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Preparation and application of bis-fluoroquinolone thiadiazole ureas N-acetyl norfloxacin derivative

A technology of fluoroquinolone thiadizuron and acetyl norfloxacin, which is applied to the preparation of such derivatives and the application of antitumor drugs. In the field of object design, to achieve the effect of innovative structure

Inactive 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-acetyl norfloxacin derivative
  • Preparation and application of bis-fluoroquinolone thiadiazole ureas N-acetyl norfloxacin derivative
  • Preparation and application of bis-fluoroquinolone thiadiazole ureas N-acetyl norfloxacin derivative

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Experimental program
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Effect test

Embodiment 1

[0034] 1-{2-[1-Ethyl-6-fluoro-7-(4-acetylpiperazin-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:

[0035]

[0036] The preparation method of the bis-fluoroquinolone thiadizuron of the present embodiment is: get ofloxacin hydroxamic acid (1 ") 1.0g (2.7mmol) and suspend in 25mL acetonitrile, add carbonyldiimidazole (CDI) 0.67g (4.1mmol), stirring at room temperature until the material is dissolved. Then add N-acetyl norfloxacin C-3 thiadiazolamide V intermediate 1.12g (2.7mmol), stir in a water bath at 55-60°C for 15 hours. Leave overnight, filter The resulting solid was collected and 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 68%, m.p.232-234°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 11.55 (brs, 1H, NH), 9.46 (s, 1H, NH), 9.17, 8...

Embodiment 2

[0038] (S)-1-{2-[1-Ethyl-6-fluoro-7-(4-acetylpiperazin-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:

[0039]

[0040] 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 ), stirred at room temperature until the material was dissolved. Then 1.12 g (2.7 mmol) of N-acetyl norfloxacin C-3 thiadiazole amide V intermediate was added, and stirred in a water bath at 55-60° C. for 10 hours. Placed overnight, and the resulting 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.218-220°C. 1 H NMR (400MHz, DMSO-d 6 )δ:11.57(brs,1H,NH),9.44(s,1H,NH),9.17,8.96(2s,2H,2×2′-H),8...

Embodiment 3

[0042] 1-{2-[1-Ethyl-6-fluoro-7-(4-acetylpiperazin-1-yl)-quinolin-4(1H)-one-3-yl]-1,3,4 -Thiadiazol-5-yl}-3-[6,7-difluoro-1,8-(1,3-oxopropyl)-quinolin-4(1H)-one-3-yl]-urea (I-3), its chemical structural formula is:

[0043]

[0044] The preparation method of the bis-fluoroquinolone thiadiazole of the present 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 room temperature until the material is dissolved. Then add 1.41g (3.4mmol) of N-acetyl norfloxacin C-3 thiadiazole amide V intermediate, and stir in a water bath at 55-60°C for 20 hours. Place overnight, filter The resulting solid was collected and washed with acetonitrile. The crude product was recrystallized from a DMF-ethanol mixed solvent to obtain a light yellow crystal (I-3), with a yield of 72%, m.p.226-228°C. 1 H NMR (400MHz, DMSO-d 6 )δ:11.54(brs,1H,NH),9.43(s,1H,NH),9.12...

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Abstract

The invention discloses a bis-fluoroquinolone thiadiazole ureas N-acetyl norfloxacin derivative and a preparation method and application thereof. The chemical structural general formula of the bis-fluoroquinolone thiadiazole ureas N-acetyl norfloxacin derivative is shown in the following formula I (shown in the specification), according to the formula I, R is ethyl or cyclopropyl or fluoroethyl oran 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-fluoroquinolonethiadiazole ureas N-acetyl norfloxacin derivative and the preparation method and application thereof, organic combination of a bis-fluoroquinolone skeleton, the thiadiazole heterocyclic ring and functional group ureas 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-acetyl norfloxacin derivative can be used as anti-tumor active substances to develop anti-tumor drugs withbrand-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-acetyl norfloxacin derivative, and also relates to the derivative The preparation method of the compound, 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
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王娜沈睿智
Owner HENAN UNIVERSITY
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