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Cephalosporin derivative containing nitrogen-containing fused-heterocycle

A technology of azabicycle and thia, applied in medical preparations containing active ingredients, organic chemistry, antibacterial drugs, etc., can solve problems affecting antibacterial efficacy and restricting applications

Active Publication Date: 2012-12-26
HAINAN SIHUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In recent years, the number of infections caused by Pseudomonas aeruginosa has been increasing, and its drug resistance has been increasing. use, resulting in a certain resistance to the fourth-generation cephalosporins, which greatly affects the antibacterial efficacy and limits its clinical application. Therefore, it is urgent to find new antibiotics through structural modification.

Method used

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  • Cephalosporin derivative containing nitrogen-containing fused-heterocycle
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  • Cephalosporin derivative containing nitrogen-containing fused-heterocycle

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Example 1 (6R, 7R)-7-[[2-[(2-aminothiazole)-4-yl]-Z-2-methoxyimino]acetamido]-3-(5-chloro- 1-methyl-1H- Indol-1-yl)methylene-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid internal salt (compound 1)

[0109] Step 1 (6R, 7R)-7-amino-3-(5-chloro-1-methyl-1H-indol-1-yl)methylene-8-oxo-5-thia-1-nitrogen Preparation of heterobicyclo[4.2.0]oct-2-ene-2-carboxylic acid inner salt

[0110] Under the protection of nitrogen, in a dry reaction flask, add 100 mL of trifluorotrichloroethane, (6R, 7R)-7-amino-3-acetoxymethyl-8-oxo-5-thia-1-nitrogen Heterobicyclo[4.2.0]oct-2-ene-2-carboxylic acid (7-ACA) 13.6g (50mmol), hexamethyldisilazamethane (HMDS) 11.5mL (55mmol), heated to reflux for 8h and protected by nitrogen Cool down to 10°C. Under nitrogen protection, TMSI 8mL (56mmol) was added dropwise at room temperature, the reaction was vigorously stirred for 6h, cooled to 0°C in an ice-water bath, stirred for 30min, and filtered under reduced pressure. The filter cake wa...

Embodiment 2

[0117] Example 2 (6R, 7R)-7-[[2-[(2-Aminothiazol)-4-yl]-2-oximino]acetamido]-3-(5-chloro-1-methyl- 1H-indol-1-yl) Preparation of methylene-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid inner salt (compound 2)

[0118] Step 1 Prepare (6R, 7R)-7-amino-3-(5-chloro-1-methyl-1H-indol-1-yl)methylene-8-oxo-5 according to step 1 of Example 1 -Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid inner salt

[0119] Step 2 (6R, 7R)-7-[[2-[(2-Aminothiazol)-4-yl]-2-oximino]acetamido]-3-(5-chloro-1-methyl-1H -Indol-1-yl)methylene-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid inner salt

[0120] The preparation method refers to step 2 in Example 1, and cast (6R, 7R)-7-amino-3-(5-chloro-1-methyl-1H-indole)methylene-8-oxo-5-sulfur Hetero-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid inner salt 9.4g (25mmol), 2-(2-amino-thiazol-4-yl)-2-oximothio Acetate (S-2-benzothiazole) ester 10.1g (30mmol) to give (6R, 7R)-7-[[2-[(2-aminothiazole)-4-yl]-2-oximo]acetamide Base]-3...

Embodiment 3

[0125] Example 3 (6R, 7R)-7-[[2-[(2-Aminothiazole)-4-yl]-Z-2-(2-carboxylic acid isopropyloxyimino)]acetamido]- 3-(5-chloro-1- Methyl-1H-indol-1-yl)methylene-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid internal salt (compound 3) Preparation

[0126] Step 1 Prepare (6R, 7R)-7-amino-3-(5-chloro-1-methyl-1H-indol-1-yl)methylene-8-oxo-5 according to step 1 of Example 1 -Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid inner salt

[0127] Step 2 (6R, 7R)-7-[[2-[(2-Aminothiazole)-4-yl]-Z-2-(2-carboxylic acid isopropyloxyimino)]acetamido]-3 -(5-Chloro-1-methyl-1H-indol-1-yl)methylene-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene Preparation of -2-carboxylic acid inner salt

[0128] The preparation method refers to step 2 in Example 1, and cast (6R, 7R)-7-amino-3-(5-chloro-1-methyl-1H-indol-1-yl)methylene-8-oxo -5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid inner salt 9.4g (25mmol), (Z)-2-(5-amino-1,2,4 -Thiadiazol-3-yl)-2-(2-carboxylic acid isopropyloxyimino t...

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Abstract

The invention belongs to the technical field of pharmacy, and in particular relates to a cephalosporin derivative containing substituted nitrogen-containing fused-heterocycles (shown as the general formula (I)) and pharmaceutically-acceptable salts thereof, wherein R1, R2, R3, R4, R5, X and n are defined in the specification. Besides, the invention provides a preparation method of the compounds, pharmaceutical compositions containing the compounds and the use of the compounds for preparation of pharmaceuticals for treating and / or preventing infectious diseases.

Description

1. Technical field [0001] The present invention belongs to the field of medical technology, and specifically relates to cephalosporin derivatives containing nitrogen-fused heterocycles and pharmaceutically acceptable salts thereof, preparation methods of these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds in the preparation of therapeutic and / Or use in medicines to prevent infectious diseases. 2. Background technology [0002] Cephalosporins (Cephalosporins) are a series of semi-synthetic antibiotics derived from cephalosporin C isolated from the culture solution of Cephalosporium cristatum and modified side chains. Its advantages are: broad antibacterial spectrum, relatively stable to acid and β-lactamase produced by various bacteria. [0003] Since the 1970s, a variety of new cephalosporins have entered the clinic, providing good treatment for bacterial infections, especially infections caused by penicillins and other antimic...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/46A61K31/546A61P31/04
CPCY02P20/55
Inventor 黄振华张敏鞠传真
Owner HAINAN SIHUAN PHARMA
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