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Metal beta-lactamase inhibitor pyridine dicarboxylic acid amine derivative and preparation method thereof

A technology for preparing dipicolinate and lactamase, which is applied in the field of novel metal β-lactamase inhibitor dipicolinate derivatives and their preparation, and can solve the problems of unsatisfactory effect of restoring meropenem sensitivity and the like , to achieve the effects of in vitro cytotoxicity and in vivo toxicity, high yield, and improved survival rate

Active Publication Date: 2021-10-01
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.)
But there is no relevant report on its application to β-lactamase inhibitors

Method used

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  • Metal beta-lactamase inhibitor pyridine dicarboxylic acid amine derivative and preparation method thereof
  • Metal beta-lactamase inhibitor pyridine dicarboxylic acid amine derivative and preparation method thereof
  • Metal beta-lactamase inhibitor pyridine dicarboxylic acid amine derivative and preparation method thereof

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Embodiment 1

[0027] The preparation of embodiment 1 compound 1:

[0028] Dimethyl pyridine-2,6-dicarboxylate (10.00g, 51.2mmol) was dissolved in methanol (250mL) solution, and sodium borohydride (7.75g, 204.95mmol) was divided into 3 times and slowly Add to solution. The reaction mixture was stirred at 0 °C for 7 h. After the reaction was completed, saturated sodium bicarbonate solution (50 mL) was added, and extracted with dichloromethane (200 mL×3). The organic phase was dried with saturated aqueous sodium chloride and anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain a white solid b (7.01 g), which was used without further purification. Yield: 82%. 1H NMR (400MHz, DMSO-d6) δ7.99(t, J=7.7Hz, 1H), 7.96–7.88(m, 1H), 7.74–7.69(m, 1H), 5.57(t, J=5.9Hz, 1H), 4.62(d, J=5.8Hz, 2H), 3.87(s, 3H).13CNMR(100MHz, DMSO-d6) δ165.3, 162.5, 146.4, 138.0, 123.8, 123.0, 64.0, 52.3, 52.3.

[0029] At 0°C, the PBr 3(11.08g, 40.92mmol) was added dropwise to a ...

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Abstract

The invention belongs to the technical field of medicinal chemistry, and relates to a metal beta-lactamase inhibitor pyridine dicarboxylic acid amine derivative, a preparation method thereof and an application thereof in the antibacterial field. The derivative has the following structural formula: the compound has better inhibition activity on metal beta-lactamase (NDM-1, IMP-4 and VIM-1), and can recover the antibacterial activity of engineering strains for producing metal beta-lactamase and clinically separated enterobacteriaceae bacteria on carbapenem antibiotics; and the drug effect of meropenem on carbapenem-resistant Escherichia coli (NDM-1-producing metal beta-lactamase) can be improved by at least 1024 times to the maximum extent. The compound 1 and meropenem are combined for use, so that strains capable of producing MBL can be quickly killed. A compound toxicity experiment proves that the compound has very small in-vitro cytotoxicity and in-vivo toxicity, and a mouse in-vivo experiment shows that the survival rate of a mouse infected with metal-producing beta-lactamase klebsiella pneumoniae can be remarkably improved through combined treatment of the compound and meropenem. The product can be used as a candidate drug of a novel metal beta-lactamase inhibitor.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to a novel metallo-beta-lactamase inhibitor pyridinedicarboxylic acid amine derivative with potential application value and a preparation method thereof. Background technique [0002] The emergence of antibiotics has brought good news to the clinical treatment of infectious diseases, but with the extensive use of antibiotics in the clinic, the effectiveness of antibiotics in the treatment of clinical infectious diseases has declined, and various drug-resistant strains have begun to appear clinically. With more and more antibiotics losing their initial effectiveness for treatment, the global situation of drug resistance is no longer to be ignored. In 2009, the Walsh research group of Cardiff University in the United Kingdom reported a new type of β-lactamase-metallo-β-lactamases. The case showed that the urine of the patient was treated with antibiotics in New Delhi, India ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/79C07D213/803A61P31/04A61P31/10
CPCC07D213/79C07D213/803A61P31/04A61P31/10Y02A50/30
Inventor 秦上尚张恩刘闻天白蒙蒙陈方方孔洪涛闫婷婷沈渤渊董会玥闫大钞彭君可李森邓荣萍武炙瑶张婷婷
Owner ZHENGZHOU UNIV
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