CN-116082321-B - Imidazo-aryl derivative, pharmaceutical composition and application thereof

Abstract

The invention discloses an imidazo-aryl derivative, a pharmaceutical composition and application thereof, wherein the imidazo-aryl derivative has a structural general formula shown in formula I, compared with a polypeptide agonist, the oral administration bioavailability of a small molecule drug has remarkable advantages, the administration is simpler and more convenient, the limitation of food or administration time is avoided, and in addition, the imidazo-aryl derivative shows good curative effect on the cellular level as the small molecule agonist, and has good pharmaceutical application prospect.

Inventors

• WANG LUN
• FU LIN
• LUO HAO
• TIAN YULIN
• TANG WEI
• WANG XUEDI

Assignees

• 华中药业股份有限公司

Dates

Publication Date

20260505

Application Date

20221223

Claims (4)

1. 1. The imidazo-aryl derivative is characterized by having a structural formula shown as formula III, formula V, formula VII or formula IX: 。
2. 2. The pharmaceutically acceptable salt of an imidazoheteroaryl derivative of claim 1.
3. 3. Use of a pharmaceutical composition comprising an imidazoaryl-like derivative according to claim 1, and a pharmaceutically acceptable carrier for the manufacture of a medicament for agonizing the GLP-1 receptor.
4. 4. The use according to claim 3, wherein the composition is for the manufacture of a medicament for the treatment and/or prophylaxis of type I diabetes, type II diabetes, adult onset diabetes of young age, latent immune diabetes in adults, gestational diabetes, diabetic complications, obesity, malnutrition-related diabetes, hyperglycemia, glucose intolerance, cardiovascular diseases, cerebral infarction, stroke, non-alcoholic fatty liver disease, parkinson's disease, dementia or insulin resistance.

Description

Imidazo-aryl derivative, pharmaceutical composition and application thereof Technical Field The invention relates to the technical field of chemical pharmacy, in particular to an imidazo aryl derivative, a pharmaceutical composition and application thereof. Background Diabetes is a group of metabolic diseases, chronic hyperglycemia caused by insulin secretion defects, insulin action, or both. The abnormal carbohydrate, fat and protein metabolism observed in diabetics is the result of the abnormal action of insulin on the target tissue and results in structural changes in many organ systems of the body, particularly those associated with the vascular system. Chronic hyperglycemia in diabetes is associated with serious long-term complications, including microvascular (e.g., retinopathy, nephropathy and neuropathy) and macrovascular (including fatal and non-fatal myocardial infarction, peripheral vascular disease and stroke) diseases. Diabetes is not a single disease, but a chronic syndrome, requiring active and long-term medication to limit its complications and to effectively manage them as they develop, as well as to prevent premature death. Thus, diabetics require continuous medical care, including multi-factor risk reduction strategies, in addition to glycemic control. Diabetes mellitus is divided into four major subtypes, type I, type II, gestational and others (i.e., a particular type of diabetes due to other causes). Glucagon-like peptide-1receptor (Glucagon-LIKE PEPTIDE-1receptor, glp-1R) controls the physiological response to the incretin hormone glucagon-like peptide-1 (Glucagon-LIKE PEPTIDE-1, glp-1) and is a major therapeutic target for the treatment of type 2 diabetes due to its broad role mediated upon activation, including promoting glucose-dependent insulin secretion, increasing insulin biosynthesis, preserving beta cell mass, improving peripheral insulin action and promoting weight loss. GLP-1 receptor agonists play an irreplaceable role in the treatment of diabetes. 7 GLP-1 receptor agonists have been co-approved since 2005, including Exenatide (Exenatide), liraglutide (Liraglutide), dolraglutide (Dulaglutide), arbutin (Albiglutide), liraglutide (Lixisenatide), semraglutide (Semaglutide), and telipopeptide (Tirzepatide). Currently, GLP-1 receptor agonists on the market are all polypeptide agonists, and small molecule agonists have not been marketed (the fastest progress is in phase II clinic). Compared with polypeptide agonists, the bioavailability of the small molecule drug for oral administration has remarkable advantages, and the administration is simpler and more convenient, and is not limited by food or administration time. Therefore, it is necessary to propose an imidazo-heteroaryl derivative which is used as a GLP-1 receptor agonist small molecule drug to be popularized and applied in drug preparation. Disclosure of Invention In view of the above, the invention provides an imidazo-aryl derivative small molecule which is used as a GLP-1 receptor agonist small molecule drug for popularization and application in drug preparation. Based on the above, the technical scheme of the invention is as follows: The imidazo-aryl derivative has a structural general formula as shown in formula I: Wherein: a is selected from 8-10 membered condensed aromatic rings; R 1 is independently selected from hydrogen, halogen, cyano, alkyl or substituted alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl; n=0, 1,2 or 3; W is O, NH, S (O) 2 or C (=o); Q 1,Q2,Q3,Q4 is independently selected from CR Z or N, R Z is independently hydrogen, fluoro, cyano, methyl or chloro; X is CH or N; r 2 is hydrogen, methyl or mono-or polysubstituted methyl, the substituents being fluorine; y 1,Y2 and Y 3 are independently selected from CR Z or N, and R Z is independently hydrogen, fluoro, cyano, methyl or chloro. Further, the imidazo-heteroaryl derivative is selected from one of the structural formulas of formulas II-IX: it is a further object of the present invention to provide isomers of the above-described imidazoaryl-based derivatives, including one or more of the tautomers, meso, racemates, enantiomers, diastereomers. Another object of the present invention is to provide pharmaceutically acceptable salts of the above-mentioned imidazoheteroaryl derivatives. It is a further object of the present invention to provide the use of a pharmaceutical composition comprising an imidazoaryl derivative as described above, or said isomer, or said pharmaceutically acceptable salt as described above, together with a pharmaceutically acceptable excipient, diluent or carrier for the manufacture of a medicament for agonizing the GLP-1 receptor. Further, the composition is used for preparing a medicament for treating and/or preventing type I diabetes, type II diabetes, adult onset diabetes of young age, latent immune diabetes of adults, gestational diabetes, diabetic complications, obesity, malnutrition-related dia