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Oxazoloindole derivatives, their preparation method and their application in medicine

A technology of drugs and compounds, which is applied in the field of oxazoloindole derivatives, their preparation and their application in medicine, and can solve the problems of high cytotoxicity, excessive hydrophilicity or lipophilicity, adverse reactions, etc.

Active Publication Date: 2019-12-13
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Many anticancer drugs show quite high anticancer activity in the development or clinical research stage, but due to their strong hydrophilicity or lipophilicity, low targeting and high cytotoxicity, they cause adverse reactions

Method used

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  • Oxazoloindole derivatives, their preparation method and their application in medicine
  • Oxazoloindole derivatives, their preparation method and their application in medicine
  • Oxazoloindole derivatives, their preparation method and their application in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0114] (S)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-carbonyl-N-(1'-carbonyl-1'H-spiro[cyclobutane- 1,3'-oxazolo[3,4-a]indol]-7'-yl)-1,2,3,5-tetrahydroindolizine-3-carboxamide

[0115]

[0116] first step

[0117] (1'-Carbonyl-1'H-spiro[cyclobutane-1,3'-oxazolo[3,4-a]indol]-7'-yl)carbamate tert-butyl ester

[0118] 5-((tert-butoxycarbonyl)amino)-1H-indole-2-carboxylic acid 1a (1.10g, 4mmol, using the known method "Journal of the American Chemical Society, 2007, 129 (17), 5384- 5390" prepared) was dissolved in 30mL tetrahydrofuran, N,N'-carbonyldiimidazole (1269mg, 8mmol) was added under ice-cooling, the reaction solution was raised to room temperature, stirred for 1.5 hours, and cyclobutanone 1b (700mg, 10mmol) was added , 1,8-Diazabicycloundec-7-ene (1.58 g, 10.4 mmol), stirred for 3 hours. Add 50mL water to the reaction solution, extract with ethyl acetate (50mL×3), collect the organic layer, wash with 50mL water and 50mL saturated sodium chloride solution successively, ...

Embodiment 2

[0130] (S)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-N-(3,3-dimethyl-1-carbonyl-1,3-dihydrooxane Azolo[3,4-a]indol-7-yl)-5-carbonyl-1,2,3,5-tetrahydroindolizine-3-carboxamide

[0131]

[0132] first step

[0133] (3,3-Dimethyl-1-carbonyl-1,3-dihydrooxazolo[3,4-a]indol-7-yl)carbamate tert-butyl ester

[0134] 5-((tert-butoxycarbonyl)amino)-1H-indole-2-carboxylic acid 1a (500mg, 1.81mmol) was dissolved in 20mL tetrahydrofuran, and N,N'-carbonyldiimidazole (734mg, 4.52mmol), the reaction solution was raised to room temperature, stirred for 1.5 hours, added 10mL of acetone, 1,8-diazabicycloundec-7-ene (720mg, 4.70mmol), stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified with a CombiFlash flash preparation apparatus with eluent system B to obtain the title product (3,3-dimethyl-1-carbonyl-1,3-dihydrooxazolo[3, 4-a] Indol-7-yl) tert-butyl carbamate 2a (375 mg, yellow solid), yield: 65.6%.

[0135] MS m / z(ES...

Embodiment 3

[0145] (S)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-carbonyl-N-(1'-carbonyl-1'H-spiro[cyclopentane- 1,3'-oxazolo[3,4-a]indol]-7'-yl)-1,2,3,5-tetrahydroindolizine-3-carboxamide

[0146]

[0147] first step

[0148] (1'-Carbonyl-1'H-spiro[cyclopentane-1,3'-oxazolo[3,4-a]indol]-7'-yl)aminomethyl tert-butyl ester

[0149]5-((tert-butoxycarbonyl)amino)-1H-indole-2-carboxylic acid 1a (500 mg, 1.81 mmol) was dissolved in 10 mL of tetrahydrofuran, and N,N'-carbonyldiimidazole (587 mg, 3.62mmol), the reaction solution was raised to room temperature, stirred for 1 hour, added cyclopentanone 3a (396mg, 4.71mmol), 1,8-diazabicycloundec-7-ene (0.7mL, 4.71mmol), Stir for 3 hours. Add 30mL water to the reaction solution, extract with ethyl acetate (30mL×3), wash with 30mL water and 30mL saturated sodium chloride solution successively, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use CombiFlash to flash The resulting...

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Abstract

The invention relates to an oxazoleindole derivative, and a preparation method and medical applications thereof, and more specifically relates to an oxazoleindole derivative with a general formula represented by formula I, a preparation method thereof, a pharmaceutical composition containing the oxazoleindole derivative, and applications of the pharmaceutical composition as a therapeutic agent, especially as an XIa factor inhibitor, and in preparing drugs used for treating diseases such as thromboembolism, wherein the substituent groups in general formula I are defined in the patent specification.

Description

technical field [0001] The present invention relates to a new class of oxazoloindole derivatives, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as a factor XIa inhibitor and in the preparation of treatment and prevention of thromboembolism, etc. Use in medicine for disease. Background technique [0002] Cardiovascular and cerebrovascular diseases such as cerebrovascular disease, cerebral infarction, myocardial infarction, coronary heart disease and arteriosclerosis claim the lives of nearly 12 million people every year in the world, accounting for nearly 1 / 4 of the total death toll in the world, becoming the number one enemy of human health. In China, more than 2.6 million people die from cardiovascular diseases every year, and 75% of the surviving patients are disabled, and more than 40% of them are seriously disabled. The thrombus problem caused by cardiovascular and cerebrovascular dise...

Claims

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Application Information

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IPC IPC(8): C07D519/00C07D471/04C07D498/20C07D498/10A61K31/437A61P9/10A61P7/02A61P9/00
CPCC07D471/04C07D498/10C07D498/20C07D519/00
Inventor 杨方龙王伟民应永铖贺峰孙飘扬
Owner JIANGSU HENGRUI MEDICINE CO LTD
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