Nitrogen heterocyclic ring substituent containing benzoxazine oxazolidinone compound as well as preparation method and application thereof

A compound, unsubstituted technology for use in medicine to address issues such as safety and efficacy interruption studies

Active Publication Date: 2018-11-02
北京协和制药二厂有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

AstraZeneca's Posizolid (AZD5847) has entered phase II clinical trials, but has recently been suspended due to safety and efficacy issues

Method used

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  • Nitrogen heterocyclic ring substituent containing benzoxazine oxazolidinone compound as well as preparation method and application thereof
  • Nitrogen heterocyclic ring substituent containing benzoxazine oxazolidinone compound as well as preparation method and application thereof
  • Nitrogen heterocyclic ring substituent containing benzoxazine oxazolidinone compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0216] Preparation of ((2R,3S)-3-(((tert-butyldimethylsilyl)oxy)methyl)epoxy-2-yl)methanol (Intermediate 1)

[0217]

[0218] Add 4A molecular sieves (7.2 g) and anhydrous dichloromethane (180 mL) into a 500 mL three-necked flask, protect the system with Ar, and cool down to -20°C. D-(-)-Diethyl tartrate (7.8 mL, 45.7 mmol) was added, followed by dropwise addition of tetraisopropyl titanate (12 mL, 39.8 mmol), and the system turned yellow. After stirring for 0.5 h, (Z)-4-((tert-butyldimethylsilyl)oxy)but-2-en-1-ol (12 g, 59.4 mmol) was added and stirred for 1 h. A toluene solution of tert-butanol peroxide (5M, 28.5 mL, 142 mmol) was added dropwise and kept stirring overnight. After TLC monitors the reaction, add FeSO-containing 4 ·7H 2 A tartaric acid solution (10%, 192 mL) of O (23.4 g, 84 mmol) was stirred at 0° C. for 5 hours, and then the layers were separated. Filter, separate the organic phase, extract the aqueous phase once with dichloromethane, and combine the o...

preparation example 2

[0220] Preparation of ((2S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)epoxy-2-yl)methanol (intermediate 2)

[0221]

[0222] In the preparation method of intermediate 1, D-(-)-diethyl tartrate was replaced by L-(+)-diethyl tartrate, and the reaction was carried out to obtain intermediate 2, 3.0 g of light yellow oil, yield 55.6%.

preparation example 3

[0224] Preparation of ((2R,3S)-3-((trityloxy)methyl)epoxy-2-yl)methanol (intermediate 3)

[0225]

[0226] Add 4A molecular sieves (12 g) and anhydrous dichloromethane (330 mL) into a 1 L four-necked flask, protect the system with Ar, and cool down to -40°C. D-(-)-diethyl tartrate (13.6 mL, 79.2 mmol) was added, followed by dropwise addition of tetraisopropyl titanate (18.8 mL, 63.4 mmol), and the system turned yellow. After stirring for 0.5 h, add (Z)-4-(trityloxy)but-2-en-1-ol (26.1 g, 79.2 mmol) in dichloromethane (120 mL), and stir for 0.5 h. A toluene solution of tert-butanol peroxide (3.8M, 50 mL, 190 mmol) was added dropwise and kept stirring for 2 h, and stirred overnight at -20°C. After TLC monitors the reaction, add FeSO-containing 4 ·7H2 A tartaric acid solution (10%, 200 mL) of O (30 g) was stirred at 0°C for 1 hour, and then the layers were separated. The organic phase was separated, and the solution phase was extracted twice with dichloromethane, and the co...

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Abstract

The invention discloses a nitrogen heterocyclic ring substituent containing benzoxazine oxazolidinone compound as well as a preparation method and application thereof in preparing medicines for treating and / or preventing mycobacterium tuberculosis caused infectious diseases. Specifically, the invention relates to a compound of formula (I) as shown in the specification, and a stereisomer thereof, apharmaceutically acceptable salt thereof, a medicinal composition with the compound, a use method thereof, and a medicine for preparing the compounds, wherein X1, X2, R1 and R2 are as shown in the specification.

Description

technical field [0001] The invention belongs to the technical field of medicine. In particular, it relates to nitrogen-containing heterocyclic substituted benzoxazine oxazolidinone compounds represented by general formula (I), their preparation methods, pharmaceutical compositions using the compounds as active ingredients, and their therapeutic and / or prophylactic Use in infectious diseases caused by Mycobacterium tuberculosis. Background technique [0002] Tuberculosis (TB) is a chronic fatal disease caused by Mycobacterium tuberculosis. It is a major infectious disease that endangers human health and causes human death. Tuberculosis, like AIDS, has become one of the leading causes of death in the world. According to World Health Organization (WHO) estimates (Global tuberculosis report 2015): 9.6 million people in the world suffered from tuberculosis in 2014 (5.4 million men, 3.2 million women and 1 million children), and 1.5 million died (1.1 million HIV-negative people) ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/04C07D519/00A61K31/541A61K31/542A61K31/5383A61P31/06
CPCA61P31/06C07D498/04C07D519/00A61K31/5383A61K31/541C07D498/06C07D513/08
Inventor 黄海洪张东峰赵红义
Owner 北京协和制药二厂有限公司
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