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Bis-fluoroquinolone oxadiazole urea derivatives containing N-methyl gatifloxacin as well as preparation method and application of derivatives

A kind of technology of fluoroquinolone-based oxadiazole and gatifloxacin, which is applied in the fields of new drug discovery and innovative drug synthesis

Inactive Publication Date: 2019-03-08
ZHENGZHOU UNIV OF IND TECH
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  • Summary
  • Abstract
  • 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, and further innovations to drive the discovery of targeted anti-tumor fluoroquinolone drugs still remain Current issues to be resolved

Method used

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  • Bis-fluoroquinolone oxadiazole urea derivatives containing N-methyl gatifloxacin as well as preparation method and application of derivatives
  • Bis-fluoroquinolone oxadiazole urea derivatives containing N-methyl gatifloxacin as well as preparation method and application of derivatives
  • Bis-fluoroquinolone oxadiazole urea derivatives containing N-methyl gatifloxacin as well as preparation method and application of derivatives

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Experimental program
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preparation example Construction

[0045] The general method for the preparation of fluoroquinolone hydroxamic acid (1″-18″) is as follows: take the aforementioned crude product of fluoroquinolone carboxylic acid imidazolamide (0.10 mol) and suspend it in 500 mL of pyridine, add 7.0 g to 35 g (0.1 to 0.50 mol) of hydroxylamine hydrochloride , stirred in a water bath at 60-75°C for 8.0-24.0 hours, cooled to room temperature, collected the solid by filtration, washed the solid with pyridine, dried it in vacuum at 60-70°C, and dispersed it in saturated sodium bicarbonate solution (500mL) again. Stir in a water bath at 65°C for 3 to 5 hours, collect the solid by filtration, wash with deionized water until the pH is 7.0, and dry to obtain a crude product. Crystallized to obtain analytically pure crystalline fluoroquinolone hydroxamic acid (1"-18").

[0046] The general method for the preparation of target compound bis-fluoroquinolone-based oxadiazole derivatives containing N-methylgatifloxacin: get each 1.0g of fluo...

Embodiment 1

[0050] 1-{2-[1-cyclopropyl-6-fluoro-8-methoxy-7-(3,4-dimethylpiperazin-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 -oxypropyl)-quinolin-4(1H)-one-3-yl]-urea (I-1), its chemical structural formula is:

[0051]

[0052] The preparation method of the two-fluoroquinolone oxadiazuron of the present embodiment is: get ofloxacin hydroxamic acid (1 ") 1.0g (2.7 mmol) and suspend in 25mL acetonitrile, add CDI0.79g (4.9mmol), Stir at room temperature until the material is dissolved. Then add 1.16g (2.7mmol) of N-methylgatifloxacin C-3 oxadiazolamide II intermediate, and stir in a water bath at 55-60°C for 15 hours. Leave it overnight and filter the resulting solid , 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 56%, m.p.214-216°C. 1 H NMR (400MHz, DMSO-d 6 )δ:11.65(brs,1H,NH), 9.47(s,1H,NH),9.32,9.16(2s,2H,2×2′-H),8....

Embodiment 2

[0054] (S)-1-{2-[1-cyclopropyl-6-fluoro-8-methoxy-7-(3,4-dimethylpiperazin-1-yl)-quinoline-4(1H )-keto-3-yl]-1,3,4-oxadiazol-5-yl}-3-[6-fluoro-7-(4-methylpiperazin-1-yl)-8,1- (1,3-oxopropyl)-quinoline-4(1H)-one-3-yl]-urea (I-1), its chemical structural formula is:

[0055]

[0056] The preparation method of the bis-fluoroquinolone oxadiazole of the present embodiment is: take levofloxacin hydroxamic acid (2 ") 1.0g (2.7 mmol) and suspend in 25mL acetonitrile, add CDI0.70g (4.3mmol), stir at room temperature until The material is dissolved. Then add 1.16g (2.7mmol) of N-methylgatifloxacin C-3 oxadiazolamine II intermediate, and stir in a water bath at 55-60°C for 10 hours. Place it overnight, collect the solid produced by filtration, and wash with acetonitrile The crude product was recrystallized from ethanol to obtain a light yellow crystal (I-2), with a yield of 46%, m.p.208-210°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 11.66 (brs, 1H, NH), 9.50 (s, 1H, NH), 9.34, 9.18 (2s, 2H, ...

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Abstract

The invention discloses bis-fluoroquinolone oxadiazole urea derivatives containing N-methyl gatifloxacin as well as a preparation method and an application of the derivatives. The general chemical structural formula of the derivatives is represented as the formula I shown in the description; in the general formula, R is -CH2-CH3, cyclopropyl or -CH2-CH2F, L is -Cl, -F, 1-piperazinyl, substituted piperazine-1-yl or nitrogenous heterocyclic ring, X is -CH, -N, -CF or -COCH3, or R and X jointly constitute an oxazine ring or a thiazine ring. According to the bis-fluoroquinolone oxadiazole urea derivatives, organic splicing of a bis-fluoroquinolone skeleton, an oxadiazole heterocyclic ring and functional ureas is realized, hopping and stacking of different pharmacophores are realized, antitumoractivity and selectivity of fluoroquinolone are improved, toxic and side effects on normal cells are reduced, and the derivatives can be used as antitumor active substances to develop antitumor drugswith brand-new structure.

Description

technical field [0001] The invention belongs to the technical field of new drug discovery and innovative drug synthesis, and specifically relates to a bis-fluoroquinolone oxadiazole derivative containing N-methylgatifloxacin, and also relates to a preparation method of the derivative. and its application in anticancer 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 us...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/06C07D413/14C07D513/06A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D413/14C07D498/06C07D513/06
Inventor 胡国强冯亚莉刘金海赵源
Owner ZHENGZHOU UNIV OF IND TECH
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