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Novel broad-spectrum β-lactamase inhibitors

A lactamase and lactam technology, applied in the field of medicine, can solve the problems of insufficient inhibition of β-lactamase diversity, narrow enzyme inhibition activity, etc., and achieve great social and economic benefits, strong growth inhibition activity, and recovery of antibacterial properties. active effect

Active Publication Date: 2018-05-18
WUHAN VISION PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Because of its narrow enzyme inhibitory activity or its own structure containing a β-lactam ring, it causes bacterial resistance. The currently available inhibitors are not enough to inhibit the increasing diversity of β-lactamase. Today, we urgently need novel broad-spectrum β-Lactamase Inhibitors to Treat Refractory Infectious Diseases Caused by Drug-Resistant Bacteria

Method used

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  • Novel broad-spectrum β-lactamase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Synthesis of compound I-1

[0041]

[0042] Compound Ⅰ-1 is compound Ⅰ in which m=1, n=0, Y is 3,5-disubstituted pyridyl-C 5 h 3 N-, R 1 with R 2 The specific structure when both are hydrogen.

[0043] 1. Synthetic (2-tert-butoxycarbonyl)-5-aminomethylpyridine-3-carboxylic acid, i.e. compound A, synthetic route is as follows:

[0044]

[0045] Step 1. Synthesis of ethyl 5-cyanonicotinate (compound A-2) In a 300ml round bottom flask, pack ethyl 5-bromonicotinate (compound A-1, 4.60 g, 20.0 mmol), zinc cyanide (9.94 g, 84.6 mmol), tetrakis(triphenylphosphine)palladium(0) (4.69 g, 4.06 mmol) and DMF (100 mL). The mixture was heated at 90°C under argon for 15 hours. After cooling, the reaction was quenched with 10% ammonium acetate solution and extracted with ethyl acetate. The combined organic extracts were washed with water, brine and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 2 / 98 (V / V, v / v) ethyl acetate / ...

Embodiment 2

[0058] Synthesis of Compound I-2

[0059]

[0060] Compound Ⅰ-2 is compound Ⅰ in which m=1, n=1, Y is 2,5-disubstituted pyridyl-C 5 h 3 N-, R 1 with R 2 The specific structure when both are hydrogen.

[0061] , 1. Synthesis of 6-tert-butoxycarbonylaminomethyl-pyridin-3-yl-acetic acid, i.e. compound C, synthetic route is as follows:

[0062]

[0063] Step 1. Synthesis of (6-bromo-pyridin-3-yl)-ethyl acetate (Compound C-2) In a 500 mL round bottom flask, diisopropylamine (13.2 mL 93.92 mmol) was mixed with THF (41 mL) , and cooled to -78 degrees Celsius. And n-butyl lithium (2.5M in hexane; 38 mL, 91.20 mmol) was added, and the mixture was stirred for 30 minutes. Then 2-bromo-5-picoline (Compound C-1, 5 mL, 46.92 mmol) dissolved in 17 mL of THF was added. And the mixture was stirred for 2 hours. Diethyl carbonate (6.2 mL, 51.40 mmol) was then added, and the mixture was stirred overnight while gradually warming to room temperature. The reaction was quenched with sa...

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Abstract

The present invention discloses a new broad-spectrum β-lactamase inhibitor. The structure of the compound is shown in the following formula I. Through the research on the activity of the compound of the present invention on four types of six β-lactamases, it is found that the compound can not only Inhibits the activity of various β-lactamases, and when they are combined with β-lactam antibiotics, they have strong growth inhibitory activity against various β-lactamase-producing bacteria, which can be expected to develop into a disease that can restore β-lactamase The antimicrobial activity of lactam antibiotics thus treats and prevents infections caused by bacteria in animals, including humans, and has great social and economic benefits.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a novel broad-spectrum beta-lactamase inhibitor. Background technique [0002] Antibiotics, especially β-lactam antibiotics (eg, penicillins, cephalosporins, and carbapenems) have been one of the most effective tools in the treatment of bacterial infectious diseases. All of these drugs have a β-lactam in their core molecular structure and have shown broad-spectrum efficacy against Gram-positive and Gram-negative bacteria, usually by inhibiting bacterial cell wall synthesis. They are widely used clinically because of their strong bactericidal effect and low toxicity. [0003] However, various pathogenic bacteria have evolved to produce β-lactamases that can inactivate β-lactams, and the ability to spread and share this tool between and within species. This enzyme inactivates β-lactam antibiotics by catalyzing the hydrolysis of the lactam ring, making it ineffective for binding ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/02A61K31/69A61P31/04
CPCC07F5/025A61K31/69A61P31/04C07F5/02
Inventor 伍世平徐洪雨胡向东
Owner WUHAN VISION PHARMA TECH CO LTD
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