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Acidamide substitution podophyllum derivative with antineoplastic activity and preparation method and application thereof

A technology of anti-tumor activity and derivatives, applied in anti-tumor drugs, organic active ingredients, medical preparations containing active ingredients, etc., can solve the problems of high toxicity and side effects, poor bioavailability, limited use, etc. Tumor curative effect, antitumor activity improvement effect

Inactive Publication Date: 2013-10-16
HUBEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, 4'-desmethyl epipodophyllotoxins have defects such as large toxic and side effects and poor bioavailability to varying degrees, which seriously limit their clinical use. Therefore, for 4'-desmethyl epipodophyllotoxins Modification of the structure of phyllotoxin to obtain podophyllin derivatives with improved anti-tumor activity or reduced side effects will be of great significance for the clinical treatment of tumors

Method used

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  • Acidamide substitution podophyllum derivative with antineoplastic activity and preparation method and application thereof
  • Acidamide substitution podophyllum derivative with antineoplastic activity and preparation method and application thereof
  • Acidamide substitution podophyllum derivative with antineoplastic activity and preparation method and application thereof

Examples

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Effect test

Embodiment 14

[0042] Example 14-Synthesis and purification of β-(2-pyrazinecarboxamide)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound 1)

[0043] (1) Synthesis of 4-β-(2-pyrazinecarboxamide)-4-deoxy-4'-desmethyl epipodophyllotoxin: Weigh 124mg 2-pyrazinecarboxylic acid, 400mg4-β-NH 2 -4-Deoxy-4′-norepipodophyllotoxin, vacuum-dried at 45°C for 2 hours; under nitrogen protection, add the dried N,N-dimethylformamide into a four-necked bottle, and add 124 mg of the dried 2-pyrazinecarboxylic acid and 162mg of 1-hydroxy-benzo-triazole and 230mg of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, stirred and reacted in ice bath for 2~4h , and then under the protection of nitrogen, add dry 4-β-NH 2 - 4-deoxy-4'-norepipodophyllotoxin, slowly add triethylamine dropwise under stirring, remove the ice bath after the addition, and react at room temperature for 24-48 hours. After the reaction, extract the reaction solution with 20 mL of water, remove the organic phase of the lower layer...

Embodiment 24

[0049] Example 24-Synthesis and purification of β-(5-methyl-2-pyrazinecarboxamide)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound 2)

[0050] (1) Synthesis of 4-β-(5-methyl-2-pyrazinecarboxamide)-4-deoxy-4'-desmethyl epipodophyllotoxin: Weigh 138mg of 5-methyl 2-pyrazinecarboxylic acid, 400mg 4-β-NH 2 -4-Deoxy-4′-norepipodophyllotoxin, vacuum-dried at 45°C for 2 hours; under nitrogen protection, add the dried N,N-dimethylformamide into a four-necked bottle, and add 138 mg of the dried 5-Methyl-2-pyrazinecarboxylic acid and 162 mg 1-hydroxy-benzo-triazole and 230 mg 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, under ice bath Stir the reaction for 2 to 4 hours, then add the dried 4-β-NH under the protection of nitrogen 2 - 4-deoxy-4'-norepipodophyllotoxin, slowly add triethylamine dropwise under stirring, remove the ice bath after the addition, and react at room temperature for 24-48 hours. After the reaction, extract the reaction solution with 20 mL of water...

Embodiment 34

[0056] Example 34-Synthesis and purification of β-(theophylline acetamide)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound 3)

[0057] (1) Synthesis of 4-β-(theophylline acetamide)-4-deoxy-4'-desmethyl epipodophyllotoxin: Weigh 238mg theophylline acetic acid, 400mg4-β-NH 2 -4-Deoxy-4′-norepipodophyllotoxin, vacuum-dried at 45°C for 2 hours; under nitrogen protection, add the dried N,N-dimethylformamide into a four-necked bottle, and add 238 mg of the dried 5. Theophylline acetic acid, 162mg 1-hydroxy-benzo-triazole and 230mg 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride were stirred and reacted in an ice bath for 2-4 hours, and then Under nitrogen protection, add dry 4-β-NH 2 - 4-deoxy-4'-norepipodophyllotoxin, slowly add triethylamine dropwise under stirring, remove the ice bath after the addition, and react at room temperature for 24-48 hours. After the reaction, extract the reaction solution with 20 mL of water, remove the organic phase of the lower layer, ...

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Abstract

The invention discloses an acidamide substitution podophyllum derivative with antineoplastic activity and a preparation method and application thereof. According to the invention, 2-pyrazine pyrazine, 5-methyl-2-pyrazine pyrazine, theophylline acetic acid and acetic acid are subjected to acidamide substitution reaction with 4'-demethylepipodophyllotoxin, so that the acidamide substitution podophyllum derivative with the antineoplastic activity, expressed by the formula (V), can be obtained. The acidamide substitution podophyllum derivative acts on cancer cells by means of multiple ways and multiple target points, and thus has better antineoplastic efficacy. As indicated by the in vitro cell activity inhibition test, the acidamide substitution podophyllum derivative disclosed by the invention has excellent antineoplastic activity and low toxic and side effects, and can be made into antineoplastic drugs for clinic antineoplastic treatment.

Description

technical field [0001] The present invention relates to podophyllotoxin derivatives, in particular to amide-substituted podophyllotoxin derivatives with antitumor activity obtained after substitution of the 4-position of the C ring of 4'-desmethyl epipodophyllotoxin and a preparation method thereof. It also relates to the use of the amide-substituted podophyllotoxin derivatives in the preparation of antitumor drugs, which belongs to the field of preparation and application of podophyllotoxin derivatives. Background technique [0002] Podophyllum plants belong to the Berberidaceae family, including the genus Anise, Podophyllum, and Heliconia. These plants have significant biological activity and have a long history of medicinal use. 4'-Demethylepipodophyllotoxin (4'-Demethylepipodophyllotoxin) is a natural active lead compound extracted from podophyllum plants with unique anti-tumor activity. However, 4'-desmethyl epipodophyllotoxins have defects such as large toxic and side...

Claims

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Application Information

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IPC IPC(8): C07D493/04C07D519/00A61K31/497A61K31/522A61K31/365A61P35/00
CPCY02P20/582
Inventor 汤亚杰陈露赵巍
Owner HUBEI UNIV OF TECH
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