Bis-fluoroquinolone-based oxadiazole urea derivative containing N-methyloxacin and preparation method and application of bis-fluoroquinolone-based oxadiazole urea derivative

A technology of fluoroquinolone-based oxadiazuron and methyllomefloxacin, which is applied in the field of new drug discovery and innovative drug synthesis

Inactive Publication Date: 2019-03-01
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-based oxadiazole urea derivative containing N-methyloxacin and preparation method and application of bis-fluoroquinolone-based oxadiazole urea derivative
  • Bis-fluoroquinolone-based oxadiazole urea derivative containing N-methyloxacin and preparation method and application of bis-fluoroquinolone-based oxadiazole urea derivative
  • Bis-fluoroquinolone-based oxadiazole urea derivative containing N-methyloxacin and preparation method and application of bis-fluoroquinolone-based oxadiazole urea derivative

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preparation example Construction

[0048] 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 7.0-35.0 g (0.1-0.5 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").

[0049] General method for the preparation of target compound bis-fluoroquinolone-based oxadiazuron derivatives containing N-methyllomefloxacin: get each 1.0g of fluoroquinolon...

Embodiment 1

[0053] 1-{2-[1-Ethyl-6,8-difluoro-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-oxopropyl )-quinoline-4(1H)-ketone-3-yl]-urea (I-1), its chemical structural formula is:

[0054]

[0055] 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 CDI 0.79g (4.9mmol), Stir at room temperature until the material is dissolved. Then add 1.09 g (2.7 mmol) of N-methyllomefloxacin C-3 oxadiazolamide II intermediate, and stir in a water bath at 55-60° C. for 16 hours. Place overnight, and collect the solid produced by filtration. 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 46%, m.p.214-216°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 11.57 (brs, 1H, NH), 9.43 (s, 1H, NH), 9.16, 8.95 (2...

Embodiment 2

[0057] (S)-1-{2-[1-ethyl-6,8-difluoro-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:

[0058]

[0059] The preparation method of the bis-fluoroquinolone oxadiazuron of the present embodiment is: take levofloxacin hydroxamic acid (2 ") 1.0g (2.7 mmol) and suspend in 25mL acetonitrile, add CDI 0.70g (4.3mmol), stir at room temperature until The material was dissolved. Then 1.09 g (2.7 mmol) of N-methyllomefloxacin C-3 oxadiazole amide II intermediate was added, stirred in a water bath at 55-60° C. for 10 hours, left overnight, and the resulting solid was collected by filtration and washed with acetonitrile. The crude product was recrystallized from ethanol to obtain a light yellow crystal (I-2), with a yield of 45%, m.p.208-210°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 11.58 (brs, 1H, NH), 9.45 (s, 1H, NH), 9.17, 8.96 (...

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Abstract

The invention discloses a bis-fluoroquinolone-based oxadiazole urea derivative containing N-methyloxacin and a preparation method and application of the bis-fluoroquinolone-based oxadiazole urea derivative. The chemical structural general formula is shown in formula I as shown in specification, in the general formula I, R is -CH2-CH3, cyclopropyl or -CH2-CH2F; L is -Cl, -F, 1-piperazinyl, substituted piperazine-1-yl or nitrogen-containing fused heterocycle; X is -CH, -N, -CF or -COCH3; or R and X jointly form an oxazine ring or phenothiazine ring. By the bis-fluoroquinolone-based oxadiazole urea derivative, organic combination of a bis-fluoroquinolone framework, an oxadiazole heterocyclic ring and functional urea is realized, therefore, transferring and overlapping of different pharmacophores are realized, the anti-tumor activity and selectivity of the fluoroquinolone are improved, toxic and side effects to normal cells are reduced, and the bis-fluoroquinolone-based oxadiazole urea derivative can serve as an anti-tumor active substance to develop an anti-tumor drug with a 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-based oxadiazole derivative containing N-methyllomefloxacin, and also relates to a preparation method of this type of derivative, 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 one hand, it is considered that fluoroquinolones ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/06C07D413/14C07D471/04C07D513/06A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D413/14C07D471/04C07D498/06C07D513/06
Inventor 卢令攀张会丽王桁杰胡国强
Owner ZHENGZHOU UNIV OF IND TECH
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