Tubulin inhibitor and preparation method and application thereof

A pharmaceutical preparation and reaction technology, applied in the field of medicinal chemistry, can solve the problems of easy drug resistance, high toxicity and side effects, and difficult synthesis, and achieve the effects of novel structure, reduction of toxicity and side effects, and enhanced specificity

Active Publication Date: 2019-10-18
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the inventors have found that the above-mentioned drugs have serious side effects, are prone to drug resistance, have complex structures, and are difficult to synthesize. Therefore, finding new, efficient, and low-toxic microtubule inhibitors has become a hot spot in the research of anti-tumor drugs today.

Method used

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  • Tubulin inhibitor and preparation method and application thereof
  • Tubulin inhibitor and preparation method and application thereof
  • Tubulin inhibitor and preparation method and application thereof

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preparation example Construction

[0037] In yet another specific embodiment of the present invention, the preparation method includes the following steps:

[0038] With 2-fluorobenzoic acid containing different substituents at the 4-position as the starting material, react with 3,4,5-trimethoxyaniline to obtain 2-fluoro-N-(3,4, 5-trimethoxyphenyl) benzamide (formula 2), the compound of formula 2 undergoes a thiolation reaction under the effect of Lawson's reagent to obtain 2-fluoro-N-(3,4,5- Trimethoxyphenyl) thiobenzamide (formula 3), the compound of formula 3 is cyclized with hydrazine hydrate to generate the compound shown in formula I.

[0039] In yet another specific embodiment of the present invention, when R is taken from a methyl group, the preparation method includes the following steps:

[0040] (1) Dissolve 2-fluoro-4-methylbenzoic acid in N,N-dimethylformamide, add triethylamine, 3,4,5-trimethoxyaniline, 2-(7-benzene oxide Triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, stirred, added...

Embodiment 1

[0068] Embodiment 1: the preparation of structural formula 1 compound

[0069] (1) Dissolve 2-fluoro-4-methylbenzoic acid (50mg) in N,N-dimethylformamide (4mL), add triethylamine (70μL), 3,4,5-trimethoxy Aniline (66mg), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (137mg), reacted for 2h, added water, extracted with ethyl acetate, Column chromatography gave 2-fluoro-4-methyl-N-(3,4,5-trimethoxyphenyl)benzamide (100 mg) with a yield of 96%. Melting point: 117-118°C.

[0070] (2) Dissolve 2-fluoro-4-methyl-N-(3,4,5-trimethoxyphenyl)benzamide (80mg) in toluene (4mL), add Lawson's reagent (71mg), 105 °C, spin to dry the solvent, and perform column chromatography to obtain crude 2-fluoro-4-methoxy-N-(3,4,5-trimethoxyphenyl)thiobenzamide.

[0071] (3) Dissolve the crude 2-fluoro-4-methyl-N-(3,4,5-trimethoxyphenyl)thiobenzamide obtained in step (2) in dimethyl sulfoxide, add hydration Hydrazine (167 μL), react at 110°C, add water, and filter with suc...

Embodiment 2

[0073] Embodiment 2: the preparation of structural formula 2 compound

[0074] (1) Dissolve 2-fluoro-4-methoxybenzoic acid (80mg) in N,N-dimethylformamide (4mL), add triethylamine (100μL), 3,4,5-trimethoxy Aniline (95mg), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (196mg), reacted for 2h, added water, extracted with ethyl acetate , and column chromatography, 2-fluoro-4-methoxy-N-(3,4,5-trimethoxyphenyl)benzamide (157 mg) was obtained with a yield of 99.6%. Melting point: 126-127°C.

[0075] (2) Dissolve 2-fluoro-4-methoxy-N-(3,4,5-trimethoxyphenyl)benzamide (80mg) in toluene (4mL), add Lawson's reagent (67mg), Spin to dry the solvent at 105°C and perform column chromatography to obtain crude 2-fluoro-4-methoxy-N-(3,4,5-trimethoxyphenyl)thiobenzamide.

[0076] (3) Dissolve the crude 2-fluoro-4-methoxy-N-(3,4,5-trimethoxyphenyl)thiobenzamide obtained in step (2) in dimethyl sulfoxide, add Hydrazine hydrate (144μL), react at 110°C, add water, a...

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Abstract

The invention discloses a tubulin inhibitor and a preparation method and application thereof. The tubulin inhibitor is a 1-methylindeno[1,2-c]pyrazoles small molecule compound with a novel structure,the structural formula is shown, and please see the specification for the formula. It is further confirmed by experiments that proliferative effect of human liver cancer cells, human non-small cell lung cancer cells, human colon cells and other tumor cells can be effectively inhibited. The mechanism of action is similar to that of colchicine, and the polymerization of tubulin can be inhibited. Thetubulin inhibitor and the preparation method and application thereof are of great significance for enhancing the specificity, effectiveness, reducing toxic side effects and preventing drug resistanceof drugs, and have good potential value for development and application.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a tubulin inhibitor and its preparation method and application. Background technique [0002] The information disclosed in this background section is only intended to increase the understanding of the general background of the present invention, and is not necessarily taken as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to those skilled in the art. [0003] Microtubules are the main components of the cytoskeleton. They are composed of α-tubulin and β-tubulin heterodimers. They have the dynamic characteristics of polymerization and depolymerization. Plays an important role in the process of transportation and so on. [0004] Antimicrotubule drugs have become a major class of chemotherapy drugs and are widely used in clinical treatment of various tumors. Tubulin inhibitors affect and interfere wi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/56A61K31/416A61P35/00
CPCA61P35/00C07D231/56
Inventor 刘兆鹏崔英杰
Owner SHANDONG UNIV
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