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Bis-fluoroquinolone oxadiazole derivatives containing levofloxacin and its preparation method and application

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

Inactive Publication Date: 2021-07-06
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 derivatives containing levofloxacin and its preparation method and application
  • Bis-fluoroquinolone oxadiazole derivatives containing levofloxacin and its preparation method and application
  • Bis-fluoroquinolone oxadiazole derivatives containing levofloxacin and its preparation method and application

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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 crude imidazolamide fluoroquinolone carboxylic acid (0.10mol) and suspend it in 500mL of pyridine, add 7.0-35.0g (0.1-0.50mol) 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, which is washed with absolute ethanol (or anhydrous ethanol-DMF mixed solvent (V 乙醇 :V DMF =5:1) recrystallized to obtain analytically pure crystalline fluoroquinolone hydroxamic acid (1″~18″).

[0049] The preparation general method of two-fluoroquinolone base oxadiazole derivatives of target compo...

Embodiment 1

[0053] (S)-1-{2-[6-fluoro-7-(4-methylpiperazin-1-yl)-8,1-(1,3-oxopropyl)-quinoline-4(1H) -Keto-3-yl]-1,3,4-oxadiazol-5-yl}-3-[6-fluoro-7-(4-methylpiperazin-1-yl)-8,1-( 1,3-oxypropyl)-quinoline-4(1H)-one-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 (2.7mmol) and suspend in 25mL acetonitrile, add CDI 0.50g (3.2mmol), Stir at room temperature until the material is dissolved. Then add 1.08g (2.7mmol) of levofloxacin C-3 oxadiazole amine II intermediate, and stir in a water bath at 55-60°C for 16 hours. Leave it overnight, collect the solid produced by filtration, and wash with acetonitrile. The crude product is washed with DMF -Recrystallization from a mixed solvent of ethanol to obtain a light yellow crystal (I-1), with a yield of 48%, m.p.216-218°C. 1 H NMR (400MHz, DMSO-d 6 )δ:11.57(brs,1H,NH),9.46(s,1H,NH),9.18,9....

Embodiment 2

[0057] (S, S)-1-{2-[6-fluoro-7-(4-methylpiperazin-1-yl)-8,1-(1,3-oxopropyl)-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-2), 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 (2.7mmol) and suspend in 25mL acetonitrile, add CDI 0.60g (3.7mmol), stir at room temperature until Material is dissolved. Then add levofloxacin C-3 oxadiazole amine II intermediate 1.08g (2.7mmol), water-bath 55~60 ℃ and stir 10 hours.Stir overnight, filter the solid that produces, acetonitrile washing.Crude ethanol recrystallization, A light yellow crystal (I-2) was obtained with a yield of 42%, m.p.207-209°C. 1 H NMR (400MHz, DMSO-d 6 )δ:11.62(brs,1H,NH),9.50(s,1H,NH),9.23,9.16(2s,2H,2×2′-H),8.26~7.83(m,2H,2×5′- H),4.97~4.83(m,6H,2×OCH 2 CHN),3.56~3.45(m,8H,2...

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Abstract

The invention discloses a bis-fluoroquinolone oxadiazuron derivative containing levofloxacin and its preparation method and application. Its general chemical structure is shown in the following formula I: in the general formula I, R is -CH 2 -CH 3 , cyclopropyl or ‑CH 2 -CH 2 F; L is -Cl, -F, 1-piperazinyl, substituted piperazin-1-yl or nitrogen-containing fused heterocycle; X is -CH, -N, -CF or -COCH 3 ; or R and X together form an oxazine ring or a thiazine ring. The bis-fluoroquinolone oxadiazole urea derivatives of the present invention realize the organic combination of bis-fluoroquinolone skeleton, oxadiazole heterocycle and functional urea, and then realize the transition and superposition of different pharmacophores, increasing the The antitumor activity and selectivity of fluoroquinolones are improved, the toxic and side effects on normal cells are reduced, and antitumor drugs with new structures can be developed as antitumor active substances.

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 oxadiazuron derivative containing levofloxacin, and also relates to a preparation method of the derivative, and its use in antitumor drugs Applications. 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 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/06C07D519/00A61P35/00A61P35/02A61K31/5383
CPCA61P35/00A61P35/02C07D498/06C07D519/00
Inventor 李珂蔡元元臧锋磊胡国强
Owner ZHENGZHOU UNIV OF IND TECH
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