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Metal β-lactamase inhibitor open chain pyridine carboxylic acid derivative and preparation method thereof

A technology of open-chain pyridine carboxylic acid and lactamase, which is applied in pharmaceutical formulations, medical preparations containing active ingredients, antibacterial drugs, etc., can solve the problem of unsatisfactory recovery of meropenem sensitivity and achieve a simple synthesis method Feasible, low toxicity, high yield effect

Active Publication Date: 2019-04-23
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In 2015, Yang Kewu's research group at Northwest University reported a series of thioglycolic acid thioester amino acid derivatives, whose IC for metallo-β-lactamase L1 50 The minimum can reach 18nM, but its in vitro activity test proves that its effect of restoring meropenem sensitivity is not ideal (Acs Medicinal Chemistry Letters 2015,6,660.)

Method used

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  • Metal β-lactamase inhibitor open chain pyridine carboxylic acid derivative and preparation method thereof
  • Metal β-lactamase inhibitor open chain pyridine carboxylic acid derivative and preparation method thereof
  • Metal β-lactamase inhibitor open chain pyridine carboxylic acid derivative and preparation method thereof

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Embodiment 1

[0024] The preparation of embodiment 1 compound b:

[0025] Take dimethyl 2,6-pyridinedicarboxylate (1.03g, 5.26mmol) in a round bottom flask, add methanol (50mL) under ice-cooling, stir for several minutes, add NaBH in batches 4 (743.80mg, 19.66mmol), connected to a three-way air balloon, and observed by TLC. After the reaction was completed, the solvent was evaporated to dryness under reduced pressure, and saturated NaHCO 3 solution to remove excess NaBH 4 , then extracted with dichloromethane (3×30mL), back-extracted with water three times, washed with saturated brine twice, and finally added anhydrous MgSO 4 After drying, it was filtered and spin-dried to obtain a white solid (661 mg) with a yield of 75%.

[0026] 1 H NMR (400MHz, CDCl 3 )δ8.21(d, J=7.8Hz, 1H), 7.90(d, J=7.7Hz, 1H), 7.74(t, J=7.8Hz, 1H), 7.51(d, J=7.8Hz, 1H) ,7.25(s,1H),4.36(s,1H),3.93(s,1H),3.88(s,3H),1.17(s,2H),0.91–0.63(m,1H). 13 C NMR (101MHz, CDCl 3 )δ165.53(s), 160.28(s), 146.95(s), 137.66(s)...

Embodiment 2

[0027] The preparation of embodiment 2 compound c:

[0028] Under ice-bath conditions, compound b (500mg) was added into chloroform (10mL), stirred and dissolved, then slowly added dropwise PBr 3 (341μL, 3.59mmol), reacted at room temperature for 4-5h, observed by TLC. After the reaction, add saturated K 2 CO 3 The solution was quenched, the solvent was distilled off under reduced pressure, extracted with dichloromethane (3×10mL), washed once with water, washed 2-3 times with saturated brine, added anhydrous MgSO4 Dry, filter, combine the organic phases, and distill off the solvent under reduced pressure to obtain 680 mg of light yellow solid with a yield of 98.8%.

[0029] 1 H NMR (400MHz, CDCl 3 )δ8.08(t, J=9.2Hz, 1H), 7.88(t, J=7.8Hz, 1H), 7.70(d, J=7.7Hz, 1H), 4.65(s, 2H), 4.02(s, 3H).

Embodiment 3

[0030] The preparation of embodiment 3 compound e:

[0031] Compound d (2 mL, 16.45 mmol) was added into a round bottom flask containing dichloromethane (45 mL), and stirred evenly. Take another small beaker, add dichloromethane (5 mL) and ethylenediamine (659 μl, 9.87 mmol), stir and mix well. Then it was gradually dropped into a round bottom flask, refluxed at 90°C, and reacted overnight. After rotary evaporation, a yellow oily liquid was obtained, which was dissolved and cooled with ethyl acetate, and 2.21 g of a yellow-white solid e was obtained by suction filtration.

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Abstract

Belonging to the field of medicinal chemistry, the invention discloses a metal beta-lactamase inhibitor open chain pyridine carboxylic acid derivative and a preparation method thereof. The compound has the following structure shown as the specification. The derivative can restore the sensitivity of metal beta-lactamase enterobacteriaceae bacteria to carbapenem antibiotics. In vitro antibacterial experiment results prove that the derivative can reduce the MIC value of carbapenem resistant Escherichia coli (producing NDM-1 type metal beta-lactamase) to meropenem by about 40960 times maximumly. In vitro red blood cell toxicity experiments also prove that the compound has very small red blood cell toxicity. Therefore, the compound is expected to be used as a candidate drug of novel metal beta-lactamase inhibitor.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to a novel metal β-lactamase inhibitor open-chain pyridine carboxylic acid derivative with potential application value and a preparation method thereof. Background technique [0002] Since antibiotics were used in the clinical treatment of bacterial infections in the 1930s, a variety of antibacterial drugs have been developed and applied clinically, opening a new era of anti-infective treatment. However, with the irrational use and abuse of antibacterial drugs, the acquired drug resistance of bacteria is becoming more and more serious, and the proportion of drug-resistant bacteria is increasing year by year, which affects the clinical treatment effect of antibacterial drugs to varying degrees. Under the pressure of antibacterial drug screening, the development of acquired drug resistance that can be transmitted horizontally is getting faster and faster, leading to the rapi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/79C07D213/803A61K31/444A61K31/407A61P31/04
CPCA61K31/407A61K31/444C07D213/79C07D213/803A61K2300/00Y02A50/30
Inventor 张恩秦上尚王铭铭崔得运白鹏燕施秀芳王平王上周萌萌王亚娜化永刚刘宏民
Owner ZHENGZHOU UNIV
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