A bis-fluoroquinolone oxadiazuron pefloxacin derivative and its preparation method and application

A technology of fluoroquinolone oxadiazoles and pefloxacin, applied to antineoplastic drugs, the field of bis-fluoroquinolone oxadiazoles and pefloxacin derivatives

Inactive Publication Date: 2021-07-06
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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  • A bis-fluoroquinolone oxadiazuron pefloxacin derivative and its preparation method and application
  • A bis-fluoroquinolone oxadiazuron pefloxacin derivative and its preparation method and application
  • A bis-fluoroquinolone oxadiazuron pefloxacin derivative and its preparation method and application

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Experimental program
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Effect test

Embodiment 1

[0049] 1-{2-[1-Ethyl-6-fluoro-7-(4-methylpiperazin-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:

[0050]

[0051] 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 dissolves. Then add pefloxacin C-3 oxadiazolamide intermediate II 1.00g (2.7mmol), stir in a water bath at 55-60°C for 12 hours. Leave overnight, filter and collect the resulting The solid was 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 62%, m.p.216-218°C. 1 H NMR (400MHz, DMSO-d 6 )δ:11.56(brs,1H,NH),9.45(s,1H,NH),9.17,8.89(2s,2H,2×2′-H),8.24...

Embodiment 2

[0053] (S)-1-{2-[1-Ethyl-6-fluoro-7-(4-methylpiperazin-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:

[0054]

[0055] 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 ), stirring at room temperature until the material is dissolved. Then add pefloxacin C-3 oxadiazolamide intermediate II 1.00g (2.7mmol), and stir in a water bath at 55-60°C for 10 hours. Place overnight, filter and collect the resulting solid, Washed with acetonitrile. The crude product was recrystallized from ethanol to obtain a light yellow crystal (I-2), with a yield of 52%, m.p.208-210°C. 1 H NMR (400MHz, DMSO-d 6 )δ:11.56(brs,1H,NH),9.46(s,1H,NH),9.17,8.92(2s,2H,2×2′-H),8.25~7.47(m,3H,2...

Embodiment 3

[0057] 1-{2-[1-Ethyl-6-fluoro-7-(4-methylpiperazin-1-yl)-quinolin-4(1H)-one-3-yl]-1,3,4 -Oxadiazol-5-yl}-3-[6,7-difluoro-8,1-(1,3-oxopropyl)-quinolin-4(1H)-on-3-yl]-urea (I-3), its chemical structural formula is:

[0058]

[0059] 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 pefloxacin C-3 oxadiazolamide intermediate II 1.27g (3.4mmol), stir in a water bath at 55~60°C for 20 hours. Leave overnight, filter and collect the resulting The solid was 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 57%, m.p.225-227°C. 1 H NMR (400MHz, DMSO-d 6 )δ:11.53(brs,1H,NH),9.42(s,1H,NH),9.16,8.96(2s,2H,2×2′-H),8....

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Abstract

The invention discloses a bis-fluoroquinolone oxadiazuron pefloxacin derivative and its preparation method and application. Its general chemical structure is shown in the following formula: in the formula, R is ethyl, cyclopropyl, Fluoroethyl, oxazine ring formed with C-8 position or thiazine ring formed with C-8 position; L is an independent chlorine atom, fluorine atom, 1-piperazinyl, substituted piperazin-1-yl Or nitrogen-fused heterocycle; X is ‑CH, N, ‑CF or ‑C‑O‑CH 3 . The bis-fluoroquinolone oxadiazole urea pefloxacin derivatives of the present invention realize the organic combination of bis-fluoroquinolone skeleton, oxadiazole heterocycle and functional urea, and then realize the migration of different pharmacophore The superposition of more and more innovates the new structure of drug molecules, which in turn increases the anti-tumor activity and selectivity of fluoroquinolones, reduces the toxic and side effects on normal cells, and can be used as an anti-tumor active substance to develop anti-tumor drugs with a new structure.

Description

technical field [0001] The invention is a drug innovation research, and specifically relates to a bis-fluoroquinolone oxadiazuron pefloxacin derivative, and also relates to a 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 one hand, it is considered that fluoroquinolones (FQs) are widely used as a class of clinical antibacterial drugs, and their antibacterial domin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/06C07D471/04C07D413/14C07D513/04A61P35/00A61P35/02A61K31/5383A61K31/496A61K31/542
CPCA61P35/00A61P35/02C07D413/14C07D471/04C07D498/06C07D513/04
Inventor 刘秋伟邵香敏毛雅君胡国强
Owner ZHENGZHOU UNIV OF IND TECH
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