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Nitrogen-substituted podophyllotoxin derivative with anti-tumor activity and preparation method and use thereof

A technology of anti-tumor activity and pyridine derivatives, applied in the preparation and application of podophyllotoxin derivatives, nitrogen-substituted podophyllin derivatives and their preparation, nitrogen-substituted podophyllin derivatives in the preparation of anti-tumor In the field of medicine, it can solve problems such as limited application, high toxicity and side effects, and poor bioavailability, and achieve the effect of improving anti-tumor activity and good anti-tumor efficacy

Inactive Publication Date: 2014-02-26
HUBEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, podophyllotoxin compounds have defects such as large toxic side effects and poor bioavailability to varying degrees, which seriously limit their clinical application in anti-tumor and need to be improved.

Method used

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  • Nitrogen-substituted podophyllotoxin derivative with anti-tumor activity and preparation method and use thereof
  • Nitrogen-substituted podophyllotoxin derivative with anti-tumor activity and preparation method and use thereof
  • Nitrogen-substituted podophyllotoxin derivative with anti-tumor activity and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Preliminary Example 1 Activation of Podophyllotoxin C-ring 4

[0040] Drying of dichloromethane: Weigh 1.5g of calcium hydride into a 1000ML round-bottom four-necked bottle, put a clean funnel into the side port, pour 500ML of dichloromethane, add 3-4 glass beads to prevent bumping, and adjust the heating When the temperature reaches the dichloromethane in a slightly boiling state, add a reflux tube to reflux for 2-3 hours, then condense and recover it into a reagent bottle filled with anhydrous calcium chloride. After collecting the liquid, put a little nitrogen into the bottle, and close the lid. Yes, you can add nitrogen after each use.

[0041] Weigh 2 grams of podophyllotoxin or 4′-desmethyl epipodophyllotoxin, and vacuum-dry at 45°C for 2 hours; under nitrogen protection, add the dried podophyllotoxin and 40ml of dried dichloromethane into a 250ml four-necked bottle , add 10ml of hydrogen bromide and react in ice bath for half an hour. After the reaction, extrac...

Embodiment 2

[0051] Example 2 Synthesis and purification of 4-N-(2-aminopyridine)-4-deoxy-podophyllotoxin (compound (2))

[0052] (1) Synthesis of 4-N-(2-aminopyridine)-4-deoxy-podophyllotoxin: Weigh 1 mol of the activated product at position 4 of the C-ring of podophyllotoxin (prepared in Preliminary Example 1), and vacuum-dry at 45°C 2 hours; under the protection of nitrogen, add the dried dichloromethane into the four-necked flask, add the activated product of the 4-position of the C ring of the dried podophyllotoxin compound and 1.2mol of 2-aminopyridine, and then add 2mol of barium carbonate, at room temperature Under the conditions, the reaction was stirred for 48 hours, and the reaction solution was spin-dried to obtain a crude product of 4-N-(2-aminopyridine)-4-deoxy-podophyllotoxin.

[0053] (2) Separation and purification of 4-N-(2-aminopyridine)-4-deoxy-podophyllotoxin:

[0054] Separation and purification using silica gel column chromatography and gel column chromatography:

...

Embodiment 3

[0060] Example 3 Synthesis and purification of 4-N-(2-amino-3-picoline)-4-deoxy-podophyllotoxin (compound (3))

[0061](1) Synthesis of 4-N-(2-amino-3-picoline)-4-deoxy-podophyllotoxin: Weigh 1 mol of the activated product at position 4 of the C-ring of podophyllotoxin (prepared in Preliminary Example 1) , vacuum-dry at 45°C for 2 hours; under nitrogen protection, add the dried dichloromethane into a four-necked flask, add the dried activated product of the 4-position of the C ring of the podophyllotoxin compound and 1.2mol of 2-amino-3-methanol base pyridine, then add 2mol barium carbonate, under normal temperature conditions, stir and react for 48 hours, and the reaction solution is spin-dried to obtain 4-N-(2-amino-3-methylpyridine)-4-deoxy-podophyllotoxin crude product.

[0062] (2) Separation and purification of 4-N-(2-amino-3-picoline)-4-deoxy-podophyllotoxin:

[0063] Separation and purification using silica gel column chromatography and gel column chromatography:

...

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Abstract

The invention discloses a nitrogen-substituted podophyllotoxin derivative with anti-tumor activity and a preparation method and use thereof. According to the method, 2-aminopyrimidine, 2-aminopyridine, 2-amino-3-methylpyridine, 2-amino-4-methylpyridine, 2-amino-5-methylpyridine, 2-amino-4,6-dimethyl pyridine, 3-aminopyridine, 3-amino-4-methylpyridine, 5-amino-2-methylpyridine, 3-amino-2-chloropyridine or 4-amino-2-chloropyridine is respectively introduced to an activated C-ring fourth position of a podophyllotoxin compound through nitrogen substitution reaction, so as to obtain the nitrogen-substituted podophyllotoxin derivative, represented by a formula (V) shown in the specification, with excellent anti-tumor activity. The nitrogen-substituted podophyllotoxin derivative disclosed by the invention acts on tumor cells through multiple ways and multiple target points, and the anti-tumor activity of the nitrogen-substituted podophyllotoxin derivative is remarkably improved compared with that of the podophyllotoxin compound. The compound disclosed by the invention can be used for preparing anti-tumor drugs and is clinically applied to anti-tumor treatment.

Description

technical field [0001] The present invention relates to derivatives of podophyllotoxin compounds, in particular to nitrogen-substituted podophyllin derivatives obtained by substituting the 4-position of the C ring of podophyllotoxin compounds and a preparation method thereof. The present invention also relates to the nitrogen-substituted podophyllum derivatives. The use of podophyllotoxin derivatives in the preparation of antitumor drugs belongs to the field of preparation and application of podophyllotoxin derivatives. Background technique [0002] Podophyllotoxin compounds are natural active lead compounds with unique anti-tumor activity extracted from podophyllum plants (for example: Berberidaceae plants Peach seven, mountain lotus leaf, star anise lotus, etc.). However, podophyllotoxin compounds have defects such as large toxic side effects and poor bioavailability to varying degrees, which seriously limit their clinical application in anti-tumor and need to be improved....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04A61K31/506A61K31/443A61P35/00
CPCC07D493/04Y02P20/582
Inventor 汤亚杰王槐赵巍李红梅
Owner HUBEI UNIV OF TECH
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