2(1H)-quinolinone derivative

A compound, morpholino-based technology, applied in the field of 2(1H)-quinolinone derivatives or its salts, can solve the problem of insufficient effect of Gram-negative bacteria, high eukaryotic toxicity, unknown GyrB/ParE inhibitory effect, etc. question

Inactive Publication Date: 2019-11-12
TAISHO PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These substances inhibit DNA gyrase, but they are rarely used clinically due to insufficient effects against Gram-negative bacteria or high toxicity against eukaryotes (Non-Patent Document 3)
[0008] In addition, as other inhibitors, Patent Documents 1 to 48, etc. and Non-Patent Documents 4 to 11, etc. are known, respectively, but it is unknown that the compound of the present invention has GyrB / ParE inhibitory action
[0009] Furthermore, 2(1H)-quinolinone derivatives having similar structures to the compounds of the present invention are known from Patent Documents 49 to 53, etc., but no GyrB / ParE inhibitory activity has been reported for these compounds

Method used

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Examples

Experimental program
Comparison scheme
Effect test

manufacture example 18

[0379] Production Example 1 8-(Methylamino)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid

[0380] 1-(1) Ethyl 8-(methylamino)-2-oxo-1,2-dihydroquinoline-3-carboxylate.

[0381] [chemical formula 18]

[0382]

[0383] Diethyl malonate (434 μL) and piperidine (263 μL) were added to a solution of 2-amino-3-(methylamino)benzaldehyde (308 mg) in ethanol (4 mL), and heated and stirred at 75° C. for 8 hours. After allowing to cool to room temperature, the precipitated solid was collected by filtration to obtain the title compound (291 mg) as a yellow solid.

[0384]

[0385] 1-(2) 8-(Methylamino)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid

[0386] [chemical formula 19]

[0387]

[0388] In tetrahydrofuran (12 mL) solution of 8-(methylamino)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ethyl ester (291 mg) obtained in Production Example 1-(1), add 1M aqueous sodium hydroxide solution (12 mL), stirred at room temperature for 8.5 hours. The reaction solution was neutralize...

manufacture example 2

[0390] Production Example 2 6-fluoro-8-(methylamino)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid

[0391] 2-(1) [5-fluoro-3-(methylamino)-2-nitrophenyl]methanol

[0392] [chemical formula 20]

[0393]

[0394] A 33% methylamine-ethanol solution (27.3 mL) was added to a solution of (3,5-difluoro-2-nitrophenyl)methanol (20.72 g) in ethanol (50 mL) at room temperature, followed by stirring for 2 hours. The generated insoluble matter was collected by filtration, washed with ethanol and ether to obtain the title compound (12.96 g) as a yellow solid.

[0395]

[0396] 2-(2)5-Fluoro-3-(methylamino)-2-nitrobenzaldehyde

[0397] [chemical formula 21]

[0398]

[0399] In the chloroform (2840mL) solution of [5-fluoro-3-(methylamino)-2-nitrophenyl]methanol (23.66g) obtained by Production Example 2-(1), add carbon dioxide at 50°C Manganese (51.38g), heated and stirred for 7 hours. The insoluble matter was separated by filtration, and the filtrate was concentrated under redu...

manufacture example 38

[0416] Production Example 3 8-(Methylamino)-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid

[0417] tert-butyl 3-(1) [2-[benzyl(methyl)amino]pyridin-3-yl]carbamate

[0418] [chemical formula 25]

[0419]

[0420] In a solution of N2-benzyl-N2-methylpyridine-2,3-diamine (20.4 g) in tetrahydrofuran (400 mL), add a solution of 1.9 M (trimethylsilyl)amide sodium in tetrahydrofuran (THF) under ice-cooling ( 111mL) and di-tert-butyl dicarbonate (23.0g), stirred under nitrogen atmosphere at room temperature for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=88:12) to obtain the title compound (26.8 g) as a red oily substance.

[0421]

[0422] tert-butyl 3-(2)[2-[benzyl(methyl)amino]-4-formylpyridin-3-...

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Abstract

Provided is a useful novel compound exhibiting antimicrobial activity on the basis of inhibitory action of DNA gyrase GyrB and topoisomerase IV ParE. Provided is a 2(1h)-quinolinone derivative represented by formula (1), or a pharmaceutically acceptable salt thereof.

Description

technical field [0001] The present invention relates to novel 2(1H)-quinolinone derivatives or salts thereof having inhibitory activity against the GyrB subunit of DNA gyrase and the ParE subunit of topoisomerase IV, and antibacterial agents containing them as active ingredients. drug. Background technique [0002] Many classes of antibacterial drugs have been developed since penicillin was sold in the 1940s. Antimicrobials have made a significant contribution to the treatment of infectious diseases, but new problems such as the emergence of drug-resistant bacteria have arisen. In particular, carbapenem-resistant Enterobacteriaceae (CRE), multidrug-resistant Pseudomonas aeruginosa (MDRP), and multidrug-resistant Acinetobacter (MDRA) are not only resistant to β-lactam drugs, but also Resistance to many antimicrobials, including quinolones, has been shown to be a major clinical problem. Therefore, there is a strong demand for the development of new antibacterial drugs in cl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/40C07D417/14C07D471/04C07D487/04A61K31/4375A61K31/4704A61K31/4709A61K31/496A61K31/498C07D413/12A61K31/506A61K31/519C07D417/12A61K31/5377A61P31/04A61P43/00C07D241/44C07D401/12C07D401/14C07D405/12
CPCC07D215/40C07D215/26C07D215/227C07D417/14C07D401/12C07D413/12C07D417/12C07D487/04C07D401/14A61P31/04Y02A50/30C07D215/54A61K31/4704A61K31/4375A61K31/4709A61K31/496A61K31/498A61K31/506A61K31/519A61K31/5377C07D241/44C07D405/12C07D471/04
Inventor 天田英明大岳宪一牛山文仁金春海竹内智起田中望
Owner TAISHO PHARMACEUTICAL CO LTD
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