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Beta-lactamase inhibitor

A lactamase and inhibitor technology, applied in the field of β-lactamase inhibitors, can solve the problems of not enough to deal with the diversity of β-lactamase, and achieve the effect of strong inhibitory effect and long half-life

Inactive Publication Date: 2016-07-27
卢来春
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently available β-lactamase inhibitors are no longer sufficient to cope with the increasing diversity of β-lactamases, therefore, new β-lactamase inhibitors need to be developed

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] 1-1a compound (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-ylsulfuric acid (S)-1-carboxy-2 -(1H-imidazol-4-yl)-ethylammonium, molecular formula C 13 H 20 N 6 O 8 S, molecular weight 420.11.

[0042] The preparation method is as follows:

[0043]

[0044] Dissolve 10.65g (50mmol) of (2S,5R)-6-hydroxy-7-oxo-1,6-diaza [3,2,1]octane-2-carboxamide in pyridine (35mL) Add triethylamine (2.5ml) and pyridine sulfur trioxide complex (9.6g), stir at room temperature for 12h, filter to remove the solid and wash with ethyl acetate, combine the filtrate and remove the solvent. The residue was dissolved in ethyl acetate (35ml), the insoluble matter was filtered off, a methanol (12ml) solution with 77.6g (50mmol) of histidine dissolved in it was added, the mixture was placed in an ice water bath at 0°C and kept stirring for 1h, filtered and used a small amount The precipitate was washed with ethyl acetate and dried to obtain 170.5 g of 1-1a white powder with a yield of 81%.

[00...

Embodiment 2

[0047] 1-1b(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-ylsulfuric acid (S)-1-carboxy-5- Amino-pentylammonium, molecular formula C 13 H 25 N 5 O 8 S, molecular weight 411.43.

[0048] The preparation method is as follows:

[0049]

[0050] Dissolve (2S,5R)-6-hydroxy-7-oxo-1,6-diaza[3,2,1]octane-2-carboxamide 92.6g (500mmol) in pyridine (350mL) Add triethylamine (25.0ml) and pyridine sulfur trioxide complex (95.5g), stir at room temperature for 12h, filter off the solid and wash with ethyl acetate, evaporate the solvent. The residue was dissolved in ethyl acetate (350ml), the insoluble matter was filtered off, and a solution of 73.1g (500mmol) of lysine dissolved in ethyl acetate (100ml) was added. The precipitate was washed with a small amount of ethyl acetate and dried to obtain 166.2 g of compound 1-1b as a white powder with a yield of 81%.

[0051] 1 HNMR (400MHz, DMSO-d6) δ: 6.11 (s, 2H), 4.85 (m, 1H), 4.55 (m, 1H), 3.79-3.68 (m, 1H), 3.34 (m, 2H), 3.06 (br ,2H),2.6...

Embodiment 3

[0053] 1-1c(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-ylsulfuric acid (S)-1-carboxy-4- Guanidine-Butylammonium, Molecular Formula C 13 H 25 N 7 O 8 S, molecular weight 439.44.

[0054] The preparation method is as follows:

[0055]

[0056] Dissolve (2S,5R)-6-hydroxy-7-oxo-1,6-diaza[3,2,1]octane-2-carboxamide 92.6g (500mmol) in pyridine (350mL) Add triethylamine (25.0ml) and pyridine sulfur trioxide complex (95.5g), stir at room temperature for 12h, filter off the solid and wash with ethyl acetate, evaporate the solvent. The residue was dissolved with ethyl acetate (350ml), the insoluble matter was filtered off, a solution of 87.1g (500mmol) of arginine hydrochloride dissolved in methanol (150ml) was added, and the mixture was placed in an ice water bath at 0°C and stirred for 1h The precipitate obtained by filtration was washed with a small amount of ethyl acetate and dried to obtain 171.1 g (78%) of white powder of compound 1-1c.

[0057] 1 HNMR (400MHz, DMSO-d6) δ: ...

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Abstract

The invention discloses a beta-lactamase inhibitor. The beta-lactamase inhibitor can inhibit A-type beta-lactamases (such as SHV, TEM and CTX), C-type beta-lactamase (mainly comprising an AmpC enzyme) and D-type beta-lactamase (such as OXA), has good inhibition effects and can reduce the lowest ceftazidime bacteriostasis concentration through combination with ceftazidime. Compared with tazobactam, the beta-lactamase inhibitor has a longer half life. A part of the beta-lactamase inhibitor has a half life longer than that of avibactam sodium. The beta-lactamase inhibitor provides more possibility for antibiotic development.

Description

【Technical Field】 [0001] The present invention relates to an enzyme inhibitor, in particular to a β-lactamase inhibitor. 【Background technique】 [0002] β-lactamase antibiotics are one of the most widely used high-efficiency, low-toxicity, and broad-spectrum anti-infective drugs in clinical practice. However, due to the emergence of antibiotic-resistant bacteria, the efficacy of these drugs has been reduced or even failed. The main reason for the existence of this resistance in gram-negative bacteria is that the β-lactamase enzyme in the bacteria can hydrolyze β-lactam antibiotics to inactivate them. Bacteria can produce various β-lactamases, including penicillinase, cephalosporinase, cephalosporinase, broad-spectrum β-lactamase and hyperspectral β-lactamase. Before the β-lactam antibiotics are hydrolyzed, the combined application of β-lactamase inhibitors and antibiotics can be used to restore the activity of the antibiotics. The currently available β-lactamase inhibitors are ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08C07D233/64A61K31/439A61K31/4545A61K45/06A61P31/04
Inventor 卢来春傅若秋毛世永吴国菻王多义李敏管海燕李卓恒罗明和于彩平
Owner 卢来春
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