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Indolizine-amide derivatives, their preparation method and their application in medicine

A compound and mixture technology, applied in the field of factor XIa inhibitors and disease drugs, can solve the problems of unpublished clinical results

Active Publication Date: 2018-04-17
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] As an emerging target, FXIa has not yet announced its clinical drug, but Bristol-Myers Squibb's BMS-654457 and BMS-262084 may have started clinical research, and the clinical results have not yet been published

Method used

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  • Indolizine-amide derivatives, their preparation method and their application in medicine
  • Indolizine-amide derivatives, their preparation method and their application in medicine
  • Indolizine-amide derivatives, their preparation method and their application in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0148] (S)-5-(7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine- 3-amido)-1H-indole-2-carboxylic acid methyl ester

[0149]

[0150]

[0151] first step

[0152] (S)-5-(7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-amido)-1H-indole -2-Carboxylic acid methyl ester

[0153] 5-Amino-1H-indole-2-carboxylic acid methyl ester 1a (124 mg, 0.64 mmol, prepared by the known method "Journal of the American Chemical Society, 2007, 129 (35), 10858-10869"), (S)-7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid 1b (200mg, 0.64mmol, using Prepared by the method disclosed in the patent application "WO2013093484"), 1-hydroxybenzotriazole (104mg, 0.77mmol), dicyclohexylcarbodiimide (160mg, 0.77mmol) were dissolved in 10mL N,N-dimethyl Formamide, stirred at room temperature for 16 hours. Filter and wash the filter cake with 20 mL of N,N-dimethylformamide. The mother liquors were combined and concentrated under re...

Embodiment 2

[0160] (S)-5-(7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine- 3-amido)-1H-indole-2-carboxylic acid

[0161]

[0162] first step

[0163] (S)-5-(7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine -3-amido)-1H-indole-2-carboxylic acid methyl ester 1 (23mg, 0.043mmol) was added to 2mL methanol and tetrahydrofuran (V / V=1:1) mixed solvent, and 0.2mL 2N hydroxide was added Lithium solution was stirred at room temperature for 2 hours. Concentrate under reduced pressure, add 10mL of water, add dropwise 2M hydrochloric acid to adjust the pH to 2~3, extract with dichloromethane and methanol (V / V=5:1, 30mL×3), combine the organic phases, wash with anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure. Purification (HPLC) of the resulting residue by preparative separation gave the title product (S)-5-(7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo -1,2,3,5-tetrahydroindolizine-3-amido)-1H-indole...

Embodiment 3

[0167] (S)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-N-(1H-indol-5-yl)-5-oxo-1,2, 3,5-Tetrahydroindolizine-3-carboxamide

[0168]

[0169]

[0170] first step

[0171] (S)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxy acid

[0172] (S)-7-(2-amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid 1b (60mg, 0.2mmol), Sodium azide (13 mg, 0.2 mmol) was dispersed in 0.3 mL of trimethyl orthoformate, and then 2 mL of glacial acetic acid was added dropwise, and the reaction was stirred at 65°C for 16 hours. Concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography with an eluent system to give the title product (S)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5 -Oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid 3a (73 mg, gray solid), yield: 98.0%.

[0173] MS m / z(ESI): 358.1[M+1]

[0174] second step

[0175] (S)-7-(5-chloro-2-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-N-(1H-i...

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Abstract

The present invention relates to an indole-amide derivative, a preparation method therefor and an application thereof in medicine. Specifically, the present invention relates to an indole-amide derivative represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the derivative, a use thereof as a therapeutic agent, especially as an XIa factor inhibitor, and a use thereof in the preparation of drugs for treating and / or preventing diseases such as thromboembolism, wherein the definition of the substituents in general formula (I) is the same as that in the specification.

Description

technical field [0001] The present invention relates to a new class of indolizine-amide 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 therapeutic and / or prophylactic Use in medicine for diseases such as thromboembolism. 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 cerebrovas...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D405/06C07D409/06A61K31/4427A61K31/4412A61P7/00A61P9/00
CPCA61K31/4412A61K31/4427C07D401/14C07D405/06C07D409/06
Inventor 杨方龙瞿健王春飞董庆孙飘扬应永铖
Owner JIANGSU HENGRUI MEDICINE CO LTD
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