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Oxazolidinone antibiotics containing five-membered heterocycles

An alkyl and alkoxy technology, applied in the field of medicine, can solve the problems of the continuous emergence of linezolid resistance, the inability to meet clinical needs, and the single variety of oxazolidinone antibiotics.

Inactive Publication Date: 2011-12-14
SHANDONG XUANZHU PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

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

Method used

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  • Oxazolidinone antibiotics containing five-membered heterocycles
  • Oxazolidinone antibiotics containing five-membered heterocycles
  • Oxazolidinone antibiotics containing five-membered heterocycles

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] Example 1N-[[(S)-3-[3-fluoro-4-[5-[(1-methyl-1H-tetrazol-5-yl)methyl]thiophen-2-yl]phenyl] -2-Oxooxazole Preparation of alk-5-yl]methyl]acetamide (compound 1)

[0112]

[0113] (1) Tri-n-butyltin azide

[0114]

[0115] Add 200 mL of tert-butyl methyl ether and tri-n-butyltin chloride (15 g) to NaN 3 (34g) in water (200mL), the mixture was stirred at room temperature for 1 hour, the organic phase was collected by separation and dried over anhydrous magnesium sulfate, and the product was concentrated as an oil (15g, 97%).

[0116] (2) 2-(5-bromothien-2-yl)acetonitrile

[0117]

[0118] At room temperature, NBS (31.6g, 0.178mol) was added to a DMF solution of 2-(thiophen-2-yl)acetonitrile (20g, 0.163mol), and the mixture was refluxed for 5 hours, washed with water and NaOH solution after cooling, The organic phase was dried and concentrated, and the crude product was obtained by column chromatography as an oil (21 g, 64%).

[0119] (3) 5-[(5-bromothiophen...

Embodiment 2

[0148] Example 2N-[[(S)-3-[4-[5-[(1H-tetrazol-5-yl)methyl]thiophen-2-yl]-3-fluorophenyl]-2-oxo Oxazolidin-5-yl] Preparation of methyl] acetamide (compound 2)

[0149]

[0150] (1) 2-(5-bromothien-2-yl)acetonitrile

[0151]

[0152] With reference to Example 1 (2), the product obtained is an oil (21g, 64%).

[0153] (2) 5-[(5-bromothiophen-2-yl)methyl]-1H-tetrazole

[0154]

[0155] With reference to Example 1 (3), the product obtained was a solid (9.06g, 97%).

[0156] (3) N-[[(S)-3-[4-[5-[(1H-tetrazol-5-yl)methyl]thiophen-2-yl]-3-fluorophenyl]-2-oxo Oxazolidin-5-yl]methyl]acetamide

[0157]

[0158] N-[[(S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] -2-Oxooxazolidin-5-yl]methyl]acetamide (1.2g, 0.003mol), 5-[(5-bromothiophen-2-yl)methyl]-1H-tetrazole (0.8g , 0.003mol), Na 2 CO 3 (0.68g, 0.006mol) and 5mL water were dissolved in 20mL DMSO, to which 0.5g Pd(dppf) was added 2 Cl 2 , the mixture was reacted at 90° C. under nitroge...

Embodiment 3

[0161] Example 3N-[[(S)-3-[4-[5-[(3H-1,2,3-triazol-4-yl)methyl]thiophen-2-yl]-3-fluorophenyl ]-2-oxooxazolidine Preparation of -5-yl] methyl] acetamide (compound 3)

[0162]

[0163] (1) 2-bromo-5-(chloromethyl)thiophene

[0164]

[0165] Add 30 mL of petroleum ether to concentrated hydrochloric acid (18 mL) and 37% formaldehyde solution (18 mL), cool to 5 ° C, add 2-bromothiophene (30 g, 0.185 mol) to it, and pass HCl gas into it under vigorous stirring And keeping the system temperature below 10°C, the organic phases were combined after petroleum ether extraction and concentrated to obtain a yellow oil (34 g, 87%).

[0166] (2) [3-(5-Bromothiophen-2-yl)-1-propynyl]trimethylsilane

[0167]

[0168] Trimethylsilylacetylene (6.7mL, 0.047mol) and ethylmagnesium bromide (15mL, 0.047mol) were dissolved in THF (30mL), and after the mixture was stirred for 0.5 hours, CuBr (0.3g, 2.4mmol) was added thereto and 2-bromo-5-(chloromethyl)thiophene (10g, 0.047mmol), reflux...

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Abstract

The present invention belongs to the technical field of medicine, and specifically relates to an oxazolidinone antibiotic containing a five-membered heterocycle represented by general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof: wherein R1, R2, R3, R4, R5, R6, R7, R8, A, X or n are as defined in the description; the present invention also relates to the preparation method of these compounds, the pharmaceutical composition containing these compounds, and the preparation of these compounds in the treatment and / or prevention of infection Use in medicine for diseases.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to oxazolidinone antibiotics containing five-membered heterocyclic rings, pharmaceutically acceptable salts or stereoisomers thereof, methods for preparing these compounds, pharmaceutical compositions containing these compounds, and Use of these compounds in preparing medicines for treating and / or preventing infectious diseases. 2. Background technology [0002] Oxazolidinone antibacterial drugs are a new type of chemically synthesized antibacterial drugs developed after sulfonamides and fluoroquinolones, which can inhibit multi-drug resistant Gram-positive bacteria. [0003] Linezolid is the first marketed oxazolidinone antibiotic. [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 bacterial protein synthesis. Linez...

Claims

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Application Information

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IPC IPC(8): C07D413/14A61K31/422A61P31/04
Inventor 黄振华
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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