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Synthesis and preparation of nitroimidazole derivative containing 1,4-benzdioxan skeleton and application of nitroimidazole derivative in anticancer drugs

A technology of benzodioxane and nitroimidazole is applied in the synthesis and preparation of a class of nitroimidazole derivatives containing 1,4-benzodioxane skeleton and its application in anticancer drugs, It can solve the problems of obvious adverse reactions and poor pharmacokinetic properties

Inactive Publication Date: 2014-02-19
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In recent years, studies have found that imidazole compounds have a variety of biological activities, especially as anticancer drugs, showing broad application prospects, but they have the characteristics of poor pharmacokinetic properties and obvious adverse reactions. Effectively modify their structures to obtain high-efficiency, Low-toxic imidazole anticancer drugs have become one of the current research hotspots in the field of medicinal chemistry

Method used

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  • Synthesis and preparation of nitroimidazole derivative containing 1,4-benzdioxan skeleton and application of nitroimidazole derivative in anticancer drugs
  • Synthesis and preparation of nitroimidazole derivative containing 1,4-benzdioxan skeleton and application of nitroimidazole derivative in anticancer drugs
  • Synthesis and preparation of nitroimidazole derivative containing 1,4-benzdioxan skeleton and application of nitroimidazole derivative in anticancer drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0012] Example 1: Preparation of (E)-2-(2-styryl-5-nitroimidazole)ethyl-4-methylbenzenesulfonate (3)

[0013]

[0014] Under stirring conditions, (E)-2-(2-styryl-5-nitroimidazole) ethanol (2.59 g, 10 mmol), 20 mL of CH 2 Cl 2 , p-toluenesulfonyl chloride (1.90g, 10mmol) and 10mL of triethylamine, stirred and reacted at room temperature for 7 hours (TLC detection reaction), filtered, washed and dried to obtain a crude product, and then the crude product was reconstituted in ethanol Crystallization gave the target compound as white crystals. Yield 83.5%.m.p.164~167℃; 1 H NMR (DMSO-d 6 , 300MHzδppm)δ: 8.01(s, 1H, C-CH-N), 7.91~7.74(m, 4H, Ph-H), 7.34~7.28(m, 5H, Ph-H), 7.04(d, J= 6.4Hz, 2H, C-CH-CH), 4.49(d, 2H, J=5.7Hz, C-CH 2 -C), 4.22(s, 2H, C-CH 2 -C), 2.44(s, 3H, CH 3 -C).

Embodiment 2

[0015] Example 2: (E)-2-(2-styryl-5-nitroimidazole) ethyl-2,3-dihydrobenzo[1,4]dioxane-6-carboxylate (4u ) preparation

[0016]

[0017] Add the above white product (2.06g, 5mmol) into a 25mL round bottom flask containing 15mL of DMF, stir until dissolved, then add 1,4-benzodioxane-6-carboxylic acid (1.7g, 7.5mmol), dissolve After adding K 2 CO 3 (5mmol, 0.69g) as catalyst. After reacting for 4 hours under reflux and stirring (TLC detection of reaction), let it stand until it cools down, then add the reactant to 20 mL of ice water, filter and dry the precipitated solid, and dissolve it with acetone and absolute ethanol for recrystallization. Yield 62.7%.m.p.173~175℃; 1 H NMR (DMSO-d 6 , 300MHz, δppm): 4.23(s, 2H, O-CH 2 -C), 4.36(s, 2H, C-CH 2 -O), 4.67(s, 2H, N-CH 2 -C), 5.01(s, 2H, C-CH 2 -O), 6.67(d, J=4.5Hz, 1H, C-CH-C), 7.23~7.35(m, 6H, C-CH-C, Ph-H), 7.45~7.55(m, 3H, Ph -H), 8.21(s, 1H, N-CH).

Embodiment 3

[0018] Example 3: (E)-2-(2-(2-fluorostyryl)-5-nitroimidazole)ethyl-2,3-dihydrobenzo[1,4]dioxane-6- Preparation of Carboxylate (4a)

[0019]

[0020] The preparation method is the same as that in Example 2, with (E)-2-(2-(2-fluorostyryl)-5-nitroimidazole)ethyl-4-methylbenzenesulfonate instead of (E)-2-( 2-Styryl-5-nitroimidazole)ethyl-4-methylbenzenesulfonate to give the yellow target compound. Yield 65.2%.m.p.176~177℃; 1 H NMR (DMSO-d 6 , 300MHz, δppm): 4.13(s, 4H, O-CH 2 -CH 2 -O), 4.58(t, J=6.2Hz, 2H, N-CH 2 -C), 5.02(s, 2H, C-CH 2 -O), 6.50(t, J=3.6Hz, 1H, C-CH-C), 6.91(d, J=8.4Hz, 1H, C-CH-C), 7.05~7.31(m, 5H, Ph- H), 7.79~7.95(m, 2H, Ph-H), 8.23(s, 1H, N-CH).

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Abstract

Synthesis of a nitroimidazole derivative containing a 1,4-benzdioxan skeleton is characterized by having the following general formula as described in the specification. The nitroimidazole derivative containing the 1,4-benzdioxan skeleton has significant inhibition effects on human lung adenocarcinoma cell lines (A549), human cervical carcinoma cell lines (HELA), human neuroastrocytoma cell lines (U251) and human hepatoma cell lines (HEPG2), so the imidazole derivative can be applied in preparation of antitumor drugs. The invention discloses a preparation method of the nitroimidazole derivative.

Description

technical field [0001] The invention relates to the synthesis, preparation and application of a class of nitroimidazole derivatives containing 1,4-benzodioxane skeleton and anticancer drugs. Background technique [0002] Imidazole derivatives, which are widely used in the treatment of anaerobic infections, such as for the treatment of intestinal and parenteral amoebiasis (such as amebic liver abscess, pleural amoebiasis, etc.), vaginal trichomoniasis, pouch Insect disease etc. In recent years, studies have found that imidazole compounds have a variety of biological activities, especially as anticancer drugs, showing broad application prospects, but they have the characteristics of poor pharmacokinetic properties and obvious adverse reactions. Effectively modify their structures to obtain high-efficiency, Low-toxic imidazole anticancer drugs have become one of the hotspots in the field of medicinal chemistry. [0003] 1,4-Benzodioxane contains two oxygen atoms, which are ea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12A61P35/00
CPCC07D405/12
Inventor 朱海亮桑亚丽段勇涛陶翔翔汤丹洁
Owner NANJING UNIV
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