A kind of bis-fluoroquinolone oxadiazuron derivative n-acetyl norfloxacin derivative and its preparation method and application

A kind of technology of fluoroquinolone oxadiazole urea and acetyl norfloxacin, which is applied in the preparation of such derivatives, and the application in antitumor drugs, bis-fluoroquinolone oxadiazole urea N-acetyl norfloxacin derivatives object design

Inactive Publication Date: 2021-07-06
ZHENGZHOU UNIV OF IND TECH
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  • Description
  • Claims
  • Application Information

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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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  • A kind of bis-fluoroquinolone oxadiazuron derivative n-acetyl norfloxacin derivative and its preparation method and application
  • A kind of bis-fluoroquinolone oxadiazuron derivative n-acetyl norfloxacin derivative and its preparation method and application
  • A kind of bis-fluoroquinolone oxadiazuron derivative n-acetyl norfloxacin derivative and its preparation method and application

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Effect test

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 bis-fluoroquinolone oxadiazuron N-acetyl norfloxacin derivative and its preparation method and application. Its general chemical structure is shown in the following formula: where R is ethyl, cyclopropane Base, fluoroethyl, oxazine ring formed with C-8 position or thiazine ring formed with C-8 position; in the formula, L is an independent chlorine atom, fluorine atom, 1-piperazinyl, substituted piperazine ‑1‑yl or nitrogen-fused heterocycle; X is ‑CH (carbon hydrogen), N (nitrogen atom), ‑CF (fluorine-substituted carbon atom) or ‑COCH 3 (carbon atom substituted with methoxy). The bis-fluoroquinolone oxadiazole urea N-acetyl norfloxacin derivative of the present invention realizes the organic combination of bis-fluoroquinolone skeleton, oxadiazole heterocycle and functional urea, and then realizes different pharmacophore The migration and superposition of fluoroquinolones increase the anti-tumor activity and selectivity of fluoroquinolones, reduce the toxic and side effects on normal cells, and can be used as anti-tumor active substances to develop anti-tumor drugs with a new structure.

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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Patent Type & Authority Patents(China)
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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