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Oxazolidinone derivatives, their preparation method and their application in medicine

An alkyl and drug technology, applied in the field of disease drugs, cholesteryl ester transfer protein inhibitors, can solve problems such as adverse reactions

Inactive Publication Date: 2015-11-25
SHANGHAI HENGRUI PHARM CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is currently no CETP inhibitor drug on the market, and the phase III clinical trial of Pfizer's CETP inhibitor torcetrapib was forced to stop due to serious adverse reactions

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0161] (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(ethyl((S)-tetrahydrofuran-3-yl)amino)-5-(tri Fluoromethyl) Phenyl)-4-methyloxazol-2-one

[0162]

[0163] first step

[0164] (S)-2-((tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)benzoic acid

[0165] Dissolve 2-fluoro-5-(trifluoromethyl)benzoic acid 1a (560mg, 2.70mmol, prepared by the known method "patent US2009306423") in 20mL N,N-dimethylformamide, add (S )-3-aminotetrahydrofuran p-toluenesulfonate (700mg, 2.70mmol) and anhydrous potassium carbonate (1.86g, 13.50mmol), stirred at 100°C for 12 hours. Cool to room temperature, add 1M hydrochloric acid dropwise until the pH of the reaction solution is 3-4, add 20mL water, extract with ethyl acetate (30mL×2), combine the organic phases, wash with saturated sodium chloride solution (30mL×2), no Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give the title product (S)-2-((tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)ben...

Embodiment 2

[0185] trans-4-((2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazolidin-3-yl )First base)-4-(trifluoromethyl)phenyl)(ethyl)amino)cyclohexanecarboxylic acid

[0186]

[0187] first step

[0188] trans-methyl 4-(ethyl(2-formyl-4-(trifluoromethyl)phenyl)amino)cyclohexanecarboxylate

[0189]2-Fluoro-5-(trifluoromethyl)benzaldehyde 1a (576mg, 3mmol) and trans-4-(Ethylamine) cyclohexanecarboxylate methyl ester (667mg, 3.60mmol, using the "patent application WO200971509" published Prepared by method) was dissolved in 10 mL of toluene, anhydrous potassium carbonate (622 mg, 4.50 mmol) was added, reacted under microwave at 150°C for 2 hours, and continued stirring at 100°C for 12 hours. Filter, extract with ethyl acetate (30mL×2), combine the organic phases, wash with saturated sodium chloride solution (30mL×2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, use silica gel column chromatography to wash The res...

Embodiment 3

[0208] (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(ethyl((R)-tetrahydrofuran-3-yl)amino)-5-(tri Fluoromethyl) Phenyl)-4-methyloxazol-2-one

[0209]

[0210]

[0211] first step

[0212] (R)-2-((tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)benzoic acid

[0213] Dissolve 2-fluoro-5-(trifluoromethyl)benzoic acid 1a (416mg, 2mmol) in 4mL N,N-dimethylformamide, add (R)-3-aminotetrahydrofuran hydrochloride (247mg, 2mmol ) and anhydrous potassium carbonate (1.38g, 10mmol), placed in a sealed tube, stirred at 100°C for 12 hours. Cool to room temperature, add 1M hydrochloric acid dropwise until the pH of the reaction solution is 3-4, add 20mL water, extract with ethyl acetate (30mL×2), combine the organic phases, wash with saturated sodium chloride solution (30mL×2), no Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give the title product (R)-2-((tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)benzoic acid 3a crude product (40...

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PUM

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Abstract

The present invention relates to an oxazolidinone derivative, the preparation method thereof and the use thereof in medicine. In particular,the present invention relates to a new oxazolidinone derivative of general formula (I), the preparation method thereof and a pharmaceutical composition containing the derivative and the use thereof as a therapeutic agent, in particular the use as a cholesteryl ester transfer protein (CETP) inhibitor and the use for preparing a drug for treating diseases such as atherosis etc, wherein each substituent of general formula (I) is the same as the definition of the description.

Description

technical field [0001] The present invention relates to a new class of oxazolidinone derivatives, their preparation methods and pharmaceutical compositions containing the derivatives and their use as therapeutic agents, especially as cholesteryl ester transfer protein (CETP) inhibitors and in the preparation of therapeutic and Use in medicines for preventing diseases such as atherosclerosis. Background technique [0002] Coronary atherosclerotic heart disease (coronary heart disease, CHD) is a coronary artery stenosis or even complete blockage caused by coronary atherosclerosis, spasm and other factors, causing insufficient blood supply and oxygen supply to the myocardium, leading to angina pectoris and even myocardial infarction diseases with clinical symptoms. It is estimated that more than 17 million people worldwide die from CHD every year, and this number is still rising as the average age of CHD patients increases and the incidence of obesity and diabetes rises sharpl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/22C07D263/20C07D405/12C07D405/06C07D413/12C07D413/06A61K31/4015A61K31/421A61P9/10
CPCC07D413/12A61K31/4015C07D211/58C07D263/20C07D307/22C07D309/14C07D401/12C07D405/12C07D413/14C07D263/22A61P3/06A61P9/10
Inventor 杨方龙董庆张羚沈光远王春飞应永铖孙飘扬
Owner SHANGHAI HENGRUI PHARM CO LTD