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Bi-fluoroquinolone oxadiazole ureas N-acetyl norfloxacin derivative and preparation method and application thereof

A technology of fluoroquinolone oxadiazuron and acetyl norfloxacin, which is applied in the design of bis-fluoroquinolone oxadiazuron derivatives of N-acetyl norfloxacin, the preparation of such derivatives, and antineoplastic drugs In the field of application, to achieve the effect of innovative structure

Inactive Publication Date: 2019-02-22
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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  • Bi-fluoroquinolone oxadiazole ureas N-acetyl norfloxacin derivative and preparation method and application thereof
  • Bi-fluoroquinolone oxadiazole ureas N-acetyl norfloxacin derivative and preparation method and application thereof
  • Bi-fluoroquinolone oxadiazole ureas N-acetyl norfloxacin derivative and preparation method and application thereof

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Embodiment 1

[0054] 1-{2-[1-Ethyl-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:

[0055]

[0056] The preparation method of the bis-fluoroquinolone oxadiazuron of the present embodiment is: get ofloxacin hydroxamic acid (1 ") 1.0g (2.7mmol) and suspend in 25mL acetonitrile, add carbonyldiimidazole (CDI) 0.67g (4.1mmol), stirring at room temperature until the material is dissolved. Then add N-acetyl norfloxacin C-3 oxadiazole amide intermediate II 1.08g (2.7mmol), stir in a water bath at 55-60°C for 16 hours. Leave overnight and filter The resulting solid was collected and washed with acetonitrile. The crude product was recrystallized from a mixed solvent of DMF-ethanol to obtain a light yellow crystal (I-1), with a yield of 61%, m.p.225-227°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 11.57 (brs, 1H, NH), 9.48 (s, 1H, NH), ...

Embodiment 2

[0058] (S)-1-{2-[1-Ethyl-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:

[0059]

[0060] 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 carbonyldiimidazole (CDI) 0.60g (3.7mmol ), stirred at room temperature until the material was dissolved. Then 1.08 g (2.7 mmol) of N-acetyl norfloxacin C-3 oxadiazolamide intermediate II was added, stirred in a water bath at 55-60° C. for 10 hours. Placed overnight, filtered and collected The solid was washed with acetonitrile. The crude product was recrystallized from ethanol to obtain a light yellow crystal (I-2), with a yield of 50%, m.p.213-215°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 11.57(brs, 1H, NH), 9.46(s, 1H, NH), 9.20, 9.03(2s...

Embodiment 3

[0062] 1-{2-[1-Ethyl-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:

[0063]

[0064] 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), stir at room temperature until the material dissolves. Then add N-acetyl norfloxacin C-3 oxadiazolamide intermediate II 1.36g (3.4mmol), stir in a water bath at 55-60°C for 24 hours. Leave overnight and filter The resulting solid was collected 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.222-224°C. 1 H NMR (400MHz, DMSO-d6 )δ:11.56(brs,1H,NH),9.47(s,1H,NH),9.16,8.92(2s,2H,2×2′...

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Abstract

The invention discloses a bi-fluoroquinolone oxadiazole ureas N-acetyl norfloxacin derivative and a preparation method and application thereof. The bi-fluoroquinolone oxadiazole ureas N-acetyl norfloxacin derivative is shown as the formula (Please please seed the specifications for the formula), wherein R is an oxazine ring constituted by ethyl, cyclopropyl, fluoroethyl and C-8 potential or is a thiazine ring constituted by the ethyl, the cyclopropyl, the fluoroethyl and the C-8 potential; L is independent helium atoms, fluorine atoms, 1-piperazinyl, substituted piperazine-1-yl or nitrogen fused heterocycle; and X is -CH (carbon hydrogen), N (notrigen atoms), -CF (fluorine-substituted carbon atoms) or -COCH3 (methoxy-substituted carbon atoms). According to the bi-fluoroquinolone oxadiazoleureas N-acetyl norfloxacin derivative, a bi-fluoroquinolone skeleton, oxadiazole heterocycle and functional base ureas are organically spliced, thus transferring and overlaying of different pharmacophore are achieved, the antitumor activity and selectivity of fluoroquinolone are improved, the toxic and side effects onof normal cells are lowered, and the bi-fluoroquinolone oxadiazole ureas N-acetyl norfloxacin derivative can be used as an antitumor active substance for developing an antitumor drug of a brand-new structureas an antitumor drug of antitumor active substance development brand-newstructure.

Description

technical field [0001] The present invention belongs to the technical field of drug innovation research, and is a complex and arduous intellectual creation process, and specifically relates to the design of a bis-fluoroquinolone oxadiazuron derivative N-acetyl norfloxacin, and also relates to the derivative The preparation method of the compound, and its application in antineoplastic 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 o...

Claims

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Application Information

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IPC IPC(8): C07D498/06C07D413/14C07D471/04C07D513/04A61P35/00A61P35/02A61K31/5383A61K31/496A61K31/542
CPCA61P35/00A61P35/02C07D413/14C07D471/04C07D498/06C07D513/04
Inventor 姜亚玲刘秋伟邵香敏胡国强
Owner ZHENGZHOU UNIV OF IND TECH
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