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Nitrogen substitution podophyllum type derivatives with antitumor activity and preparation method and application thereof

A technology of anti-tumor activity and nitrogen substitution, applied in the preparation and application of podophyllotoxin derivatives, nitrogen-substituted podophyllotoxin derivatives in the preparation of anti-tumor drugs, nitrogen-substituted podophyllotoxin derivatives and their preparation fields, can Solve the problems of limited use and low anti-tumor activity, and achieve the effect of improved anti-tumor activity and good anti-tumor efficacy

Inactive Publication Date: 2013-01-16
HUBEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, Podophyllotoxin (Podophyllotoxin) or 4'-desmethyl epipodophyllotoxin has defects such as low anti-tumor activity to varying degrees, which seriously limits their clinical use.

Method used

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  • Nitrogen substitution podophyllum type derivatives with antitumor activity and preparation method and application thereof
  • Nitrogen substitution podophyllum type derivatives with antitumor activity and preparation method and application thereof
  • Nitrogen substitution podophyllum type derivatives with antitumor activity and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1 Synthesis and purification of 4-N-(1-(3-aminopropyl)imidazole-1)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound (1))

[0041] (1) Synthesis of 4-N-(1-(3-aminopropyl)imidazole-1)-4-deoxy-4'-desmethyl epipodophyllotoxin: Weigh 1mol 4'-desmethyl epipodophyllotoxin The activated product at the 4-position of the C ring of the toxin (prepared in Preliminary Example 1) was vacuum-dried at 45°C for 2 hours; ) into a four-neck flask, add the dried activated product of 4′-demethylepipodophyllotoxin C ring 4 and 3mol 1-(3-aminopropyl)imidazole, stir and react at 80°C for 48 hours, and the reaction After the liquid was spin-dried, the crude product of 4-N-(1-(3-aminopropyl)imidazole-1)-4-deoxy-4'-desmethyl epipodophyllotoxin was obtained.

[0042] (2) Isolation and purification of 4-N-(1-(3-aminopropyl)imidazole-1)-4-deoxy-4'-desmethyl epipodophyllotoxin:

[0043] Separation and purification using silica gel column chromatography and gel column chromatography:

[00...

Embodiment 2

[0047] Example 2 Synthesis and purification of 4-N-(benzimidazole)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound (2))

[0048] (1) Synthesis of 4-N-(benzimidazole)-4-deoxy-4'-desmethyl epipodophyllotoxin: Weigh 1mol of 4'-desmethyl epipodophyllotoxin C ring 4 activation product ( Prepared in Preparatory Example 1), vacuum-dry at 45°C for 2 hours; under nitrogen protection, add dried acetonitrile (the drying method is the same as that of dichloromethane in Preparatory Example 1) into a four-necked bottle, and add the dried The activated product of the 4th position of the C ring of 4'-desmethyl epipodophyllotoxin and 3mol benzimidazole were stirred and reacted at 80°C for 48 hours; after the reaction was completed, the reaction solution was spin-dried, and dissolved by adding 50ml of ethyl acetate and then cleaned with an ultrasonic cleaner Ultrasound for 5 minutes, there will be insoluble matter at this time, and the insoluble matter obtained after filtering with filter pap...

Embodiment 3

[0054] Example 3 Synthesis and purification of 4-N-(2-thienylamine)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound (3))

[0055] (1) Synthesis of 4-N-(2-thiophenemethylamine)-4-deoxy-4′-desmethyl epipodophyllotoxin: Weigh 1 mol of 4′-desmethyl epipodophyllotoxin C ring 4 activation The product (prepared in Preliminary Example 1) was vacuum-dried at 45°C for 2 hours; under nitrogen protection, the dried acetonitrile (drying method was the same as that of dichloromethane in Preparatory Example 1) was added to a four-necked flask, and dried A good 4′-demethyl epipodophyllotoxin C-ring 4-activated product and 3mol thiophene-2-methylamine (80°C stirred and reacted for 48 hours, and the reaction solution was spin-dried to obtain the crude product

[0056] (2) Separation and purification:

[0057] Separation and purification using silica gel column chromatography and gel column chromatography:

[0058] (A) Use a normal phase silica gel column (normal phase silica gel: China Qing...

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Abstract

The invention discloses nitrogen substitution podophyllum type derivatives with antitumor activity and a preparation method and application thereof. The nitrogen substitution podophyllum type derivatives (as formula V) with fine antitumor activity are prepared by introducing 1-(3-amino propyl) imidazole, benzimidazole, 2-thienylmethylamine or trihydroxymethyl aminomethane to C ring 4-position activated by 4-demethylation surface podophyllotoxin. The nitrogen substitution podophyllum type derivatives can act on tumor cells with multiple paths and multiple target points, and accordingly better antitumor curative effect is achieved. Antitumor activity of the derivatives is evidently increased compared with that of the 4-demethylation surface podophyllotoxin. The derivatives can be prepared into antitumor drugs to apply to antitumor therapies.

Description

technical field [0001] The present invention relates to podophyllotoxin derivatives, in particular to nitrogen-substituted podophyllotoxin derivatives obtained by substituting the 4-position of the C ring of 4'-desmethyl epipodophyllotoxin and a preparation method thereof. The present invention also relates to said The use of nitrogen-substituted podophyllotoxin derivatives in the preparation of antitumor drugs belongs to the field of preparation and application of podophyllotoxin derivatives. Background technique [0002] Podophyllotoxin and 4′-Demethylepipodophyllotoxin (4′-Demethylepipodophyllotoxin) are extracted from podophyllum plants (for example: Berberidaceae plant Taoerqi, mountain lotus leaf, star anise lotus, etc.) The obtained natural active lead compound with unique antitumor activity. However, Podophyllotoxin or 4'-desmethylepipodophyllotoxin has defects such as low anti-tumor activity to varying degrees, which severely limits their clinical use. Contents o...

Claims

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Application Information

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IPC IPC(8): C07D493/04A61K31/4184A61K31/381A61K31/4178A61K31/365A61P35/00
CPCY02P20/582
Inventor 汤亚杰肖黎
Owner HUBEI UNIV OF TECH
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