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Preparation and application of bis-fluoroquinolone thiadiazole urea fleroxacin derivatives

A technology of fluoroquinolone thiadizuron and fleroxacin, its application in antineoplastic drugs, the design of bis-fluoroquinolone thiadizuron-like fleroxacin derivatives, and the field of preparation of such derivatives

Pending Publication Date: 2019-05-17
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 of targeted small molecule leads, and further innovations to drive the discovery of targeted anti-tumor fluoroquinolone drugs still remain Issues to be solved urgently

Method used

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  • Preparation and application of bis-fluoroquinolone thiadiazole urea fleroxacin derivatives
  • Preparation and application of bis-fluoroquinolone thiadiazole urea fleroxacin derivatives
  • Preparation and application of bis-fluoroquinolone thiadiazole urea fleroxacin derivatives

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] 1-{2-[1-(2-fluoroethyl)-6,8-difluoro-7-(4-methylpiperazin-1-yl)-quinolin-4(1H)-one-3- Base]-1,3,4-thiadiazol-5-yl}-3-[6-fluoro-7-(4-methylpiperazin-1-yl)-8,1-(1,3-oxo Propyl)-quinoline-4(1H)-ketone-3-yl]-urea (I-1), its chemical structural formula is:

[0035]

[0036] The preparation method of the bis-fluoroquinolone thiadizuron of the present embodiment is: take ofloxacin hydroxamic acid (II-1 ") 1.0g (2.7 mmol) and suspend in 25mL acetonitrile, add carbonyldiimidazole (CDI) 0.79g (4.9mmol), stir at room temperature until the material is dissolved. Then add 1.14g (2.7mmol) of fleroxacin C-3 thiadiazole amine IV intermediate, and stir in a water bath at 55-60°C for 15 hours. Leave it overnight 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 67%, m.p.226-228°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 11.57 (brs, 1H, NH), 9.45 (s, 1H...

Embodiment 2

[0038] (S)-1-{2-[1-(2-fluoroethyl)-6,8-difluoro-7-(4-methylpiperazin-1-yl)-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)-quinolin-4(1H)-one-3-yl]-urea (I-1), its chemical structural formula is:

[0039]

[0040] The preparation method of the bis-fluoroquinolone thiadizuron of the present embodiment is: take levofloxacin hydroxamic acid (II-2 ") 1.0g (2.7 mmol) and suspend in 25mL acetonitrile, add carbonyldiimidazole (CDI) 0.70g ( 4.3mmol), stirring at room temperature until the material is dissolved. Then add 1.14g (2.7mmol) of fleroxacin C-3 thiadiazole amine IV intermediate, and stir in a water bath at 55-60°C for 10 hours. Place overnight, filter the resulting solid, acetonitrile Wash. The crude product was recrystallized from ethanol to obtain a light yellow crystal (I-2), with a yield of 46%, m.p.214-216°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 11.53 (brs, 1H, NH), 9.56 (s, 1H, NH), 9.23, 9.16 (2s, 2H, 2×2′-H...

Embodiment 3

[0042] 1-{2-[1-(2-fluoroethyl)-6,8-difluoro-7-(4-methylpiperazin-1-yl)-quinolin-4(1H)-one-3- Base]-1,3,4-thiadiazol-5-yl}-3-[6,7-difluoro-8,1-(1,3-oxopropyl)-quinoline-4(1H)- Keto-3-base]-urea (I-3), its chemical structural formula is:

[0043]

[0044] The preparation method of the bis-fluoroquinolone thiadizuron of this 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), stir at room temperature until the material is dissolved. Then add 1.44g (3.4mmol) of fleroxacin C-3 thiadiazole amine IV intermediate, and stir in a water bath at 55-60°C for 20 hours. Leave 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 67%, m.p.225-227°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 11.53 (brs, 1H, NH), 9.41 (s, 1H, NH)...

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Abstract

The invention discloses bis-fluoroquinolone thiadiazole urea fleroxacin derivatives as well as a preparation method and an application thereof. The general chemical structure formula of the derivatives is shown in the formula I as follows in the description. In the formula I, R is ethyl, cyclopropyl, fluoroethyl, an oxazine ring formed with C-8 or a thiazine ring formed with C-8; L is an independent Cl or F atom, 1-piperazinyl, substituted piperazine-1-yl or a nitrogen fused heterocyclic ring; X is CH, N atom or F-substituted C atom (F-C) or a methoxy substituted C atom (CH3O-C). The bis-fluoroquinolone thiadiazole urea fleroxacin derivatives realize organic combination of a bis-fluoroquinolone skeleton and the thiadiazole heterocyclic ring with functional urea pharmacophores, so that transition and superposition of different pharmacophores are realized, anti-tumor activity and selectivity of fluoroquinolone are increased, toxic and side effects on normal cells are reduced, and the derivatives can be taken as an anti-tumor active substance for developing anti-tumor drugs with novel structures.

Description

technical field [0001] The present invention belongs to the technical field of drug innovation research, and is a complex and arduous intellectual creation process, and specifically relates to the design of a bis-fluoroquinolone thiadiazuron derivative of fleroxacin, and also relates to the preparation method of such derivatives, 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 a key link to promote their development into finished drugs. The 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 consid...

Claims

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Application Information

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IPC IPC(8): C07D498/06C07D417/14C07D471/04C07D513/06A61P35/00A61P35/02
CPCY02A50/30
Inventor 侯莉莉张呈霞胡国强孙姣姣王娜沈睿智
Owner HENAN UNIVERSITY
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