A kind of 3,3'-methylene-bisfluoroquinolone derivative of chiral oxazinoquinoline ring and its preparation method and application

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

Inactive Publication Date: 2016-11-23
HENAN UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • A kind of 3,3'-methylene-bisfluoroquinolone derivative of chiral oxazinoquinoline ring and its preparation method and application
  • A kind of 3,3'-methylene-bisfluoroquinolone derivative of chiral oxazinoquinoline ring and its preparation method and application
  • A kind of 3,3'-methylene-bisfluoroquinolone derivative of chiral oxazinoquinoline ring and its preparation method and application

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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-ylidenemethyl]-quinolin-4(1H)-one (I-1), its chemical The structural formula is:

[0036]

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

[0038] The preparation method of the compound is: 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-piperazin-1-yl-2,3-dihydro-quinolin-4(1H)-one (III-1) 0.44g (1.6mmol) was dissolved in 20mL of absolute ethanol, 0.2mL of piperidine was added dropwise, and the reaction was refluxed for 24h. After standing for 12 hours, the resulting solid was collected by filtration and recrystallized from DMF-ethanol (V:V=3:1) to obtain a light yellow crystal (I-1), with a yield of 82%, m.p.228-232°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 7.91~7.88(brs,2H,2-H,3-CH=),7.7...

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-ylidenemethyl]-quinolin-4(1H)-one (I -2), its chemical structural formula is:

[0041]

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

[0043]The preparation method of the compound is: 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)- Ketone (III-2) 0.50g (1.7mmol) was dissolved in 20mL absolute ethanol, triethylamine 0.2mL was added dropwise, and the reaction was refluxed for 20h. After standing for 12 hours, the resulting solid was collected by filtration and recrystallized with DMF-ethanol (V:V=3:1) to obtain a light yellow crystal (I-2), with a yield of 85%, m.p.225-227°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 7.90~7.87(brs,2H,2-H,3-...

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-ylidenemethyl]-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: 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-cyclopropyl-6-fluoro-7-piperazin-1-yl-2,3-dihydro-quinolin-4(1H)-one (III-3 ) 0.52g (1.8mmol) was dissolved in 20mL absolute ethanol, piperidine 0.2mL was added dropwise, and the reaction was refluxed for 22h. After standing for 24 hours, the resulting solid was collected by filtration and recrystallized from DMF-ethanol (V:V=5:1) to obtain a light yellow crystal (I-3), with a yield of 86%, m.p.232-234°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 7.92~7.88(brs,2H,2-H,3-CH=),7...

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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, and specifically relates to a 3,3′-methylene-bisfluoroquinolone derivative compound of a chiral oxazinoquinoline ring, and also relates to a 3, A preparation method of 3'-methylene-bisfluoroquinolone derivative and its application in antineoplastic drugs. Background technique [0002] Tumor is one of the biggest diseases that threaten human life and health. Due to the high toxicity of current anti-tumor drugs and poor tolerance of patients, the cure rate of tumor diseases is low. Therefore, it is increasingly urgent to develop antitumor drugs with new structures. 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. Based on the similarity in sequence and function between the target enzyme of antibacterial fluoroquinolones—topoisomerase and the corresponding topoiso...

Claims

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Application Information

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Patent Type & Authority Patents(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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