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Imidazopyridine derivative and application thereof

A technology of imidazo and pyridine, which is applied in the field of medicine and can solve problems such as drug restrictions

Pending Publication Date: 2022-06-17
HANGZHOU ZHONGMEI HUADONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Currently available drugs for the treatment of type II diabetes are the following: insulin secretagogues, metformin, α-glucosidase inhibitors, insulin sensitizers, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase -4 (DPP-4) inhibitors, GLP-1 receptor agonists, insulin and its similar drugs, among which insulin and GLP-1 receptor agonists are one of the most effective drugs for diabetes treatment, and insulin preparations are still the global The most used diabetes drug, about 30-40% of type 2 diabetic patients will eventually need to use insulin. GLP-1 preparations mainly include exenatide, liraglutide, semaglutide, etc., suitable for metformin, sulfo Type 2 diabetics whose blood sugar cannot be adequately controlled by the combination of ureides and other drugs
However, the current insulin preparations and GLP-1 preparations are basically polypeptide drugs and injection preparations. Even oral semaglutide still has many limitations in drug use, so it is still necessary to further develop small molecules for GLP-1 receptors agonist drug

Method used

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  • Imidazopyridine derivative and application thereof
  • Imidazopyridine derivative and application thereof
  • Imidazopyridine derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] Compound of formula I 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxa Preparation method of cyclobutan-2-ylmethyl)imidazo[1,2-a]pyridine-6-carboxylic acid (hereinafter referred to as "compound 1")

[0096]

[0097] (1) Preparation of compound 1-2

[0098]

[0099] Compound 1-1 (20.0 g, 181.8 mmol) and TBSCl (27.4 g, 181.8 mmol) were added to DMF (300 mL) followed by imidazole (12.3 g, 181.8 mmol) and DMAP (5.5 g, 45.4 mmol), respectively. Under a nitrogen atmosphere, the reaction solution was reacted at room temperature for 16 hours. join H 2 O (500 mL), the reaction solution was extracted with EtOAc (3 x 500 mL). with H 2 The combined organic phases were washed with O (3 x 500 mL) and brine (400 mL), dried (Na 2 SO 4 ), filtered and concentrated. Flash chromatography (SiO 2 , 10% EtOAc-hexane) to give compound 1-2 (35.5 g, 86.7%), [ 1 H NMR(400MHz,DMSO-d6)δ5.13(d,J=5.1Hz,1H),3.68-3.45(m,5H),0.84-0.80(m,9H),0.02-0.03(m,6H)...

Embodiment 2

[0141] 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(morpholinomethyl) ) Preparation method of imidazo[1,2-a]pyridine-6-carboxylic acid (compound 2)

[0142]

[0143] (1) Preparation of compound 2-2

[0144]

[0145] The flask containing dry DMF (50 mL) was cooled to 0°C and phosphorous oxychloride (8.5 mL, 93 mmol) was added. The cooling bath was removed and the solution was stirred at room temperature for 1 hour. The red reaction mixture was treated with a solution of ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate (10 g, 37.2 mmol) in dry DMF (50 mL) and after 3 h the mixture was heated to 60 °C , the reaction mixture was poured into ice water (100 mL), and extracted with dichloromethane (3 x 80 mL) by adding 2N aqueous sodium hydroxide solution. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to give compound 2-2 (5.6 g, 34%), [ 1 H NMR (400MHz, CDCl 3 )δ10.66(s,1H),9.83(dd,J=1.9,0.8Hz,1H),7.7...

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Abstract

The invention relates to an imidazopyridine derivative and application thereof, and provides an imidazopyridine-derived GLP-1 receptor agonist compound, namely 2-((4-(6-((4-cyano-2-fluorobenzyl) oxy) pyridine-2-yl) piperidine-1-yl) methyl)-3-(oxetan-2-yl methyl) imidazo [1, 2-a] pyridine-6-formic acid as well as a preparation method and pharmaceutical application of the imidazopyridine-derived GLP-1 receptor agonist compound. The compound can be used for preparing medicines for treating or preventing GLP-1 mediated diseases and related diseases. The invention further provides 2-(hydroxymethyl)-3-(oxetan-2-ylmethyl) imidazo [1, 2-a] pyridine-6-carboxylic acid methyl ester and a preparation method thereof, and the imidazo [1, 2-a] pyridine-6-carboxylic acid methyl ester can also be used as a synthesis intermediate of a medicine.

Description

technical field [0001] The present invention relates to the technical field of medicine, in particular to GLP-1 receptor agonist compounds and preparation methods, as well as the use of the compounds in the preparation of medicines for the treatment or prevention of GLP-1 mediated diseases and related diseases. Background technique [0002] Imidazopyridines are typical nitrogen-containing heterocyclic compounds, which are widely found in natural products of medicines. Imidazopyridine and its derivatives are widely used in the field of new drug research and development, including blood diseases, tumors, neurological diseases, endocrine diseases, digestive system diseases, etc. At present, a variety of imidazopyridine skeleton drugs have been used in clinical practice. [0003] There are many reports on the synthesis methods of imidazopyridine and its derivatives, for example, imidazole ring is constructed with pyridine ring compound as the basic skeleton, or pyridine ring is ...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/4545A61P3/10A61P13/12A61P25/00A61P3/04A61P3/06A61P5/50A61P27/02
CPCC07D471/04A61P3/10A61P13/12A61P25/00A61P3/04A61P3/06A61P5/50A61P27/02
Inventor 翟文强张智敏王哲王前郭刘斌刘东舟
Owner HANGZHOU ZHONGMEI HUADONG PHARMA
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