration. Table 6 and Figure 3 show that the uric acid levels in Cohorts 1, 2, and 3 were all significantly lower than those in the placebo group and dulaglutide control group, with the most significant declines in Cohort 1 and Cohort 3. [Table 6]

Claims

1. A pharmaceutical composition for reducing the uric acid level in a patient, comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. 【Chemical 1】

2. The pharmaceutical composition according to claim 1, wherein the compound or its pharmaceutically acceptable salt is one of the sole active ingredients or effective ingredients of the pharmaceutical composition.

3. The pharmaceutical composition according to claim 1, further comprising tris(hydroxymethyl)aminomethane and mannitol.

4. The pharmaceutical composition according to claim 3, further comprising sucrose or propylene glycol.

5. The pharmaceutical composition according to claim 2, further comprising tris(hydroxymethyl)aminomethane and mannitol.

6. The pharmaceutical composition according to claim 5, further comprising sucrose or propylene glycol.

7. The uric acid level is greater than 280 μmol / L, and / or the patient suffers from gout, hyperuricemia, uremia, atherosclerosis, hypertension, fatty liver, diabetes, obesity, or overweight with complications, and the uric acid level is the uric acid level in the patient's serum before reduction. The pharmaceutical composition according to any one of claims 1 to 6.

8. The uric acid level is greater than 420 μmol / L. The pharmaceutical composition according to claim 7.

9. The pharmaceutical composition according to any one of claims 1 to 6, which is administered once a week at a dose of 1.0 mg to 10 mg.

10. The pharmaceutical composition according to claim 7, which is administered once a week at a dose of 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 4.0 mg, 4.5 mg, 5 mg, 6 mg, 7.5 mg, 9 mg or 10 mg.

11. The pharmaceutical composition according to claim 10, which is administered once a week at a dose of 2.0 mg, 3.0 mg, 4.0 mg, 6 mg or 9 mg.

12. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition is administered once a week at at least one increasing dose for at least 4 weeks and then once a week at at least one maintenance dose for at least 4 weeks, where the increasing dose is selected from 1.0 mg and 2.0 mg, and where the maintenance dose is selected from 3.0 mg, or The pharmaceutical composition is administered once a week at at least one escalating dose for a minimum of 4 weeks, and then once a week at at least one maintenance dose for a minimum of 4 weeks after the escalating dose, where the escalating dose is selected from 1.5 mg and 3.0 mg, and where the maintenance dose is selected from 4.5 mg, or The pharmaceutical composition is administered once a week at at least one escalating dose for a minimum of 4 weeks, and then once a week at at least one maintenance dose for a minimum of 4 weeks after the escalating dose, where the escalating dose is selected from 2.0 mg and 4.0 mg, and where the maintenance dose is selected from 6.0 mg. Pharmaceutical composition.

13. The pharmaceutical composition according to claim 12, wherein the pharmaceutical composition is administered once a week at at least one escalating dose for a minimum of 4 weeks, and then once a week at at least one maintenance dose for a minimum of 4 weeks after the escalating dose, where the escalating dose is selected from 2.0 mg and 4.0 mg, and where the maintenance dose is 6.0 mg.

14. The pharmaceutical composition according to claim 12, wherein the compound or the pharmaceutically acceptable salt is administered once a week at an escalating dose of 2.0 mg for 4 weeks, and then once a week at a maintenance dose of 4.0 mg for a minimum of 4 weeks.

15. The pharmaceutical composition according to claim 12, wherein the compound or the pharmaceutically acceptable salt is administered once a week at an escalating dose of 4.0 mg for 4 weeks, and then once a week at a maintenance dose of 6.0 mg for a minimum of 4 weeks.

16. The pharmaceutical composition according to claim 12, wherein the compound or the pharmaceutically acceptable salt is administered once a week at an escalating dose of 2.0 mg for 4 weeks, then once a week at an escalating dose of 4.0 mg for 4 weeks, and then once a week at a maintenance dose of 6.0 mg for a minimum of 4 weeks.

17. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients having diabetes, obesity, or overweight with complications, 【Chemical 2】 wherein the compound or the pharmaceutically acceptable salt thereof is administered once a week at a dose of 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 4.0 mg, 4.5 mg, 5 mg, 6 mg, 7.5 mg, 9 mg or 10 mg.

18. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients having gout or hyperuricemia, 【Chemical 3】 The pharmaceutical composition wherein the compound or a pharmaceutically acceptable salt thereof is administered once a week at a dose of 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 4.0 mg, 4.5 mg, 5 mg, 6 mg, 7.5 mg, 9 mg or 10 mg.

19. The compound or a pharmaceutically acceptable salt thereof is administered once a week, administered at least once a week at a gradually increasing dose for at least 4 weeks and then at least once a week at a maintenance dose for at least 4 weeks, where the gradually increasing dose is selected from 2.0 mg and 4.0 mg, and where the maintenance dose is selected from 6.0 mg. The pharmaceutical composition according to claim 17 or 18.

20. The compound or the pharmaceutically acceptable salt thereof is administered once a week at a gradually increasing dose of 2.0 mg for 4 weeks and then once a week at a maintenance dose of 4.0 mg for at least 4 weeks. The pharmaceutical composition according to claim 17 or 18.

21. The compound or the pharmaceutically acceptable salt thereof is administered once a week at a gradually increasing dose of 4.0 mg for 4 weeks and then once a week at a maintenance dose of 6.0 mg for at least 4 weeks. The pharmaceutical composition according to claim 17 or 18.

22. The compound or the pharmaceutically acceptable salt thereof is administered once a week at a gradually increasing dose of 2.0 mg for 4 weeks, then once a week at a gradually increasing dose of 4.0 mg for 4 weeks, and then once a week at a maintenance dose of 6.0 mg for at least 4 weeks. The pharmaceutical composition according to claim 17 or 18.

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