Lycorine beta-aryl acrylate derivative as well as preparation method and application thereof

A technology of aryl acrylate and lycorine, applied in the field of biomedicine, can solve the problems of large cell damage and exacerbation of the disease, and achieve good anti-tumor application prospects

Active Publication Date: 2021-09-21
SHANDONG DYNE MARINE BIOTECHCAL PHARM HLDG CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Traditional tumor treatment uses a combination of radiotherapy and chemotherapy, which causes great damage to normal cells, and patients will experience many adverse reactions in the middle and later stages, which will further aggravate the disease. Therefore, it is urgent to find new tumor treatment targets and develop new tumor treatment drugs. especially important

Method used

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  • Lycorine beta-aryl acrylate derivative as well as preparation method and application thereof
  • Lycorine beta-aryl acrylate derivative as well as preparation method and application thereof
  • Lycorine beta-aryl acrylate derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Example 1 : 2-tert-butyldimethylsilyl-lycorine (INB)

[0098] INB structure:

[0099] Lycorine (100.0mmol) and Im (150.0mmol) were dissolved in 300ml DMF in a 2000ml round bottom reaction flask, and TBSCl (150.0mmol) was slowly added under vigorous stirring at room temperature. Raise the temperature to 40° C. to completely dissolve the reaction system. After 4 hours of heat preservation and stirring, HPLC traces and detects that the residual amount of lycorine in the starting material is less than 5%. Add 500ml of ethyl acetate and 800ml of purified water to the reaction system in sequence, stir at room temperature for 10 minutes, then separate the liquid, wash the organic phase with 500ml of 10% sodium chloride solution, dry the liquid with 100.0g of anhydrous sodium sulfate, filter, and reduce pressure Concentration, separation and purification by column chromatography gave INB as a white solid. 1 HNMR (500MHz, CDCl 3 )δ6.80(s,1H),6.56(s,1H),5.89(d,J=1.1Hz,2H),5...

Embodiment 2

[0100] Example 2 : 1-(2-fluorocinnamoyl)-lycorine (S1)

[0101] S1 structure:

[0102] a: Dissolve 2-tert-butyldimethylsilyl-lycorine INB (10.0mmol) and 2-fluorocinnamic acid (12.0mmol) in 50ml dichloromethane in a 250ml round-bottomed reaction flask, and put it under nitrogen protection at room temperature EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were added sequentially. After the addition is complete, heat-preserve and stir the reaction at 35° C., and post-process after detecting that the remaining amount of INB is less than 8% by HPLC. The reaction liquid was washed with 100 ml of purified water and 100 ml of 10% sodium chloride solution in turn, concentrated under reduced pressure and then used for later use.

[0103] b: Dissolve the above product in 50 ml of absolute ethanol in a 250 ml round-bottomed reaction bottle, and slowly add 5.0 mL of concentrated hydrochloric acid dropwise with stirring at room temperature. After the dropwise addition, stir and react at 80°C ...

Embodiment 3

[0104] Example 3 : 1-(3-fluorocinnamoyl)-lycorine (S2)

[0105] S2 structure:

[0106] a: Dissolve 2-tert-butyldimethylsilyl-lycorine INB (10.0mmol) and 3-fluorocinnamic acid (12.0mmol) in 50ml dichloromethane in a 250ml round-bottomed reaction flask, and place under nitrogen protection at room temperature EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were added sequentially. After the addition is complete, heat-preserve and stir the reaction at 35° C., and post-process after detecting that the remaining amount of INB is less than 8% by HPLC. The reaction liquid was washed with 100 ml of purified water and 100 ml of 10% sodium chloride solution in turn, concentrated under reduced pressure and then used for later use.

[0107] b: Dissolve the above product in 50 ml of absolute ethanol in a 250 ml round-bottomed reaction bottle, and slowly add 5.0 mL of concentrated hydrochloric acid dropwise with stirring at room temperature. After the dropwise addition, stir and react at 80°C f...

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PUM

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Abstract

The invention provides a lycorine beta-aryl acrylate derivative as well as a preparation method and application thereof. The lycorine beta-aryl acrylate derivative has a structure as shown in a formula I, Ar is C6-12 aromatic hydrocarbon or C3-10 aromatic heterocycle, and heteroatoms in the aromatic heterocycle are selected from N, O and S; R is a substituent group on the Ar, is monosubstituted or polysubstituted, and the R is independently selected from hydrogen, halogen, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, nitryl, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkenyl, C3-6 cycloalkyl and phenyl. The lycorine beta-aryl acrylate derivative disclosed by the invention has good anti-tumor activity and a relatively good medicinal prospect.

Description

technical field [0001] The present application relates to the field of biomedicine, in particular to a lycorine β-aryl acrylate derivative and its preparation method and application. Background technique [0002] The information disclosed in the background of the application is intended to enhance the understanding of the general background of the application, and the disclosure should not necessarily be regarded as an acknowledgment or any form of suggestion that the information has become the prior art known to those skilled in the art. [0003] In recent years, the morbidity and mortality of tumors have been on the rise, and malignant tumors are seriously threatening human health and life safety. According to statistics, more than 14 million people around the world suffer from cancer every year, and cancer ranks second among the causes of death in the world. Traditional tumor treatment uses a combination of radiotherapy and chemotherapy, which causes great damage to norm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/16A61K31/437A61K31/444A61P35/00
CPCC07D491/16A61P35/00Y02P20/55
Inventor 颜世强王鹏曹焕英杨杰何淑旺王文笙景亚军
Owner SHANDONG DYNE MARINE BIOTECHCAL PHARM HLDG CO LTD
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