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CA-4 antitumor drug, synthesizing method and application thereof

A technology of anti-tumor drugs and synthesis methods, applied in the field of drug synthesis, to achieve the effect of improving tumor blood vessel targeting activity

Active Publication Date: 2017-11-24
浙江华理生物制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The B ring of CA4 has a modifiable phenolic hydroxyl group. There are many studies on CA4 before, but there is no report on the introduction of sulfamate group derivatives at the 3' position. The introduction of sulfamate is also equivalent to a Prodrug modification, hydrolysis by aryl sulfonate enzymes releases CA4 with high anti-tumor activity, so the sulfamate of CA4 may play a multi-target anti-tumor effect

Method used

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  • CA-4 antitumor drug, synthesizing method and application thereof
  • CA-4 antitumor drug, synthesizing method and application thereof
  • CA-4 antitumor drug, synthesizing method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1: the synthesis of 3-trityloxy-4-methoxybenzaldehyde

[0048] 3-Hydroxy-4-methoxybenzaldehyde (8g, 52.58mmol), trityl chloride (16.8g, 60.47mmol), triethylamine (17.4g, 17.23mmol), dry tetrahydrofuran (30ml) were added to 100ml in the flask. The temperature was raised to reflux, and the reaction was carried out for 5 hours. TLC detects that the reaction is complete. Add an appropriate amount of water to the reaction system to stop the reaction, add ethyl acetate / n-heptane (1:1), a light yellow granular solid is formed, filter, wash the filter cake with distilled water, and dry in vacuo to obtain 3-trityl Oxy-4-methoxybenzaldehyde 15.8g, yield 76.7%.

Embodiment 2

[0049] Example 2: Synthesis of (Z / E)-3,4,5-trimethoxy-4'-methoxy-3'-hydroxyl stilbene

[0050] Under nitrogen protection, trimethoxyphenylmethylenetriphenylphosphonium bromide (13.3g, 25.37mmol) and dry tetrahydrofuran (30ml) were added to a 250ml three-necked flask, cooled to -78°C, and slowly Add n-butyllithium solution (15ml) dropwise, stir for 1 hour after the dropwise addition, slowly add a solution of 3-trityloxy-4-methoxybenzaldehyde (10g, 25.37mmol) in tetrahydrofuran (20ml), rise to room temperature. TLC detected the completion of the reaction, added saturated brine, separated the water layer, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Dissolve the residue with toluene and add 37% concentrated hydrochloric acid to react at room temperature for 3 hours. The end of the reaction was detected by TLC, an appropriate amount of water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and ...

Embodiment 3

[0051] Example 3: Synthesis of (Z / E)-3,4,5-trimethoxy-4'-methoxy-3'-sulfamate stilbene

[0052] N 2 Under protection, NaH (0.15g, 6.32mmol) was added to a three-necked flask, and (Z / E)-3,4,5-trimethoxy-4'-methoxy-3'-hydroxyl was slowly added dropwise at 0°C A DMF solution (10ml) of stilbene (1g, 3.16mmol) was reacted at this temperature for 1h, and then a DMF solution (2ml) of sulfamoyl chloride (0.82g, 6.32mmol) was slowly added dropwise to the reaction system, rising to React overnight at room temperature. After the reaction was completed, add water to quench, wash with saturated aqueous sodium chloride solution, extract with EA, combine organic phases, anhydrous Na2SO4 4 After drying, filtering, and concentration, petroleum ether / ethyl acetate (3 / 1) column chromatography separated to obtain 0.72 g of light yellow solid with a yield of 72%.

[0053] (Z)-3,4,5-Trimethoxy-4'-methoxy-3'-sulfamate stilbene (A1-1)

[0054]

[0055] 1 H NMR (500MHz, CDCl 3 ): δ7.21(s,1H),...

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Abstract

The invention discloses a CA-4 antitumor drug, a synthesizing method and an application thereof. The CA-4 antitumor drug is formed in the manner of introducing the alkoxy or fluorine-containing alkoxy into 4' site of natural product combretastatin and functionally chemical modifying 3' site thereof. The CA-4 antitumor drug disclosed by the invention has higher capacity of restraining tubulin gathering and can be used for anti-tumor therapy.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a CA-4 antitumor drug, a synthesis method and an application thereof. Background technique [0002] In today's world, cancer is one of the diseases with the highest morbidity and mortality in the world. It seriously affects the health and life of all human beings, and has become the second killer that threatens the current health of human beings. In recent years, the research and development of antitumor drugs has made great progress in the method of chemotherapy for tumors. Combretastatin-4 (CA-4) is a class of stilbene compounds extracted and isolated from the trunk of the South African shrub willow bark Combretum caffrum. It has a strong anti-tumor effect, and its mechanism of action is related to the inhibition of tubulin polymerization. It is one of the most active compounds among known tubulin inhibitors. It is comparable to traditional tubulin inhibitors paclitaxel ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C307/02C07C303/34A61P35/00A61P9/00A61P19/02A61P3/10A61P27/06A61P27/02A61P17/06A61P17/10A61P31/10A61P31/04A61P17/00A61P37/06A61P31/18
CPCC07C307/02Y02P20/55
Inventor 吴范宏黄磊磊黄金文李英姿谢达胡美晨
Owner 浙江华理生物制药有限公司
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