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Podophyllotoxin derivative as well as salt, preparation method and application thereof

A technology of podophyllotoxin and derivatives, applied in the field of podophyllotoxin derivatives, which can solve problems such as interference with DNA replication

Inactive Publication Date: 2014-01-29
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, VP16 and VM26 are different from podophyllotoxin, mainly inhibiting DNA topoisomerase 2, thereby interfering with DNA replication

Method used

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  • Podophyllotoxin derivative as well as salt, preparation method and application thereof
  • Podophyllotoxin derivative as well as salt, preparation method and application thereof
  • Podophyllotoxin derivative as well as salt, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1 Preparation of 4β-4-(2", 4"-dimethoxyphenylacrylamide)-4-deoxy-4'-norepipodophyllotoxin (1)

[0073] 2,4-dimethoxycinnamic acid (115mg, 0.55mmol), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI) (96mg, 0.5mmol), 1-hydroxybenzotriazole (70mg, 0.5mmol), were added into dichloromethane (10ml), under nitrogen protection, stirred at room temperature (10°C-25°C) for 30min, then added compound 4β-amino-4 '-O-norepipodophyllotoxin (200 mg) was added dropwise with 0.2 ml of N,N-diisopropylethylamine for reaction, TLC followed the reaction end point, and the reaction lasted for about three hours. The reaction was stopped, washed with 1M HCl acid, then washed with water, dried overnight with anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated to dryness under reduced pressure to obtain a white solid. In DCM / CH 3 OH was used for gradient elution with developing solvent (volume ratio: 40:1-10:1). The...

Embodiment 2

[0096] Example 2 Preparation of 4β-4-(2,3-dimethoxyphenylacrylamide)-4-deoxy-4'-norepipodophyllotoxin (2)

[0097] 115mg of 2,3-dimethoxycinnamic acid, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI) (96mg, 0.5mmol), 1 -Hydroxybenzotriazole (70mg, 0.5mmol), was added into dichloromethane (10ml), stirred for 30min, then compound 4β-amino-4'-O-norepipodophyllotoxin (200mg) was added dropwise 0.2ml N, N-diisopropylethylamine, react at room temperature. Post-treatment process: the reaction solution was first acid-washed with 1M HCl, then washed with water, and dried overnight with anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was evaporated to dryness, purified by column chromatography, and purified with DCM / CH 3 OH (volume ratio: 40:1 ~ 10:1) was used for gradient elution of the developing solvent to obtain the pure product. The post-treatment of the rest of the compounds is the same as this method. 220 mg ...

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Abstract

The invention discloses a podophyllotoxin derivative I or pharmaceutically acceptable salt thereof. In the derivative, R1, R2 and R3 are independently selected from hydrogen, nitryl, halogen, trifluoromethyl and C1-C6 alkoxy. The invention also discloses a method for preparing the podophyllotoxin derivative I, which comprises the step of performing a condensation reaction between a compound II and a compound III in a solvent under the action of a condensing agent and alkali. The invention also discloses application of the podophyllotoxin derivative I or pharmaceutically acceptable salt thereof in the aspect of preparation of anti-tumor medicaments. The podophyllotoxin derivative I is a novel compound with anti-tumor activity, provides a new research direction for research and development of anti-cancer medicaments, and expands the research range of podophyllotoxin derivative anti-cancer medicaments.

Description

technical field [0001] The present invention relates to a podophyllotoxin derivative, its salt, its preparation method and application. Background technique [0002] Podophyllotoxin has significant antitumor activity, but its application is limited due to its strong toxicity and side effects. Derivatives etoposide (etoposide, vepesid, etoposide, etoposide, VP16) and teniposide (teniposide, podophylloside, teniposide, VM26) obtained by structural modification of podophyllotoxin ) has become a representative anti-cancer drug for clinical application. They are effective against small cell lung cancer, testicular cancer, acute leukemia and malignant lymphoma. Podophyllotoxin binds to tubulin, inhibits microtubule polymerization, and disrupts spindle formation. However, VP16 and VM26 are different from podophyllotoxin, which mainly inhibit DNA topoisomerase 2, thereby interfering with DNA replication. It is a cell cycle non-specific drug, mainly acting on cells in S phase and...

Claims

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Application Information

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IPC IPC(8): C07D493/04A61K31/365A61P35/00
CPCC07D493/04
Inventor 肖旭华刘全海闫琪孙文劼刘珉宇蔡立肖璘黄晓玲邓轶方张瑱徐智儒陈仁海郑红艳
Owner SHANGHAI INST OF PHARMA IND
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