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Preparation and application of bis-fluoroquinolone thiadiazole urea levofloxacin derivative

A technology of fluoroquinolone thiadizuron and levofloxacin, applied to antineoplastic drugs, the field of bis-fluoroquinolone thiadizuron levofloxacin derivatives

Pending Publication Date: 2019-04-26
HENAN UNIVERSITY
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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 o

Method used

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  • Preparation and application of bis-fluoroquinolone thiadiazole urea levofloxacin derivative
  • Preparation and application of bis-fluoroquinolone thiadiazole urea levofloxacin derivative
  • Preparation and application of bis-fluoroquinolone thiadiazole urea levofloxacin derivative

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Experimental program
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Effect test

Embodiment 1

[0038] (S)-1-{2-[6-fluoro-7-(4-methylpiperazin-1-yl)-8,1-(1,3-oxopropyl)-quinoline-4(1H) -Keto-3-yl]-1,3,4-thiadiazol-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:

[0039]

[0040] The preparation method of the bis-fluoroquinolone thiadizuron of this embodiment is: take levofloxacin hydroxamic acid (1″) 1.0g (2.7mmol) and suspend in 25mL acetonitrile, add carbonyldiimidazole (CDI) 0.50g (3.2mmol ), stirring at room temperature until the material dissolves. Then add 1.10 g (2.7 mmol) of levofloxacin C-3 thiadiazole amine IV intermediate, and stir in a water bath at 55 to 60 ° C for 12 hours. Place overnight, collect the solid produced by filtration, and wash with acetonitrile. Crude product Recrystallized with DMF-ethanol mixed solvent to obtain pale yellow crystal (I-1), with a yield of 52%, m.p.224-226°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 11.56 (brs, 1H, NH), 9.44 (s, 1H, NH), 9.1...

Embodiment 2

[0042] (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-thiadiazol-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:

[0043]

[0044] The preparation method of the bis-fluoroquinolone thiadizuron of this 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 1.1 g (2.7 mmol) of levofloxacin C-3 thiadiazole amine IV intermediate, and stir in a water bath at 55 to 60° C. for 16 hours. Place overnight, collect the solid produced by filtration, and wash with acetonitrile. Crude product Recrystallized with ethanol to obtain a light yellow crystal (I-2), with a yield of 46%, m.p.212-214°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 11.57 (brs, 1H, NH), 9.45 (s, 1H, NH), 9.16, 9.14 (2...

Embodiment 3

[0046] (S)-1-{2-[6-fluoro-7-(4-methylpiperazin-1-yl)-8,1-(1,3-oxopropyl)-quinoline-4(1H) -Keto-3-yl]-1,3,4-thiadiazol-5-yl}-3-[6,7-difluoro-8,1-(1,3-oxopropyl)-quinoline- 4(1H)-ketone-3-yl]-urea (I-3), its chemical structural formula is:

[0047]

[0048] The preparation method of the bis-fluoroquinolone thiadizuron of the present embodiment is: take 1.0 g (3.4 mmol) of oxyfluorocarboxylic acid hydroxamic acid (II-3″) and suspend it in 25 mL of acetonitrile, add carbonyldiimidazole (CDI) 0.82g (5.1mmol), stirring at room temperature until the material is dissolved. Then add 1.40g (3.4mmol) of levofloxacin C-3 thiadiazole amine IV intermediate, and stir in a water bath at 55-60°C for 18 hours. Leave it overnight and collect the resulting The solid was washed with acetonitrile. The crude product was recrystallized from a mixed solvent of DMF-ethanol 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:11.51(brs,1H,NH),9.3...

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Abstract

The invention discloses a bis-fluoroquinolone thiadiazole urea levofloxacin derivative and preparation method and application thereof. The chemical structural general formula of the fluoroquinolone thiadiazole urea levofloxacin derivative is shown in the following formula I (shown in the specification), according to the formula I, R is ethyl or cyclopropyl or fluoroethyl or an oxazine ring formedwith a C-8 position or a thiazine ring formed with the C-8 position, L is independent chlorine atom or fluorine atom or 1-piperazinyl or substituted piperazine-1-yl or a nitrogen fused heterocyclic ring, and X is hydrocarbon (CH) or nitrogen atom or fluorine-substituted carbon atom (F-C) or methoxy-group-substituted carbon atom (CH3O-C). According to the bis-fluoroquinolone thiadiazole urea levofloxacin derivative and preparation method and application thereof, organic combination of a bis-fluoroquinolone skeleton, the thiadiazole heterocyclic ring and functional group urea pharmacophore is achieved, the charge transfer and superposition of different pharmacophore are further achieved, the anti-tumor activity and selectivity of fluoroquinolone are increased, toxic and side effects on normal cells are reduced, and the bis-fluoroquinolone thiadiazole urea levofloxacin derivative can be used as anti-tumor active substances to develop anti-tumor drugs with brand-new structures.

Description

technical field [0001] The invention is a drug innovation research, and specifically relates to a bis-fluoroquinolone thiadizuron levofloxacin 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 dom...

Claims

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Application Information

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IPC IPC(8): C07D519/00C07D498/06A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D498/06C07D519/00
Inventor 胡国强孙姣姣张呈霞
Owner HENAN UNIVERSITY
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