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3,3'-methene-difluoroquinolone derivative of chiral oxazine quinoline ring as well as preparation method and application of 3,3'-methene-difluoroquinolone derivative

A kind of technology of difluoroquinolone and quinoline ring, applied in the field of drug synthesis

Inactive Publication Date: 2015-04-29
HENAN UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are many ways to discover new drugs, the structural modification of existing drugs is still the most successful and economical strategy for new drug development

Method used

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  • 3,3'-methene-difluoroquinolone derivative of chiral oxazine quinoline ring as well as preparation method and application of 3,3'-methene-difluoroquinolone derivative
  • 3,3'-methene-difluoroquinolone derivative of chiral oxazine quinoline ring as well as preparation method and application of 3,3'-methene-difluoroquinolone derivative
  • 3,3'-methene-difluoroquinolone derivative of chiral oxazine quinoline ring as well as preparation method and application of 3,3'-methene-difluoroquinolone derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0035] (S)-6-Fluoro-7-(4-methyl-piperazin-1-yl)-1,8-(3,1-oxopropyl)-3-[1-ethyl-6-fluoro- 7-Piperazin-1-yl-2,3-dihydro-quinolin-4(1H)-one-3-idenemethyl]-quinolin-4(1H)-one (I-1), its chemical The structural formula is:

[0036]

[0037] That is, R in formula I is ethyl, and R 1 and R 2 is a hydrogen atom, and X is a hydrocarbon group.

[0038] The preparation method of the compound is as follows: take 6-fluoro-7-(4-methyl-piperazin-1-yl)-1,8-(3,1-oxopropyl)-quinoline-4(1H)- Ketone (VI) 0.55 g (1.6 mmol) and 1-ethyl-6-fluoro-7-piperazin-1-yl-2,3-dihydro-quinolin-4(1H)-one (III-1) 0.44 g (1.6 mmol) was dissolved in 20 mL of absolute ethanol, 0.2 mL of piperidine was added dropwise, and the reaction was refluxed for 24 h. After standing for 12 hours, the resulting solid was collected by filtration and recrystallized with DMF-ethanol (V:V=3:1) to obtain pale yellow crystals (I-1), yield 82%, m.p.228~232°C. 1 H NMR (400MHz, DMSO-d 6 )δ:7.91~7.88(brs,2H,2-H,3-CH=),7.76(d,1H...

Embodiment 2

[0040] (S)-6-Fluoro-7-(4-methyl-piperazin-1-yl)-1,8-(3,1-oxopropyl)-3-[1-ethyl-6-fluoro- 7-(4-Methylpiperazin-1-yl)-2,3-dihydro-quinolin-4(1H)-one-3-idenemethyl]-quinolin-4(1H)-one (I -2), its chemical structural formula is:

[0041]

[0042] That is, R in formula I is ethyl, and R 1 is methyl, R 2 is a hydrogen atom, and X is CH.

[0043]The preparation method of the compound is as follows: take 6-fluoro-7-(4-methyl-piperazin-1-yl)-1,8-(3,1-oxopropyl)-quinoline-4(1H)- Ketone (VI) 0.55g (1.6mmol) and 1-ethyl-6-fluoro-7-(4-methylpiperazin-1-yl)-2,3-dihydro-quinoline-4(1H)- 0.50 g (1.7 mmol) of ketone (III-2) was dissolved in 20 mL of absolute ethanol, 0.2 mL of triethylamine was added dropwise, and the reaction was refluxed for 20 h. After standing for 12h, the generated solid was collected by filtration and recrystallized with DMF-ethanol (V:V=3:1) to obtain pale yellow crystals (I-2), yield 85%, m.p.225~227°C. 1 H NMR (400MHz, DMSO-d 6 )δ:7.90~7.87(brs,2H,2-H,3-CH=)...

Embodiment 3

[0045] (S)-6-Fluoro-7-(4-methyl-piperazin-1-yl)-1,8-(3,1-oxopropyl)-3-[1-cyclopropyl-6-fluoro -7-Piperazin-1-yl-2,3-dihydro-quinolin-4(1H)-one-3-idenemethyl]-quinolin-4(1H)-one (I-3), which The chemical structural formula is:

[0046]

[0047] That is, R in formula I is cyclopropyl, R 1 and R 2 is a hydrogen atom, and X is a hydrocarbon group.

[0048] The preparation method of the compound is as follows: take 6-fluoro-7-(4-methyl-piperazin-1-yl)-1,8-(3,1-oxopropyl)-quinoline-4(1H)- Ketone (VI) 0.55 g (1.6 mmol) and 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-2,3-dihydro-quinolin-4(1H)-one (III-3 ) 0.52g (1.8mmol) was dissolved in 20mL of absolute ethanol, 0.2mL of piperidine was added dropwise, and the reaction was refluxed for 22h. After standing for 24 hours, the resulting solid was collected by filtration and recrystallized with DMF-ethanol (V:V=5:1) to obtain pale yellow crystals (I-3), yield 86%, m.p.232~234°C. 1 H NMR (400MHz, DMSO-d 6 )δ:7.92~7.88(brs,2H,2-H,3-CH...

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Abstract

The invention discloses a 3,3'-methene-difluoroquinolone derivative of a chiral oxazine quinoline ring as well as a preparation method and application of the 3,3'-methene-difluoroquinolone derivative. The 3,3'-methene-difluoroquinolone derivative has a chemical general structural formula I shown in the specification, wherein R represents cyclopropyl or ethyl or fluoroethyl; R1 represents a hydrogen atom or methyl or ethyl; R2 represents a hydrogen atom or methyl; X represents a nitrogen atom or a hydrocarbon (CH) group or a fluoro-substituted carbon atom (F-C) or a methoxyl-substituted carbon atom (CH3O-C). The 3,3'-methene-difluoroquinolone derivative of the chiral oxazine quinoline ring, disclosed by the invention, can be used for realizing the superposition of a difluoroquinolone framework and alpha, beta-unsaturated ketone pharmacophores, so that the antitumor activity of a new compound is improved, the toxic and side effects on normal cells can be reduced, and the 3,3'-methene-difluoroquinolone derivative can be used as an antitumor active substance for developing an antitumor drug of a totally new structure.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to a 3,3'-methylene-difluoroquinolone derivative compound of a chiral oxazinoquinoline ring, and also to a 3,3'-methylene-difluoroquinolone derivative compound of a chiral oxazinoquinoline ring. The preparation method of 3'-methylene-difluoroquinolone derivatives and the application thereof in antitumor drugs. Background technique [0002] Tumor is one of the biggest diseases threatening human life and health. Due to the high toxicity of current antitumor drugs and poor patient tolerance, the cure rate of tumor diseases is low. Therefore, it is increasingly urgent to develop antitumor drugs with novel structures. Although there are many ways to discover new drugs, structural modification of existing drugs is still the most successful and economical strategy for new drug development. Based on the similarity in sequence and function between topoisomerase, the target enzyme o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/06C07D519/00A61K31/5383A61P35/00
CPCC07D498/06C07D519/00
Inventor 闫强胡海廷吴书敏倪礼礼李涛冯焱飞高留州谢玉锁胡国强
Owner HENAN UNIVERSITY
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