Indole compounds containing alpha-methylene-gamma-butyrolactone structures, preparation method and application thereof

A compound, butyrolactone technology, applied in the application of tubulin inhibitors in anti-tumor activity, the field of new indole compounds containing α-methylene-γ-butyrolactone structure, which can solve the difficulty of synthesis Large, normal cell effects, neurotoxicity, etc., to achieve short steps, high yield, good activity and broad-spectrum effects

Active Publication Date: 2015-04-22
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although the development of microtubule-targeting agents has been very successful, paclitaxel and vinblastine compounds that act on tubulin have been widely used in clinical treatment of various tumors, however, these tubulin inhibitors often have the following problems: as structurally complex Natural product, its source is limited, and its synthesis is difficult; it will affect normal cells and has neurotoxicity; the existence of multi-drug resistance glycoprotein (P-gp) makes it lack long-term effect

Method used

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  • Indole compounds containing alpha-methylene-gamma-butyrolactone structures, preparation method and application thereof
  • Indole compounds containing alpha-methylene-gamma-butyrolactone structures, preparation method and application thereof
  • Indole compounds containing alpha-methylene-gamma-butyrolactone structures, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1 As shown in the general formula (III), R 1 Preparation of derivative (III-1) of =-H

[0026] Add 40mL DMF into the round bottom flask, slowly add POCl dropwise under ice bath 3 (11.9mL0.128mol), keep stirring in an ice bath for 30min after the dropwise addition, then add dropwise a DMF (20mL) solution of indole (10g, 0.085mol), keep the reaction at room temperature for 3h after dropping, then add 300mL of ice water, and then drop Add 10% by mass NaOH aqueous solution, adjust the pH to 7-8, stir at room temperature overnight, a large amount of white solid precipitates, filter with suction, wash, and dry to obtain 10.74 g of compound III-1, with a yield of 86.7%.

Embodiment 2

[0027] Example 2 As shown in general formula (III), R 1 = Preparation of derivative (III-2) of 5-Cl

[0028] Take the same method as in Example 1 to prepare III-2, R 1 = 5-Cl.

[0029] Add 40mL DMF into the round bottom flask, slowly add POCl dropwise under ice bath 3 (9.2mL0.099mol), keep stirring in an ice bath for 30min after the dropwise addition, then add dropwise a solution of 5-chloroindole (10g, 0.066mol) in DMF (20mL), keep the reaction at room temperature for 3h after dropping, then add 300mL of ice water , and then dropwise added 10% NaOH aqueous solution to adjust the pH to 7-8, stirred overnight at room temperature, a large amount of white solids were precipitated, and were filtered and dried to obtain 10.02 g of compound III-2, with a yield of 84.5%.

Embodiment 3

[0030] Example 3 As shown in general formula (IV), R 1=-H,R 2 = Preparation of derivative (IV-1) of p-F-Bn- After concentrated under reduced pressure, recrystallized with ethanol, and suction filtered to obtain 1.33 g of white solid (IV-1), yield: 76.3%. 1 H NMR (400MHz, CDCl 3 )δ:10.01(s,1H),8.40-8.29(m,1H),7.71(s,1H),7.48-7.26(m,3H),7.21-7.12(m,2H),7.12-6.96(m, 2H), 5.34(s, 2H); 13 C NMR (101MHz, CDCl 3 )δ184.62, 138.26, 131.14, 129.05, 128.96, 125.55, 124.27, 123.18, 122.25, 118.63, 116.26, 116.05, 110.30, 50.27.

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Abstract

The invention discloses a novel indole compounds containing alpha-methylene-gamma-butyrolactone structures, a preparation method thereof and an application thereof serving as tubulin inhibitors in antitumor activity, and belongs to the field of medicinal chemistry. According to the invention, an alpha-methylene-gamma-butyrolactone structure unit is combined with different N substituted indole structures by a simple, convenient and efficient synthetic method to synthesize the indole compounds containing alpha-methylene-gamma-butyrolactone structures, the indole compounds have the following structural general formula shown in the description, in vitro antitumor activity evaluation indicates that the compounds have excellent in vitro antitumor activity in a broad spectrum, and the compounds can be further used as tubulin inhibitors to serve as antitumor candidates or develop lead compounds.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a class of novel indole compounds containing α-methylene-γ-butyrolactone structure, their preparation method and their application in anti-tumor activity as tubulin inhibitors . Background technique [0002] Tubulin is the main component of the cytoskeleton, and plays an important role in maintaining cell shape, cell division, signal transduction, etc., and the tubulin inhibitors acting on the microtubule system can be different from the tubulin The combination of sites, inhibiting the polymerization or depolymerization of microtubules, interfering with the cell cycle, inducing apoptosis, and causing tumor shrinkage or necrosis have become one of the important directions for the research and development of new anticancer drugs. Due to the small cavity volume of the colchicine site on tubulin and the relatively simple structure of the corresponding inhibitor, the resear...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/06C07D405/14A61K31/4439A61K31/404A61P35/00
CPCC07D405/06C07D405/14
Inventor 徐海伟王晓娟刘宏民郑晨星丁丽娜赵玲杰黄瑞彬张国臣吕春涛
Owner ZHENGZHOU UNIV
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