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Oxazolidinone compound containing double ring fused bicyclic ring and its preparation and application

A technology for fused bicyclic compounds, which is applied in the field of oxazolidinone compounds containing double-fused bicyclic rings and its preparation and application, can solve the problems of continuous emergence of linezolid drug resistance, single type of oxazolidinone antibiotics, Gram-positive bacteria serious and other problems

Active Publication Date: 2016-10-19
JILIN SIHUAN PHARM CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the drug resistance of Gram-positive bacteria is becoming more and more serious clinically, The variety of oxazolidinone antibiotics in clinical use is single, which cannot meet the clinical needs, and the drug resistance of linezolid is also emerging

Method used

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  • Oxazolidinone compound containing double ring fused bicyclic ring and its preparation and application
  • Oxazolidinone compound containing double ring fused bicyclic ring and its preparation and application
  • Oxazolidinone compound containing double ring fused bicyclic ring and its preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0159] Embodiment 1: (5 S )-N-[[3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Base] -2-oxo- Preparation of oxazolidin-5-yl]methyl]acetamide

[0160]

[0161] Add 30mL 1,4-dioxane, 3.31g (10mmol) (5S)-N-[[3-(3-fluoro-4-bromophenyl)-2-oxo- Oxazolidin-5-yl] methyl] acetamide, 2.54g (10mmol) dipivaleroyl diborane, and 0.98g (10mmol) potassium acetate, and to which argon is passed into, then add 0.3g Pd (PPh 3 ) 2 Cl 2 , continue to feed argon into the reaction solution, and stir the reaction overnight at 90°C. The resulting reaction mixture was cooled to room temperature, filtered with diatomaceous earth, extracted with ethyl acetate and brine, the organic layer was dried over anhydrous sodium sulfate, concentrated, a gray solid was precipitated, and 3.22 g of the product was obtained by filtration, with a yield of 85.2%. ((5S)-N-[[3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 used in the following examples -yl)phenyl]-2-oxo- Oxa...

Embodiment 2

[0162] Embodiment 2: N-[[(5 S )-3-[4-[1-[(1 h -1,2,3-triazol-5-yl)methylamino]- 2 , 3-Dihydro-1 h -indene- 5-yl]-3-fluorophenyl]-2-oxo- Preparation of oxazolidin-5-yl]methyl]acetamide hydrochloride (compound 1 hydrochloride)

[0163](1) Preparation of 5-bromo-N-(2-propynyl)-2,3-dihydro-1H-inden-1-amine

[0164]

[0165] Dissolve 6.6g (0.12mol) of propargylamine and 22.9g (0.109mol) of 5-bromo-1-indanone in 1,2-dichloroethane (300mL), and add 30.02g (141mmol) NaBH(OAc) 3 , after the addition, the mixture was stirred and reacted at room temperature for 40 hours, the organic phase was washed with water (50 mL×2) and NaCl (150 mL×2) successively, and dried over anhydrous magnesium sulfate to obtain 8.9 g of the target product.

[0166] (2) Preparation of tert-butyl 5-bromo-2,3-dihydro-1H-inden-1-yl (2-propynyl)carbamate

[0167]

[0168] Dissolve 8.9g (0.036mol) of 5-bromo-N-(2-propynyl)-2,3-dihydro-1H-inden-1-amine in 50mL of methanol, add 7.2g (0.071mol) o...

Embodiment 3

[0183] Embodiment 3: N-[[(5 S ）-3-[4-[1-[2-( 1 H-1,2,3-triazol-5-yl)ethyl]indoline-5-yl]-3- Fluorophenyl]-2-oxo- Preparation of oxazolidin-5-yl]methyl]acetamide (compound 2)

[0184] (1) Preparation of 3-butynyl methanesulfonate

[0185]

[0186] In a 250mL reaction flask, dissolve 0.5g (7.13mmol) of 3-butyn-1-alcohol and 2.17g (21.4mmol) of triethylamine with 80mL of dichloromethane, and slowly add 1.06g (9.23 mmol) methanesulfonyl chloride, about 10 minutes. After the cooling bath was removed, the reaction was stirred at room temperature for 5 hours. The organic phase was washed successively with 1M HCl (aqueous solution) and sodium chloride, then dried with anhydrous magnesium sulfate, filtered and evaporated to dryness under reduced pressure to obtain 0.93 g of oily 3-butane Alkynyl mesylate, yield 88%.

[0187] (2) Preparation of 5-bromo-1-(3-butynyl)indoline

[0188]

[0189] Add 5.3g (50mmol) Na to a toluene solution (50mL) of 4.95g (25mmol) 5-bromoi...

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Abstract

Oxazolidinone compounds containing ring-fused bicyclic ring represented by the general formula (I), pharmaceutically acceptable salts and stereoisomers thereof are disclosed, wherein R1, R2, R3, R4, R5, R6, and -Y- are defined as in the description. Also disclosed are the preparation methods of such compounds, pharmaceutical compositions and pharmaceutical preparations containing the same and uses of the same in the manufacture of medicaments for treating and / or preventing infectious diseases, and in the treatment and / or prevention of infectious diseases.

Description

technical field [0001] The present invention relates to containing and ring-fused bicyclic Oxazolidinone compounds and their pharmaceutically acceptable salts and their stereoisomers, their preparation methods, pharmaceutical compositions containing the compounds, and the preparation of the compounds and pharmaceutical compositions for the treatment and / or prevention of infection Drugs and applications in the treatment and / or prevention of infectious diseases. Background technique [0002] Oxazolidinone antibacterial drugs are a new type of chemically synthetic antibacterial drugs developed after sulfonamides and fluoroquinolones, which can inhibit multi-drug resistant Gram-positive bacteria. [0003] Linezolid was the first to market oxazolidinone antibiotics, [0004] [0005] It has a strong inhibitory effect on Gram-positive bacteria and has no cross-resistance with other antibacterial drugs. Its unique mechanism of action inhibits the early stages of bacteria...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/12C07D413/14C07D413/10C07D417/14C07D471/04C07D513/04A61K31/422A61K31/4709A61K31/4725A61K31/498A61K31/428A61K31/423A61K31/517A61K31/435A61K31/437A61P31/04
CPCA61P31/04C07D413/12C07D413/14C07D417/14C07D471/04C07D513/04
Inventor 黄振华周广连宋运涛
Owner JILIN SIHUAN PHARM CO LTD