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Bis-fluoroquinolone oxadiazole urea N-acetyl ciprofloxacin derivative, and preparation method and application thereof

A kind of technology of fluoroquinolone oxadiazole urea and fluoroquinolone cyclooxadiazole urea, which is applied in the field of drug innovation research to achieve the effect of innovative structure

Inactive Publication Date: 2019-02-15
ZHENGZHOU UNIV OF IND TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the question is what type of carboxyl isostere to choose and what kind of connection to the fluoroquinolone skeleton will be conducive to the discovery of targeted small molecule leads. Further innovations to drive the discovery of targeted anti-tumor fluoroquinolone drugs are still a Current issues to be resolved

Method used

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  • Bis-fluoroquinolone oxadiazole urea N-acetyl ciprofloxacin derivative, and preparation method and application thereof
  • Bis-fluoroquinolone oxadiazole urea N-acetyl ciprofloxacin derivative, and preparation method and application thereof
  • Bis-fluoroquinolone oxadiazole urea N-acetyl ciprofloxacin derivative, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] 1-{2-[1-cyclopropyl-6-fluoro-7-(4-acetylpiperazin-1-yl)-quinolin-4(1H)-one-3-yl]-1,3, 4-Oxadiazol-5-yl}-3-[6-fluoro-7-(4-methylpiperazin-1-yl)-8,1-(1,3-oxopropyl)-quinoline- 4(1H)-ketone-3-yl]-urea (I-1), its chemical structural formula is:

[0057]

[0058] The preparation method of the two-fluoroquinolone oxadiazuron of the present embodiment is: get ofloxacin hydroxamic acid (1 ") 1.0g (2.7mmol) and suspend in 25mL acetonitrile, add carbonyldiimidazole (CDI) 0.79g (4.9mmol), stirring at room temperature until the material dissolves. Then add N-acetyl ciprofloxacin C-3 oxadiazolamide intermediate II 1.11g (2.7mmol), stir in a water bath at 55~60°C for 15 hours.Stand overnight, The resulting solid was collected by filtration and washed with acetonitrile. The crude product was recrystallized from a DMF-ethanol mixed solvent to obtain a light yellow crystal (I-1), with a yield of 60%, m.p.218-220°C. 1 H NMR (400MHz, DMSO-d 6 )δ:11.62(brs,1H,NH),9.47(s,1H,NH),9.22,9...

Embodiment 2

[0060] (S)-1-{2-[1-cyclopropyl-6-fluoro-7-(4-acetylpiperazin-1-yl)-quinolin-4(1H)-one-3-yl]- 1,3,4-oxadiazol-5-yl}-3-[6-fluoro-7-(4-methylpiperazin-1-yl)-8,1-(1,3-oxopropyl) -quinoline-4(1H)-ketone-3-yl]-urea (I-1), its chemical structural formula is:

[0061]

[0062] The preparation method of the bis-fluoroquinolone oxadiazuron of the present embodiment is: take levofloxacin hydroxamic acid (2″) 1.0g (2.7mmol) and suspend in 25mL acetonitrile, add carbonyl diimidazole (CDI) 0.70g (4.3mmol ), stirred at room temperature until the material was dissolved. Then, N-acetylciprofloxacin C-3 oxadiazolamide intermediate II 1.11g (2.7mmol) was added, stirred in a water bath at 55-60°C for 10 hours. Placed overnight, filtered and collected The resulting solid was washed with acetonitrile. The crude product was recrystallized from ethanol to obtain a light yellow crystal (I-2), with a yield of 47%, m.p.212-214°C. 1 H NMR (400MHz, DMSO-d 6 )δ:11.63(brs,1H,NH),9.52(s,1H,NH),9.22,9.1...

Embodiment 3

[0064] 1-{2-[1-cyclopropyl-6-fluoro-7-(4-acetylpiperazin-1-yl)-quinolin-4(1H)-one-3-yl]-1,3, 4-oxadiazol-5-yl}-3-[6,7-difluoro-1,8-(1,3-oxopropyl)-quinolin-4(1H)-one-3-yl]- Urea (I-3), its chemical structural formula is:

[0065]

[0066]The preparation method of the bis-fluoroquinolone oxadiazuron of the present embodiment is: take 1.0 g (3.4 mmol) of oxyfluorocarboxylic acid hydroxamic acid (3″) and suspend it in 25 mL of acetonitrile, add 0.82 g of carbonyldiimidazole (CDI) (5.1mmol), stirring at room temperature until the material dissolves. Then add N-acetyl ciprofloxacin C-3 oxadiazolamide intermediate II 1.40g (3.4mmol), stir in a water bath at 55-60°C for 24 hours. Leave overnight, The resulting solid was collected by filtration and washed with acetonitrile. The crude product was recrystallized from a DMF-ethanol mixed solvent to obtain a light yellow crystal (I-3), with a yield of 65%, m.p.224-226°C. 1 H NMR (400MHz, DMSO-d 6 )δ:11.50(brs,1H,NH),9.43(s,1H,NH),9....

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Abstract

The invention discloses a bis-fluoroquinolone oxadiazole urea N-acetyl ciprofloxacin derivative, and a preparation method and application thereof. The chemical general molecular formula of the derivative is as shown in the description, wherein R adopts an oxazine ring comprising ethyl, cyclopropyl, fluoroethyl and C-8 locus or a thiazine ring comprising C-8 locus; L adopts independent chlorine atom, fluorine atom, 1- piperazinyl, substituted piperazine-1-base or fused nitrogen heterocycle; and X adopts -CH, -N, -CF or -COCH3. The derivative realizes organic combination of a bis-fluoroquinolonescaffold, an oxadiazole heterocyclic ring and functional base urea, further realizes hopping and overlaying of different pharmacophores, improves the antitumor activity and selectivity of fluoroquinolone, reduces toxic and side effect on normal cells, and can serve as an antitumor activity substance to develop antitumor drugs with brand new structures.

Description

technical field [0001] The present invention belongs to the technical field of drug innovation research, and is a complicated and arduous intellectual creation process, and specifically relates to the design of a bis-fluoroquinolone oxadiazuron derivative N-acetyl ciprofloxacin, and also relates to this kind of The preparation method of the derivative, and its application in antitumor drugs. Background technique [0002] The research and development of new drugs originates from the discovery of lead substances, and the structural optimization of lead substances is the key link to promote their development into finished drugs. A rational drug design strategy based on structure or mechanism, using the dominant skeleton or pharmacophore fragments of existing drugs to create new small molecule leads with therapeutic and functional regulation for major diseases such as malignant tumors is the most economical and effective strategy for new drug development. Based on this, on the ...

Claims

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Application Information

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IPC IPC(8): C07D498/06C07D413/14C07D471/04C07D513/06A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D413/14C07D471/04C07D498/06C07D513/06
Inventor 冯亚莉姜亚玲耿胜男胡国强
Owner ZHENGZHOU UNIV OF IND TECH