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Preparation and application of bis-fluoroquinolone thiadiazole ureas N-methyl ciprofloxacin derivative

A technology of fluoroquinolone thiadizuron and methyl ciprofloxacin, which is applied to the preparation of such derivatives and the application of antineoplastic drugs, bis-fluoroquinolone thiadizuron N-methyl ciprofloxacin The field of design of star derivatives to achieve the effect of innovative structure

Pending Publication Date: 2019-04-26
HENAN UNIVERSITY
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  • 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. Further innovations to drive the discovery of targeted anti-tumor fluoroquinolone drugs are still a Current issues to be resolved

Method used

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  • Preparation and application of bis-fluoroquinolone thiadiazole ureas N-methyl ciprofloxacin derivative
  • Preparation and application of bis-fluoroquinolone thiadiazole ureas N-methyl ciprofloxacin derivative
  • Preparation and application of bis-fluoroquinolone thiadiazole ureas N-methyl ciprofloxacin derivative

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Experimental program
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Effect test

Embodiment 1

[0033] 1-{2-[1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-quinolin-4(1H)-one-3-yl]-1,3, 4-Thiadiazol-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:

[0034]

[0035] The preparation method of the bis-fluoroquinolone thiadizuron of the present embodiment is: get ofloxacin hydroxamic acid (1 ") 1.0g (2.7 mmol) and suspend in 25mL acetonitrile, add carbonyldiimidazole (CDI) 0.84g (5.2mmol), stirring at normal temperature until the material dissolves. Then add N-methylciprofloxacin C-3 thiadiazole amine IV intermediate 1.08g (2.7mmol), stir in a water bath at 55~60°C for 16 hours.Stand overnight, The resulting solid was collected by filtration and 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 58%, m.p.224-226°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 11.47 (brs, 1H, NH), 9.38 (...

Embodiment 2

[0037] (S)-1-{2-[1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-quinolin-4(1H)-one-3-yl]- 1,3,4-Thiadiazol-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:

[0038]

[0039] 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) 0.70g (4.3mmol ), stirred at room temperature until the material was dissolved. Then 1.08 g (2.7 mmol) of N-methylciprofloxacin C-3 thiadiazole amine IV intermediate was added, stirred in a water bath at 55-60°C for 10 hours. Placed overnight, filtered to produce The solid was washed with acetonitrile. The crude product was recrystallized from ethanol to obtain a light yellow crystal (I-2), with a yield of 54%, m.p.214-216°C. 1 H NMR (400 MHz, DMSO-d 6 )δ: 11.46 (brs, 1H, NH), 9.37 (s, 1H, NH), 9.16, 8.94 ...

Embodiment 3

[0041] 1-{2-[1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-quinolin-4(1H)-one-3-yl]-1,3, 4-Thiadiazol-5-yl}-3-[6,7-difluoro-8,1-(1,3-oxopropyl)-quinolin-4(1H)-one-3-yl]- Urea (I-3), its chemical structural formula is:

[0042]

[0043] The preparation method of the bis-fluoroquinolone thiadizuron of this embodiment is: take 1.0 g (3.4 mmol) of oxyfluorocarboxylic acid hydroxamic acid (3″) and suspend it in 25 mL of acetonitrile, add 0.82 g of carbonyldiimidazole (CDI) (5.1mmol), stirring at normal temperature until the material dissolves. Then add N-methylciprofloxacin C-3 thiadiazole amine IV intermediate 1.36g (3.4mmol), stir in a water bath at 55~60°C for 24 hours.Stand overnight, The resulting solid was collected by filtration and 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 64%, m.p.235-237°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 11.45 (brs, 1H, NH), 9.38 (s, 1...

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Abstract

The invention discloses a bis-fluoroquinolone thiadiazole ureas N-methyl ciprofloxacin derivative and a preparation method and application thereof. The chemical structural general formula of the bis-fluoroquinolone thiadiazole ureas N-methyl ciprofloxacin 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 formed with 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 ureas N-methyl ciprofloxacin derivative and the preparation method and application thereof, organic combination of a bis-fluoroquinolone skeleton, the thiadiazole heterocyclic ring and functional group urea 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 ureas N-methyl ciprofloxacin derivative can be used as anti-tumor active substances to develop anti-tumor drugs with brand-new structures.

Description

technical field [0001] The present invention belongs to the technical field of drug innovation research, and is a complicated and arduous intellectual creation process, and specifically relates to the design of a bis-fluoroquinolone thiadiazole derivative N-methylciprofloxacin derivative, and also relates to this kind of The 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 thi...

Claims

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Application Information

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IPC IPC(8): C07D498/06C07D417/14C07D471/04C07D513/06A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D417/14C07D471/04C07D498/06C07D513/06
Inventor 胡国强张呈霞孙姣姣沈睿智王娜
Owner HENAN UNIVERSITY
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