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Novel broad-spectrum beta-lactamase inhibitor

A C3-C6, -C5H3N- technology, applied in the field of medicine, can solve the problems of insufficient inhibition of β-lactamase diversity and narrow enzyme inhibitory activity, and achieve great social and economic benefits, strong growth inhibitory activity, and recovery The effect of antibacterial activity

Active Publication Date: 2016-07-27
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 beta-lactamase inhibitor

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 satu...

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Abstract

The invention discloses a novel broad-spectrum beta-lactamase inhibitor. The structure of the compound is shown in the formula I, by means of research on activity of six beta-lactamases in four types with the compound, it is found that the compound can inhibit activity of multiple beta-lactamases, when the compound is combined with beta-lactam antibiotics, the combination has powerful growth inhibiting activity on bacteria generating beta-lactamase, it can be expected that a drug which can recover antibacterial activity of the beta-lactam antibiotics to treat and prevent infection caused by bacteria of animals including human can be developed, and the novel broad-spectrum beta-lactamase inhibitor 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 Applications(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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