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3‑(1,2,4‑triazolo[4,3‑a]pyridin‑3‑yl)‑4‑(1h‑indol‑3‑yl)maleimide derivatives and preparation thereof Methods and Applications

A technology of maleimide and triazole, applied in drug combination, cardiovascular system diseases, organic chemistry, etc., can solve problems such as easy bleeding and narrow time window, and achieve low equipment requirements and good product yield , the effect of simple operation

Active Publication Date: 2017-03-08
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although some progress has been made in the current clinical treatment of stroke, such as the thrombolytic drug tissue plasminogen activator (t-PA), this method has certain limitations, such as a narrow time window for effective treatment , prone to bleeding

Method used

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  • 3‑(1,2,4‑triazolo[4,3‑a]pyridin‑3‑yl)‑4‑(1h‑indol‑3‑yl)maleimide derivatives and preparation thereof Methods and Applications
  • 3‑(1,2,4‑triazolo[4,3‑a]pyridin‑3‑yl)‑4‑(1h‑indol‑3‑yl)maleimide derivatives and preparation thereof Methods and Applications
  • 3‑(1,2,4‑triazolo[4,3‑a]pyridin‑3‑yl)‑4‑(1h‑indol‑3‑yl)maleimide derivatives and preparation thereof Methods and Applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: 2-(1,2,4-triazolo[4,3- a Preparation of ]-3-yl)ethyl acetate (2)

[0032] Add 3.0 g (45.8 mmol) 2-hydrazinopyridine, 22.0 g (137.5 mmol) diethyl malonate and 60 mL phosphorus oxychloride into the three-necked flask, and reflux for 3 h. After the reaction, the reaction liquid is cooled. Pour into 300 mL of ice water, neutralize to weak alkalinity with sodium bicarbonate, fully extract with ethyl acetate, combine organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use silica gel column chromatography (petroleum ether) for the residue : ethyl acetate=2:1) ​​purified to obtain 2.7g white solid 2, yield 48%, melting point: 113-115 o c. 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.45 (d, J = 7.0 Hz, 1H), 7.77 (d, J = 9.2Hz, 1H), 7.48-7.30 (m, 1H), 7.01 (t, J = 6.8 Hz, 1H), 4.42 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H).

Embodiment 2

[0033] Example 2: 2-(1,2,4-triazolo[4,3- a Preparation of ]-3-yl)acetamide (3)

[0034] Add 2.0 g (9.8 mmol) 2, 30 mL of saturated methanol solution of ammonia to the pressure reaction vessel, 90 o C reacted for 6 h. The reaction solution was cooled and filtered, the filter cake was washed with a small amount of methanol, and dried to obtain 0.88 g of white solid 3, the yield was 51.3%, and the melting point was 247-249 o c. 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.39 (d, J = 7.0 Hz, 1H), 7.81(s, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.39-7.31 (m, 1H), 7.24 (s, 1H), 6.96 (t, J = 6.8 Hz, 1H), 4.13 (s, 2H). 13 C NMR (125 MHz, DMSO- d 6 ) δ168.76, 149.31,142.61, 127.22, 124.42, 114.96, 112.80, 31.47. ESI-MS: m / z [M+H] + 177. A nal.Calcd for C 8 h 8 N 4 o 2 : C, 54.54; H, 4.58; N, 31.80. Found: C, 54.66; H, 4.31; N,31.64.

Embodiment 3

[0035] Example 3: Preparation of 2-(1H-indol-3-yl)-2-oxoacetic acid methyl ester (5a)

[0036] Add 3.0 g (0.026 mol) of indole and 30 mL of anhydrous ether into a three-neck flask, stir to dissolve, and control the temperature from 0 to 5 o C, Slowly add 3.4 g (0.026 mol) of oxalyl chloride in anhydrous ether (5 mL) solution, keep it warm for 1 h after the drop, then cool down to about -25 ℃, add dropwise 16.3 g of sodium methoxide in methanol solution (17.5 %, 0.052 mol), kept stirring for 30 min after dropping, poured the reaction solution into 100 mL of ice water, filtered it with suction, washed with water (3 × 10 mL), washed with dichloromethane (2 × 10 mL), and dried to obtain 4.5 g pale yellow solid 5a, yield 86.3%, melting point: 208-210 o c. 1 H NMR (500 MHz, DMSO- d 6 ) δ 12.48 (brs, 1H), 8.46 (d, J = 3.5 Hz, 1H), 8.16 (d, J = 7.0 Hz,1H), 7.55 (d, J = 7.0 Hz, 1H), 7.32-7.26 (m, 2H), 3.90 (s, 3H).

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Abstract

The invention provides a 3-(1,2,4-triazolo(4,3-a)pyridine-3-yl)-4-(1H-indole-3-yl)maleimide derivative with a novel structure and a preparation method and application of the derivative. The compound can be used for treating ischemic cerebral apoplexy. The general structural formula of the compound is shown in the specification.

Description

technical field [0001] The present invention relates to a kind of 3-(1,2,4-triazolo[4,3-a]pyridin-3-yl)-4-(1H-indol-3-yl)maleimides Derivative and its preparation method and application in ischemic cerebral apoplexy. Background technique [0002] Stroke seriously endangers human health and is one of the main causes of death worldwide. About 6 million people die from this disease every year, and the disability rate of survivors is also very high. Ischemic stroke accounts for 85% of all strokes. It is a common and frequently-occurring disease among middle-aged and elderly people, and has the characteristics of high incidence, disability, mortality and recurrence. The damage of brain tissue caused by ischemic stroke is due to the excitotoxicity of neurotransmitters (glutamic acid), oxidative stress, inflammation, apoptosis caused by hypoxia and glucose, lack of serum, etc. produced by the action of factors. Although some progress has been made in the current clinical treatme...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61P9/10
CPCC07D471/04
Inventor 叶青李佳庞涛高建荣周宇波许磊毛伟丽
Owner ZHEJIANG UNIV OF TECH